Conjoint Professor Chris Levi

Background: Intracranial occlusion site, contrast permeability, and clot burden are thrombus characteristics that influence alteplase-associated reperfusion. In this study, we assessed the reperfusion efficacy of tenecteplase and alteplase in subgroups based on these characteristics in a pooled analysis of the EXTEND-IA TNK trial (Tenecteplase Versus Alteplase Before Endovascular Therapy for Ischemic Stroke). Methods: Patients with large vessel occlusion were randomized to treatment with tenecteplase (0.25 or 0.4 mg/kg) or alteplase before thrombectomy in hospitals across Australia and New Zealand (2015-2019). The primary outcome, early reperfusion, was defined as the absence of retrievable thrombus or >50% reperfusion on first-pass angiogram. We compared the effect of tenecteplase versus alteplase overall, and in subgroups, based on the following measured with computed tomography angiography: intracranial occlusion site, contrast permeability (measured via residual flow grades), and clot burden (measured via clot burden scores). We adjusted for covariates using mixed effects logistic regression models. Results: Tenecteplase was associated with higher odds of early reperfusion (75/369 [20%] versus alteplase: 9/96 [9%], adjusted odds ratio [aOR], 2.18 [95% CI, 1.03-4.63]). The difference between thrombolytics was notable in occlusions with low clot burden (tenecteplase: 66/261 [25%] versus alteplase: 5/67 [7%], aOR, 3.93 [95% CI, 1.50-10.33]) when compared to high clot burden lesions (tenecteplase: 9/108 [8%] versus alteplase: 4/29 [14%], aOR, 0.58 [95% CI, 0.16-2.06]; Pinteraction=0.01). We did not observe an association between contrast permeability and tenecteplase treatment effect (permeability present: aOR, 2.83 [95% CI, 1.00-8.05] versus absent: aOR, 1.98 [95% CI, 0.65-6.03]; Pinteraction=0.62). Tenecteplase treatment effect was superior with distal M1 or M2 occlusions (53/176 [30%] versus alteplase: 4/42 [10%], aOR, 3.73 [95% CI, 1.25-11.11]), but both thrombolytics had limited efficacy with internal carotid artery occlusions (tenecteplase 1/73 [1%] versus alteplase 1/19 [5%], aOR, 0.22 [95% CI, 0.01-3.83]; Pinteraction=0.16). Conclusions: Tenecteplase demonstrates superior early reperfusion versus alteplase in lesions with low clot burden. Reperfusion efficacy remains limited in internal carotid artery occlusions and lesions with high clot burden. Further innovation in thrombolytic therapies are required.

Background: Intensive blood pressure lowering may adversely affect evolving cerebral ischaemia. We aimed to determine whether intensive blood pressure lowering altered the size of cerebral infarction in the 2196 patients who participated in the Enhanced Control of Hypertension and Thrombolysis Stroke Study, an international randomised controlled trial of intensive (systolic target 130¿140 mm Hg within 1 h; maintained for 72 h) or guideline-recommended (systolic target <180 mm Hg) blood pressure management in patients with hypertension (systolic blood pressure >150 mm Hg) after thrombolysis treatment for acute ischaemic stroke between March 3, 2012 and April 30, 2018. Methods: All available brain imaging were analysed centrally by expert readers. Log-linear regression was used to determine the effects of intensive blood pressure lowering on the size of cerebral infarction, with adjustment for potential confounders. The primary analysis pertained to follow-up computerised tomography (CT) scans done between 24 and 36 h. Sensitivity analysis were undertaken in patients with only a follow-up magnetic resonance imaging (MRI) and either MRI or CT at 24¿36 h, and in patients with any brain imaging done at any time during follow-up. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: There were 1477 (67.3%) patients (mean age 67.7 [12.1] y; male 60%, Asian 65%) with available follow-up brain imaging for analysis, including 635 patients with a CT done at 24¿36 h. Mean achieved systolic blood pressures over 1¿24 h were 141 mm Hg and 149 mm Hg in the intensive group and guideline group, respectively. There was no effect of intensive blood pressure lowering on the median size (ml) of cerebral infarction on follow-up CT at 24¿36 h (0.3 [IQR 0.0¿16.6] in the intensive group and 0.9 [0.0¿12.5] in the guideline group; log ¿mean -0.17, 95% CI -0.78 to 0.43). The results were consistent in sensitivity and subgroup analyses. Interpretation: Intensive blood pressure lowering treatment to a systolic target <140 mm Hg within several hours after the onset of symptoms may not increase the size of cerebral infarction in patients who receive thrombolysis treatment for acute ischaemic stroke of mild to moderate neurological severity. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; UK Dementia Research Institute; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Background: Failure to reperfuse a¿cerebral occlusion resulting in a¿persistent penumbral pattern has not been fully described. Methods: We retrospectively reviewed patients with anterior large vessel occlusion who did not receive reperfusion, and underwent repeated perfusion imaging, with baseline imaging <¿6¿h after onset and follow-up scans from 16¿168¿h. A¿persistent target mismatch (PTM) was defined as core volume of <¿100¿mL, mismatch ratio >¿1.2, and mismatch volume >¿10¿mL on follow-up imaging. Patients were divided into PTM or non-PTM groups. Ischemic core and penumbral volumes were compared between baseline and follow-up imaging between the two groups, and collateral flow status assessed using CT perfusion collateral index. Results: A total of 25 patients (14¿PTM and 11¿non-PTM) were enrolled in the study. Median core volumes increased slightly in the PTM group, from 22 to 36¿ml. There was a¿much greater increase in the non-PTM group, from 57 to 190¿ml. Penumbral volumes were stable in the PTM group from a¿median of 79¿ml at baseline to 88¿ml at follow-up, whereas penumbra was reduced in the non-PTM group, from 120 to 0¿ml. Collateral flow status was also better in the PTM group and the median collateral index was 33% compared with 44% in the non-PTM group (p¿= 0.043). Conclusion: Multiple patients were identified with limited core growth and large penumbra (persistent target mismatch) >¿16¿h after stroke onset, likely due to more favorable collateral flow.

Introduction: Computed tomography perfusion (CTP) imaging is widely used in cases of suspected acute ischemic stroke to positively identify ischemia and assess suitability for treatment through identification of reversible and irreversible tissue injury. Traditionally, this has been done via setting single perfusion thresholds on two or four CTP parameter maps. We present an alternative model for the estimation of tissue fate using multiple perfusion measures simultaneously. Methods: We used machine learning (ML) models based on four different algorithms, combining four CTP measures (cerebral blood flow, cerebral blood volume, mean transit time and delay time) plus 3D-neighborhood (patch) analysis to predict the acute ischemic core and perfusion lesion volumes. The model was developed using 86 patient images, and then tested further on 22 images. Results: XGBoost was the highest-performing algorithm. With standard threshold-based core and penumbra measures as the reference, the model demonstrated moderate agreement in segmenting core and penumbra on test images. Dice similarity coefficients for core and penumbra were 0.38 ± 0.26 and 0.50 ± 0.21, respectively, demonstrating moderate agreement. Skull-related image artefacts contributed to lower accuracy. Discussion: Further development may enable us to move beyond the current overly simplistic core and penumbra definitions using single thresholds where a single error or artefact may lead to substantial error.

Objectives: There are several reports of the association between SARS-CoV-2 infection (COVID-19) and cerebral venous sinus thrombosis (CVST). In this study, we aimed to compare the hospitalization rate of CVST before and during the COVID-19 pandemic (before vaccination program). Materials and methods: In this retrospective cohort study, the hospitalization rate of adult CVST patients in Namazi hospital, a tertiary referral center in the south of Iran, was compared in two periods of time. We defined March 2018 to March 2019 as the pre-COVID-19 period and March 2020 to March 2021 as the COVID-19 period. Results: 50 and 77 adult CVST patients were hospitalized in the pre-COVID-19 and COVID-19 periods, respectively. The crude CVST hospitalization rate increased from 14.33 in the pre-COVID-19 period to 21.7 per million in the COVID-19 era (P = 0.021). However, after age and sex adjustment, the incremental trend in hospitalization rate was not significant (95% CrI: -2.2, 5.14). Patients > 50-year-old were more often hospitalized in the COVID-19 period (P = 0.042). SARS-CoV-2 PCR test was done in 49.3% out of all COVID-19 period patients, which were positive in 6.5%. Modified Rankin Scale (mRS) score =3 at three-month follow-up was associated with age (P = 0.015) and malignancy (P = 0.014) in pre-COVID period; and was associated with age (P = 0.025), altered mental status on admission time (P<0.001), malignancy (P = 0.041) and COVID-19 infection (P = 0.008) in COVID-19 period. Conclusion: Since there was a more dismal outcome in COVID-19 associated CVST, a high index of suspicion for CVST among COVID-19 positive is recommended.

Background: The benefit of combined treatment with intravenous thrombolysis before endovascular thrombectomy in patients with acute ischaemic stroke caused by large vessel occlusion remains unclear. We hypothesised that the clinical outcomes of patients with stroke with large vessel occlusion treated with direct endovascular thrombectomy within 4·5 h would be non-inferior compared with the outcomes of those treated with standard bridging therapy (intravenous thrombolysis before endovascular thrombectomy). Methods: DIRECT-SAFE was an international, multicentre, prospective, randomised, open-label, blinded-endpoint trial. Adult patients with stroke and large vessel occlusion in the intracranial internal carotid artery, middle cerebral artery (M1 or M2), or basilar artery, confirmed by non-contrast CT and vascular imaging, and who presented within 4·5 h of stroke onset were recruited from 25 acute-care hospitals in Australia, New Zealand, China, and Vietnam. Eligible patients were randomly assigned (1:1) via a web-based, computer-generated randomisation procedure stratified by site of baseline arterial occlusion and by geographic region to direct endovascular thrombectomy or bridging therapy. Patients assigned to bridging therapy received intravenous thrombolytic (alteplase or tenecteplase) as per standard care at each site; endovascular thrombectomy was also per standard of care, using the Trevo device (Stryker Neurovascular, Fremont, CA, USA) as first-line intervention. Personnel assessing outcomes were masked to group allocation; patients and treating physicians were not. The primary efficacy endpoint was functional independence defined as modified Rankin Scale score 0¿2 or return to baseline at 90 days, with a non-inferiority margin of ¿0·1, analysed by intention to treat (including all randomly assigned and consenting patients) and per protocol. The intention-to-treat population was included in the safety analyses. The trial is registered with ClinicalTrials.gov, NCT03494920, and is closed to new participants. Findings: Between June 2, 2018, and July 8, 2021, 295 patients were randomly assigned to direct endovascular thrombectomy (n=148) or bridging therapy (n=147). Functional independence occurred in 80 (55%) of 146 patients in the direct thrombectomy group and 89 (61%) of 147 patients in the bridging therapy group (intention-to-treat risk difference ¿0·051, two-sided 95% CI ¿0·160 to 0·059; per-protocol risk difference ¿0·062, two-sided 95% CI ¿0·173 to 0·049). Safety outcomes were similar between groups, with symptomatic intracerebral haemorrhage occurring in two (1%) of 146 patients in the direct group and one (1%) of 147 patients in the bridging group (adjusted odds ratio 1·70, 95% CI 0·22¿13·04) and death in 22 (15%) of 146 patients in the direct group and 24 (16%) of 147 patients in the bridging group (adjusted odds ratio 0·92, 95% CI 0·46¿1·84). Interpretation: We did not show non-inferiority of direct endovascular thrombectomy compared with bridging therapy. The additional information from our study should inform guidelines to recommend bridging therapy as standard treatment. Funding: Australian National Health and Medical Research Council and Stryker USA.

Background and aims: Observational studies have demonstrated that the pneumococcal polysaccharide vaccine (PPV) is associated with reduced risk of cardiovascular events. This may be mediated through IgM antibodies to OxLDL, which have previously been associated with cardioprotective effects. The Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE) is a double-blind, randomised controlled trial (RCT) of PPV in preventing ischaemic events. Participants received PPV or placebo once at baseline and are being followed-up for incident fatal and non-fatal myocardial infarction or stroke over 6 years. Methods: A subgroup of participants at one centre (Canberra; n = 1,001) were evaluated at 1 month and 2 years post immunisation for changes in surrogate markers of atherosclerosis, as pre-specified secondary outcomes: high-sensitive C-reactive protein (CRP), pulse wave velocity (PWV), and carotid intima-media thickness (CIMT). In addition, 100 participants were randomly selected in each of the intervention and control groups for measurement of anti-pneumococcal antibodies (IgG, IgG2, IgM) as well as anti-OxLDL antibodies (IgG and IgM to CuOxLDL, MDA-LDL, and PC-KLH). Results: Concentrations of anti-pneumococcal IgG and IgG2 increased and remained high at 2 years in the PPV group compared to the placebo group, while IgM increased and then declined, but remained detectable, at 2 years. There were statistically significant increases in all anti-OxLDL IgM antibodies at 1 month, which were no longer detectable at 2 years; there was no increase in anti-OxLDL IgG antibodies. There were no significant changes in CRP, PWV or CIMT between the treatment groups at the 2-year follow-up. Conclusions: PPV engenders a long-lasting increase in anti-pneumococcal IgG, and to a lesser extent, IgM titres, as well as a transient increase in anti-OxLDL IgM antibodies. However, there were no detectable changes in surrogate markers of atherosclerosis at the 2-year follow-up. Long-term, prospective follow-up of clinical outcomes is continuing to assess if PPV reduces CVD events.

Aims: Hunter-8 and ACT-FAST are two stroke scales used in Australia for the pre-hospital identification of large vessel occlusion (LVO) stroke, but they have not previously been compared. Moreover, their use in identifying distal arterial occlusions has not previously been assessed. We therefore aimed to describe the area under the receiver operating curve (AUC) of Hunter-8 versus ACT-FAST for the detection of LVO stroke. Methods: Both scales were performed on consecutive patients presenting with stroke-like symptoms within 24 hours of symptom onset presenting to the emergency department at a tertiary referral hospital between June 2018 and January 2019. The AUC of Hunter-8 and ACT-FAST was calculated for the detection of LVO using different definitions (classic LVO ¿ proximal segment of the middle cerebral artery (MCA-M1), terminal internal carotid artery (T-ICA) or tandem occlusions ¿ and extended LVO ¿ classic LVO plus proximal MCA-M2 and basilar occlusions). Results: Of 126 suspected stroke patients, there were 24 classic LVO and 34 extended LVO. For detection of classic LVO, Hunter-8 had an AUC of 0.79 and ACT-FAST had an AUC of 0.77. For extended LVO, the AUC was 0.71 and 0.70 respectively. The AUC for the subgroup of patients with MCA-M2 and basilar occlusions was 0.42 and 0.43 respectively. Conclusion: Both scales represent a significant opportunity to identify patients with proven potential benefit from thrombectomy (classic LVO), however M2 and basilar occlusions may be more challenging to identify with these scales.

Background and ObjectivesDetailed study of tenecteplase (TNK) in patients older than 80 years is limited. The objective of our study was to assess the safety and efficacy of TNK at 0.25 and 0.40 mg/kg doses in patients older than 80 years with large vessel occlusion.MethodsWe performed a pooled analysis of the EXTEND-IA TNK randomized controlled trials (n = 502). Patients were adults presenting with ischemic stroke due to occlusion of the intracranial internal carotid, middle cerebral, or basilar artery presenting within 4.5 hours of symptom onset. We compared the treatment effect of TNK 0.25 mg/kg, TNK 0.40 mg/kg, and alteplase 0.90 mg/kg, stratifying for patient age (>80 years). Outcomes evaluated include 90-day modified Rankin Scale (mRS) score, all-cause mortality, and symptomatic ICH. Treatment effect was adjusted for baseline NIH Stroke Score, age, and time from symptom onset to puncture via mixed effects proportional odds and logistic regression models.ResultsIn patients >80 years (n = 137), TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, adjusted common odds ratio (acOR) 2.70, 95% CI 1.23-5.94) and reduced mortality (acOR 0.34, 95% CI 0.13-0.91) vs 0.40 mg/kg. TNK 0.25 mg/kg was associated with improved 90-day mRS (median 3 vs 4, acOR 2.28, 95% CI 1.03-5.05) vs alteplase. No difference in 90-day mRS or mortality was detected between alteplase and TNK 0.40 mg/kg. Symptomatic ICH was observed in 4 patients treated with TNK 0.40 mg/kg, 1 patient treated with alteplase, and 0 patients treated with TNK 0.25 mg/kg. In patients =80 years, no differences in 90-day mRS, mortality, or symptomatic ICH were observed among TNK 0.25 mg/kg, alteplase, and TNK 0.40 mg/kg.DiscussionTNK 0.25 mg/kg was associated with improved 90-day mRS and lower mortality in patients older than 80 years. No differences among the doses were observed in younger patients.Trial Registration InformationNCT02388061, NCT03340493.Classification of EvidenceThis study provides Class II evidence that tenecteplase 0.25 mg/kg given before endovascular therapy in patients >80 years old with large vessel occlusion stroke is associated with better functional outcomes at 90 days and reduced mortality when compared to tenecteplase 0.40 mg/kg or alteplase 0.90 mg/kg.

Whole blood viscosity (WBV) is the intrinsic resistance to flow developed due to the frictional force between adjacent layers of flowing blood. Elevated WBV is an independent risk factor for stroke. Poor microcirculation due to elevated WBV can prevent adequate perfusion of the brain and might act as an important secondary factor for hypoperfusion in acute ischaemic stroke. In the present study, we examined the association of WBV with basal cerebral perfusion assessed by CT perfusion in acute ischaemic stroke. Confirmed acute ischemic stroke patients (n = 82) presenting in hours were recruited from the single centre. Patients underwent baseline multimodal CT (non-contrast CT, CT angiography and CT perfusion). Where clinically warranted, patients also underwent follow-up DWI. WBV was measured in duplicate within 2¿h after sampling from 5-mL EDTA blood sample. WBV was significantly correlated with CT perfusion parameters such as perfusion lesion volume, ischemic core volume and mismatch ratio; DWI volume and baseline NIHSS. In a multivariate linear regression model, WBV significantly predicted acute perfusion lesion volume, core volume and mismatch ratio after adjusting for the effect of occlusion site and collateral status. Association of WBV with hypoperfusion (increased perfusion lesion volume, ischaemic core volume and mismatch ratio) suggest the role of erythrocyte rheology in cerebral haemodynamic of acute ischemic stroke. The present findings open new possibilities for therapeutic strategies targeting erythrocyte rheology to improve cerebral microcirculation in stroke.

Background: Multi-phenotype analysis of genetically correlated phenotypes can increase the statistical power to detect loci associated with multiple traits, leading to the discovery of novel loci. This is the first study to date to comprehensively analyze the shared genetic effects within different hemostatic traits, and between these and their associated disease outcomes. Objectives: To discover novel genetic associations by combining summary data of correlated hemostatic traits and disease events. Methods: Summary statistics from genome wide-association studies (GWAS) from seven hemostatic traits (factor VII [FVII], factor VIII [FVIII], von Willebrand factor [VWF] factor XI [FXI], fibrinogen, tissue plasminogen activator [tPA], plasminogen activator inhibitor 1 [PAI-1]) and three major cardiovascular (CV) events (venous thromboembolism [VTE], coronary artery disease [CAD], ischemic stroke [IS]), were combined in 27 multi-trait combinations using metaUSAT. Genetic correlations between phenotypes were calculated using Linkage Disequilibrium Score Regression (LDSC). Newly associated loci were investigated for colocalization. We considered a significance threshold of 1.85¿×¿10-9 obtained after applying Bonferroni correction for the number of multi-trait combinations performed (n¿=¿27). Results: Across the 27 multi-trait analyses, we found 4 novel pleiotropic loci (XXYLT1, KNG1, SUGP1/MAU2, TBL2/MLXIPL) that were not significant in the original individual datasets, were not described in previous GWAS for the individual traits, and that presented a common associated variant between the studied phenotypes. Conclusions: The discovery of four novel loci contributes to the understanding of the relationship between hemostasis and CV events and elucidate common genetic factors between these traits.

Introduction: Continuous surveillance of stroke admissions has been conducted in the Hunter region, Australia, over the past two decades. We aimed to describe the trends in incidence rates of hospitalised stroke and case-fatality rates in this region, 2001-2019. Methods: From a hospital-based stroke registry, data for admitted adult stroke patients residing in the Hunter region were collected using ICD-10 codes for ischemic and haemorrhagic stroke. Negative binomial regression and logistic regression analysis were used to analyse trends for age-standardised and age-specific incidence rates of hospitalised stroke and 28-day case-fatality rates. Results: A total of 14,662 hospitalisations for stroke in 13,242 individuals were registered. The age-standardised incidence rate declined from 123 per 100,000 population in the 2001-2005 epoch to 96 in the 2016-2019 epoch (mean annual change -2.0%, incidence rate ratio (IRR) = 0.980 [95%CI: 0.976-0.984]). Age-specific analyses identified significant reduction in the group aged 75-84 (1039 per 100,000 population in 2001-2005 to 633 in 2016-2019, annual change -3.5%, IRR= 0.965 [95%CI: 0.960-0.970]). The 28-day case-fatality rates fluctuated over time (18.5% in 2001-2005, 20.8% in 2010-2015, and 17.8% in 2016-2019). Projected population aging suggests annual volume of patients with new stroke will increase by 77% by 2041 if incidence rates remain unchanged at the 2016-2019 level. Conclusion: Although age-standardised hospitalised stroke incidence rates have declined in the Hunter region, the health system will face an increase in stroke hospitalisations related to the aging population.

Stroke is the second most common cause of death and remains a persistent health challenge globally. Due to its highly time-sensitive nature, earlier stroke treatments should be enforced for improved patient outcome. The mobile stroke unit (MSU) was conceptualized and implemented to deliver the diagnosis and treatment to a stroke patient in the ultra-early time window (<1 h) in the pre-hospital setting and has shown to be clinically effective. However, due to geographical challenges, most rural communities are still unable to receive timely stroke intervention, as access to specialized stroke facilities for optimal stroke treatment poses a challenge. Therefore, the aircraft counterpart (Air-MSU) of the conventional road MSU offers a plausible solution to this shortcoming by expanding the catchment area for regional locations in Australia. The implementation of Air-MSU is currently hindered by several technical limitations, where current commercially available CT scanners are still oversized and too heavy to be integrated into a conventional helicopter emergency medical service (HEMS). In collaboration with the Australian Stroke Alliance and Melbourne Brain Centre, this article aims to explore the possibilities and methodologies in reducing the weight and, effectively, the size of an existing CT scanner, such that it can be retrofitted into the proposed search and rescue helicopter¿Agusta Westland AW189. The result will be Australia¿s first-ever customized CT scanner structure designed to fit in a search-and-rescue helicopter used for Air-MSU.

Background: Emergency departments (ED) are challenging environments but critical for early management of patients with stroke. Purpose: To identify how context affects the provision of stroke care in 26 Australian EDs. Method: Nurses perceptions of ED context was assessed with the Alberta Context Tool. Medical records were audited for quality of stroke care and patient outcomes. Findings: Collectively, emergency nurses (n = 558) rated context positively with several nurse and hospital characteristics impacting these ratings. Despite these positive ratings, regression analysis showed no significant differences in the quality of stroke care (n = 1591 patients) and death or dependency (n = 1165 patients) for patients in EDs with high or low rated context. Discussion: Future assessments of ED context may need to examine contextual factors beyond the scope of the Alberta Context Tool which may play an important role for the understanding of stroke care and patient outcomes in EDs.

Background: Hospital arrival via ambulance influences treatment of acute stroke. We aimed to determine the factors associated with use of ambulance and access to evidence-based care among patients with stroke. Methods: Patients with first-ever strokes from the Australian Stroke Clinical Registry (2010¿2013) were linked with administrative data (emergency, hospital admissions). Multilevel, multivariable regression models were used to determine patient, clinical and system factors associated with arrival by ambulance. Results: Among the 6,262 patients with first-ever stroke, 4,737 (76%) arrived by ambulance (52% male; 80% ischaemic). Patients who were older, frailer, with comorbidities or were unable to walk on admission (stroke severity) were more likely to arrive by ambulance to hospital. Compared to those using other means of transport, those who used ambulances arrived to hospital sooner after stroke onset (minutes, 124 vs 397) and were more likely to receive reperfusion therapy (adjusted odds ratio, 1.57, 95% CI: 1.09, 2.27). Conclusion: Patients with stroke who use ambulances arrived faster and were more likely to receive reperfusion therapy compared to those using personal transport. Further public education about using ambulance services at all times, instead of personal transport when stroke is suspected is needed to optimise access to time critical care.

We aimed to compare Perfusion Imaging Mismatch (PIM) and Clinical Core Mismatch (CCM) criteria in ischemic stroke patients to identify the effect of these criteria on selected patient population characteristics and clinical outcomes. Patients from the INternational Stroke Perfusion Imaging REgistry (INSPIRE) who received reperfusion therapy, had pre-treatment multimodal CT, 24-h imaging, and 3 month outcomes were analyzed. Patients were divided into 3 cohorts: endovascular thrombectomy (EVT), intravenous thrombolysis alone with large vessel occlusion (IVT-LVO), and intravenous thrombolysis alone without LVO (IVT-nonLVO). Patients were classified using 6 separate mismatch criteria: PIM-using 3 different measures to define the perfusion deficit (Delay Time, Tmax, or Mean Transit Time); or CCM-mismatch between age-adjusted National Institutes of Health Stroke Scale and CT Perfusion core, defined as relative cerebral blood flow <30% within the perfusion deficit defined in three ways (as above). We assessed the eligibility rate for each mismatch criterion and its ability to identify patients likely to respond to treatment. There were 994 patients eligible for this study. PIM with delay time (PIM-DT) had the highest inclusion rate for both EVT (82.7%) and IVT-LVO (79.5%) cohorts. In PIM positive patients who received EVT, recanalization was strongly associated with achieving an excellent outcome at 90-days (e.g., PIM-DT: mRS 0-1, adjusted OR 4.27, P = 0.005), whereas there was no such association between reperfusion and an excellent outcome with any of the CCM criteria (all p > 0.05). Notably, in IVT-LVO cohort, 58.2% of the PIM-DT positive patients achieved an excellent outcome compared with 31.0% in non-mismatch patients following successful recanalization (P = 0.006). Conclusion: PIM-DT was the optimal mismatch criterion in large vessel occlusion patients, combining a high eligibility rate with better clinical response to reperfusion. No mismatch criterion was useful to identify patients who are most likely response to reperfusion in non-large vessel occlusion patients.

Objective: To investigate the association of blood pressure BP excursions, defined as greater than 185 SBP or greater than 105 DBP, with the probability of intracranial hemorrhage (ICH) and worse functional outcomes in patients with acute ischemic stroke (AIS) treated with tissue plasminogen activator (tPA). Methods: We performed a post hoc analysis of the CLOTBUST-ER trial. Serial BP measurements were conducted using automated cuff recording according to the recommended BP protocol guidelines for tPA administration. The outcomes were prespecified efficacy and safety endpoints of CLOTBUST-ER. Results: The mean number of serial BP recordings per patient was 37. Of the 674 patients, 227 (34%) had at least one BP excursion (>185/105 mmHg) during the first 24 h following tPA-bolus. The majority of BP excursions (46%) occurred within the first 75min from tPA-bolus. Patients with at least one BP excursion in the first 24 h following tPA bolus had significantly lower rates of independent functional outcome at 90 days (31 vs. 40.1%, P=0.028). The total number of BP excursions was associated with decreased odds of 24-h clinical recovery (OR=0.88, 95% CI:0.80-0.96), 24-h neurological improvement (OR=0.87, 95% CI: 0.81-0.94), 7-day functional improvement (common OR=0.92, 95% CI: 0.87-0.97), 90-day functional improvement (common OR=0.94, 95% CI: 0.88-0.98) and 90-day independent functional outcome (OR=0.90, 95% CI: 0.82-0.98) in analyses adjusted for potential confounders. DBP excursions were independently associated with increased odds of any intracranial hemorrhage (OR=1.26, 95% CI: 1.04-1.53). Conclusion: BP excursions above guideline thresholds during the first 24 h following tPA administration for AIS are common and are independently associated with adverse clinical outcomes.

Objectives Dizziness is a common and challenging clinical presentation in general practice. Failure to determine specific aetiologies can lead to significant morbidity and mortality. We aimed to establish frequency and associations of general practitioner (GP) trainees' (registrars') specific vertigo provisional diagnoses and their non-specific symptomatic problem formulations. Design A cross-sectional analysis of Registrar Clinical Encounters in Training (ReCEnT) cohort study data between 2010 and 2018. ReCEnT is an ongoing, prospective cohort study of registrars in general practice training in Australia. Data collection occurs once every 6 months midtraining term (for three terms) and entails recording details of 60 consecutive clinical consultations on hardcopy case report forms. The outcome factor was whether dizziness-related or vertigo-related presentations resulted in a specific vertigo provisional diagnosis versus a non-specific symptomatic problem formulation. Associations with patient, practice, registrar and consultation independent variables were assessed by univariate and multivariable logistic regression. Setting Australian general practice training programme. The training is regionalised and delivered by regional training providers (RTPs) (2010-2015) and regional training organisations (RTOs) (2016-2018) across Australia (from five states and one territory). Participants All general practice registrars enrolled with participating RTPs or RTOs undertaking GP training terms. Results 2333 registrars (96% response rate) recorded 1734 new problems related to dizziness or vertigo. Of these, 546 (31.5%) involved a specific vertigo diagnosis and 1188 (68.5%) a non-specific symptom diagnosis. Variables associated with a non-specific symptom diagnosis on multivariable analysis were lower socioeconomic status of the practice location (OR 0.94 for each decile of disadvantage, 95% CIs 0.90 to 0.98) and longer consultation duration (OR 1.02, 95% CIs 1.00 to 1.04). A specific vertigo diagnosis was associated with performing a procedure (OR 0.52, 95% CIs 0.27 to 1.00), with some evidence for seeking information from a supervisor being associated with a non-specific symptom diagnosis (OR 1.39, 95% CIs 0.92 to 2.09; p=0.12). Conclusions Australian GP registrars see dizzy patients as frequently as established GPs. The frequency and associations of a non-specific diagnosis are consistent with the acknowledged difficulty of making diagnoses in vertigo/dizziness presentations. Continuing emphasis on this area in GP training and encouragement of supervisor involvement in registrars' diagnostic processes is indicated.

Objective: To determine whether brain volume is associated with functional outcome after acute ischemic stroke (AIS). Patients and Methods: This study was conducted between July 1, 2014, and March 16, 2019. We analyzed cross-sectional data of the multisite, international hospital-based MRI-Genetics Interface Exploration study with clinical brain magnetic resonance imaging obtained on admission for index stroke and functional outcome assessment. Poststroke outcome was determined using the modified Rankin Scale score (0-6; 0 = asymptomatic; 6 = death) recorded between 60 and 190 days after stroke. Demographic characteristics and other clinical variables including acute stroke severity (measured as National Institutes of Health Stroke Scale score), vascular risk factors, and etiologic stroke subtypes (Causative Classification of Stroke system) were recorded during index admission. Results: Utilizing the data from 912 patients with AIS (mean ± SD age, 65.3±14.5 years; male, 532 [58.3%]; history of smoking, 519 [56.9%]; hypertension, 595 [65.2%]) in a generalized linear model, brain volume (per 155.1 cm3) was associated with age (ß -0.3 [per 14.4 years]), male sex (ß 1.0), and prior stroke (ß -0.2). In the multivariable outcome model, brain volume was an independent predictor of modified Rankin Scale score (ß -0.233), with reduced odds of worse long-term functional outcomes (odds ratio, 0.8; 95% CI, 0.7-0.9) in those with larger brain volumes. Conclusion: Larger brain volume quantified on clinical magnetic resonance imaging of patients with AIS at the time of stroke purports a protective mechanism. The role of brain volume as a prognostic, protective biomarker has the potential to forge new areas of research and advance current knowledge of the mechanisms of poststroke recovery.

Background and purpose: After an initial stroke, the risk of recurrent stroke is high. Models that implement best-practice recommendations for risk factor management in stroke survivors to prevent stroke recurrence remain elusive. We examined a model which focuses on vascular risk factor management to prevent stroke recurrence in survivors returning to their primary care physicians. This model is coordinated from the stroke unit, integrates specialist stroke services with primary care physicians, and directly involves patients and carers in risk factor management. It is underpinned by the shared care principle in which there is joint participation of specialists as well as primary care physicians in a planned, integrated delivery of care with ongoing involvement of patients and carers, a structure which encourages implementation of best-practice recommendations as well as transferability and sustainability. We hypothesized that an integrated, multimodal intervention based on a shared-care model which supports joint participation of stroke specialists and primary care physicians would improve the implementation of best-practice recommendations for risk factor management in stroke survivors returning to the community. Methods: We undertook a double-blind randomized controlled trial, testing the model in three Australian cities using stroke survivors admitted to stroke units and discharged from hospital to return to their primary care physicians. The model was a shared care, multifaceted integrated program which included bidirectional feedback between general practitioner and specialist unit, education, and engagement of patient and carer in self-management with ongoing input from a multidisciplinary team. The primary endpoint was improvement or abolition of risk factors such as raised blood pressure, diabetes, hyperlipidemia, the modification of adverse life-style factors such as lack of exercise, smoking and alcohol abuse and adherence to preventive medication at one year. Intermediate measurement points were scheduled at three monthly intervals. Analysis was by intention to treat, evaluated by covariance or a linear model adjusting for confounding factors or variance of base-line risk factors. The study was registered as ACTRN = 1261100026498. Results: The study population was as follows: intervention (n = 112), control (n = 137). At baseline, there was no statistical difference between the groups for any variable. At the 12-month evaluation, there was a significant decrease in systolic blood pressure from baseline in the intervention group of 5.2 mmHg (p < 0.01). This change was not observed in the control group (p = 0.29). Moreover, at 12 months the mean systolic blood pressure in the intervention group was 129.4 mmHg (SD 14.7), a result which was not obtained in controls. Fasting total cholesterol as well as triglycerides was reduced significantly in the intervention group (both p < 0.01) but this was not the case in the control group (p = 0.11 and p = 0.27, respectively). At 12 months, there was no change in BMI in the intervention group but there was a significant increase in BMI (p = 0.02) in the control group. At 12 months in the intervention group, the mean distance walked with ease compared to the baseline measurements was increased by a mean distance of 600 m while in the control group the distance walked with ease was reduced compared to that measured at baseline. At 12 months, the Barthel index in the intervention group demonstrated improved function (p = 0.01), but no change was observed in controls. At 12 months in the intervention group, there was a significant decrease in number of standard alcoholic drinks consumed per week compared to the baseline (p = 0.04). This was not observed in the control group (p = 0.34). Conclusion: In stroke survivors, the ICARUSS (Integrated Care for the Reduction of Secondary Stroke) model is superior to usual care with respect to best-practice recommendations for traditi...

Importance: Intravenous thrombolysis with tenecteplase improves reperfusion prior to endovascular thrombectomy for ischemic stroke compared with alteplase. Objective: To determine whether 0.40 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion ischemic stroke. Design, Setting, and Participants: Randomized clinical trial at 27 hospitals in Australia and 1 in New Zealand using open-label treatment and blinded assessment of radiological and clinical outcomes. Patients were enrolled from December 2017 to July 2019 with follow-up until October 2019. Adult patients (N = 300) with ischemic stroke due to occlusion of the intracranial internal carotid, \basilar, or middle cerebral artery were included less than 4.5 hours after symptom onset using standard intravenous thrombolysis eligibility criteria. Interventions: Open-label tenecteplase at 0.40 mg/kg (maximum, 40 mg; n = 150) or 0.25 mg/kg (maximum, 25 mg; n = 150) given as a bolus before endovascular thrombectomy. Main Outcomes and Measures: The primary outcome was reperfusion of greater than 50% of the involved ischemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists. Prespecified secondary outcomes were level of disability at day 90 (modified Rankin Scale [mRS] score; range, 0-6); mRS score of 0 to 1 (freedom from disability) or no change from baseline at 90 days; mRS score of 0 to 2 (functional independence) or no change from baseline at 90 days; substantial neurological improvement at 3 days; symptomatic intracranial hemorrhage within 36 hours; and all-cause death. Results: All 300 patients who were randomized (mean age, 72.7 years; 141 [47%] women) completed the trial. The number of participants with greater than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.40 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI, -8.9% to -8.9%]; adjusted risk ratio, 1.03 [95% CI, 0.66-1.61]; P =.89). Among the 6 secondary outcomes, there were no significant differences in any of the 4 functional outcomes between the 0.40 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%]; unadjusted risk difference, 2.7% [95% CI, -5.6% to 11.0%]) or symptomatic intracranial hemorrhage (7 [4.7%] vs 2 [1.3%]; unadjusted risk difference, 3.3% [95% CI, -0.5% to 7.2%]). Conclusions and Relevance: Among patients with large vessel occlusion ischemic stroke, a dose of 0.40 mg/kg, compared with 0.25 mg/kg, of tenecteplase did not significantly improve cerebral reperfusion prior to endovascular thrombectomy. The findings suggest that the 0.40-mg/kg dose of tenecteplase does not confer an advantage over the 0.25-mg/kg dose in patients with large vessel occlusion ischemic stroke in whom endovascular thrombectomy is planned. Trial Registration: ClinicalTrials.gov Identifier: NCT03340493.

Background: Currently there are multiple variations of imaging-based patient selection mismatch methods in ischemic stroke. In the present study, we sought to compare the two most common mismatch methods and identify if there were different effects on the outcome of a randomized clinical trial depending on the mismatch method used. Aims: Investigate the effect of clinical and imaging-based mismatch criteria on patient outcomes of a pooled cohort from randomized trials of intravenous tenecteplase versus alteplase. Methods: Baseline clinical and imaging scores were used to categorize patients as meeting either the DAWN mismatch (baseline NIHSS = 10, and age cut-offs for ischemic core volume) or DEFUSE 2 mismatch criteria (mismatch volume > 15 mL, mismatch ratio > 1.8 and ischemic core < 70 mL). We then investigated whether tenecteplase-treated patients had favorable odds of less disability (on modified Rankin scale, mRS) compared to those treated with alteplase, for clinical and imaging mismatch, respectively. Results: From 146 pooled patients, 71 received alteplase and 75 received tenecteplase. The overall pooled group did not show improved patient outcomes when treated with tenecteplase (mRS 0-1 OR 1.77, 95% CI 0.89¿3.51, p = 0.102) compared with alteplase. A total of 39 (27%) patients met both clinical and imaging mismatch criteria, 25 (17%) patients met only imaging criteria, 36 (25%) met only clinical mismatch criteria and, finally, 46 (31%) did not meet either of imaging or mismatch criteria. Patients treated with tenecteplase had more favorable outcomes when they met either imaging mismatch (mRS 0¿1, OR 2.33, 95% CI 1.13¿5.94, p = 0.032) or clinical mismatch criteria (mRS 0¿1, OR 2.15, 95% CI 1.142, 8.732, p = 0.027) but with differing proportions. Conclusion: Target mismatch selection was more inclusive and exhibited in a larger treatment effect between tenecteplase and alteplase.

Background: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. Methods: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0¿1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0¿2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4¿6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. Findings: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10¿2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05¿1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06¿2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4¿6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52¿1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03¿4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22¿25·50]; p=0·024). Interpretation: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. Funding: None.

Objective: We sought to examine the diagnostic utility of existing predictors of any hemorrhagic transformation (HT) and compare them with new perfusion imaging permeability measures in ischemic stroke patients receiving alteplase only. Methods: A pixel-based analysis of pretreatment CT perfusion (CTP) was undertaken to define the optimal CTP permeability thresholds to predict the likelihood of HT. We then compared previously proposed predictors of HT using regression analyses and receiver operating characteristic curve analysis to produce an area under the curve (AUC). We compared AUCs using ¿2 analysis. Results: From 5 centers, 1,407 patients were included in this study; of these, 282 had HT. The cohort was split into a derivation cohort (1,025, 70% patients) and a validation cohort (382 patients or 30%). The extraction fraction (E) permeability map at a threshold of 30% relative to contralateral had the highest AUC at predicting any HT (derivation AUC 0.85, 95% confidence interval [CI], 0.79¿0.91; validation AUC 0.84, 95% CI 0.77¿0.91). The AUC improved when permeability was assessed within the acute perfusion lesion for the E maps at a threshold of 30% (derivation AUC 0.91, 95% CI 0.86¿0.95; validation AUC 0.89, 95% CI 0.86¿0.95). Previously proposed associations with HT and parenchymal hematoma showed lower AUC values than the permeability measure. Interpretation: In this large multicenter study, we have validated a highly accurate measure of HT prediction. This measure might be useful in clinical practice to predict hemorrhagic transformation in ischemic stroke patients before receiving alteplase alone. ANN NEUROL 2020;88:466¿476.

Background: 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. Methods: 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 of >7, intracerebral haemorrhage volume <70 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 or >6 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). Findings: 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. Interpretation: 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. Funding: National Health and Medical Research Council, Royal Melbourne Hospital Foundation.

Background and purpose: Blood pressure (BP) variability has been associated with worse neurological outcomes in acute ischaemic stroke (AIS) patients receiving treatment with intravenous thrombolysis (IVT). However, no study to date has investigated whether pulse pressure (PP) variability may be a superior indicator of the total cardiovascular risk, as measured by clinical outcomes. Methods: Pulse pressure variability was calculated from 24-h PP measurements following tissue plasminogen activator bolus in AIS patients enrolled in the Combined Lysis of Thrombus using Ultrasound and Systemic Tissue Plasminogen Activator for Emergent Revascularization (CLOTBUST-ER) trial. The outcomes of interest were the pre-specified efficacy and safety end-points of CLOTBUST-ER. All associations were adjusted for potential confounders in multivariable regression models. Results: Data from 674 participants was analyzed. PP variability was identified as the BP parameter with the most parsimonious fit in multivariable models of all outcomes, and was independently associated (P¿<¿0.001) with lower likelihood of both 24-h neurological improvement and 90-day independent functional outcome. PP variability was also independently related to increased odds of any intracranial bleeding (P¿=¿0.011) and 90-day mortality (P¿<¿0.001). Every 5-mmHg increase in the 24-h PP variability was independently associated with a 36% decrease in the likelihood of 90-day independent functional outcome (adjusted odds ratio 0.64, 95% confidence interval 0.52¿0.80) and a 60% increase in the odds of 90-day mortality (adjusted odds ratio 1.60, 95% confidence interval 1.23¿2.07). PP variability was not associated with symptomatic intracranial bleeding at either 24 or 36¿h after IVT administration. Conclusions: Increased PP variability appears to be independently associated with adverse short-term and long-term functional outcomes of AIS patients treated with IVT.

Aims: Penumbral selection is best-evidence practice for thrombectomy in the 6-24¿hour window. Moreover, it helps to identify the best responders to thrombolysis. Multimodal computed tomography (mCT) at the primary centre¿including noncontrast CT, CT perfusion, and CT angiography¿may enhance reperfusion therapy decision-making. We developed a network with five spoke primary stroke sites and assessed safety, feasibility, and influence of mCT in rural hospitals on decision-making for thrombolysis. Methods: Consecutive patients assessed via telemedicine from April 2013 to June 2018. Clinical outcomes were measured, and decision-making compared using theoretical models for reperfusion therapy applied without mCT guidance. Symptomatic intracranial hemorrhage (sICH) was assessed according to Safe Implementation of Treatments in Stroke Thrombolysis Registry criteria. Results: A total of 334 patients were assessed, 240 received mCT, 58 were thrombolysed (24.2%). The mean age of thrombolysed patients was 70¿years, median baseline National Institutes of Health Stroke Scale was 10 (IQR 7-18) and 23 (39.7%) had a large vessel occlusion. 1.7% had sICH and 3.5% parenchymal hematoma. Three months poststroke, 55% were independent, compared with 70% in the non-thrombolysed group. Conclusion: Implementation of CTP in rural centers was feasible and led to high thrombolysis rates with low rates of sICH.

Background: Transient ischemic attacks are common and place patients at risk of subsequent stroke. The 2007 EXPRESS and SOS-TIA studies demonstrated the efficacy of rapid treatment initiation. We hypothesized that with these findings having informed subsequent transient ischemic attacks management protocols, transient ischemic attacks prognosis in contemporary (2008 and later) patient cohorts would be more favorable than in historical cohorts. Methods: A systematic review and meta-analysis of cohort studies and randomized control trial placebo-arms of transient ischemic attack (published 2008¿2015). The primary outcome was stroke. Secondary outcomes were mortality, transient ischemic attack, and myocardial infarction. Studies were excluded if the outcome of transient ischemic attack patients was not reported separately. The systematic review included all studies of transient ischemic attack. The meta-analysis excluded studies of restricted transient ischemic attack patient types (e.g. only patients with atrial fibrillation). The pooled cumulative risks of stroke recurrence were estimated from study-specific estimates at 2, 7, 30, and 90 days post-transient ischemic attack, using a multivariate Bayesian model. Results: We included 47 studies in the systematic review and 40 studies in the meta-analysis. In the systematic review (191,202 patients), stroke at 2 days was reported in 13/47 (27.7%) of studies, at 7 days in 20/47 (42.6%), at 30 days in 12/47 (25.5%), and at 90 days in 33/47 (70.2%). Studies included in the meta-analysis recruited 68,563 patients. The cumulative risk of stroke was 1.2% (95% credible interval (CI) 0.6¿2.2), 3.4% (95% CI 2.0¿5.5), 5.0% (95% CI 2.9¿8.9), and 7.4% (95% CI 4.3¿12.4) at 2, 7, 30, and 90 days post-transient ischemic attack, respectively. Conclusion: In contemporary settings, transient ischemic attack prognosis is more favorable than reported in historical cohorts where a meta-analysis suggests stroke risk of 3.1% at two days.

Objective: We assessed patient clinical outcomes based on occlusion location, focusing on distal occlusions to understand if occlusion location was an independent predictor of outcome, and tested the relationship between occlusion location and baseline ischemic core, a known predictor of modified Rankin Scale (mRS) score at 90 days. Methods: We analyzed a prospectively collected cohort of thrombolysis-eligible ischemic stroke patients from the International Stroke Perfusion Imaging Registry who underwent multimodal CT pretreatment. For the primary analysis, logistic regression was used to predict the effect of occlusion location and ischemic core on the likelihood of excellent (mRS 0-1) and favorable (mRS 0-2) 90-day outcomes. Results: This study included 945 patients. The rates of excellent and favorable outcome in patients with distal occlusion (M2, M3 segment of middle cerebral artery, anterior cerebral artery, and posterior cerebral artery) were higher than M1 occlusions (mRS 0%-1%, 55% vs 37%; mRS 0%-2%, 73% vs 50%, p < 0.001). Vessel occlusion location was not a strong predictor of outcomes compared to baseline ischemic core (area under the curve, mRS 0-1, 0.64 vs 0.83; mRS 0-2, 0.70 vs 0.86, p < 0.001). There was no interaction between occlusion location and ischemic core (interaction coefficient 1.00, p = 0.798). Conclusions: Ischemic stroke patients with a distal occlusion have higher rate of excellent and favorable outcome than patients with an M1 occlusion. The baseline ischemic core was shown to be a more powerful predictor of functional outcome than the occlusion location, but the relationship between ischemic core and outcome does not different by occlusion locations.

Importance: Extracranial carotid and vertebral artery dissection is an important cause of stroke, particularly in younger individuals. In some but not all observational studies, it has been associated with a high risk of recurrent stroke. Both antiplatelet agents (APs) and anticoagulants (ACs) are used to reduce stroke risk, but whether 1 treatment strategy is more effective is unknown. Objective: To determine whether AP or AC therapy is more effective in preventing stroke in cervical dissection and the risk of recurrent stroke in a randomized clinical trial setting. A secondary outcome was to determine the effect on arterial imaging outcomes. Design, Setting, and Participants: Randomized, prospective, open-label international multicenter parallel design study with central blinded review of both clinical and imaging end points. Recruitment was conducted in 39 stroke and neurology secondary care centers in the United Kingdom and 7 centers in Australia between February 24, 2006, and June 17, 2013. One-year follow-up and analysis was conducted in 2018. Two hundred fifty participants with extracranial carotid and vertebral dissection with symptom onset within the last 7 days were recruited. Follow-up data at 1 year were available for all participants. Interventions: Randomization to AP or AC (heparin followed by warfarin) for 3 months, after which the choice of AP and AC agents was decided by the local clinician. Main Outcomes and Measures: The primary end point was ipsilateral stroke and death. A planned per protocol (PP) analysis was performed in patients meeting the inclusion criteria following central review of imaging to confirm the diagnosis of dissection. A secondary end point was angiographic recanalization in those with imaging confirmed dissection. Results: Two hundred fifty patients were randomized (118 carotid and 132 vertebral), 126 to AP and 124 to AC. Mean (SD) age was 49 (12) years. Mean (SD) time to randomization was 3.65 (1.91) days. The recurrent stroke rate at 1 year was 6 of 250 (2.4%) on ITT analysis and 5 of 197 (2.5%) on PP analysis. There were no significant differences between treatment groups for any outcome. Of the 181 patients with confirmed dissection and complete imaging at baseline and 3 months, there was no difference in the presence of residual narrowing or occlusion between those receiving AP (n = 56 of 92) vs those receiving AC (n = 53 of 89) (P =.97). Conclusions and Relevance: During 12 months of follow-up, the number of recurrent strokes was low. There was no difference between treatment groups in outcome events or the rate of recanalization. Trial Registration: ISRCTN.com Identifier: CTN44555237.

Background: Systolic blood pressure of more than 185 mm Hg is a contraindication to thrombolytic treatment with intravenous alteplase in patients with acute ischaemic stroke, but the target systolic blood pressure for optimal outcome is uncertain. We assessed intensive blood pressure lowering compared with guideline-recommended blood pressure lowering in patients treated with alteplase for acute ischaemic stroke. Methods: We did an international, partial-factorial, open-label, blinded-endpoint trial of thrombolysis-eligible patients (age =18 years) with acute ischaemic stroke and systolic blood pressure 150 mm Hg or more, who were screened at 110 sites in 15 countries. Eligible patients were randomly assigned (1:1, by means of a central, web-based program) within 6 h of stroke onset to receive intensive (target systolic blood pressure 130¿140 mm Hg within 1 h) or guideline (target systolic blood pressure <180 mm Hg) blood pressure lowering treatment over 72 h. The primary outcome was functional status at 90 days measured by shift in modified Rankin scale scores, analysed with unadjusted ordinal logistic regression. The key safety outcome was any intracranial haemorrhage. Primary and safety outcome assessments were done in a blinded manner. Analyses were done on intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT01422616. Findings: Between March 3, 2012, and April 30, 2018, 2227 patients were randomly allocated to treatment groups. After exclusion of 31 patients because of missing consent or mistaken or duplicate randomisation, 2196 alteplase-eligible patients with acute ischaemic stroke were included: 1081 in the intensive group and 1115 in the guideline group, with 1466 (67·4%) administered a standard dose among the 2175 actually given intravenous alteplase. Median time from stroke onset to randomisation was 3·3 h (IQR 2·6¿4·1). Mean systolic blood pressure over 24 h was 144·3 mm Hg (SD 10·2) in the intensive group and 149·8 mm Hg (12·0) in the guideline group (p<0·0001). Primary outcome data were available for 1072 patients in the intensive group and 1108 in the guideline group. Functional status (mRS score distribution) at 90 days did not differ between groups (unadjusted odds ratio [OR] 1·01, 95% CI 0·87¿1·17, p=0·8702). Fewer patients in the intensive group (160 [14·8%] of 1081) than in the guideline group (209 [18·7%] of 1115) had any intracranial haemorrhage (OR 0·75, 0·60¿0·94, p=0·0137). The number of patients with any serious adverse event did not differ significantly between the intensive group (210 [19·4%] of 1081) and the guideline group (245 [22·0%] of 1115; OR 0·86, 0·70¿1·05, p=0·1412). There was no evidence of an interaction of intensive blood pressure lowering with dose (low vs standard) of alteplase with regard to the primary outcome. Interpretation: Although intensive blood pressure lowering is safe, the observed reduction in intracranial haemorrhage did not lead to improved clinical outcome compared with guideline treatment. These results might not support a major shift towards this treatment being applied in those receiving alteplase for mild-to-moderate acute ischaemic stroke. Further research is required to define the underlying mechanisms of benefit and harm resulting from early intensive blood pressure lowering in this patient group. Funding: National Health and Medical Research Council of Australia; UK Stroke Association; Ministry of Health and the National Council for Scientific and Technological Development of Brazil; Ministry for Health, Welfare, and Family Affairs of South Korea; Takeda.

Purpose: Collateral grading may vary on single-phase CTA (sCTA) depending on whether the CTA is arterial (A), arteriovenous (AV), or venous (V) weighted. We studied the impact of sCTA weighting on collateral grading using the Tan, MAAS, and Menon methods, and their ability to predict infarct and clinical outcome hypothesizing that AV-weighted sCTA should better predict these outcomes. Methods: Multicenter retrospective analysis of 212 patients undergoing baseline CTP/sCTA. sCTA weighting was determined by comparing ICA to torcula AV ratios with those from concomitant CTP time-density curves at peak arterial or venous contrast attenuation. A generalized linear mixed model investigated the predictive value for infarct volume or 90-day mRS of the three collateral scores stratified by sCTA weighting and adjusting for age, sex, clot burden score (CBS), and NIHSS. Bayesian information criterion (BIC) differences were calculated between the null and fitted models. Results: Mean age, baseline median NIHSS, ASPECTS, and onset to treatment time were 69.89 ± 14.45, 13 (6¿18), 10 (8¿10), and 128 (66¿181) minutes. sCTA scans were AV-weighted in 137/212 (65%) and A-weighted in 73 (34%). No association was demonstrated between sCTA weighting, hospital site, and sCTA technique. All collateral scores were related to infarct volume irrespective of sCTA weighting, with greatest fit with the regional leptomeningeal score (BIC 18.29, p = 0.0001). No association was shown between sCTA weighting, collateral grade, and clinical outcome. Conclusion: sCTA weighting did not significantly impact collateral grade using three common collateral scores or their ability to predict final infarct.

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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..

Background: CT perfusion may improve diagnostic accuracy in posterior circulation stroke. The posterior circulation Acute Stroke Prognosis Early CT score (pc-ASPECTS) on Computed Tomography Angiography source images (CTA-SI) predicts functional outcome in patients with basilar artery occlusion. Aims: We assessed the prognostic value of pc-ASPECTS on CT perfusion in patients with vertebral and basilar artery occlusion (VBAO) in comparison with CTA-SI. Methods: Whole-brain CT perfusion from consecutive stroke patients with VBAO at four stroke centers was retrospectively analyzed. pc-ASPECTS ¿ a 10-point score assessing hypoattenuation on CTA-SI ¿ was calculated from CT perfusion parameters as focally reduced cerebral blood flow or cerebral blood volume, focally increased time to peak of the deconvolved tissue residue function (Tmax) or mean transit time. Two investigators independently reviewed the images. Reliability was assessed with intraclass correlation coefficient. Good outcome was defined as modified Rankin scale =3 at three months. Results: We included 60 patients with VBAO. After assessment of four CT perfusion maps simultaneously, area-under-ROC curve (AROC) was 0.83 (95%CI 0.72¿0.93) for cerebral blood volume, 0.76 (95%CI 0.64¿0.89) for cerebral blood flow, 0.77 (95%CI 0.64¿0.89) for Tmax, 0.70 (95%CI 0.56¿0.84) for mean transit time versus area-under-ROC curve 0.64 (95%CI 0.50¿0.79) for CTA-SI. Cerebral blood volume had greater accuracy compared with CTA-SI for poor outcome (p = 0.04). In logistic regression analysis, cerebral blood volume pc-ASPECTS=8 was independently associated with poor outcome (OR 9.3 95%CI 2.2¿41; p = 0.003, adjusted for age and clinical severity). Inter-rater agreement was substantial for cerebral blood volume pc-ASPECTS (intraclass correlation coefficient 0.82 95%CI 0.71¿0.90 versus 0.67 for CTA-SI 95%CI 0.43¿0.81). Conclusions: Cerebral blood volume pc-ASPECTS may identify VBAO patients at higher risk of disability.

Background: Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods: We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score =10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4·5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov, number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings: Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1·05 (95% CI 0·77¿1·45; p=0·74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1·24, 95% CI 0·80¿1·92; p=0·37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1·12, 0·79¿1·60; p=0·53). Interpretation: Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. Funding: Cerevast Therapeutics.

ObjectiveTo determine whether serum magnesium and calcium concentrations are causally associated with ischemic stroke or any of its subtypes using the mendelian randomization approach.MethodsAnalyses were conducted using summary statistics data for 13 single-nucleotide polymorphisms robustly associated with serum magnesium (n = 6) or serum calcium (n = 7) concentrations. The corresponding data for ischemic stroke were obtained from the MEGASTROKE consortium (34,217 cases and 404,630 noncases).ResultsIn standard mendelian randomization analysis, the odds ratios for each 0.1 mmol/L (about 1 SD) increase in genetically predicted serum magnesium concentrations were 0.78 (95% confidence interval [CI] 0.69-0.89; p = 1.3 × 10-4) for all ischemic stroke, 0.63 (95% CI 0.50-0.80; p = 1.6 × 10-4) for cardioembolic stroke, and 0.60 (95% CI 0.44-0.82; p = 0.001) for large artery stroke; there was no association with small vessel stroke (odds ratio 0.90, 95% CI 0.67-1.20; p = 0.46). Only the association with cardioembolic stroke was robust in sensitivity analyses. There was no association of genetically predicted serum calcium concentrations with all ischemic stroke (per 0.5 mg/dL [about 1 SD] increase in serum calcium: odds ratio 1.03, 95% CI 0.88-1.21) or with any subtype.ConclusionsThis study found that genetically higher serum magnesium concentrations are associated with a reduced risk of cardioembolic stroke but found no significant association of genetically higher serum calcium concentrations with any ischemic stroke subtype.

Background: The quality of care and outcomes for people who experience stroke whilst in hospital for another condition has not been previously studied in Australia. Aims: To explore differences in long-term outcomes among patients with in-hospital events treated in stroke units (SUs) compared to those managed in other hospital wards. Methods: Forty-five hospitals participating in the Australian Stroke Clinical Registry between January 2010 and December 2014 contributed data. Survival of all patients with in-hospital stroke to 180 days after stroke and health-related quality of life, using EQ-5D-3L among 73% eligible, were compared using multilevel, multivariable regression models. Models were adjusted for age, sex, index of relative socioeconomic disadvantage, ability to walk, stroke type, transfer from another hospital, and history of stroke. Results: Among 20,786 stroke events, 1182 (5.1%) occurred in-hospital (median age 77 years, 49% male). Patients with in-hospital stroke treated in SUs died less often within 30 days (Hazard Ratio 0.56; 95% CI 0.39-0.81) than those not admitted to SUs. Survivors reported similar health-related quality of life between 90 and 180 days compared to those treated in other wards (coefficient = 0.01, 95% CI ¿0.06-0.09, P =.78). Patients managed in SUs more often received recommended management (e.g. swallowing screening). Conclusion: The benefits of SU care may extend to patients experiencing in-hospital stroke. Validation, including accounting for potential residual confounding factors, is required.

Objectives: To examine the effectiveness of different strategies for recruiting participants for a large Australian randomised controlled trial (RCT), the Australian Study for the Prevention through Immunisation of Cardiovascular Events (AUSPICE). Design, setting, participants: Men and women aged 55¿60 years with at least two cardiovascular risk factors (hypertension, hypercholesterolaemia, overweight/obesity) were recruited for a multicentre placebo-controlled RCT assessing the effectiveness of 23-valent pneumococcal polysaccharide vaccine (23vPPV) for preventing cardiovascular events. Methods: Invitations were mailed by the Australian Department of Human Services to people in the Medicare database aged 55¿60 years; reminders were sent 2 weeks later. Invitees could respond in hard copy or electronically. Direct recruitment was supplemented by asking invitees to extend the invitation to friends and family (snowball sampling) and by Facebook advertising. Main outcome: Proportions of invitees completing screening questionnaire and recruited for participation in the RCT. Results: 21¿526 of 154¿992 invited people (14%) responded by completing the screening questionnaire, of whom 4725 people were eligible and recruited for the study. Despite the minimal study burden (one questionnaire, one clinic visit), the overall participation rate was 3%, or an estimated 10% of eligible persons. Only 16% of eventual participants had responded within 2 weeks of the initial invitation letter (early responders); early and late responders did not differ in their demographic or medical characteristics. Socio-economic disadvantage did not markedly influence response rates. Facebook advertising and snowball sampling did not increase recruitment. Conclusions: Trial participation rates are low, and multiple concurrent methods are needed to maximise recruitment. Social media strategies may not be successful in older age groups. Trial registration: Australian New Zealand Clinical Trials Registry, ACTRN12615000536561.

Objective To explore genetic and lifestyle risk factors of MRI-defined brain infarcts (BI) in large population-based cohorts. Methods We performed meta-analyses of genome-wide association studies (GWAS) and examined associations of vascular risk factors and their genetic risk scores (GRS) with MRI-defined BI and a subset of BI, namely, small subcortical BI (SSBI), in 18 population-based cohorts (n=20,949) from 5 ethnicities (3,726 with BI, 2,021 with SSBI). Top loci were followed up in 7 population-based cohorts (n = 6,862; 1,483 with BI, 630 with SBBI), and we tested associations with related phenotypes including ischemic stroke and pathologically defined BI. Results The mean prevalence was 17.7% for BI and 10.5% for SSBI, steeply rising after age 65. Two loci showed genome-wide significant association with BI: FBN2, p = 1.77 × 10-8; and LINC00539/ZDHHC20, p = 5.82 × 10-9. Both have been associated with blood pressure (BP)-related phenotypes, but did not replicate in the smaller follow-up sample or show associations with related phenotypes. Age- and sex-adjusted associations with BI and SSBI were observed for BP traits (p value for BI, p[BI] = 9.38 × 10-25; p [SSBI] = 5.23 × 10-14 for hypertension), smoking (p[BI]= 4.4 × 10-10; p [SSBI] = 1.2 × 10 -4), diabetes (p[BI] = 1.7 × 10 -8; p [SSBI] = 2.8 × 10 -3), previous cardiovascular disease (p [BI] = 1.0 × 10-18; p [SSBI] = 2.3 × 10-7), stroke (p [BI] = 3.9 × 10-69; p [SSBI] = 3.2 × 10 -24), and MRI-defined white matter hyperintensity burden (p [BI]=1.43 × 10-157; p [SSBI] = 3.16 × 10-106), but not with body mass index or cholesterol. GRS of BP traits were associated with BI and SSBI (p = 0.0022), without indication of directional pleiotropy. Conclusion In this multiethnic GWAS meta-analysis, including over 20,000 population-based participants, we identified genetic risk loci for BI requiring validation once additional large datasets become available. High BP, including genetically determined, was the most significant modifiable, causal risk factor for BI.

Background: 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. Methods: 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. Findings: 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). Interpretation: 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. Funding: None.

Background: The Quality in Acute Stroke Care Trial implemented nurse-initiated protocols to manage fever, hyperglycaemia and swallowing (Fever, Sugar, Swallow clinical protocols) achieving a 16% absolute improvement in death and dependency 90-day post-stroke. Objective: To examine associations between 90-day death and dependency, and monitoring and treatment processes of in-hospital nursing stroke care targeted in the trial. Design: Secondary data analysis from a single-blind cluster randomised control trial. Setting: 19 acute stroke units in New South Wales, Australia. Participants: English-speakers =18 years with ischaemic stroke or intracerebral haemorrhage arriving at participating stroke units <48 h of stroke onset, excluding those for palliation and without a telephone. Method: Data from patients in the 10 intervention hospitals and the nine control hospitals in the QASC trial post-intervention cohort, who had both hospital process of care data and 90-day outcome data were included. Associations between independence at 90-day (modified Rankin Score =1) and processes of care for fever, hyperglycaemia, and dysphagia screening were examined using multiple logistic regression adjusting for treatment group, sex, age group, premorbid modified Rankin scale, marital status, education, stroke severity and correlation within hospitals. Results: Of 1126 patients in the post-intervention cohort (intervention or control), 970 had both in-hospital processes of care data and 90-day outcome data. Patients had significantly lower odds of 90-day independence if, within the first 72 h of stroke unit admission, they had one or more: febrile event (=37.5 °C) (OR 0.47; 95%CI:0.35-0.61; P < 0.0001), higher mean temperature (OR:0.25; 95%CI:0.14-0.45; P < 0.0001), finger-prick blood glucose reading =11 mmol/L (OR:0.61; 95%CI:0.47-0.79; P = 0.0002), higher mean blood glucose (OR 0.89; 95%CI:0.84-0.95; P = 0.0006), or failed the swallowing screen (OR 0.35; 95%CI:0.22-0.56; P < 0.0001). Patients had greater odds of independence when: venous blood glucose was taken on admission to hospital or within 2 h of stroke unit admission (OR 1.4; 95%CI:1.01¿1.83; P = 0.04); finger-prick blood glucose was measured within 72 h of stroke unit admission (OR 1.3; 95%CI:1.02-1.55; P = 0.03); or when swallowing screening or assessment was performed within 24 h of stroke unit admission (OR 1.8; 95%CI:1.29-2.55; P = 0.0006). Conclusion: We have provided robust evidence of the importance of monitoring patients¿ temperature, blood glucose and swallowing status to improve 90-day stroke outcomes. Routine nursing care can result in significant reduction in death and dependency post-stroke.

Background and Purpose - Poststroke fatigue affects a large proportion of stroke survivors and is associated with a poor quality of life. In a recent trial, modafinil was shown to be an effective agent in reducing poststroke fatigue; however, not all patients reported a significant decrease in fatigue with therapy. We sought to investigate clinical and radiological predictors of fatigue reduction with modafinil therapy in a stroke survivor cohort. Methods - Twenty-six participants with severe fatigue (multidimensional fatigue inventory-20 =60) underwent magnetic resonance imaging at baseline and during the last week of a 6-week treatment period of 200 mg modafinil taken daily. Resting-state functional magnetic resonance imaging and high-resolution structural imaging data were obtained, and functional connectivity and regional brain volumes within the fronto-striato-thalamic network were obtained. Linear regression analysis was used to identify predictors of modafinil-induced fatigue reduction. Results - Multiple regression analysis showed that baseline multidimensional fatigue inventory-20 score (ß=0.576, P=0.006) and functional connectivity between the dorsolateral prefrontal cortex and the caudate nucleus (ß=-0.424, P=0.008) were significant predictors of modafinil-associated decreases in poststroke fatigue (adjusted r2=0.52, area under the receiver operator characteristic curve=0.939). Conclusions - Fronto-striato-thalamic functional connectivity predicted modafinil response for poststroke fatigue. Fatigue in other neurological disease has been attributed to altered function of the fronto-striato-thalamic network and may indicate that poststroke fatigue has a similar mechanism to other neurological injury related fatigue. Self-reported fatigue in patients with normal fronto-striato-thalamic functional connectivity may have a different mechanism and require alternate therapeutic approaches.

ObjectiveTo discover common genetic variants associated with poststroke outcomes using a genome-wide association (GWA) study.MethodsThe study comprised 6,165 patients with ischemic stroke from 12 studies in Europe, the United States, and Australia included in the GISCOME (Genetics of Ischaemic Stroke Functional Outcome) network. The primary outcome was modified Rankin Scale score after 60 to 190 days, evaluated as 2 dichotomous variables (0-2 vs 3-6 and 0-1 vs 2-6) and subsequently as an ordinal variable. GWA analyses were performed in each study independently and results were meta-analyzed. Analyses were adjusted for age, sex, stroke severity (baseline NIH Stroke Scale score), and ancestry. The significance level was p < 5 × 10-8.ResultsWe identified one genetic variant associated with functional outcome with genome-wide significance (modified Rankin Scale scores 0-2 vs 3-6, p = 5.3 × 10-9). This intronic variant (rs1842681) in the LOC105372028 gene is a previously reported trans-Expression quantitative trait locus for PPP1R21, which encodes a regulatory subunit of protein phosphatase 1. This ubiquitous phosphatase is implicated in brain functions such as brain plasticity. Several variants detected in this study demonstrated suggestive association with outcome (p < 10-5), some of which are within or near genes with experimental evidence of influence on ischemic stroke volume and/or brain recovery (e.g., NTN4, TEK, and PTCH1).ConclusionsIn this large GWA study on functional outcome after ischemic stroke, we report one significant variant and several variants with suggestive association to outcome 3 months after stroke onset with plausible mechanistic links to poststroke recovery. Future replication studies and exploration of potential functional mechanisms for identified genetic variants are warranted.

Background: The quality of stroke care may diminish on weekends. Aims: We aimed to compare the quality of care and outcomes for patients with stroke/transient ischemic attack discharged on weekdays compared with those discharged on weekends. Methods: Data from the Australian Stroke Clinical Registry from January 2010 to December 2015 (n = 45 hospitals) were analyzed. Differences in processes of care by the timing of discharge are described. Multilevel regression and survival analyses (up to 180 days postevent) were undertaken. Results: Among 30,649 registrants, 2621 (8.6%) were discharged on weekends (55% male; median age 74 years). Compared to those discharged on weekdays, patients discharged on weekends were more often patients with a transient ischemic attack (weekend 35% vs. 19%; p < 0.001) but were less often treated in a stroke unit (69% vs. 81%; p < 0.001), prescribed antihypertensive medication at discharge (65% vs. 71%; p < 0.001) or received a care plan if discharged to the community (47% vs. 53%; p < 0.001). After accounting for patient characteristics and clustering by hospital, patients discharged on weekends had a 1 day shorter length of stay (coefficient = -1.31, 95% confidence interval [CI] = -1.52, -1.10), were less often discharged to inpatient rehabilitation (aOR = 0.39, 95% CI = 0.34, 0.44) and had a greater hazard of death within 180 days (hazard ratio = 1.22, 95% CI = 1.04, 1.42) than those discharged on weekdays. Conclusions: Patients with stroke/transient ischemic attack discharged on weekends were more likely to receive suboptimal care and have higher long-term mortality. High quality of stroke care should be consistent irrespective of the timing of hospital discharge.

Many stroke patients are discharged home due to advances in treatment approaches and reduced residual disability. The aim of this study was to understand health professionals¿ perspectives on the discharge process and continuity of care during the transition between hospital and home for stroke survivors. In this qualitative, descriptive study, we used focus groups with 25 health professionals involved in discharge processes for transition from hospital to home in 2014, in a regional area of Australia. Discontinuity in the discharge process was affected by pressure to discharge patients, discharge medications and associated risks, inadequate or late discharge summaries, and challenges involving carers. Discontinuity in post-discharge services and follow up was affected by availability of post-discharge services, number of services arranged at the time of discharge, general practitioner follow up after discharge, delays and waiting lists, carer problems, and long-term follow up. There were complex organizational barriers to the continuity of care for stroke survivors discharged home. It is important to address these deficits so that stroke survivors and their carers can make the transition home with minimal risk and adequate support following a stroke.

ObjectiveTo assess whether complete reperfusion after IV thrombolysis (IVT-R) would result in similar clinical outcomes compared to complete reperfusion after endovascular thrombectomy (EVT-R) in patients with a large vessel occlusion (LVO).MethodsEVT-R patients were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to IVT-R patients from the International Stroke Perfusion Imaging Registry (INSPIRE). Only patients with complete reperfusion on follow-up imaging were included. The excellent clinical outcome rates at day 90 on the modified Rankin Scale (mRS) were compared between EVT-R vs IVT-R patients within quintiles of increasing baseline ischemic core and penumbral volumes.ResultsFrom INSPIRE, there were 141 EVT-R patients and 141 matched controls (IVT-R) who met the eligibility criteria. In patients with a baseline core <30 mL, EVT-R resulted in a lower odds of achieving an excellent outcome at day 90 compared to IVT-R (day 90 mRS 0-1 odds ratio 0.01, p < 0.001). The group with a baseline core <30 mL contained mostly patients with distal M1 or M2 occlusions, and good collaterals (p = 0.01). In patients with a baseline ischemic core volume >30 mL (internal carotid artery and mostly proximal M1 occlusions), EVT-R increased the odds of patients achieving an excellent clinical outcome (day 90 mRS 0-1 odds ratio 1.61, p < 0.001) and there was increased symptomatic intracranial hemorrhage in the IVT-R group with core >30 mL (20% vs 3% in EVT-R, p = 0.008).ConclusionFrom this observational cohort, LVO patients with larger baseline ischemic cores and proximal LVO, with poorer collaterals, clearly benefited from EVT-R compared to IVT-R alone. However, for distal LVO patients, with smaller ischemic cores and better collaterals, EVT-R was associated with a lower odds of favorable outcome compared to IVT-R alone.

Background and Purpose-We aimed to evaluate the effectiveness of an intervention to improve triage, treatment, and transfer for patients with acute stroke admitted to the emergency department (ED). Methods-A pragmatic, blinded, multicenter, parallel group, cluster randomized controlled trial was conducted between July 2013 and September 2016 in 26 Australian EDs with stroke units and tPA (tissue-type plasminogen activator) protocols. Hospitals, stratified by state and tPA volume, were randomized 1:1 to intervention or usual care by an independent statistician. Eligible ED patients had acute stroke <48 hours from symptom onset and were admitted to the stroke unit via ED. Our nurse-initiated T3 intervention targeted (1) Triage to Australasian Triage Scale category 1 or 2; (2) Treatment: tPA eligibility screening and appropriate administration; clinical protocols for managing fever, hyperglycemia, and swallowing; (3) prompt (<4 hours) stroke unit Transfer. It was implemented using (1) workshops to identify barriers and solutions; (2) face-to-face, online, and written education; (3) national and local clinical opinion leaders; and (4) email, telephone, and site visit follow-up. Outcomes were assessed at the patient level. Primary outcome: 90-day death or dependency (modified Rankin Scale score of =2); secondary outcomes: functional dependency (Barthel Index =95), health status (Short Form [36] Health Survey), and ED quality of care (Australasian Triage Scale; monitoring and management of tPA, fever, hyperglycemia, swallowing; prompt transfer). Intention-to-treat analysis adjusted for preintervention outcomes and ED clustering. Patients, outcome assessors, and statisticians were masked to group allocation. Results-Twenty-six EDs (13 intervention and 13 control) recruited 2242 patients (645 preintervention and 1597 postintervention). There were no statistically significant differences at follow-up for 90-day modified Rankin Scale (intervention: n=400 [53.5%]; control n=266 [48.7%]; P=0.24) or secondary outcomes. Conclusions-This evidence-based, theory-informed implementation trial, previously effective in stroke units, did not change patient outcomes or clinician behavior in the complex ED environment. Implementation trials are warranted to evaluate alternative approaches for improving ED stroke care. Clinical Trial Registration-URL: http://www.anzctr.org.au. Unique identifier: ACTRN12614000939695.

We aimed to investigate optimal perfusion thresholds defining ischemic core and penumbra for hemispheric-cortical gray matter (GM) and subcortical white matter (WM). A total of 65 sub-6 h ischemic stroke patients were assessed, who underwent acute computed tomography perfusion (CTP) and acute magnetic resonance imaging. CTP maps were generated by both standard singular value deconvolution (sSVD) and SVD with delay and dispersion correction (ddSVD). Analyses were undertaken to calculate sensitivity, specificity, and area under the curve (AUC) for each CTP threshold for core and penumbra in GM and WM. With sSVD, the core was best defined in GM by cerebral blood flow (CBF) < 30% (AUC: 0.73) and in WM by CBF < 20% (AUC: 0.67). With ddSVD, GM core was best defined by CBF < 35% (AUC: 0.75) and in WM by CBF < 25% (AUC: 0.68). A combined GM/WM threshold overestimated core compared to diffusion-weighted imaging, CBF < 25% from sSVD (1.88 ml, P = 0.007) and CBF < 30% from ddSVD (1.27 ml, P = 0.011). The perfusion lesion was best defined by T max > 5 s (AUC: 0.80) in GM and T max > 7 s (AUC: 0.75) in WM. With sSVD, a delay time (DT) > 3 s from ddSVD was the optimal for both GM (AUC: 0.78) and WM (AUC: 0.75). Using tissue-specific thresholds for GM/WM provides more accurate estimation of acute ischemic core.

Background: Computed tomography perfusion is becoming widely accepted and used in acute stroke treatment. Computed tomography perfusion provides pathophysiological information needed in the acute decision making. Moreover, computed tomography perfusion shows excellent correlation with diffusion-weighted imaging and perfusion-weighted sequences to evaluate core and penumbra volumes. Multimodal computed tomography perfusion has practical advantages over magnetic resonance imaging, including availability, accessibility, and speed. Nevertheless, it bears some limitations, as the limited accuracy for small ischemic lesions or brainstem ischemia. Interpretation of the computed tomography perfusion maps can sometimes be difficult. The stroke neurologist faces complex or atypical cases of cerebral ischemia and stroke mimics, and needs to decide whether the ¿lesions¿ on computed tomography perfusion are real or artifact. Aims: The purpose of this review is, based on clinical cases from a comprehensive stroke center, to describe the added value that computed tomography perfusion can provide to the stroke physician in the acute phase before a treatment decision is made.

Background and hypothesis: Intravenous thrombolysis with alteplase remains standard care prior to thrombectomy for eligible patients within 4.5 h of ischemic stroke onset. However, alteplase only succeeds in reperfusing large vessel arterial occlusion prior to thrombectomy in a minority of patients. We hypothesized that tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram, when administered within 4.5 h of ischemic stroke onset, in patients planned to undergo endovascular therapy. Study design: EXTEND-IA TNK is an investigator-initiated, phase II, multicenter, prospective, randomized, open-label, blinded-endpoint non-inferiority study. Eligibility requires a diagnosis of ischemic stroke within 4.5 h of stroke onset, pre-stroke modified Rankin Scale=3 (no upper age limit), large vessel occlusion (internal carotid, basilar, or middle cerebral artery) on multimodal computed tomography and absence of contraindications to intravenous thrombolysis. Patients are randomized to either IV alteplase (0.9 mg/kg, max 90 mg) or tenecteplase (0.25 mg/kg, max 25 mg) prior to thrombectomy. Study outcomes: The primary outcome measure is reperfusion on the initial catheter angiogram, assessed as modified treatment in cerebral infarction 2 b/3 or the absence of retrievable thrombus. Secondary outcomes include modified Rankin Scale at day 90 and favorable clinical response (reduction in National Institutes of Health Stroke Scale by =8 points or reaching 0¿1) at day 3. Safety outcomes are death and symptomatic intracerebral hemorrhage. Trial registration: ClinicalTrials.gov NCT02388061.

Background and Purpose - This study aimed to assess the efficacy of modafinil, a wakefulness-promoting agent in alleviating post-stroke fatigue =3 months after stroke. We hypothesized that 200 mg of modafinil daily for 6 weeks would result in reduced symptoms of fatigue compared with placebo. Methods - This single-center phase 2 trial used a randomized, double-blind, placebo-controlled, crossover design. The key inclusion criterion was a multidimensional fatigue inventory score of =60. Patients were randomized to either modafinil or placebo for 6 weeks of therapy, then after a 1 week washout period swapped treatment arms for a second 6 weeks of therapy. The primary outcome was the multidimensional fatigue inventory; secondary outcomes included the Montreal cognitive assessment, the Depression, Anxiety, and Stress Scale (DASS), and the Stroke-Specific Quality of Life (SSQoL) scale. The multidimensional fatigue inventory is a self-administered questionnaire with a range of 0 to 100. Treatment efficacy was assessed using linear regression by estimating within-person, baseline-adjusted differences in mean outcomes after therapy. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12615000350527). Results - A total of 232 stroke survivors were screened and 36 were randomized. Participants receiving modafinil reported a significant decrease in fatigue (multidimensional fatigue inventory, -7.38; 95% CI, -21.76 to -2.99; P<0.001) and improved quality of life (SSQoL, 11.81; 95% CI, 2.31 to 21.31; P=0.0148) compared with placebo. Montreal cognitive assessment and DASS were not significantly improved with modafinil therapy during the study period (P>0.05). Conclusions - Stroke survivors with nonresolving fatigue reported reduced fatigue and improved quality of life after taking 200 mg daily treatment with modafinil.

Telestroke services have been shown to increase stroke therapy access in rural areas. The implementation of advanced CT imaging for patient assessment may improve patient selection and detection of stroke mimics in conjunction with telestroke. We implemented a telestroke service supported by multimodal CT imaging in a rural hospital in Australia. Over 21¿months we conducted an evaluation of service activation, thrombolysis rates and use of multimodal imaging to assess the feasibility of the service. Rates of symptomatic intracranial haemorrhage and 90-day modified Rankin Score were used as safety outcomes. Fifty-eight patients were assessed using telestroke, of which 41 were regarded to be acute ischemic strokes and 17 to be stroke mimics on clinical grounds. Of the 41 acute stroke patients, 22 patients were deemed eligible for thrombolysis. Using multimodal CT imaging, 8 more patients were excluded from treatment because of lack of treatment target. Multimodal imaging failed to be obtained in one patient. For the 14 treated patients, median door-imaging time was 38¿min. Median door-treatment time was 91¿min. A 90-day mRS ¿2 was achieved in 40% of treated patients. We conclude that a telestroke service using advanced CT imaging for therapy decision assistance can be successfully implemented in regional Australia and can be used to guide acute stroke treatment decision-making and improve access to thrombolytic therapy. Efficiency and safety is comparable to established telestroke services.

Immunomodulatory therapies after stroke have the potential to provide clinical benefit to a subset of patients, but risk subverting the protective, healing aspects of the innate immune response. Neutrophils clear necrotic cerebral tissue and are important in immunomodulation, but can also contribute to tissue injury. Human trials for immunomodulatory stroke treatments in the sub-acute time frame have attempted to prevent peripheral neutrophil infiltration, but none have been successful and one trial demonstrated harm. These unselected trials had broad inclusion criteria and appear to not have had a specific treatment target. Unfortunately, due to the heterogeneous nature of brain ischemia in humans resulting in variation in clinical severity, the negative effect of thrombolytic drugs on the blood¿brain barrier, and the heterogeneity of immune response, it may only be a subset of stroke patients who can realistically benefit from immunomodulation therapies. Translational research strategies require both an understanding of lab practices which create highly controlled environments in contrast to clinical practice where the diagnosis of stroke does not require the identification of a vessel occlusion. These differences between lab and clinical practices can be resolved through the integration of appropriate patient selection criteria and use of advanced imaging and ridged patient selection practices in clinical trials which will be an important part to the success of any future trials of translational research such as immunomodulation.

Background: Transient Ischaemic Attack (TIA) requires urgent investigation and management. Urgent management reduces the risk of subsequent stroke markedly, but non-presentation or delays in patient presentation to health services have been found to compromise timely management. We aimed to explore general practice patients' anticipated responses to TIA symptoms. Methods: This was a qualitative study employing semi-structured telephone interviews. Participants were recruited from respondents in an earlier quantitative study based in Australian general practices. Maximum variation purposive sampling of patients from that study (on the basis of age, rurality, gender and previous experience of stroke/TIA) continued until thematic saturation was achieved. After initial interviews explored knowledge of TIA and potential responses, subsequent interviews further explored anticipated responses via clinical vignettes containing TIA and non-TIA symptoms. Transcribed interviews were coded independently by two researchers. Data collection and analysis were concurrent and cumulative, using a process of iterative thematic analysis and constant comparison. A schema explaining participants' anticipated actions emerged during this process and was iteratively tested in later interviews. Results: Thirty-seven interviews were conducted and a 'spectrum of action', from watchful waiting (only responding if symptoms recurred) to summoning an ambulance immediately, was established. Intermediate actions upon the spectrum were: intending to mention the episode to a general practitioner (GP) at a routine appointment; consulting a GP non-urgently; consulting a general practitioner (GP) urgently; and attending an Emergency Department urgently. The substrate for decision-making relating to this spectrum operated via three constructs: the 'individual set' of the participant (their inherent disposition towards action in response to health matters in general), their 'discriminatory power' (the ability to discriminate TIA symptoms from non-TIA symptoms) and their 'effective access' to health-care services. Conclusions: Policies to improve patients' accessing care (and accessing care urgently) post-TIA should address these three determinants of anticipated action.

Background and Purpose: In alteplase-treated patients with acute ischemic stroke, we investigated the relationship between penumbral reperfusion at 24 hours and clinical outcomes, with and without adjustment for baseline ischemic core volume. Methods: Data were collected from consecutive acute ischemic stroke patients with baseline and follow-up perfusion imaging presenting to hospital within 4.5 hours of symptom onset at 7 hospitals. Logistic regression models were used for predicting the effect of the reperfused penumbral volume on the dichotomized modified Rankin Scale (MRS) at 90 days and improvement of National Institutes of Health Stroke Scale at 24 hours, both adjusted for baseline ischemic core volume. Results: This study included 1507 patients. Reperfused penumbral volume had moderate ability to predict 90-day MRS 0 to 1 (area under the curve, 0.77; R2, 0.28; P<0.0001). However, after adjusting for baseline ischemic core volume, the reperfused penumbral volume was a strong predictor of good functional outcome (area under the curve, 0.946; R2, 0.55; P<0.0001). For every 1% increase in penumbral reperfusion, the odds of achieving MRS 0 to 1 at day 90 increased by 7.4%. Improvement in acute 24-hour National Institutes of Health Stroke Scale was also significantly related to the degree of reperfused penumbra (R2, 0.31; P<0.0001). This association was again stronger after adjustment for baseline ischemic core volume (R2, 0.41; P<0.0001). For each 1% of penumbra that was reperfused, the 24-hour National Institutes of Health Stroke Scale decreased by 0.069 compared with baseline. Conclusions: In patients treated with alteplase, the extent of the penumbra that is reperfused is a powerful predictor of early and late clinical outcomes, particularly when baseline ischemic core is taken into account.

Primary Objective: This study reviewed the available sideline Sport Concussion Assessment Tool-Third Edition (SCAT3) performance of players who were removed from play using the ¿concussion interchange rule¿ (CIR), the available video footage of these incidences, and associated return to play and concussion diagnosis decisions. Research Design: Descriptive, observational case series. Methods and Procedures: Data were collected from all NRL players who used the CIR during the 2014 season. Main Outcomes and Results: Complete SCAT3 and video analysis data were available for 38 (23%) of 167 uses of the concussion interchange rule, of which 20 (52.6%) players were medically diagnosed with concussion. Those with video evidence of unresponsiveness performed more poorly on the modified Balance Error Scoring System (M-BESS; p¿=.04; Cohen¿s d¿=.69) and reported greater symptoms (p¿=.03; d¿=.51). Similarly, players with a vacant stare reported greater symptoms (p¿=.05; d¿=.78). Those who demonstrated three signs (unresponsiveness, vacant stare and gait ataxia) performed more poorly on the M-BESS (p¿=.03; d¿=¿1.4) and reported greater symptoms than those with no observable signs (p¿=.03; d¿=¿1.4). Conclusions: The SCAT3 is sensitive to the acute effects of concussion in professional athletes; however, a minority of injured athletes might go undetected by this test.

Objective: Genome-wide association studies (GWAS) have been successful at identifying associations with stroke and stroke subtypes, but have not yet identified any associations solely with small vessel stroke (SVS). SVS comprises one quarter of all ischemic stroke and is a major manifestation of cerebral small vessel disease, the primary cause of vascular cognitive impairment. Studies across neurological traits have shown that younger-onset cases have an increased genetic burden. We leveraged this increased genetic burden by performing an age-at-onset informed GWAS meta-analysis, including a large younger-onset SVS population, to identify novel associations with stroke. Methods: We used a three-stage age-at-onset informed GWAS to identify novel genetic variants associated with stroke. On identifying a novel locus associated with SVS, we assessed its influence on other small vessel disease phenotypes, as well as on messenger RNA (mRNA) expression of nearby genes, and on DNA methylation of nearby CpG sites in whole blood and in the fetal brain. Results: We identified an association with SVS in 4,203 cases and 50,728 controls on chromosome 16q24.2 (odds ratio [OR; 95% confidence interval {CI}] = 1.16 [1.10¿1.22]; p = 3.2 × 10-9). The lead single-nucleotide polymorphism (rs12445022) was also associated with cerebral white matter hyperintensities (OR [95% CI] = 1.10 [1.05¿1.16]; p = 5.3 × 10-5; N = 3,670), but not intracerebral hemorrhage (OR [95% CI] = 0.97 [0.84¿1.12]; p = 0.71; 1,545 cases, 1,481 controls). rs12445022 is associated with mRNA expression of ZCCHC14 in arterial tissues (p = 9.4 × 10-7) and DNA methylation at probe cg16596957 in whole blood (p = 5.3 × 10-6). Interpretation: 16q24.2 is associated with SVS. Associations of the locus with expression of ZCCHC14 and DNA methylation suggest the locus acts through changes to regulatory elements. Ann Neurol 2017;81:383¿394.

Objective: To compare the accuracy of Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and CT perfusion to detect established infarction in acute anterior circulation stroke. Methods: We performed an observational study in 59 acute anterior circulation ischemic stroke patients who underwent brain noncontrast CT, CT perfusion, and MRI within 100 minutes from CT imaging. ASPECTS scores were calculated by 4 blinded vascular neurologists. The accuracy of ASPECTS and CT perfusion core volume to detect an acute MRI diffusion lesion of =70 mL was evaluated using receiver operating characteristics analysis and optimum cutoff values were calculated using Youden J. Results: Median ASPECTS score was 8 (interquartile range [IQR] 5-9). Median CT perfusion core volume was 22 mL (IQR 10.4-71.9). Median MRI diffusion lesion volume was 24.5 mL (IQR 10-63.9). No significant difference was found between the accuracy of CT perfusion and ASPECTS (c statistic 0.95 vs 0.87, p value for difference = 0.17). The optimum ASPECTS cutoff score to detect a diffusion-weighted imaging lesion =70 mL was <7 (sensitivity 0.74, specificity 0.86, Youden J = 0.60) and the optimum CT perfusion core volume cutoff was =50 mL (sensitivity 0.86, specificity 0.97, Youden J = 0.84). The CT perfusion core lesion covered a median of 100% (IQR 86%-100%) of the acute MRI lesion volume (Pearson R = 0.88; R 2 = 0.77). Conclusions: We found no significant difference between the accuracy of CT perfusion and ASPECTS to predict hyperacute MRI lesion volume in ischemic stroke.

Objective: To test whether patients with complete vessel occlusion show greater recanalization at 24 hours and have improved clinical outcomes at 24 hours and 90 days when treated with tenecteplase compared to alteplase. Methods: Pooled clinical and imaging data from 2 phase 2 randomized trials comparing tenecteplase with alteplase allowed CT angiography (CTA) scans to be assessed centrally for occlusion status at baseline and at 24 hours post thrombolysis using the modified thrombolysis in cerebral infarction (TICI) scale. Twenty-four-hour poststroke NIH Stroke Scale (NIHSS) and 90-day modified Rankin Scale (mRS) scores were also compared between treatment groups using linear regression to generate odds ratios (ORs). Results: From 146 pooled patients, 69 had a TICI 0/1 occlusion overall at baseline. Tenecteplase-treated patients with a complete vessel occlusion had greater complete recanalization rates at 24 hours (71% for tenecteplase vs 43% for alteplase, p < 0.001). Patients with a TICI 0/1 occlusion who were treated with tenecteplase also showed greater early clinical improvement (median NIHSS change with tenecteplase was 9, interquartile range [IQR] 6, alteplase 1, IQR 1, p = 0.001) and higher rates of favorable 90-day outcomes (mRS 0-1 of tenecteplase compared with alteplase, OR 4.82, 95% confidence interval 1.02-7.84, p = 0.05). Conclusions: Tenecteplase may offer greater recanalization efficacy compared to alteplase, possibly exaggerated in patients with complete vessel occlusions on baseline CTA.

Background Survival into adult life in patients with aortic coarctation is typical following surgical and catheter-based techniques to relieve obstruction. Late sequelae are recognised, including stroke, hypertension, and intracerebral aneurysm formation, with the underlying mechanisms being unclear. We hypothesised that patients with a history of aortic coarctation may have abnormalities of cerebral blood flow compared with controls. Methods Patients with a history of aortic coarctation underwent assessment of cerebral vascular function. Vascular responsiveness of intracranial vessels to hypercapnia and degree of cerebral artery stiffness using Doppler-derived pulsatility indices were used. Response to photic stimuli was used to assess neurovascular coupling, which reflects endothelial function in response to neuronal activation. Patient results were compared with age- and sex-matched controls. Results A total of 13 adult patients (males=10; 77%) along with 13 controls underwent evaluation. The mean age was 36.1±3.7 years in the patient group. Patients with a background of aortic coarctation were noted to have increased pulse pressure on blood pressure assessment at baseline with increased intracranial artery stiffness compared with controls. Patients with a history of aortic coarctation had less reactive cerebral vasculature to hypercapnic stimuli and impaired neurovascular coupling compared with controls. Results Adult patients with aortic coarctation had increased intracranial artery stiffness compared with controls, in addition to cerebral vasculature showing less responsiveness to hypercapnic and photic stimuli. Further studies are required to assess the aetiology and consequences of these documented abnormalities in cerebral blood flow in terms of stroke risk, cerebral aneurysm formation, and cognitive dysfunction.

Background: Given the potential differences in etiology and impact, the treatment and outcome of younger patients (aged 18-64 years) require examination separately to older adults (aged =65 years) who experience acute stroke. Methods: Data from the Australian Stroke Clinical Registry (2010-2015) including demographic and clinical characteristics, provision of evidence-based therapies and health-related quality of life (HRQoL) post-stroke was used. Descriptive statistics and multilevel regression models were used for group comparisons. Results: Compared to older patients (age =65 years) among 26,220 registrants, 6,526 (25%) younger patients (age 18-64 years) were more often male (63 vs. 51%; p < 0.001), born in Australia (70 vs. 63%; p < 0.001), more often discharged home from acute care (56 vs. 38%; p < 0.001), and less likely to receive antihypertensive medication (61 vs. 73%; p < 0.001). Younger patients had a 74% greater odds of having lower HRQoL compared to an equivalent aged-matched general population (adjusted OR 1.74, 95% CI 1.56-1.93, p < 0.001). Conclusions: Younger stroke patients exhibited distinct differences from their older counterparts with respect to demographic and clinical characteristics, prescription of antihypertensive medications and residual health status.

To derive the reperfusion index best predicting clinical outcome of ischemic stroke patients, we retrospectively analysed the acute and 24-h computed tomography perfusion data of 116 patients, collected from two centres equipped with whole-brain computed tomography perfusion. Reperfusion index was defined by the percentage of the ischemic region reperfused from acute to 24-h computed tomography perfusion. Recanalization was graded by arterial occlusive lesion system. Receiver operator characteristic analysis was performed to assess the prognostic value of reperfusion and recanalization in predicting good clinical outcome, defined as modified Rankin Score of 0¿2 at 90 days. Among previous reported reperfusion measurements, reperfusion of the Tmax>6 s region resulted in higher prognostic value than recanalization at predicting good clinical outcome (area under the curve = 0.88 and 0.74, respectively, p = 0.002). Successful reperfusion of the Tmax>6 s region (=60%) had 89% sensitivity and 78% specificity in predicting good clinical outcome. A reperfusion index defined by Tmax>2 s or by mean transit time>145% had much lower area under the curve in comparison to Tmax>6 s measurement (p < 0.001 and p = 0.003, respectively), and had no significant difference to recanalization at predicting clinical outcome (p = 0.58 and 0.63, respectively). In conclusion, reperfusion index calculated by Tmax>6 s is a stronger predictor of clinical outcome than recanalization or other reperfusion measures.

Background and Purpose - Advanced imaging to identify tissue pathophysiology may provide more accurate prognostication than the clinical measures used currently in stroke. This study aimed to derive and validate a predictive model for functional outcome based on acute clinical and advanced imaging measures. Methods - A database of prospectively collected sub-4.5 hour patients with ischemic stroke being assessed for thrombolysis from 5 centers who had computed tomographic perfusion and computed tomographic angiography before a treatment decision was assessed. Individual variable cut points were derived from a classification and regression tree analysis. The optimal cut points for each assessment variable were then used in a backward logic regression to predict modified Rankin scale (MRS) score of 0 to 1 and 5 to 6. The variables remaining in the models were then assessed using a receiver operating characteristic curve analysis. Results - Overall, 1519 patients were included in the study, 635 in the derivation cohort and 884 in the validation cohort. The model was highly accurate at predicting MRS score of 0 to 1 in all patients considered for thrombolysis therapy (area under the curve [AUC] 0.91), those who were treated (AUC 0.88) and those with recanalization (AUC 0.89). Next, the model was highly accurate at predicting MRS score of 5 to 6 in all patients considered for thrombolysis therapy (AUC 0.91), those who were treated (0.89) and those with recanalization (AUC 0.91). The odds ratio of thrombolysed patients who met the model criteria achieving MRS score of 0 to 1 was 17.89 (4.59-36.35, P<0.001) and for MRS score of 5 to 6 was 8.23 (2.57-26.97, P<0.001). Conclusions - This study has derived and validated a highly accurate model at predicting patient outcome after ischemic stroke.

Large artery atherosclerotic stroke (LAS) shows substantial heritability not explained by previous genome-wide association studies. Here, we explore the role of coding variation in LAS by analyzing variants on the HumanExome BeadChip in a total of 3,127 cases and 9,778 controls from Europe, Australia, and South Asia. We report on a nonsynonymous single-nucleotide variant in serpin family A member 1 (SERPINA1) encoding alpha-1 antitrypsin [AAT; p.V213A; P = 5.99E-9, odds ratio (OR) = 1.22] and confirm histone deacetylase 9 (HDAC9) as a major risk gene for LAS with an association in the 3?-UTR (rs2023938; P = 7.76E-7, OR = 1.28). Using quantitative microscale thermophoresis, we show that M1 (A213) exhibits an almost twofold lower dissociation constant with its primary target human neutrophil elastase (NE) in lipoprotein-containing plasma, but not in lipid-free plasma. Hydrogen/deuterium exchange combined with mass spectrometry further revealed a significant difference in the global flexibility of the two variants. The observed stronger interaction with lipoproteins in plasma and reduced global flexibility of the Val-213 variant most likely improve its local availability and reduce the extent of proteolytic inactivation by other proteases in atherosclerotic plaques. Our results indicate that the interplay between AAT, NE, and lipoprotein particles is modulated by the gate region around position 213 in AAT, far away from the unaltered reactive center loop (357-360). Collectively, our findings point to a functionally relevant balance between lipoproteins, proteases, and AAT in atherosclerosis.

Background Patients with acute ischemic stroke and large vessel occlusion (LVO) may benefit from prehospital identification and transfer to a center offering endovascular therapy. Aims We aimed to assess the accuracy of an existing 8-item stroke scale (National Institutes of Health Stroke Scale-8 [NIHSS-8]) for identification of patients with acute stroke with LVO. Methods We retrospectively calculated NIHSS-8 scores in a population of consecutive patients with presumed acute stroke assessed by emergency medical services (EMS). LVO was identified on admission computed tomography angiography. Accuracy to identify LVO was calculated using receiver operating characteristics analysis. We used weighted Cohen's kappa statistics to assess inter-rater reliability for the NIHSS-8 score between the EMS and the hospital stroke team on a prospectively evaluated subgroup. Results Of the 551 included patients, 381 had a confirmed ischemic stroke and 136 patients had an LVO. NIHSS scores were significantly higher in patients with LVO (median 18; interquartile range 14-22). The NIHSS-8 score reliably predicted the presence of LVO (area under the receiver operating characteristic curve.82). The optimum NIHSS-8 cutoff of 8 or more had a sensitivity of.81, specificity of.75, and Youden index of.56 for prediction of LVO. The EMS and the stroke team reached substantial agreement (¿ =.69). Conclusions Accuracy of the NIHSS-8 to identify LVO in a population of patients with suspected acute stroke is comparable to existing prehospital stroke scales. The scale can be performed by EMS with reasonable reliability. Further validation in the field is needed to assess accuracy of the scale to identify patients with LVO eligible for endovascular treatment in a prehospital setting.

Background: We pooled 2 clinical trials of tenecteplase compared with alteplase for the treatment of acute ischemic stroke, 1 that demonstrated superiority of tenecteplase and the other that showed no difference between the treatments in patient clinical outcomes. We tested the hypotheses that reperfusion therapy with tenecteplase would be superior to alteplase in improving functional outcomes in the group of patients with target mismatch as identified with advanced imaging. Methods: We investigated whether tenecteplase-Treated patients had a different 24-hour reduction in the National Institutes of Health Stroke Scale and a favorable odds ratio of a modified Rankin scale score of 0 to 1 versus 2 to 6 compared with alteplase-Treated patients using linear regression to generate odds ratios. Imaging outcomes included rates of vessel recanalization and infarct growth at 24 hours and occurrence of large parenchymal hematoma. Baseline computed tomography perfusion was analyzed to assess whether patients met the target mismatch criteria (absolute mismatch volume >15 mL, mismatch ratio >1.8, baseline ischemic core <70 mL, and volume of severely hypoperfused tissue <100 mL). Patients meeting target mismatch criteria were analyzed as a subgroup to identify whether they had different treatment responses from the pooled group. Results: Of 146 pooled patients, 71 received alteplase and 75 received tenecteplase. Tenecteplase-Treated patients had greater early clinical improvement (median National Institutes of Health Stroke Scale score change: Tenecteplase, 7; alteplase, 2; P=0.018) and less parenchymal hematoma (2 of 75 versus 10 of 71; P=0.02). The pooled group did not show improved patient outcomes when treated with tenecteplase (modified Rankin scale score 0-1: odds ratio, 1.77; 95% confidence interval, 0.89-3.51; P=0.102) compared with alteplase therapy. However, in patients with target mismatch (33 tenecteplase, 35 alteplase), treatment with tenecteplase was associated with greater early clinical improvement (median National Institutes of Health Stroke Scale score change: Tenecteplase, 6; alteplase, 1; P<0.001) and better late independent recovery (modified Rankin scale score 0-1: odds ratio, 2.33; 95% confidence interval, 1.13-5.94; P=0.032) than those treated with alteplase. Conclusions: Tenecteplase may offer an improved efficacy and safety profile compared with alteplase, benefits possibly exaggerated in patients with baseline computed tomography perfusion-defined target mismatch. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01472926. URL: https://www.anzctr.org.au. Unique identifier: ACTRN12608000466347.

Background Cervical artery dissection (CAD) is a leading cause of stroke among middle-aged adults, but the etiology is unclear. Some reports of seasonal variation in CAD incidence have been suggested but may reflect extreme climatic conditions. Seasonal variation may implicate more transient seasonal causes such as proinflammatory or hypercoagulable states. This study aimed to assess whether CAD incidence varied with season between UK and Australian sites. Also, this study aimed to determine whether there was a different pattern of seasonal variation between arteries (carotid and vertebral) and any association between CAD incidence and clinical factors. Methods This was a retrospective observational study of patients older than 18 years with radiological diagnosis of internal carotid or vertebral arterial dissection, from sites in Australia and the UK. Clinical variables were compared between autumn-winter and spring-summer and site of dissection. Results A total of 133 CAD cases were documented in Australia and 242 in the UK. There was a seasonal pattern to CAD incidence in countries in both the northern and the southern hemispheres, with a trend for dissection to occur more commonly in autumn, winter, and spring than in summer (incidence rate ratios [IRR] 1.4-1.5, P¿<¿.05). CAD counts were also slightly higher in internal carotid than in vertebral artery (IRRs 1.168, 1.43, and 1.127, respectively). Neither systolic blood pressure nor pulse pressure was significantly associated with CAD counts. Conclusions CAD occurs more commonly in cooler months regardless of geographical location, suggesting transient seasonal causes may be important in the pathophysiology. This effect was slightly higher in internal carotid than in vertebral artery, suggesting differing trigger mechanisms between dissection sites.

Background and Purpose-Uncertainty exists over whether quality improvement strategies translate into better health-related quality of life (HRQoL) and survival after acute stroke. We aimed to determine the association of best practice recommended interventions and outcomes after stroke. Methods-Data are from the Australian Stroke Clinical Registry during 2010 to 2014. Multivariable regression was used to determine associations between 3 interventions: received acute stroke unit (ASU) care and in various combinations with prescribed antihypertensive medication at discharge, provision of a discharge care plan, and outcomes of survival and HRQoL (EuroQoL 5-dimensional questionnaire visual analogue scale) at 180 days, by stroke type. An assessment was also made of outcomes related to the number of processes patients received. Results-There were 17 585 stroke admissions (median age 77 years, 47% female; 81% managed in ASUs; 80% ischemic stroke) from 42 hospitals (77% metropolitan) assessed. Cumulative benefits on outcomes related to the number of care processes received by patients. ASU care was associated with a reduced likelihood of death (hazard ratio, 0.49; 95% confidence interval, 0.43-0.56) and better HRQoL (coefficient, 21.34; 95% confidence interval, 15.50-27.18) within 180 days. For those discharged from hospital, receiving ASU+antihypertensive medication provided greater 180-day survival (hazard ratio, 0.45; 95% confidence interval, 0.38-0.52) compared with ASU care alone (hazard ratio, 0.64; 95% confidence interval, 0.54-0.76). HRQoL gains were greatest for patients with intracerebral hemorrhage who received care bundles involving discharge processes (range of increase, 11%-19%). Conclusions-Patients with stroke who receive best practice recommended hospital care have improved long-term survival and HRQoL.

Aims: To determine if community-dwelling stroke survivors can achieve exercise intensities sufficient to improve cardiorespiratory fitness during a single session of circuit training using an interval training approach. Methods: Thirteen independently ambulant participants within 1 year of stroke were included in this observational study (females=54%; median age=65.6 years; interquartile range=23.9). Exercise intensities were assessed throughout an individually tailored circuit of up to seven 5-minute workstations from a selection of nine functional (e.g. walking, stairs, balance) and three ergometer (upright cycle, rower, treadmill) workstations. The interval durations ranged from 5¿60 seconds. Oxygen consumption (VO2) was recorded continuously using a portable metabolic system. The average VO2 during each 30-second epoch was determined. VO2=10.5 mL/kg/min was categorised as =moderate intensity. Findings: Participants exercised at VO2=10.5 mL/kg/min for the majority of the time on the workstations [functional: 369/472 epochs (78%), ergometer: 170/204 epochs (83%)]. Most (69%) participants exercised for =30 minutes. No serious adverse events occurred. Conclusions: Applying interval training principles to a circuit of functional and ergometer workstations enabled ambulant participants to exercise at an intensity and for a duration that can improve cardiorespiratory fitness. The training approach appears feasible, safe and a promising way to incorporate both cardiorespiratory fitness and functional training into post-stroke management.

Objective: To determine the natural history of dissecting aneurysm (DA) and whether DA is associated with an increased recurrent stroke risk and whether type of antithrombotic drugs (antiplatelets vs anticoagulants) modifies the persistence or development of DA. Methods: We included 264 patients with extracranial cervical artery dissection (CAD) from the Cervical Artery Dissection in Stroke Study (CADISS), a multicenter prospective study that compared antiplatelet with anticoagulation therapy. Logistic regression was used to estimate age- and sex-adjusted odds ratios. We conducted a systematic review of published studies assessing the natural history of DA and stroke risk in patients with non-surgically-treated extracranial CAD with DA. Results: In CADISS, DA was present in 24 of 264 patients at baseline. In 36 of 248 patients with follow-up neuroimaging at 3 months, 12 of the 24 baseline DAs persisted, and 24 new DA had developed. There was no association between treatment allocation (antiplatelets vs anticoagulants) and whether DA at baseline persisted at follow-up or whether new DA developed. During 12 months of follow-up, stroke occurred in 1 of 48 patients with DA and in 7 of 216 patients without DA (age- and sex-adjusted odds ratio 0.84; 95% confidence interval 0.10-7.31; p = 0.88). Published studies, mainly retrospective, showed a similarly low risk of stroke and no evidence of an increased stroke rate in patients with DA. Conclusions: The results of CADISS provide evidence suggesting that DAs may have benign prognosis and therefore medical treatment should be considered.

Focal hyperperfusion after acute ischaemic stroke could be of prognostic value depending upon its spatial localisation and temporal dynamics. Factors associated with late stage (12-24 h) perilesional hyperperfusion, identified using arterial spin labelling, are poorly defined. A prospective cohort of acute ischaemic stroke patients presenting within 4.5 h of symptom onset were assessed with multi-modal computed tomography acutely and magnetic resonance imaging at 24 ± 8 h. Multivariate logistic regression analysis and receiver operating characteristics curves were used. One hundred and nineteen hemispheric acute ischaemic stroke patients (mean age = 71 ± 12 years) with 24 h arterial spin labelling imaging were included. Forty-Two (35.3%) patients showed perilesional hyperperfusion on arterial spin labelling at 24 h. Several factors were independently associated with perilesional hyperperfusion: good collaterals (71% versus 29%, P < 0.0001; OR = 5, 95% CI = [1.6, 15.7], P = 0.005), major reperfusion (81% versus 48%, P = < 0.0001; OR = 7.5, 95% CI = [1.6, 35.1], P = 0.01), penumbral salvage (76.2% versus 47%, P = 0.002; OR = 6.6, 95% CI = [1.8, 24.5], P = 0.004), infarction in striatocapsular (OR = 9.5, 95% CI = [2.6, 34], P = 0.001) and in cortical superior division middle cerebral artery (OR = 4.7, 95% CI = [1.4, 15.7], P = 0.012) territory. The area under the receiver operating characteristic curve was 0.91. Our results demonstrate good arterial collaterals, major reperfusion, penumbral salvage, and infarct topographies involving cortical superior middle cerebral artery and striatocapsular are associated with perilesional hyperperfusion.

Task-switching performance relies on a broadly distributed frontoparietal network and declines in older adults. In this study, they investigated whether this age-related decline in task switching performance was mediated by variability in global or regional white matter microstructural health. Seventy cognitively intact adults (43¿87 years) completed a cued-trials task switching paradigm. Microstructural white matter measures were derived using diffusion tensor imaging (DTI) analyses on the diffusion-weighted imaging (DWI) sequence. Task switching performance decreased with increasing age and radial diffusivity (RaD), a measure of white matter microstructure that is sensitive to myelin structure. RaD mediated the relationship between age and task switching performance. However, the relationship between RaD and task switching performance remained significant when controlling for age and was stronger in the presence of cardiovascular risk factors. Variability in error and RT mixing cost were associated with RaD in global white matter and in frontoparietal white matter tracts, respectively. These findings suggest that age-related increase in mixing cost may result from both global and tract-specific disruption of cerebral white matter linked to the increased incidence of cardiovascular risks in older adults. Hum Brain Mapp 38:1588¿1603, 2017. © 2016 Wiley Periodicals, Inc.

Introduction: We aimed to identify whether acute ischemic stroke patients with known complete reperfusion after thrombectomy had the same baseline computed tomography perfusion (CTP) ischemic core threshold to predict infarction as thrombolysis patients with complete reperfusion. Methods: Patients who underwent thrombectomy were matched by age, clinical severity, occlusion location, and baseline perfusion lesion volume to patients who were treated with intravenous alteplase alone from the International Stroke Perfusion Imaging Registry. A pixel-based analysis of coregistered pretreatment CTP and 24-hour diffusion-weighted imaging (DWI) was then undertaken to define the optimum CTP thresholds for the ischemic core. Results: There were 132 eligible thrombectomy patients and 132 matched controls treated with alteplase alone. Baseline National Institutes of Health Stroke Scale (median, 15; interquartile range [IQR], 11¿19), age (median, 65; IQR, 59¿80), and time to intravenous treatment (median, 153 minutes; IQR, 82¿315) were well matched (all p > 0.05). Despite similar baseline CTP ischemic core volumes using the previously validated measure (relative cerebral blood flow [rCBF], <30%), thrombectomy patients had a smaller median 24-hour infarct core of 17.3ml (IQR, 11.3¿32.8) versus 24.3ml (IQR, 16.7¿42.2; p = 0.011) in alteplase-treated controls. As a result, the optimal threshold to define the ischemic core in thrombectomy patients was rCBF <20% (area under the curve [AUC], 0.89; 95% CI, 0.84, 0.94), whereas in alteplase controls the optimal ischemic core threshold remained rCBF <30% (AUC, 0.83; 95% CI, 0.77, 0.85). Interpretation: Thrombectomy salvaged tissue with lower CBF, likely attributed to earlier reperfusion. For patients who achieve rapid reperfusion, a stricter rCBF threshold to estimate the ischemic core should be considered. Ann Neurol 2017;82:995¿1003.

Background and Purpose - Implementation of nurse-initiated protocols to manage fever, hyperglycemia, and swallowing dysfunction decreased death and disability 90 days poststroke in the QASC trial (Quality in Acute Stroke Care) conducted in 19 Australian acute stroke units (2005-2010). We now examine long-term all-cause mortality. Methods - Mortality was ascertained using Australia's National Death Index. Cox proportional hazards regression compared time to death adjusting for correlation within stroke units using the cluster sandwich (Huber-White estimator) method. Primary analyses included treatment group only unadjusted for covariates. Secondary analysis adjusted for age, sex, marital status, education, and stroke severity using multiple imputation for missing covariates. Results - One thousand and seventy-six participants (intervention n=600; control n=476) were followed for a median of 4.1 years (minimum 0.3 to maximum 70 months), of whom 264 (24.5%) had died. Baseline demographic and clinical characteristics were generally well balanced by group. The QASC intervention group had improved long-term survival (>20%), but this was only statistically significant in adjusted analyses (unadjusted hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.58-1.07; P=0.13; adjusted HR, 0.77; 95% CI, 0.59-0.99; P=0.045). Older age (75-84 years; HR, 4.9; 95% CI, 2.8-8.7; P<0.001) and increasing stroke severity (HR, 1.5; 95% CI, 1.3-1.9; P<0.001) were associated with increased mortality, while being married (HR, 0.70; 95% CI, 0.49-0.99; P=0.042) was associated with increased likelihood of survival. Cardiovascular disease (including stroke) was listed either as the primary or secondary cause of death in 80% (211/264) of all deaths. Conclusions - Our results demonstrate the potential long-term and sustained benefit of nurse-initiated multidisciplinary protocols for management of fever, hyperglycemia, and swallowing dysfunction. These protocols should be a routine part of acute stroke care.

Stroke shortens an individual¿s disability-free life. We aimed to assess the relative prognostic influence of pre- and post-treatment perfusion computed tomography imaging variables (e.g. ischaemic core and penumbral volumes) compared to standard clinical predictors (such as onset-to-treatment time) on long-term stroke disability in patients undergoing thrombolysis. We used data from a prospectively collected international, multicentre, observational registry of acute ischaemic stroke patients who had perfusion computed tomography and computed tomography angiography before treatment with intravenous alteplase. Baseline perfusion computed tomography and follow-up magnetic resonance imaging were analysed to derive the baseline penumbra volume, baseline ischaemic core volume, and penumbra salvaged from infarction. The primary outcome measure was the effect of imaging and clinical variables on Disability-Adjusted Life Year. Clinical variables were age, sex, National Institutes of Health Stroke Scale score, and onset-to-treatment time. Age, sex, country, and 3-month modified Rankin Scale were extracted from the registry to calculate disability-adjusted life-year due to stroke, such that 1 year of disability-adjusted life-year equates to 1 year of healthy life lost due to stroke. There were 772 patients receiving alteplase therapy. The number of disability-adjusted life-year days lost per 1 ml of baseline ischaemic core volume was 17.5 (95% confidence interval, 13.2¿21.9 days, P 5 0.001). For every millilitre of penumbra salvaged, 7.2 days of disability-adjusted life-year days were saved (b = 7.2, 95% confidence interval, 10.4 to 4.1 days, P 5 0.001). Each minute of earlier onset-to-treatment time resulted in a saving of 4.4 disability-free days after stroke (1.3¿7.5 days, P = 0.006). However, after adjustment for imaging variables, onset-to-treatment time was not significantly associated with savings in disability-adjusted life-year days. Pretreatment perfusion computed tomography can (independently of clinical variables) predict significant gains, or loss, of disability-free life in patients undergoing reperfusion therapy for stroke. The effect of earlier treatment on disability-free life appears explained by salvage of penumbra, particularly when the ischaemic core is not too large.

Background: The discovery of disease-associated loci through genome-wide association studies (GWAS) is the leading genetic approach to the identification of novel biological pathways underlying diseases in humans. Until recently, GWAS in ischaemic stroke have been limited by small sample sizes and have yielded few loci associated with ischaemic stroke. We did a large-scale GWAS to identify additional susceptibility genes for stroke and its subtypes. Methods: To identify genetic loci associated with ischaemic stroke, we did a two-stage GWAS. In the first stage, we included 16 851 cases with state-of-the-art phenotyping data and 32 473 stroke-free controls. Cases were aged 16 to 104 years, recruited between 1989 and 2012, and subtypes of ischaemic stroke were recorded by centrally trained and certified investigators who used the web-based protocol, Causative Classification of Stroke (CCS). We constructed case-control strata by identifying samples that were genotyped on nearly identical arrays and were of similar genetic ancestral background. We cleaned and imputed data by use of dense imputation reference panels generated from whole-genome sequence data. We did genome-wide testing to identify stroke-associated loci within each stratum for each available phenotype, and we combined summary-level results using inverse variance-weighted fixed-effects meta-analysis. In the second stage, we did in-silico lookups of 1372 single nucleotide polymorphisms identified from the first stage GWAS in 20 941 cases and 364 736 unique stroke-free controls. The ischaemic stroke subtypes of these cases had previously been established with the Trial of Org 10 172 in Acute Stroke Treatment (TOAST) classification system, in accordance with local standards. Results from the two stages were then jointly analysed in a final meta-analysis. Findings: We identified a novel locus (G allele at rs12122341) at 1p13.2 near TSPAN2 that was associated with large artery atherosclerosis-related stroke (first stage odds ratio [OR] 1·21, 95% CI 1·13-1·30, p=4·50 × 10-8; joint OR 1·19, 1·12-1·26, p=1·30 × 10-9). Our results also supported robust associations with ischaemic stroke for four other loci that have been reported in previous studies, including PITX2 (first stage OR 1·39, 1·29-1·49, p=3·26 × 10-19; joint OR 1·37, 1·30-1·45, p=2·79 × 10-32) and ZFHX3 (first stage OR 1·19, 1·11-1·27, p=2·93 × 10-7; joint OR 1·17, 1·11-1·23, p=2·29 × 10-10) for cardioembolic stroke, and HDAC9 (first stage OR 1·29, 1·18-1·42, p=3·50 × 10-8; joint OR 1·24, 1·15-1·33, p=4·52 × 10-9) for large artery atherosclerosis stroke. The 12q24 locus near ALDH2, which has previously been associated with all ischaemic stroke but not with any specific subtype, exceeded genome-wide significance in the meta-analysis of small artery stroke (first stage OR 1·20, 1·12-1·28, p=6·82 × 10-8; joint OR 1·17, 1·11-1·23, p=2·92 × 10-9). Other loci associated with stroke in previous studies, including NINJ2, were not confirmed. Interpretation: Our results suggest that all ischaemic stroke-related loci previously implicated by GWAS are subtype specific. We identified a novel gene associated with large artery atherosclerosis stroke susceptibility. Follow-up studies will be necessary to establish whether the locus near TSPAN2 can be a target for a novel therapeutic approach to stroke prevention. In view of the subtype-specificity of the associations detected, the rich phenotyping data available in the Stroke Genetics Network (SiGN) are likely to be crucial for further genetic discoveries related to ischaemic stroke. Funding: US National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Although a wide range of strategies have been established to improve intravenous tissue plasminogen activator (IV-tPA) treatment rates, international benchmarking has not been regularly used as a systems improvement tool. We compared acute stroke codes (ASC) between two hospitals in Australia and Japan to study the activation process and potentially improve the implementation of thrombolysis. Consecutive patients who were admitted to each hospital via ASC were prospectively collected. We compared IV-tPA rates, factors contributing to exclusion from IV-tPA, and pre- and in-hospital process of care. IV-tPA treatment rates were significantly higher in the Australian hospital than in the Japanese (41% versus 25% of acute ischaemic stroke patients, p = 0.0016). In both hospitals, reasons for exclusion from IV-tPA treatment were intracerebral haemorrhage, mild symptoms, and stroke mimic. Patients with baseline National Institutes of Health Stroke Scale score =5 were more likely to be excluded from IV-tPA in the Japanese hospital. Of patients treated with IV-tPA, the door-to-needle time (median, 63 versus 54 minutes, p = 0.0355) and imaging-to-needle time (34 versus 27 minutes, p = 0.0220) were longer in the Australian hospital. Through international benchmarking using cohorts captured under ASC, significant differences were noted in rates of IV-tPA treatment and workflow speed. This variation highlights opportunity to improve and areas to focus targeted practice improvement strategies.

Introduction: Presence of white matter hyperintensity (WMH) on MRI is a marker of cerebral small vessel disease and is associated with increased small vessel stroke and increased risk of hemorrhagic transformation (HT) after thrombolysis. Aim: We sought to determine whether white matter hypoperfusion (WMHP) on perfusion CT (CTP) was related to WMH, and if WMHP predisposed to acute lacunar stroke subtype and HT after thrombolysis. Methods: Acute ischemic stroke patients within 12 h of symptom onset at 2 centers were prospectively recruited between 2011 and 2013 for the International Stroke Perfusion Imaging Registry. Participants routinely underwent baseline CT imaging, including CTP, and follow-up imaging with MRI at 24 h. Results: Of 229 ischemic stroke patients, 108 were Caucasians and 121 Chinese. In the contralateral white matter, patients with acute lacunar stroke had lower cerebral blood flow (CBF) and cerebral blood volume (CBV), compared to those with other stroke subtypes (P = 0.041). There were 46 patients with HT, and WMHP was associated with increased risk of HT (R 2 = 0.417, P = 0.002). Compared to previously reported predictors of HT, WMHP performed better than infarct core volume (R 2 = 0.341, P = 0.034), very low CBV volume (R 2 = 0.249, P = 0.026), and severely delayed perfusion (Tmax>14 second R 2 = 0.372, P = 0.011). Patients with WMHP also had larger acute infarcts and increased infarct growth compared to those without WMHP (mean 28 mL vs. 13 mL P < 0.001). Conclusion: White matter hypoperfusion remote to the acutely ischemic region on CTP is a marker of small vessel disease and was associated with increased HT, larger acute infarct cores, and greater infarct growth.

Background The cardiorespiratory fitness of stroke survivors is low. Center-based exercise programs that include an aerobic component have been shown to improve poststroke cardiorespiratory fitness. This pilot study aims to determine the feasibility, safety, and preliminary efficacy of an individually tailored home- and community-based exercise program to improve cardiorespiratory fitness and walking capacity in stroke survivors. Methods Independently ambulant, community-dwelling stroke survivors were recruited. The control (n¿=¿10) and intervention (n¿=¿10) groups both received usual care. In addition the intervention group undertook a 12-week, individually tailored, home- and community-based exercise program, including once-weekly telephone or e-mail support. Assessments were conducted at baseline and at 12 weeks. Feasibility was determined by retention and program participation, and safety by adverse events. Efficacy measures included change in cardiorespiratory fitness (peak oxygen consumption [VO2peak]) and distance walked during the Six-Minute Walk Test (6MWT). Analysis of covariance was used for data analysis. Results All participants completed the study with no adverse events. All intervention participants reported undertaking their prescribed program. VO2peak improved more in the intervention group (1.17¿±¿.29¿L/min to 1.35¿±¿.33¿L/min) than the control group (1.24¿±¿.23¿L/min to 1.24¿±¿.33¿L/min, between-group difference¿=¿.18¿L/min, 95% confidence interval [CI]:.01-.36). Distance walked improved more in the intervention group (427¿±¿123¿m to 494¿±¿67m) compared to the control group (456¿±¿101m to 470¿±¿106m, between-group difference¿=¿45¿m, 95% CI:.3-90). Conclusions Our individually tailored approach with once-weekly telephone or e-mail support was feasible and effective in selected stroke survivors. The 16% greater improvement in VO2peak during the 6MWT achieved in the intervention versus control group is comparable to improvements attained in supervised, center-based programs.

Background: The kidney-brain interaction has been a topic of growing interest. Past studies of the effect of kidney function on intracerebral hemorrhage (ICH) outcomes have yielded inconsistent findings. Although the second, main phase of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2) suggests the effectiveness of early intensive blood pressure (BP) lowering in improving functional recovery after ICH, the balance of potential benefits and harms of this treatment in those with decreased kidney function remains uncertain. Study Design: Secondary analysis of INTERACT2, which randomly assigned patients with ICH with elevated systolic BP (SBP) to intensive (target SBP < 140 mm Hg) or contemporaneous guideline-based (target SBP < 180 mm Hg) BP management. Setting & Participants: 2,823 patients from 144 clinical hospitals in 21 countries. Predictors Admission estimated glomerular filtration rates (eGFRs) of patients were categorized into 3 groups based on the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) creatinine equation: normal or high, mildly decreased, and moderately to severely decreased (>90, 60-90, and <60 mL/min/1.73 m2, respectively). Outcomes: The effect of admission eGFR on the primary outcome of death or major disability at 90 days (defined as modified Rankin Scale scores of 3-6) was analyzed using a multivariable logistic regression model. Potential effect modification of intensive BP lowering treatment by admission eGFR was assessed by interaction terms. Results: Of 2,623 included participants, 912 (35%) and 280 (11%) had mildly and moderately/severely decreased eGFRs, respectively. Patients with moderately/severely decreased eGFRs had the greatest risk for death or major disability at 90 days (adjusted OR, 1.82; 95% CI, 1.28-2.61). Effects of early intensive BP lowering were consistent across different eGFRs (P = 0.5 for homogeneity). Limitations: Generalizability issues arising from a clinical trial population. Conclusions: Decreased eGFR predicts poor outcome in acute ICH. Early intensive BP lowering provides similar treatment effects in patients with ICH with decreased eGFRs.

Although the relationship between aging and cognitive decline is well established, there is substantial individual variability in the degree of cognitive decline in older adults. The present study investigates whether variability in cognitive performance in community-dwelling older adults is related to the presence of whole brain or tract-specific changes in white matter microstructure. Specifically, we examine whether age-related decline in performance on the Montreal Cognitive Assessment (MoCA), a cognitive screening tool, is mediated by the white matter microstructural decline. We also examine if this relationship is driven by the presence of cardiovascular risk factors or variability in cerebral arterial pulsatility, an index of cardiovascular risk. Sixty-nine participants (aged 43-87) completed behavioral and MRI testing including T1 structural, T2-weighted FLAIR, and diffusion-weighted imaging (DWI) sequences. Measures of white matter microstructure were calculated using diffusion tensor imaging analyses on the DWI sequence. Multiple linear regression revealed that MoCA scores were predicted by radial diffusivity (RaD) of white matter beyond age or other cerebral measures. While increasing age and arterial pulsatility were associated with increasing RaD, these factors did not mediate the relationship between total white matter RaD and MoCA. Further, the relationship between MoCA and RaD was specific to participants who reported at least one cardiovascular risk factor. These findings highlight the importance of cardiovascular risk factors in the presentation of cognitive decline in old age. Further work is needed to establish whether medical or lifestyle management of these risk factors can prevent or reverse cognitive decline in old age.

Objectives: To investigate differences in management and outcomes for patients admitted to the hospital with TIA according to care on a stroke unit (SU) or alternate ward setting up to 180 days post event. Methods: TIA admissions from 40 hospitals participating in the Australian Stroke Clinical Registry during 2010-2013 were assessed. Propensity score matching was used to assess outcomes by treatment group including Cox proportional hazards regression to compare survival differences and other appropriate multivariable regression models for outcomes including health-related quality of life and readmissions. Results: Among 3,007 patients with TIA (mean age 73 years, 54% male), 1,110 pairs could be matched. Compared to management elsewhere in hospitals, management in an SU was associated with improved cumulative survival at 180 days post event (hazard ratio 0.57, 95% confidence interval 0.35-0.94; p 5 0.029), despite not being statistically significant at 90 days (hazard ratio 0.66, 95% confidence interval 0.33-1.31; p 5 0.237). Overall, there were no differences for being discharged on antihypertensive medication or with a care plan, and the 90- to 180-day self-reported outcomes between these groups were similar. In subgroup analyses of 461matched pairs treated in hospitals in one Australian state (Queensland), patients treated in an SU were more often prescribed aspirin within 48 hours (73% vs 62%, p , 0.001) and discharged on antithrombotic medications (84% vs 71%, p , 0.001) than those not treated in an SU. Conclusions: Hospitalized patients with TIA managed in SUs had better survival at 180 days than those treated in alternate wards, potentially through better management, but further research is needed.

Background Genetic determinants of stroke, the leading neurological cause of death and disability, are poorly understood and have seldom been explored in the general population. Our aim was to identify additional loci for stroke by doing a meta-analysis of genome-wide association studies. Methods For the discovery sample, we did a genome-wide analysis of common genetic variants associated with incident stroke risk in 18 population-based cohorts comprising 84⿿961 participants, of whom 4348 had stroke. Stroke diagnosis was ascertained and validated by the study investigators. Mean age at stroke ranged from 45·8 years to 76·4 years, and data collection in the studies took place between 1948 and 2013. We did validation analyses for variants yielding a significant association (at p<5⿿ÿ⿿10⿿6) with all-stroke, ischaemic stroke, cardioembolic ischaemic stroke, or non-cardioembolic ischaemic stroke in the largest available cross-sectional studies (70⿿804 participants, of whom 19⿿816 had stroke). Summary-level results of discovery and follow-up stages were combined using inverse-variance weighted fixed-effects meta-analysis, and in-silico lookups were done in stroke subtypes. For genome-wide significant findings (at p<5⿿ÿ⿿10⿿8), we explored associations with additional cerebrovascular phenotypes and did functional experiments using conditional (inducible) deletion of the probable causal gene in mice. We also studied the expression of orthologs of this probable causal gene and its effects on cerebral vasculature in zebrafish mutants. Findings We replicated seven of eight known loci associated with risk for ischaemic stroke, and identified a novel locus at chromosome 6p25 (rs12204590, near FOXF2) associated with risk of all-stroke (odds ratio [OR] 1·08, 95% CI 1·05⿿1·12, p=1·48⿿ÿ⿿10⿿8; minor allele frequency 21%). The rs12204590 stroke risk allele was also associated with increased MRI-defined burden of white matter hyperintensity⿿a marker of cerebral small vessel disease⿿in stroke-free adults (n=21⿿079; p=0·0025). Consistently, young patients (aged 2⿿32 years) with segmental deletions of FOXF2 showed an extensive burden of white matter hyperintensity. Deletion of Foxf2 in adult mice resulted in cerebral infarction, reactive gliosis, and microhaemorrhage. The orthologs of FOXF2 in zebrafish (foxf2b and foxf2a) are expressed in brain pericytes and mutant foxf2b⿿/⿿ cerebral vessels show decreased smooth muscle cell and pericyte coverage. Interpretation We identified common variants near FOXF2 that are associated with increased stroke susceptibility. Epidemiological and experimental data suggest that FOXF2 mediates this association, potentially via differentiation defects of cerebral vascular mural cells. Further expression studies in appropriate human tissues, and further functional experiments with long follow-up periods are needed to fully understand the underlying mechanisms. Funding NIH, NINDS, NHMRC, CIHR, European national research institutions, Fondation Leducq.

Background and Purpose - White matter hyperintensities (WMH) are increased in patients with lacunar stroke. Whether this is because of shared pathogenesis remains unknown. Using genetic data, we evaluated whether WMH-associated genetic susceptibility factors confer risk of lacunar stroke, and therefore whether they share pathogenesis. Methods - We used a genetic risk score approach to test whether single nucleotide polymorphisms associated with WMH in community populations were associated with magnetic resonance imaging-confirmed lacunar stroke (n=1,373), as well as cardioembolic (n=1,331) and large vessel (n=1,472) Trial of Org 10172 in Acute Stroke Treatment subtypes, against 9,053 controls. Second, we separated lacunar strokes into those with WMH (n=568) and those without (n=787) and tested for association with the risk score in these 2 groups. In addition, we evaluated whether WMH-associated single nucleotide polymorphisms are associated with lacunar stroke, or in the 2 groups. Results - The WMH genetic risk score was associated with lacunar stroke (odds ratio [OR; 95% confidence interval [CI]]=1.14 [1.06-1.22]; P=0.0003), in patients both with and without WMH (WMH: OR [95% CI]=1.15 [1.05-1.26]; P=0.003 and no WMH: OR [95% CI]=1.11 [1.02-1.21]; P=0.019). Conversely, the risk score was not associated with cardioembolic stroke (OR [95% CI]=1.03 [0.97-1.09]; P=0.63) or large vessel stroke (OR [95% CI]=0.99 [0.93,1.04]; P=0.39). However, none of the WMH-associated single nucleotide polymorphisms passed Bonferroni-corrected significance for association with lacunar stroke. Conclusions - Genetic variants that influence WMH are associated with an increased risk of lacunar stroke but not cardioembolic or large vessel stroke. Some genetic susceptibility factors seem to be shared across different radiological manifestations of small vessel disease.

BACKGROUND: Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage. METHODS: Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control. RESULTS: The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07). CONCLUSIONS: This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase.

Background: Cognitive decline post-cardiac surgery is of clinical concern. To better understand it a sensitive and specific measure of post-surgery brain impairment is required. The cerebral territory most likely to be adversely affected by surgery is the posterior "watershed" territory. Methods: We have designed a psychophysical task involving reading letters defined by motion aimed at measuring the integrity of a cortical area (MT) located in this territory. Patients undergoing coronary artery bypass grafting (CABG) and a healthy control group were given the psychophysical test twice, pre- and post-surgery for the patient group. Results: There was no overall difference in performance between the surgery group and the control group at either pre- or post-surgery testing. However, multivariate analysis of surgical variables such as body temperature and embolic load to the brain as measured by Transcranial Doppler showed that patients with warmer core temperatures and higher embolic loads performed significantly worse on the motion defined letter reading tasks than those with more favourable surgical variables. Conclusions: These results demonstrate that high embolic load and warm core body temperatures lead to poor motion perception post-cardiac surgery, implying damage to the posterior watershed cortex.

Background and Purpose - Although a genetic contribution to ischemic stroke is well recognized, only a handful of stroke loci have been identified by large-scale genetic association studies to date. Hypothesizing that genetic effects might be stronger for early-versus late-onset stroke, we conducted a 2-stage meta-analysis of genome-wide association studies, focusing on stroke cases with an age of onset < 60 years. Methods. The discovery stage of our genome-wide association studies included 4505 cases and 21968 controls of European, South-Asian, and African ancestry, drawn from 6 studies. In Stage 2, we selected the lead genetic variants at loci with association P<5×10-6 and performed in silico association analyses in an independent sample of =1003 cases and 7745 controls. Results.One stroke susceptibility locus at 10q25 reached genome-wide significance in the combined analysis of all samples from the discovery and follow-up stages (rs11196288; odds ratio =1.41; P=9.5×10-9). The associated locus is in an intergenic region between TCF7L2 and HABP2. In a further analysis in an independent sample, we found that 2 single nucleotide polymorphisms in high linkage disequilibrium with rs11196288 were significantly associated with total plasma factor VII.activating protease levels, a product of HABP2. Conclusions.HABP2, which encodes an extracellular serine protease involved in coagulation, fibrinolysis, and inflammatory pathways, may be a genetic susceptibility locus for early-onset stroke.

Background and Purpose-Collateral circulation is recognized to influence the life expectancy of the ischemic penumbra in acute ischemic stroke. The best method to quantify collateral status on acute imaging is uncertain. We aimed to determine the relationship between visual collateral status, quantitative collateral assessments, baseline computed tomographic perfusion measures, and tissue outcomes on follow-up imaging. Methods-Sixty-six consecutive patients with acute ischemic stroke clinically eligible for recanalization therapy and with M1 or M2 middle cerebral artery occlusion were evaluated. We compared the visual collateral scoring with measures of contrast peak time delay and contrast peak density. We also compared these measures for their ability to predict perfusion lesion and infarct core volumes, final infarct, and infarct growth. Results-Shorter contrast peak time delay (P=0.041) and higher contrast peak density (P=0.002) were associated with good collateral status. Shorter contrast peak time delay correlated with higher contrast peak density (ß=-4.413; P=0.037). In logistic regression analysis after adjustment for age, sex, onset-computed tomographic time, and occlusion site, higher contrast peak density was independently associated with good collateral status (P=0.009). Multiple regression analysis showed that higher contrast peak density was an independent predictor of smaller perfusion lesion volume (P=0.029), smaller ischemic core volume (P=0.044), smaller follow-up infarct volume (P=0.005), and smaller infarct growth volume (P=0.010). Conclusions-Visual collateral status, contrast peak density, and contrast peak time delay were inter-related, and good collateral status was strongly associated with contrast peak density. Contrast peak density in collateral vessel may be an important factor in tissue fate in acute ischemic stroke.

Objective: Although commonly used in clinical practice, there remains much uncertainty about whether perfusion computed tomography (CTP) should be used to select stroke patients for acute reperfusion therapy. In this study, we tested the hypothesis that a small acute perfusion lesion predicts good clinical outcome regardless of thrombolysis administration. Methods: We used a prospectively collected cohort of acute ischemic stroke patients being assessed for treatment with IV-alteplase, who had CTP before a treatment decision. Volumetric CTP was retrospectively analyded to identify patients with a small perfusion lesion (<15ml in volume). The primary analysis was excellent 3-month outcome in patients with a small perfusion lesion who were treated with alteplase compared to those who were not treated. Results: Of 1526 patients, 366 had a perfusion lesion <15ml and were clinically eligible for alteplase (212 being treated and 154 not treated). Median acute National Institutes of Health Stroke Scale score was 8 in each group. Of the 366 patients with a small perfusion lesion, 227 (62%) were modified Rankin Scale (mRS) 0 to 1 at day 90. Alteplase-treated patients were less likely to achieve 90-day mRS 0 to 1 (57%) than untreated patients (69%; relative risk [RR] = 0.83; 95% confidence interval [CI], 0.71¿0.97; p = 0.022) and did not have different rates of mRS 0 to 2 (72% treated patients vs 77% untreated; RR, 0.93; 95% CI, 0.82¿1.95; p = 0.23). Interpretation: This large observational cohort suggests that a portion of ischemic stroke patients clinically eligible for alteplase therapy with a small perfusion lesion have a good natural history and may not benefit from treatment. Ann Neurol 2016;80:286¿293.

Background: White matter hyperintensities (WMH) are a common radiographic finding and may be a useful endophenotype for small vessel diseases. Given high heritability of WMH, we hypothesised that certain genotypes may predispose individuals to these lesions and consequently, to an increased risk of stroke, dementia and death. We performed a meta-analysis of studies investigating candidate genes and WMH to elucidate the genetic susceptibility to WMH and tested associated variants in a new independent WMH cohort. We assessed a causal relationship of WMH to methylene tetrahydrofolate reductase (MTHFR). Methods: Database searches through March 2014 were undertaken and studies investigating candidate genes in WMH were assessed. Associated variants were tested in a new independent ischaemic cohort of 1202 WMH patients. Mendelian randomization was undertaken to assess a causal relationship between WMH and MTHFR. Results: We identified 43 case-control studies interrogating eight polymorphisms in seven genes covering 6,314 WMH cases and 15,461 controls. Fixedeffects meta-analysis found that the C-allele containing genotypes of the aldosterone synthase CYP11B2 T(-344)C gene polymorphism were associated with a decreased risk of WMH (OR=0.61; 95% CI, 0.44 to 0.84; p=0.003). Using mendelian randomisation the association among MTHFR C677T, homocysteine levels and WMH, approached, but did not reach, significance (expected OR=1.75; 95% CI, 0.90-3.41; observed OR=1.68; 95% CI, 0.97-2.94). Neither CYP11B2 T(-344)C nor MTHFR C677T were significantly associated when tested in a new independent cohort of 1202 patients with WMH. Conclusions: There is a genetic basis to WMH but anonymous genome wide and exome studies are more likely to provide novel loci of interest.

Objective: For 3,670 stroke patients from the United Kingdom, United States, Australia, Belgium, and Italy, we performed a genome-wide meta-analysis of white matter hyperintensity volumes (WMHV) on data imputed to the 1000 Genomes reference dataset to provide insights into disease mechanisms. Methods: We first sought to identify genetic associations with white matter hyperintensities in a stroke population, and then examined whether genetic loci previously linked to WMHV in community populations are also associated in stroke patients. Having established that genetic associations are shared between the 2 populations, we performed a meta-analysis testing which associations with WMHV in stroke-free populations are associated overall when combined with stroke populations. Results: There were no associations at genome-wide significance with WMHV in stroke patients. All previously reported genome-wide significant associations with WMHV in community populations shared direction of effect in stroke patients. In a meta-analysis of the genome-wide significant and suggestive loci (p < 5 × 10-6) from community populations (15 single nucleotide polymorphisms in total) and from stroke patients, 6 independent loci were associated with WMHV in both populations. Four of these are novel associations at the genome-wide level (rs72934505 [NBEAL1], p 2.2 × 10-8; rs941898 [EVL], p 4.0 × 10-8; rs962888 [C1QL1], p 1.1 × 10-8; rs9515201 [COL4A2], p 6.9 × 10-9). Conclusions: Genetic associations with WMHV are shared in otherwise healthy individuals and patients with stroke, indicating common genetic susceptibility in cerebral small vessel disease.

Introduction: We aimed to assess metabolite profiles in peri-infarct tissue with magnetic resonance spectroscopy (MRS) and correlate these with early and late clinical recovery. Methods: One hundred ten anterior circulation ischemic stroke patients presenting to hospital within 4.5¿h of symptom onset and treated with intravenous thrombolysis were studied. Patients underwent computer tomography perfusion (CTP) scanning and subsequently 3-T magnetic resonance imaging (MRI) 24¿h after stroke onset, including single-voxel, short-echo-time (30¿ms) MRS, and diffusion- and perfusion-weighted imaging (DWI and PWI). MRS voxels were placed in the peri-infarct region in reperfused penumbral tissue. A control voxel was placed in the contralateral homologous area. Results: The concentrations of total creatine (5.39 vs 5.85¿mM, p = 0.044) and N-acetylaspartic acid (NAA, 6.34 vs 7.13¿mM ± 1.57, p < 0.001) were reduced in peri-infarct tissue compared to the matching contralateral region. Baseline National Institutes of Health Stroke Score was correlated with glutamate concentration in the reperfused penumbra at 24¿h (r2 = 0.167, p = 0.017). Higher total creatine was associated with better neurological outcome at 24¿h (r2 = 0.242, p = 0.004). Lower peri-infarct glutamate was a stronger predictor of worse 3-month clinical outcome (area under the curve (AUC) 0.89, p < 0.001) than DWI volume (AUC = 0.79, p < 0.001). Conclusion: Decreased glutamate, creatine, and NAA concentrations are associated with poor neurological outcome at 24¿h and greater disability at 3¿months. The significant metabolic variation in salvaged tissue may potentially explain some of the variability seen in stroke recovery despite apparently successful reperfusion.

Elevated plasma homocysteine levels are associated with stroke. However, this might be a reflection of bias or confounding because trials have failed to demonstrate an effect from homocysteine lowering in stroke patients, although a possible benefit has been suggested in lacunar stroke. Genetic studies could potentially overcome these issues because genetic variants are inherited randomly and are fixed at conception. Therefore, we tested the homocysteine levels-associated genetic variant MTHFR C677T for association with magnetic resonance imaging-confirmed lacunar stroke and compared this with associations with large artery and cardioembolic stroke subtypes. Methods-We included 1359 magnetic resonance imaging-confirmed lacunar stroke cases, 1824 large artery stroke cases, 1970 cardioembolic stroke cases, and 14 448 controls, all of European ancestry. Furthermore, we studied 3670 ischemic stroke patients in whom white matter hyperintensities volume was measured. We tested MTHFR C677T for association with stroke subtypes and white matter hyperintensities volume. Because of the established association of homocysteine with hypertension, we additionally stratified for hypertension status. Results-MTHFR C677T was associated with lacunar stroke (P=0.0003) and white matter hyperintensity volume (P=0.04), but not with the other stroke subtypes. Stratifying the lacunar stroke cases for hypertension status confirmed this association in hypertensive individuals (P=0.0002), but not in normotensive individuals (P=0.30). Conclusions-MTHFR C677T was associated with magnetic resonance imaging-confirmed lacunar stroke, but not large artery or cardioembolic stroke. The association may act through increased susceptibility to, or interaction with, high blood pressure. This heterogeneity of association might explain the lack of effect of lowering homocysteine in secondary prevention trials which included all strokes.

The significance of structural changes associated with cerebral small-vessel disease (SVD), including white matter lesions (WML), lacunes, and brain atrophy, to outcome from acute intracerebral hemorrhage is uncertain. We determined associations of computed tomographic radiological manifestations of cerebral SVD and outcomes, and in terms of any differential effect of early intensive blood pressure-lowering treatment, in the large-scale Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Methods-We graded WML (van Swieten scale), the presence of lacunes, and brain atrophy (2 linear measurements and visual rating) for 2069 of 2839 patients with available baseline brain computed tomography (<6 hours of intracerebral hemorrhage onset) by 3 independent neurologists blind to clinical data. Results-WML grade and 2 linear measurements of brain atrophy were associated with death or major disability at 90 days: multivariable-adjusted odds ratios for WML (grade 3 and 4 versus 0), frontal ratio, and third ventricle Sylvian fissure distance (most versus least severe atrophy quartile) were 1.42 (95% confidence interval, 1.02-1.98), 1.47 (1.08-1.99), and 1.64 (1.21-2.22), respectively (all P for trend <0.05). There was no association between lacunes and outcomes. There were no significant differences in the effects of intensive blood pressure-lowering across subgroups of cerebral SVD. Conclusions-Preexisting cerebral SVD manifestations of WML and brain atrophy predict poor outcome in acute intracerebral hemorrhage. There is no apparent hazard of early intensive lowering of blood pressure according to the INTERACT2 protocol, in patients with underlying cerebral SVD.

Background and Purpose: Controversy persists over statins and risk of intracerebral hemorrhage. We determined associations of premorbid lipid-lowering therapy and outcomes among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT). Methods: The pooled data of INTERACT 1 and 2 (international, multicenter, prospective, open, blinded end point, randomized controlled trials of patients with intracerebral hemorrhage [<6 hours] and elevated systolic blood pressure) were analyzed with regard to associations of baseline lipid-lowering treatment and clinical outcomes of 3184 participants in a multivariate model. Associations of lipid-lowering therapy and hematoma growth (baseline to 24 hours) in computed tomographic substudies participants (n=1310) were estimated in ANCOVA. Results: Among 204 patients (6.5%) with baseline lipid-lowering treatment, 90-day clinical outcomes were not significantly different after adjustment for confounding variables including region and age. In the computed tomographic substudy, 24-hour hematoma growth was greater in 124 patients (9%) with, compared with those without, prior lipid-lowering therapy. However, this association was not significant between groups (9.2 versus 6.8 mL; P<0.13), after adjustment for prior antithrombotic therapy. Conclusions: No independent associations were found between lipid-lowering medication and adverse outcomes in patients with intracerebral hemorrhage.

BACKGROUND AND PURPOSE - : Epidemiological studies suggest that white matter hyperintensities (WMH) are extremely heritable, but the underlying genetic variants are largely unknown. Pathophysiological heterogeneity is known to reduce the power of genome-wide association studies (GWAS). Hypertensive and nonhypertensive individuals with WMH might have different underlying pathologies. We used GWAS data to calculate the variance in WMH volume (WMHV) explained by common single nucleotide polymorphisms (SNPs) as a measure of heritability (SNP heritability [HSNP]) and tested the hypothesis that WMH heritability differs between hypertensive and nonhypertensive individuals. METHODS - : WMHV was measured on MRI in the stroke-free cerebral hemisphere of 2336 ischemic stroke cases with GWAS data. After adjustment for age and intracranial volume, we determined which cardiovascular risk factors were independent predictors of WMHV. Using the genome-wide complex trait analysis tool to estimate HSNP for WMHV overall and within subgroups stratified by risk factors found to be significant in multivariate analyses. RESULTS - : A significant proportion of the variance of WMHV was attributable to common SNPs after adjustment for significant risk factors (HSNP=0.23; P=0.0026). HSNP estimates were higher among hypertensive individuals (HSNP=0.45; P=7.99×10); this increase was greater than expected by chance (P=0.012). In contrast, estimates were lower, and nonsignificant, in nonhypertensive individuals (HSNP=0.13; P=0.13). CONCLUSIONS - : A quarter of variance is attributable to common SNPs, but this estimate was greater in hypertensive individuals. These findings suggest that the genetic architecture of WMH in ischemic stroke differs between hypertensives and nonhypertensives. Future WMHV GWAS studies may gain power by accounting for this interaction.

Background: The majority of strokes, both ischaemic and haemorrhagic, are attributable to a relatively small number of risk factors which are readily manageable in primary care setting. Implementation of best-practice recommendations for risk factor management is calculated to reduce stroke recurrence by around 80%. However, risk factor management in stroke survivors has generally been poor at primary care level. A model of care that supports long-term effective risk factor management is needed. Aim: To determine whether the model of Integrated Care for the Reduction of Recurrent Stroke (ICARUSS) will, through promotion of implementation of best-practice recommendations for risk factor management reduce the combined incidence of stroke, myocardial infarction and vascular death in patients with recent stroke or transient ischaemic attack (TIA) of the brain or eye. Design: A prospective, Australian, multicentre, randomized controlled trial. Setting: Academic stroke units in Melbourne, Perth and the John Hunter Hospital, New South Wales. Subjects: 1000 stroke survivors recruited as from March 2007 with a recent (<3 months) stroke (ischaemic or haemorrhagic) or a TIA (brain or eye). Randomization: Randomization and data collection are performed by means of a central computer generated telephone system (IVRS). Intervention: Exposure to the ICARUSS model of integrated care or usual care. Primary outcome: The composite of stroke, MI or death from any vascular cause, whichever occurs first. Secondary outcomes: Risk factor management in the community, depression, quality of life, disability and dementia. Statistical power: With 1000 patients followed up for a median of one-year, with a recurrence rate of 7-10% per year in patients exposed to usual care, the study will have at least 80% power to detect a significant reduction in primary end-points Conclusion: The ICARUSS study aims to recruit and follow up patients between 2007 and 2013 and demonstrate the effectiveness of exposure to the ICARUSS model in stroke survivors to reduce recurrent stroke or vascular events and promote the implementation of best practice risk factor management at primary care level.

Objectives: We hypothesized that common variants in the collagen genes COL4A1/COL4A2 are associated with sporadic forms of cerebral small vessel disease. Methods: We conducted meta-analyses of existing genotype data among individuals of European ancestry to determine associations of 1,070 common single nucleotide polymorphisms (SNPs) in the COL4A1/COL4A2 genomic region with the following: intracerebral hemorrhage and its subtypes (deep, lobar) (1,545 cases, 1,485 controls); ischemic stroke and its subtypes (cardioembolic, large vessel disease, lacunar) (12,389 cases, 62,004 controls); and white matter hyperintensities (2,733 individuals with ischemic stroke and 9,361 from population-based cohorts with brain MRI data). We calculated a statistical significance threshold that accounted for multiple testing and linkage disequilibrium between SNPs (p < 0.000084). Results: Three intronic SNPs in COL4A2 were significantly associated with deep intracerebral hemorrhage (lead SNP odds ratio [OR] 1.29, 95% confidence interval [CI] 1.14-1.46, p = 0.00003; r2 > 0.9 between SNPs). Although SNPs associated with deep intracerebral hemorrhage did not reach our significance threshold for association with lacunar ischemic stroke (lead SNP OR 1.10, 95% CI 1.03-1.18, p = 0.0073), and with white matter hyperintensity volume in symptomatic ischemic stroke patients (lead SNP OR 1.07, 95% CI 1.01-1.13, p = 0.016), the direction of association was the same. There was no convincing evidence of association with white matter hyperintensities in population-based studies or with non-small vessel disease cerebrovascular phenotypes. Conclusions: Our results indicate an association between common variation in the COL4A2 gene and symptomatic small vessel disease, particularly deep intracerebral hemorrhage. These findings merit replication studies, including in ethnic groups of non-European ancestry.

Background: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes. Methods: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (.8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days. Results: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P = 0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P = 0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage. Conclusions: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.)

Background: Multi-modal CT (MMCT) to guide decision making for reperfusion treatment is increasingly used, but there remains a perceived risk of contrast-induced nephropathy (CIN). At our center, MMCT is used empirically without waiting for serum-creatinine (sCR) or renal profiling. Aims: To determine the incidence of CIN, examine the risk factors predisposing to its development, and investigate its effects on clinical outcome in the acute stroke population. Methods: An institution-wide protocol was implemented for acute stroke presentations to have MMCT (100-150ml nonionic tri-iodinated contrast, perfusion CT and CT angiography) without waiting for serum-creatinine to minimize delays. Intravenous saline is routinely infused (80-125ml/h) for at least 24-h after MMCT. Serial creatinine levels were measured at baseline, risk period, and follow-up. Renal profiles and clinical progress were reviewed up to 90 days. Results: We analyzed 735 consecutive patients who had MMCT for the evaluation of acute ischemic or hemorrhagic stroke during the last five-years. A total of 623 patients met the inclusion criteria for analysis: 16 cases (2·6%) biochemically qualified as CIN; however, the risk period serum-creatinine for 15 of these cases was confounded by dehydration, urinary tract infection, or medications. None of the group had progression to chronic kidney disease or required dialysis. Conclusions: The incidence of CIN is low when MMCT is used routinely to assess acute stroke patients. In this population, CIN was a biochemical phenomenon that did not have clinical manifestations, cause chronic kidney disease, require dialysis, or negatively impact on 90-day mRS outcomes. Renal profiling and waiting for a baseline serum-creatinine are an unnecessary delay to emergency reperfusion treatment. International Journal of Stroke

Background and Purpose-Evidence from epidemiological studies points to differences in factors predisposing to stroke by age and sex. Whether these arise because of different genetic influences remained untested. Here, we use data from 4 genome-wide association data sets to study the relationship between genetic influence on stroke with both age and sex. Methods-Using genomic-relatedness-matrix restricted maximum likelihood methods, we performed 4 analyses: (1) we calculated the genetic correlation between groups divided by age and (2) by sex, (3) we calculated the heritability of age-at-stroke-onset, and (4) we evaluated the evidence that heritability of stroke is greater in women than in men. Results-We found that genetic factors influence age at stroke onset (h2 [SE]=18.0 [6.8]; P=0.0038), with a trend toward a stronger influence in women (women: h2 [SE]=21.6 [3.5]; Men: h2 [SE]=13.9 [2.8]). Although a moderate proportion of genetic factors was shared between sexes (rG [SE]=0.68 [0.16]) and between younger and older cases (rG [SE]=0.70 [0.17]), there was evidence to suggest that there are genetic susceptibility factors that are specific to sex (P=0.037) and to younger or older groups (P=0.056), particularly for women (P=0.0068). Finally, we found a trend toward higher heritability of stroke in women although this was not significantly greater than in men (P=0.084). Conclusions-Our results indicate that there are genetic factors that are either unique to or have a different effect between younger and older age groups and between women and men. Performing large, well-powered genome-wide association study analyses in these groups is likely to uncover further associations.

Objectives: Concussion remains one of the inherent risks of participation in rugby league. While other injuries incurred by rugby league players have been well studied, less focus and attention has been directed towards concussion. Review method: The current review examined all articles published in English from 1900 up to June 2013 pertaining to concussion in rugby league players. Data sources: Publications were retrieved via six databases using the key search terms: rugby league, league, football; in combination with injury terms: athletic injuries, concussion, sports concussion, sports-related concussion, brain concussion, brain injury, brain injuries, mild traumatic brain injury, mTBI, traumatic brain injury, TBI, craniocerebral trauma, head injury and brain damage. Observational, cohort, correlational, cross-sectional and longitudinal studies were all included. Results: 199 rugby league injury publications were identified. 39 (20%) were related in some way to concussion. Of the 39 identified articles, 6 (15%) had the main aim of evaluating concussion, while the other 33 reported on concussion incidence as part of overall injury data analyses. Rugby league concussion incidence rates vary widely from 0.0 to 40.0/1000 playing hours, depending on the definition of injury (time loss vs no time loss). The incidence rates vary across match play versus training session, seasons (winter vs summer) and playing position (forwards vs backs). The ball carrier has been found to be at greater risk for injury than tacklers. Concussion accounts for 29% of all injuries associated with illegal play, but only 9% of injuries sustained in legal play. Conclusions: In comparison with other collision sports, research evaluating concussion in rugby league is limited. With such limited published rugby league data, there are many aspects of concussion that require attention, and future research may be directed towards these unanswered questions.

© 2015 Grady et al. Background: Emergency department staff play a crucial role in the triage of stroke patients and therefore the capacity to deliver time-dependent treatments such as tissue Plasminogen Activator. This study aimed to identify among emergency physicians, (1) rates of agreement with evidence supporting tissue Plasminogen Activator use in acute stroke care; and (2) individual and hospital factors associated with high agreement with evidence supporting tissue Plasminogen Activator use. Methods: Australian fellows and trainees of the Australasian College for Emergency Medicine were invited to complete an online cross-sectional survey assessing perceptions of tissue Plasminogen Activator use in acute stroke. Demographic and hospital characteristics were also collected. Results: 429 Australasian College for Emergency Medicine members responded (13% response rate). Almost half (47.2%) did not agree with any statements regarding the benefits of tissue Plasminogen Activator use for acute stroke. Perceived routine administration of tissue Plasminogen Activator by the head of respondents' emergency department was significantly associated with high agreement with the evidence supporting tissue Plasminogen Activator use in acute stroke. Conclusions: Agreement with evidence supporting tissue Plasminogen Activator use in acute stroke is not high among responding Australian emergency physicians. In order for tissue Plasminogen Activator treatment to become widely accepted and adopted in emergency settings, beliefs and attitudes towards treatment need to be in accordance with clinical practice guidelines.

Intracranial haemorrhage (ICH) is a rare life-threatening consequence of venom induced consumption coagulopathy in snake-bite. It is unclear why certain patients haemorrhage. We aimed to investigate ICH in snake envenoming. Cases of venom-induced consumption coagulopathy from July 2005-June 2014 were identified from the Australian Snakebite Project, a prospective multicentre cohort of snake-bites. Cases with venom-induced consumption coagulopathy were extracted with data on the snake-bite, clinical effects, laboratory investigations, treatment and outcomes. 552 cases had venom-induced consumption coagulopathy; median age, 40 y (2-87 y), 417 (76%) males, 253 (46%) from brown snakes and 17 died (3%). There were 6/552 (1%) cases of ICH; median age, 71 y (59-80 y), three males and five from brown snakes. All received antivenom and five died. All six had a history of hypertension. Time to onset of clinical effects consistent with ICH was 8-12 h in four cases, and within 3 h in two. Difficult to manage hypertension and vomiting were common. One patient had a normal cerebral CT on presentation and after the onset of focal neurological effects a repeat CT showed an ICH. ICH is rare in snake-bite with only 1% of patients with coagulopathy developing one. Older age and hypertension were associated with ICH.

Background: The Age, Blood pressure, Clinical features, Duration of symptoms, Diabetes (ABCD2) score can be used to predict early recurrent stroke risk following Transient ischemic attack (TIA). Given that recurrent stroke risk can be as high as 20% in the first week, international guidelines recommend ''high-risk'' TIAs (ABCD2 .3) be seen by specialist services such as dedicated acute neurovascular clinics within 24 hours. The goal of this study was to examine the associations of both quality of referrals to a specialist acute clinic and of "guideline congruence" of time-to-clinic consultation after TIA/minor stroke. We hypothesized highquality referrals containing key clinical elements would be associated with greater guideline congruence. Methods: A retrospective analysis of referrals to an acute neurovascular clinic within a tertiary care hospital of consecutive patients with TIA/minor stroke. Quality of general practitioner and emergency department referrals was defined on the basis of information content enabling ABCD2-based risk stratification by the clinic triage service. Time-to-clinic consultation was used to define "guideline congruence." Results: Referrals of 148 consecutive eligible patients were reviewed. Sixty-six percent of cases were subsequently neurologist-diagnosed as TIA or minor stroke. Seventy-nine percent were referred by general practitioners. Fifty-three percent of referrals were of high quality, but quality was not associated with guideline congruence. Of the high-risk patients, only 3.6% were seen at the clinic within 24 hours of index event and 31.3% within 24 hours of referral. Conclusions: Current guidelines are pathophysiologically logical and evidence based, but are difficult to implement. Improving quality of primary-secondary communication by improved referral quality is unlikely to improve guideline compliance. Alternative strategies are needed to reduce recurrent stroke risk after TIA/minor stroke.

Background: Patients who have suffered from cerebral ischemia have a high risk of recurrent vascular events. Predictive models based on classical risk factors typically have limited prognostic value. Given that cerebral ischemia has a heritable component, genetic information might improve performance of these risk models. Our aim was to develop and compare two models: one containing traditional vascular risk factors, the other also including genetic information. Methods and Results: We studied 1020 patients with cerebral ischemia and genotyped them with the Illumina Immunochip. Median follow-up time was 6.5 years; the annual incidence of new ischemic events (primary outcome, n=198) was 3.0%. The prognostic model based on classical vascular risk factors had an area under the receiver operating characteristics curve (AUC-ROC) of 0.65 (95% confidence interval 0.61-0.69). When we added a genetic risk score based on prioritized SNPs from a genome-wide association study of ischemic stroke (using summary statistics from the METASTROKE study which included 12389 cases and 62004 controls), the AUC-ROC remained the same. Similar results were found for the secondary outcome ischemic stroke. Conclusions: We found no additional value of genetic information in a prognostic model for the risk of ischemic events in patients with cerebral ischemia of arterial origin. This is consistent with a complex, polygenic architecture, where many genes of weak effect likely act in concert to influence the heritable risk of an individual to develop (recurrent) vascular events. At present, genetic information cannot help clinicians to distinguish patients at high risk for recurrent vascular events.

Rationale: Controversy exists over the optimal dose of intravenous (iv) recombinant tissue plasminogen activator (rt-PA) and degree of blood pressure (BP) control in acute ischaemic stroke (AIS). Asian studies suggest low-dose (0·6mg/kg) is more efficacious than standard-dose (0·9mg/kg) iv rt-PA, and guidelines recommend reducing systolic BP to <185mmHg before and <180mmHg after use of iv rt-PA, despite observational studies indicating better outcomes at much lower (<140mmHg) systolic BP levels in this patient group. Aims: The study aims to assess in thrombolysis-eligible AIS patients whether: (i) low-dose (0·6mg/kg body weight; maximum 60mg) iv rt-PA has non-inferior efficacy and lower risk of symptomatic intracerebral haemorrhage (sICH) compared to standard-dose (0·9mg/kg body weight; maximum 90mg) iv rt-PA; and (ii) early intensive BP lowering (systolic target 130-140mmHg) has superior efficacy and lower risk of any ICH compared to guideline-recommended BP control (systolic target<180mmHg). Design: The ENhanced Control of Hypertension And Thrombolysis strokE stuDy (ENCHANTED) trial is an independent,2×2 quasi-factorial, active-comparison, prospective, randomized, open blinded endpoint (PROBE), clinical trial that is evaluating Arm [A] 'rt-PA dose' and/or Arm [B] 'BP control', using central Internet randomization and data collection in patients fulfilling local criteria for thrombolysis and clinician uncertainty over the study treatments. The treatment arms will be analyzed separately. Study outcomes: The primary study outcome in both trial Arms is death or disability according to the modified Rankin scale (mRS, scores 2-6) assessed at 90 days. Secondary outcomes include sICH, any ICH, a shift ('improvement') in function across mRS scores, separately on death and disability, early neurological deterioration, recurrent major vascular events, health-related quality of life, length of hospital stay, need for permanent residential care, and health care costs. Results: Following launch of the trial in February 2012, the study has recruited more than 2500 patients across a global network of approximately 100 sites in 15 countries. The required sample sizes are 3300 for Arm [A] and 2300 for Arm [B], which will provide >90% power to detect non-inferiority of low-dose iv rt-PA and superiority of intensive BP lowering on the primary clinical outcome, respectively. Conclusions: Low-dose iv rt-PA and early intensive BP lowering could provide more affordable and safer use of thrombolysis treatment for patients with AIS worldwide.

The overall population benefit of intravascular recombinant tissue plasminogen activator (rtPA) on functional outcome in ischaemic stroke is clear, but there are some treated patients who are harmed by early symptomatic intracranial haemorrhage (ICH). Although several clinical and radiological factors increase the risk of rtPA-related ICH, none of the currently available risk prediction tools are yet useful for practical clinical decision-making, probably reflecting our limited understanding of the underlying mechanisms. Finding new methods to identify patients at highest risk of rtPArelated ICH, or new measures to limit risk, are urgent challenges in acute stroke therapy research. In this article, we focus on the potential underlying mechanisms of rtPA-related ICH, highlight promising candidate risk biomarkers and suggest future research directions.

Background: The Quality in Acute Stroke Care (QASC) trial evaluated systematic implementation of clinical treatment protocols to manage fever, sugar, and swallow (FeSS protocols) in acute stroke care. This cluster-randomised controlled trial was conducted in 19 stroke units in Australia. Aim: To describe perceived barriers and enablers preimplementation to the introduction of the FeSS protocols and, postimplementation, to determine which of these barriers eventuated as actual barriers. Methods: Preimplementation: Workshops were held at the intervention stroke units (n = 10). The first workshop involved senior clinicians who identified perceived barriers and enablers to implementation of the protocols, the second workshop involved bedside clinicians. Postimplementation, an online survey with stroke champions from intervention sites was conducted. Results: A total of 111 clinicians attended the preimplementation workshops, identifying 22 barriers covering four main themes: (a) need for new policies, (b) limited workforce (capacity), (c) lack of equipment, and (d) education and logistics of training staff. Preimplementation enablers identified were: support by clinical champions, medical staff, nursing management and allied health staff; easy adaptation of current protocols, care-plans, and local policies; and presence of specialist stroke unit staff. Postimplementation, only five of the 22 barriers identified preimplementation were reported as actual barriers to adoption of the FeSS protocols, namely, no previous use of insulin infusions; hyperglycaemic protocols could not be commenced without written orders; medical staff reluctance to use the ASSIST swallowing screening tool; poor level of engagement of medical staff; and doctors' unawareness of the trial. Linking Evidence to Action: The process of identifying barriers and enablers preimplementation allowed staff to take ownership and to address barriers and plan for change. As only five of the 22 barriers identified preimplementation were reported to be actual barriers at completion of the trial, this suggests that barriers are often overcome whilst some are only ever perceived rather than actual barriers.

The use of perfusion imaging to guide selection of patients for stroke thrombolysis remains controversial because of lack of supportive phase three clinical trial evidence. We aimed to measure the outcomes for patients treated with intravenous recombinant tissue plasminogen activator (rtPA) at a comprehensive stroke care facility where perfusion computed tomography was routinely used for thrombolysis eligibility decision assistance. Our overall hypothesis was that patients with 'target' mismatch on perfusion computed tomography would have improved outcomes with rtPA. This was a prospective cohort study of consecutive ischaemic stroke patients who fulfilled standard clinical/non-contrast computed tomography eligibility criteria for treatment with intravenous rtPA, but for whom perfusion computed tomography was used to guide the final treatment decision. The 'real-time' perfusion computed tomography assessments were qualitative; a large perfusion computed tomography ischaemic core, or lack of significant perfusion lesion-core mismatch were considered relative exclusion criteria for thrombolysis. Specific volumetric perfusion computed tomography criteria were not used for the treatment decision. The primary analysis compared 3-month modified Rankin Scale in treated versus untreated patients after 'off-line' (post-treatment) quantitative volumetric perfusion computed tomography eligibility assessment based on presence or absence of 'target' perfusion lesion-core mismatch (mismatch ratio >1.8 and volume >15 ml, core <70 ml). In a second analysis, we compared outcomes of the perfusion computed tomography-selected rtPA-treated patients to an Australian historical cohort of non-contrast computed tomography-selected rtPA-treated patients. Of 635 patients with acute ischaemic stroke eligible for rtPA by standard criteria, thrombolysis was given to 366 patients, with 269 excluded based on visual real-time perfusion computed tomography assessment. After off-line quantitative perfusion computed tomography classification: 253 treated patients and 83 untreated patients had 'target' mismatch, 56 treated and 31 untreated patients had a large ischaemic core, and 57 treated and 155 untreated patients had no target mismatch. In the primary analysis, only in the target mismatch subgroup did rtPA-treated patients have significantly better outcomes (odds ratio for 3-month, modified Rankin Scale 0-2 = 13.8, P < 0.001). With respect to the perfusion computed tomography selected rtPA-treated patients (n = 366) versus the clinical/non-contrast computed tomography selected rtPA-treated patients (n = 396), the perfusion computed tomography selected group had higher adjusted odds of excellent outcome (modified Rankin Scale 0-1 odds ratio 1.59, P = 0.009) and lower mortality (odds ratio 0.56, P = 0.021). Although based on observational data sets, our analyses provide support for the hypothesis that perfusion computed tomography improves the identification of patients likely to respond to thrombolysis, and also those in whom natural history may be difficult to modify with treatment.

Background Consensus guidelines for transient ischaemic attack (TIA) recommend urgent investigation and management, but delays in management occur and are attributable to patient and health system factors. Aim To establish general practice patients' anticipated responses to TIA symptoms, and associations of appropriate responses. Design and setting A cross-sectional questionnaire-based study in Australian general practices. Method Consecutive patients attending general practices completed questionnaires that contained the Stroke Action Test (STAT) adapted for TIA about demographic, health system use, and stroke risk factors. STAT elicits appropriate or inappropriate anticipated responses to 28 symptom complexes. Anticipated actions in-hours and out-of-hours were elicited. Associations of independent variables with adapted-STAT scores were tested with multiple linear regression. Results There were 854 participants (response rate 76.9%). Urgent healthcare-seeking responses to transient neurological symptoms ranged from 96.8% for right-sided weakness with dysphasia to 59.1% for sudden dizziness. Associations of higher adapted-STAT scores were older age, Indigenous status, previous after-hours services use, self-perception of health as poor, and familiarity with a stroke public awareness campaign. A personal or family history of stroke, smoking status, and time of event (in-hours/out-of-hours) were not significantly associated with adapted-STAT scores. Conclusion Most general practice attendees expressed intentions to seek health care urgently for most symptoms suggestive of TIA, with highest levels of urgency observed in high stroke-risk scenarios. Intentions were not associated with a number of major risk factors for TIA and might be improved by further educational interventions, either targeted or at population level.