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Transcranial magnetic stimulation (TMS) is used to examine corticospinal tract integrity after stroke, however, generating motor-evoked potentials (MEPs) in the lower limb (LL) can be difficult. Previous studies have used activation of the target leg to facilitate MEPs in the LL but this may not be possible after stroke due to hemiplegia. The dominance of the target limb may also be important, however the neurophysiological effects of LL dominance are not known. We investigated whether voluntary activation of the non-target leg combined with optimal TMS coil orientation increases corticomotor excitability in healthy adults, and whether limb dominance influences these results. TMS was delivered to induce a posterior-anterior (PA) and a medial-lateral (ML) cortical current in 22 healthy adults. MEPs were recorded in tibialis anterior (TA) with the participant at rest and when activating the non-target leg. We found that non-target leg activation increased corticomotor excitability in the target leg (reduced rest motor threshold (RMT) and MEP latency, and increased recruitment curve slope). ML cortical current also reduced RMT and MEP latency. The degree of footedness correlated with the degree of RMT asymmetry, with a PA but not ML cortical current direction. In summary, cross-facilitation by activating the non-target leg in a task requiring postural stabilisation and inducing ML current increase corticomotor excitability regardless of limb dominance. This protocol may have practical application in testing CST integrity after stroke when paretic limb thresholds are high, by increasing the likelihood of eliciting a MEP.

Background and Purpose— There have been few recent population-based studies reporting the incidence (first ever) and attack rates (incident and recurrent) of transient ischemic attack (TIA). Methods— The fourth Auckland Regional Community Stroke study (ARCOS IV) used multiple overlapping case ascertainment methods to identify all hospitalized and nonhospitalized cases of TIA that occurred in people ≥16 years of age usually resident in Auckland (population ≥16 years of age is 1.12 million), during the 12 months from March 1, 2011. All first-ever and recurrent new TIAs (any new TIA 28 days after the index event) during the study period were recorded. Results— There were 785 people with TIA (402 [51.2%] women, mean [SD] age 71.5 [13.8] years); 614 (78%) of European origin, 84 (11%) Māori/Pacific, and 75 (10%) Asian/Other. The annual incidence of TIA was 40 (95% confidence interval, 36–43), and attack rate was 63 (95% confidence interval, 59–68), per 100 000 people, age standardized to the World Health Organization world population. Approximately two thirds of people were known to be hypertensive or were being treated with blood pressure–lowering agents, half were taking antiplatelet agents and just under half were taking lipid-lowering therapy before the index TIA. Two hundred ten (27%) people were known to have atrial fibrillation at the time of the TIA, of whom only 61 (29%) were taking anticoagulant therapy, suggesting a failure to identify or treat atrial fibrillation. Conclusions— This study describes the burden of TIA in an era of aggressive primary and secondary vascular risk factor management. Education programs for medical practitioners and patients around the identification and management of atrial fibrillation are required.

Importance Intravenous alteplase reduces disability after ischemic stroke in patients 4.5 to 9 hours after onset and with wake-up onset stroke selected using perfusion imaging mismatch. However, whether the benefit is consistent across the 4.5- to 6-hours, 6- to 9-hours, and wake-up stroke epochs is uncertain. Objective To examine the association of reperfusion with reduced disability, including by onset-to-randomization time strata in the Extending the Time for Thrombolysis in Emergency Neurological Deficits (EXTEND) and Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) randomized clinical trials. Design, Setting, and Participants Individual patient meta-analysis of randomized clinical trials performed from August 2001 to June 2018 with 3-month follow-up. Patients had acute ischemic stroke with 4.5-to 9-hours poststroke onset or with wake-up stroke were randomized to alteplase or placebo after perfusion mismatch imaging. Analysis began July 2019 and ended May 2020. Exposures Reperfusion was defined as more than 90% reduction in time to maximum of more than 6 seconds’ lesion volume at 24- to 72-hour follow-up. Main Outcomes and Measures Ordinal logistic regression adjusted for baseline age and National Institutes of Health Stroke Scale score was used to analyze functional improvement in day 90 modified Rankin Scale score overall, including a reperfusion × time-to-randomization multiplicative interaction term, and in the 4.5- to 6-hours, 6- to 9-hours, and wake-up time strata. Symptomatic hemorrhage was defined as large parenchymal hematoma with a National Institutes of Health Stroke Scale score increase of 4 points or more. Results Reperfusion was assessable in 270 of 295 patients (92%), 68 of 133 (51%) in the alteplase group, and 38 of 137 (28%) in the placebo reperfused group (P

Ischaemic brain damage induces autoimmune responses, including the production of autoantibodies with potential neuroprotective effects. Platelets share unexplained similarities with neurons, and the formation of anti-platelet antibodies has been documented in neurological disorders. The aim of this study was to investigate the presence of anti-platelet antibodies in the peripheral blood of patients after ischaemic stroke and determine any clinical correlations. Using a flow cytometry-based platelet immunofluorescence method, we detected platelet-reactive antibodies in 15 of 48 (31%) stroke patients and two of 50 (4%) controls (p &lt, 0.001). Western blotting revealed heterogeneous reactivities with platelet proteins, some of which overlapped with brain proteins. Stroke patients who carried anti-platelet antibodies presented with larger infarcts and more severe neurological dysfunction, which manifested as higher scores on the National Institutes of Health Stroke Scale (NIHSS, p = 0.009), but they had a greater recovery in the NIHSS by the time of hospital discharge (day 7 &plusmn, 2) compared with antibody-negative patients (p = 0.043). Antibodies from stroke sera reacted more strongly with activated platelets (p = 0.031) and inhibited platelet aggregation by up to 30.1 &plusmn, 2.8% (p &lt, 0.001), suggesting the potential to interfere with thrombus formation. In conclusion, platelet-reactive antibodies can be found in patients soon after ischaemic stroke and correlate with better short-term outcomes, suggesting a potential novel mechanism limiting thrombosis.

There is high inter-individual variability in recovery after stroke, which reduces statistical power in rehabilitation trials. This could be addressed by using biomarkers for patient selection. Corticospinal tract function assessed with transcranial magnetic stimulation (TMS) is a candidate biomarker for trials aiming to improve upper-limb motor recovery. Patients in whom TMS can elicit motor evoked potentials (MEPs) have a functionally intact lateral corticospinal tract and better motor recovery. We used an existing data set to estimate the sample sizes required to detect rehabilitation benefits on upper-limb motor performance 90 days after stroke. Baseline clinical assessments were made and MEP status of the paretic upper-limb determined within 7 days post-stroke. Upper-limb Fugl-Meyer (UE-FM) and Action Research Arm Test (ARAT) scores were obtained 90 days after stroke. Analyses were carried out for the full sample, and repeated for the MEP+ subset. Population estimates of the UE-FM and ARAT scores 90 days post-stroke were used to calculate the sample sizes required to detect clinically meaningful treatment effects of 7 points on the UE-FM and ARAT scores. Baseline and 90-day assessments were completed by 207 patients (103 women, mean 70.6 SD 15.1 years). The full sample and MEP+ subset (n=177) had similar demographic and baseline clinical characteristics. The estimated required sample sizes to detect treatment effects for MEP+ patients were only 27-29% of those for the full sample of patients. The estimated percentage of patients who are MEP+ was 85.5% (95%CI 81.2%-89.9%). Biomarkers could be used to enrich samples for stroke rehabilitation trials. Selecting patients on the basis of MEP status reduces variance, thereby reducing required sample size by around 75% without significantly limiting the pool of participants. Using biomarkers for patient selection could markedly increase rehabilitation trial sensitivity and efficiency, with associated decreases in costs and time required for completion.

Background CT perfusion (CTP) and diffusion or perfusion MRI might assist patient selection for endovascular thrombectomy. We aimed to establish whether imaging assessments of irreversibly injured ischaemic core and potentially salvageable penumbra volumes were associated with functional outcome and whether they interacted with the treatment effect of endovascular thrombectomy on functional outcome.Methods In this systematic review and meta-analysis, the HERMES collaboration pooled patient-level data from all randomised controlled trials that compared endovascular thrombectomy (predominantly using stent retrievers) with standard medical therapy in patients with anterior circulation ischaemic stroke, published in PubMed from Jan 1,2010, to May 31, 2017. The primary endpoint was functional outcome, assessed by the modified Rankin Scale (mRS) at 90 days after stroke. Ischaemic core was estimated, before treatment with either endovascular thrombectomy or standard medical therapy, by CTP as relative cerebral blood flow less than 30% of normal brain blood flow or by MRI as an apparent diffusion coefficient less than 620 mu m(2)/s. Critically hypoperfused tissue was estimated as the volume of tissue with a CTP time to maximum longer than 6 s. Mismatch volume (ie, the estimated penumbral volume) was calculated as critically hypoperfused tissue volume minus ischaemic core volume. The association of ischaemic core and penumbral volumes with 90-day mRS score was analysed with multivariable logistic regression (functional independence, defined as mRS score 0-2) and ordinal logistic regression (functional improvement by at least one mRS category) in all patients and in a subset of those with more than 50% endovascular reperfusion, adjusted for baseline prognostic variables. The meta-analysis was prospectively designed by the HERMES executive committee, but not registered.Findings We identified seven studies with 1764 patients, all of which were included in the meta-analysis. CTP was available and assessable for 591 (34%) patients and diffusion MRI for 309 (18%) patients. Functional independence was worse in patients who had CTP versus those who had diffusion MRI, after adjustment for ischaemic core volume (odds ratio [OR] 0.47 [95% CI 0.30-0.72], p=0.0007), so the imaging modalities were not pooled. Increasing ischaemic core volume was associated with reduced likelihood of functional independence (CTP OR 0.77 [0.69-0.86] per 10 mL, p(interaction)=0.29; diffusion MRI OR 0.87 [0.81-0.94] per 10 mL, p(interaction)=0.94). Mismatch volume, examined only in the CTP group because of the small numbers of patients who had perfusion MRI, was not associated with either functional independence or functional improvement. In patients with CTP with more than 50% endovascular reperfusion (n=186), age, ischaemic core volume, and imaging-to-reperfusion time were independently associated with functional improvement. Risk of bias between studies was generally low.Interpretation Estimated ischaemic core volume was independently associated with functional independence and functional improvement but did not modify the treatment benefit of endovascular thrombectomy over standard medical therapy for improved functional outcome. Combining ischaemic core volume with age and expected imagingto-reperfusion time will improve assessment of prognosis and might inform endovascular thrombectomy treatment decisions. Copyright (C) 2018 Elsevier Ltd. All rights reserved.

Supplemental Material for The International comparison of Systems of care and patient outcomes In minor Stroke and Tia (InSIST) study: A community-based cohort study by Christopher R Levi, Daniel Lasserson, Debbie Quain, Jose Valderas, Helen M Dewey, P Alan Barber, Neil Spratt, Dominique A Cadilhac, Valery Feigin, Hossein Zareie, Carlos Garcia Esperon, Andrew Davey, Nashwa Najib and Parker Magin in International Journal of Stroke

Stroke endovascular clot retrieval (ECR) in patients with large proximal vessel occlusion improves clinical outcomes. We present the New Zealand ECR experience.All New Zealand patients treated with ECR since 2011 were included. Patients were considered eligible if they were independent prior to stroke and had proximal intracranial arterial occlusion.Three hundred and twelve patients [136 women, mean (SD) age of 64 (17) years] from 11 district health boards have been treated between March 2011 and April 2018. There were 260 (83%) patients with anterior and 52 (17%) with posterior circulation arterial occlusion. One hundred and ninety-three (62%) patients were pre-treated with intravenous alteplase. The median time from symptom onset to groin puncture was 210 (range 65-985) minutes. Complete or near-complete recanalisation (Thrombolysis in Cerebral Infarction scores of 3 or 2b) was achieved in 260 of 300 (87%) and the National Institutes of Health Stroke Scale score improved from a median of 18 at baseline to 7 at 24 hours. By day 90, 55% of the anterior circulation patients and 40% of the posterior circulation patients were living independently at home. Mortality rates were 20% for anterior circulation patients and 30% for the posterior circulation patients.This study has shown that stroke endovascular clot retrieval is being provided safely and effectively in New Zealand. However, there remain discrepancies in service provision, and ongoing regional, inter-regional and inter-sector collaboration is essential to implement comprehensive and equitable ECR services across the country.

TIAs are predictors of high risk of subsequent stroke and require urgent intervention to maximize secondary prevention and minimize adverse health outcomes. TIA patients are often admitted to the hospital to facilitate rapid investigation and comprehensive management. However, over the last 2 decades, alternative service models have emerged in an effort to optimize health resource utilization without compromising patient outcomes. This article reviews recommended interventions and then discusses the inpatient and 6 alternative TIA service models to help modern stroke services determine the model best suited to their local health service environment.

Objective For most patients, resolution of upper limb impairment during the first 6 months poststroke is 70% of the maximum possible. We sought to identify candidate mechanisms of this proportional recovery. We hypothesized that proportional resolution of upper limb impairment depends on ipsilesional corticomotor pathway function, is mirrored by proportional recovery of excitability in this pathway, and is unaffected by upper limb therapy dose. Methods Upper limb impairment was measured in 93 patients at 2, 6, 12, and 26 weeks after first-ever ischemic stroke. Motor evoked potentials (MEPs) and motor threshold were recorded from extensor carpi radialis using transcranial magnetic stimulation, and fractional anisotropy (FA) in the posterior limbs of the internal capsules was determined with diffusion-weighted magnetic resonance imaging. Results Initial impairment score, presence of MEPs and FA asymmetry were the only predictors of impairment resolution, indicating a key role for corticomotor tract function. By 12 weeks, upper limb impairment resolved by 70% in patients with MEPs regardless of their initial impairment, and ipsilesional rest motor threshold also resolved by 70%. Resolution of impairment was insensitive to upper limb therapy dose. Interpretation These findings indicate that upper limb impairment resolves by 70% of the maximum possible, regardless of initial impairment, but only for patients with intact corticomotor function. Impairment resolution seems to reflect spontaneous neurobiological processes that involve the ipsilesional corticomotor pathway. A better understanding of these mechanisms could lead to interventions that increase resolution of impairment above 70%. Ann Neurol 2015;78:848–859

Background. Recovery of upper limb function is important for regaining independence after stroke. Objective. To test the effects of priming upper limb physical therapy with intermittent theta burst stimulation (iTBS), a form of noninvasive brain stimulation. Methods. Eighteen adults with first-ever chronic monohemispheric subcortical stroke participated in this randomized, controlled, triple-blinded trial. Intervention consisted of priming with real or sham iTBS to the ipsilesional primary motor cortex immediately before 45 minutes of upper limb physical therapy, daily for 10 days. Changes in upper limb function (Action Research Arm Test [ARAT]), upper limb impairment (Fugl-Meyer Scale), and corticomotor excitability, were assessed before, during, and immediately, 1 month and 3 months after the intervention. Functional magnetic resonance images were acquired before and at one month after the intervention. Results. Improvements in ARAT were observed after the intervention period when therapy was primed with real iTBS, but not sham, and were maintained at 1 month. These improvements were not apparent halfway through the intervention, indicating a dose effect. Improvements in ARAT at 1 month were related to balancing of corticomotor excitability and an increase in ipsilesional premotor cortex activation during paretic hand grip. Conclusions. Two weeks of iTBS-primed therapy improves upper limb function at the chronic stage of stroke, for at least 1 month postintervention, whereas therapy alone may not be sufficient to alter function. This indicates a potential role for iTBS as an adjuvant to therapy delivered at the chronic stage.

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

BACKGROUND: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care.METHODS: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered.FINDINGS: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09-2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75-3·10, pINTERPRETATION: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons.FUNDING: Medtronic.

Background The greatest potential to reduce the burden of stroke is by primary prevention of first-ever stroke, which constitutes three quarters of all stroke. In addition to population-wide prevention strategies (the ‘mass’ approach), the ‘high risk’ approach aims to identify individuals at risk of stroke and to modify their risk factors, and risk, accordingly. Current methods of assessing and modifying stroke risk are difficult to access and implement by the general population, amongst whom most future strokes will arise. To help reduce the burden of stroke on individuals and the population a new app, the Stroke Riskometer™, has been developed. We aim to explore the validity of the app for predicting the risk of stroke compared with current best methods. Methods 752 stroke outcomes from a sample of 9501 individuals across three countries (New Zealand, Russia and the Netherlands) were utilized to investigate the performance of a novel stroke risk prediction tool algorithm (Stroke Riskometer™) compared with two established stroke risk score prediction algorithms (Framingham Stroke Risk Score [FSRS] and QStroke). We calculated the receiver operating characteristics (ROC) curves and area under the ROC curve (AUROC) with 95% confidence intervals, Harrels C-statistic and D-statistics for measure of discrimination, R2 statistics to indicate level of variability accounted for by each prediction algorithm, the Hosmer-Lemeshow statistic for calibration, and the sensitivity and specificity of each algorithm. Results The Stroke Riskometer™ performed well against the FSRS five-year AUROC for both males (FSRS = 75·0% (95% CI 72·3%–77·6%), Stroke Riskometer™ = 74·0(95% CI 71·3%–76·7%) and females [FSRS = 70·3% (95% CI 67·9%–72·8%, Stroke Riskometer™ = 71·5% (95% CI 69·0%–73·9%)], and better than QStroke [males–59·7% (95% CI 57·3%–62·0%) and comparable to females = 71·1% (95% CI 69·0%–73·1%)]. Discriminative ability of all algorithms was low (C-statistic ranging from 0·51–0·56, D-statistic ranging from 0·01–0·12). Hosmer-Lemeshow illustrated that all of the predicted risk scores were not well calibrated with the observed event data ( P < 0·006). Conclusions The Stroke Riskometer™ is comparable in performance for stroke prediction with FSRS and QStroke. All three algorithms performed equally poorly in predicting stroke events. The Stroke Riskometer™ will be continually developed and validated to address the need to improve the current stroke risk scoring systems to more accurately predict stroke, particularly by identifying robust ethnic/race ethnicity group and country specific risk factors.

The socioeconomic and health effect of stroke and other noncommunicable disorders (NCDs) that share many of the same risk factors with stroke, such as heart attack, dementia, and diabetes mellitus, is huge and increasing.1–4 Collectively, NCDs account for 34.5 million deaths (66% of deaths from all causes)3 and 1344 million disability-adjusted life years lost worldwide in 2010.2 The burden of NCDs is likely to burgeon given the aging of the world’s population and the epidemiological transition currently observed in many low- to middle-income countries (LMICs).5,6 In addition, there is low awareness in the population about these NCDs and their risk factors,7–10 particularly in LMICs.11 These factors, coupled with underuse of strategies for primary prevention of stroke/NCDs on an individual level and the lack of accurate data on the prevalence and effect of risk factors in different countries and populations have been implicated in the ever-increasing worldwide burden of the NCDs.12–15 Of particular concern is a significant increase in the number of young adults (aged

Objective\ud Recovery of motor function is important for regaining independence after stroke, but difficult to predict for individual patients. Our aim was to develop an efficient, accurate, and accessible algorithm for use in clinical settings. Clinical, neurophysiological, and neuroimaging biomarkers of corticospinal integrity obtained within days of stroke were combined to predict likely upper limb motor outcomes 3 months after stroke.\ud \ud Methods\ud Data from 207 patients recruited within 3 days of stroke [103 females (50%), median age 72 (range 18–98) years] were included in a Classification and Regression Tree analysis to predict upper limb function 3 months poststroke.\ud \ud Results\ud The analysis produced an algorithm that sequentially combined a measure of upper limb impairment; age; the presence or absence of upper limb motor evoked potentials elicited with transcranial magnetic stimulation; and stroke lesion load obtained from MRI or stroke severity assessed with the NIHSS score. The algorithm makes correct predictions for 75% of patients. A key biomarker obtained with transcranial magnetic stimulation is required for one third of patients. This biomarker combined with NIHSS score can be used in place of more costly magnetic resonance imaging, with no loss of prediction accuracy.\ud \ud Interpretation\ud The new algorithm is more accurate, efficient, and accessible than its predecessors, which may support its use in clinical practice. While further work is needed to potentially incorporate sensory and cognitive factors, the algorithm can be used within days of stroke to provide accurate predictions of upper limb functional outcomes at 3 months after stroke. www.presto.auckland.ac.nz

Background and Purpose— Major pathological stroke types (ischemic stroke [IS], primary intracerebral hemorrhage [ICH], and subarachnoid hemorrhage) and IS subtypes, have differing risk factors, management, and prognosis. We report changes in major stroke types and IS subtypes incidence during 10 years using data from the ARCOS (Auckland Regional Community Stroke Study) III performed during 12 months in 2002 to 2003 and the fourth ARCOS study (ARCOS-IV) performed in 2011 to 2012. Methods— ARCOS-III and ARCOS-IV were population-based registers of all new strokes in the greater Auckland region (population aged >15 years, 1 119 192). Strokes were classified into major pathological types (IS, ICH, subarachnoid hemorrhage, and undetermined type). Crude annual age-, sex-, and ethnic-specific stroke incidence with 95% confidence intervals was calculated. ISs were subclassified using TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria into 5 etiologic groups. Rate ratios with 95% confidence intervals were calculated for differences in age-standardized rates between the 2 studies. Results— In ARCOS-IV, there were 1329 (81%) ISs, 211 (13%) ICHs, 79 (5%) subarachnoid hemorrhages, and 24 (1%) undetermined type strokes. The proportional distribution of IS subtypes was 29% cardioembolism, 21% small-vessel occlusion, 15% large-artery atherosclerosis, 5% other determined etiology, and 31% undetermined type. Between 2002 and 2011, age-standardized incidence decreased for subarachnoid hemorrhage (rate ratios, 0.73; 95% confidence intervals, 0.54–0.99) and undetermined type (rate ratios, 0.14; 95% confidence intervals, 0.09–0.22). Rates were stable for IS and ICH. Among IS subtypes, large-artery atherosclerosis and small-vessel occlusion rates increased significantly. The frequency of all risk factors increased in IS. Ethnic differences were observed for both stroke subtype rates and their risk factor frequencies. Conclusions— A lack of change in IS and ICH incidence may reflect a trend toward increased incidence of younger strokes. Increased rates of large-artery atherosclerosis and small-vessel occlusion are associated with increased smoking and high blood pressure. Ethnic differences in the proportional distribution of pathological stroke subtypes suggest differential exposure and susceptibility to risk factors.

Background Atrial fibrillation (AF) is associated with increased risk of cardiovascular disease (CVD) complications including stroke. We investigated the assessment and management of cardiovascular risk among patients with AF aged 35–74years, by ethnic group, in a large cohort of people receiving a CVD risk assessment in primary care (PREDICT). Methods PREDICT was linked to national dispensing, hospitalisation and mortality records. AF was present if recorded in PREDICT or during a prior hospitalisation; medications were those dispensed ≤6months before or after a PREDICT assessment; the CHA 2 DS 2 -VASc score and a New Zealand (NZ) adjusted Framingham CVD risk were calculated. Data were linked to outcomes of stroke or major adverse cardiovascular event (MACE). Results 12,739 (2.8%) of 447,020 people aged 35–74years had AF. Māori, the indigenous population of NZ, had the highest proportion of AF, which by age group, was similar to that among Europeans 10years older. 77% were at high stroke risk, of whom 42% received anticoagulation; 54% were at high CVD risk, of whom 67% received both lipid- and blood pressure-lowering medication. Per category of predicted risk, stroke risk was overestimated and risk of MACE was underestimated. Conclusions The burden of AF and risk factors differed by ethnic group thus recommendations to screen for AF above a universal age threshold may introduce inequity in the detection and management of associated risk. The high burden of comorbidities at younger ages among many ethnic groups contributes to the poor performance of available risk assessment tools, further compounding potential inequity.

To describe trends in treatment delays and short-term outcome over the first 18 months of the New Zealand stroke thrombolysis register.The National Stroke Network introduced a central register of all ischaemic stroke patients treated with intravenous alteplase on January 1, 2015. The aim was to increase thrombolysis treatment rates and drive improvements in safety.From January 1, 2015 to June 30, 2016, alteplase was given to 623 patients [344 men, mean (range) age 70 (22-98) years] out of a total of 8,857 ischaemic and unspecified stroke patients, giving a thrombolysis rate of 7.0%. Between the first and second halves of the audit, there were more patients thrombolysed [350 of 4,456 (7.9%) versus 273 of 4,401 (6.8%); p=0.001] and more treated within 60 minutes of hospital arrival [137 of 325 (42%) versus 71 of 250 (28%), p=0.001]. Door-to-needle time reduced from 77 minutes to 64 minutes (p=0.002) and the onset-to-treatment reduced from 162 minutes to 140 minutes (p=0.070). Rates of symptomatic intracranial haemorrhage (4.3% patients) and survival at day seven (93%) were stable.There have been improvements in stroke thrombolysis rates and treatment delays in New Zealand hospitals since the institution of the National Stroke Network thrombolysis register. The Network will continue to adjust key performance indicators, and stroke thrombolysis targets for individual DHBs have been increased to 8% for 2017 and 10% for 2018.

To obtain an overall picture of the organisation of stroke thrombolysis provision in New Zealand hospitals and compare changes between 2011 and 2016.Surveys were distributed to all New Zealand district health boards (DHBs) in 2011 and 2016, and included questions about the infrastructure, staffing, training, guidelines and audit provided for stroke thrombolysis.Responses were received from all DHBs, with 86% offering stroke thrombolysis in 2011 and 100% in 2016. In 2016, thrombolysis rosters of large DHBs (those with a population250,000 people) had a mean (range) of 14 (5-34) clinicians, approximately double that of medium-sized DHBs (population 125-250,000) who had eight (3-15) and small DHBs (population125,000) with seven, (2-13) clinicians. While a similar distribution of senior medical officer clinical specialty was seen across medium and small DHBs in both years, large DHBs in 2016 had a higher number of neurologists (5, 1-12) and an increasing number of general physicians (8, 0-30) rostered to provide thrombolysis compared to 2011. Thrombolysis services at medium and small DHBs are chiefly managed by general physicians and geriatricians, while telestroke support was only available in three medium-sized DHBs. In 2016, all hospitals had developed thrombolysis guidelines and audited thrombolysed patients in the National Stroke Thrombolysis Register, which is an improvement compared with 2011 when only seven (39%) DHBs reported regular audit. Challenges in staffing and training remain greatest in smaller and geographically isolated DHBs.While there have been improvements in the provision of stroke thrombolysis throughout New Zealand, regional variations in service quality remains. The needs for better solutions to geographical barriers and formal training must be addressed as priorities.

GluN1 is a mandatory component of N-methyl-D-aspartate receptors (NMDARs) best known for their roles in the brain, but with increasing evidence for relevance in peripheral tissues, including platelets. Certain anti-GluN1 antibodies reduce brain infarcts in rodent models of ischaemic stroke. There is also evidence that human anti-GluN1 autoantibodies reduce neuronal damage in stroke patients, but the underlying mechanism is unclear. This study investigated whether anti-GluN1-mediated neuroprotection involves inhibition of platelet function. Four commercial anti-GluN1 antibodies were screened for their abilities to inhibit human platelet aggregation. Haematological parameters were examined in rats vaccinated with GluN1. Platelet effects of a mouse monoclonal antibody targeting the glycine-binding region of GluN1 (GluN1-S2) were tested in assays of platelet activation, aggregation and thrombus formation. The epitope of anti-GluN1-S2 was mapped and the mechanism of antibody action modelled using crystal structures of GluN1. Our work found that rats vaccinated with GluN1 had a mildly prolonged bleeding time and carried antibodies targeting mostly GluN1-S2. The monoclonal anti-GluN1-S2 antibody (from BD Biosciences) inhibited activation and aggregation of human platelets in the presence of adrenaline, adenosine diphosphate, collagen, thrombin and a protease-activated receptor 1-activating peptide. When human blood was flowed over collagen-coated surfaces, anti-GluN1-S2 impaired thrombus growth and stability. The epitope of anti-GluN1-S2 was mapped to α-helix H located within the glycine-binding clamshell of GluN1, where the antibody binding was computationally predicted to impair opening of the NMDAR channel. Our results indicate that anti-GluN1-S2 inhibits function of human platelets, including dense granule release and thrombus growth. Findings add to the evidence that platelet NMDARs regulate thrombus formation and suggest a novel mechanism by which anti-GluN1 autoantibodies limit stroke-induced neuronal damage.

Objective This double-blind sham-controlled crossover study investigated the interactions between primary sensory and motor cortex after stroke and their response to Theta Burst Stimulation (TBS). Methods Thirteen chronic subcortical stroke patients with upper limb impairment performed standardised dexterity training primed with ipsilesional M1 intermittent TBS (iTBS iM1 ), contralesional M1 continuous TBS (cTBS cM1 ) or sham TBS. The effects on sensorimotor integration, corticomotor excitability, sensation and grip-lift kinetics were examined. Results After iTBS iM1 , improvements in paretic grip-lift performance were accompanied by an immediate facilitation of ipsilesional M1 excitability and a subsequent increase in ipsilesional short latency afferent inhibition (SAI) during training. Precision grip-lift performance improved after cTBS cM1 and training, alongside increased ipsilesional M1 excitability with no effect on ipsilesional SAI. There were no effects on sensory performance. Conclusion Primary motor cortex iTBS not only modulates M1 corticospinal excitability but also increases M1 receptiveness to sensory input. Significance Priming with iTBS iM1 may enhance ipsilesional sensorimotor integration and facilitate better quality sensorimotor training after subcortical stroke.

The integrity of descending white matter pathways, measured by fractional anisotropy from DW-MRI, is a key prognostic indicator of motor recovery after stroke. Barriers to translation of fractional anisotropy measures into routine clinical practice include the time required for manually delineating volumes of interest (VOIs), and inter-examiner variability in this process. This study investigated whether registering and then editing template volumes of interest ‘as required’ would improve inter-examiner reliability compared with manual delineation, without compromising validity. MRI was performed with 30 sub-acute stroke patients with motor deficits (mean NIHSS = 11, range 0–17). Four independent examiners manually delineated VOIs for the posterior limbs of the internal capsules on T1 images, or edited template VOIs that had been registered to the T1 images if they encroached on ventricles or basal ganglia. Fractional anisotropy within each VOI and interhemispheric asymmetry were then calculated. We found that 13/30 registered template VOIs required editing. Edited template VOIs were more spatially similar between examiners than the manually delineated VOIs (p = 0.005). Both methods produced similar asymmetry values that correlated with clinical scores with near perfect levels of agreement between examiners. Contralesional fractional anisotropy correlated with age when edited template VOIs were used but not when VOIs were manually delineated. Editing template VOIs as required is reliable, increases the validity of fractional anisotropy measurements in the posterior limb of the internal capsule, and is less time-consuming compared to manual delineation. This approach could support the use of FA asymmetry measures in routine clinical practice., Highlights • Fractional anisotropy in the PLIC is a key prognostic indicator of motor recovery after stroke. • Editing template PLIC volumes of interest is valid, reliable and efficient. • A template-based approach may translate FA asymmetry measures to clinical practice.

Background Blunt cerebrovascular injury (BCVI) occurs in 0.2–2.7% of blunt trauma patients and has up to 30% mortality. Conventional screening does not recognize up to 20% of BCVI patients. To improve diagnosis of BCVI, both an expanded battery of screening criteria and a multi-detector computed tomography angiography (CTA) have been suggested. The aim of this study is to investigate whether the use of CTA restricted to the Denver protocol screen-positive patients would reduce the unnecessary use of CTA as a pre-emptive screening tool. Methods This is a registry-based study of blunt trauma patients admitted to Auckland City Hospital from 1998 to 2012. The diagnosis of BCVI was confirmed or excluded with CTA, magnetic resonance angiography and, if these imaging were non-conclusive, four-vessel digital subtraction angiography. Results Thirty (61%) BCVI and 19 (39%) non-BCVI patients met eligibility criteria. The Denver protocol applied to our cohort of patients had a sensitivity of 97% (95% confidence interval (CI): 83–100%) and a specificity of 42% (95% CI: 20–67%). With a prevalence of BCVI in blunt trauma patients of 0.2% and 2.7%, post-test odds of a screen-positive test were 0.03 (95% CI: 0.002–0.005) and 0.046 (95% CI: 0.314–0.068), respectively. Conclusions Application of the CTA to the Denver protocol screen-positive trauma patients can decrease the use of CTA as a pre-emptive screening tool by 95–97% and reduces its hazards.

Independence after stroke depends on the recovery of motor function, but this is difficult to accurately predict for individual patients. We have previously described an algorithm for predicting potential for recovery of upper limb function for individual patients after stroke. The Predict REcovery Potential (PREP) algorithm begins with a bedside assessment of paretic shoulder abduction and finger extension strength (SAFE score out of 10), followed by transcranial magnetic stimulation (TMS), and magnetic resonance imaging (MRI), as required. Patients are predicted to have potential for an Excellent, Good, Limited or Poor recovery of upper limb function within 12 weeks. The algorithm was developed with data from 40 patients with first-ever ischaemic stroke. This study evaluated and refined the algorithm with a larger, more heterogeneous cohort. Inclusion criteria were confirmed stroke (ischaemic or haemorrhagic), new upper limb motor symptoms, and age at least 18 years. Previous stroke, thrombolysis and thrombectomy were allowed. Exclusion criteria were cerebellar stroke, contraindications to TMS and MRI for those patients who required these tests, and reduced capacity for consent. The Action Research Arm Test was used to measure paretic upper limb function 12 weeks post-stroke. A sample of 192 patients was recruited within 3 days of stroke (106 men, mean age 72 y, 100 right hemisphere), and 157 patients completed the 12 week assessment. The algorithm was refined by combining the SAFE score with age (

Objective Very low cerebral blood volume (VLCBV), diffusion, and hypoperfusion lesion volumes have been proposed as predictors of hemorrhagic transformation following stroke thrombolysis. We aimed to compare these parameters, validate VLCBV in an independent cohort using DEFUSE study data, and investigate the interaction of VLCBV with regional reperfusion. Methods The EPITHET and DEFUSE studies obtained diffusion and perfusion magnetic resonance imaging (MRI) in patients 3 to 6 hours from onset of ischemic stroke. EPITHET randomized patients to tissue plasminogen activator (tPA) or placebo, and all DEFUSE patients received tPA. VLCBV was defined as cerebral blood volume2 ml VLCBV threshold defined in EPITHET predicted PH with 100% sensitivity, 72% specificity, 35% positive predictive value, and 100% negative predictive value. Pooling EPITHET and DEFUSE (163 patients, including 23 with PH), regression models using VLCBV (p 8 seconds lesion volumes. Excluding VLCBV in regions without reperfusion improved specificity from 61 to 78% in the pooled analysis. Interpretation VLCBV predicts PH after stroke thrombolysis and appears to be a more powerful predictor than baseline diffusion or hypoperfusion lesion volumes. Reperfusion of regions of VLCBV is strongly associated with post-thrombolysis PH. VLCBV may be clinically useful to identify patients at significant risk of hemorrhage following reperfusion. ANN NEUROL 2013;73:510–519

Background and Purpose— In people with preserved corticospinal tract (CST) function after stroke, upper limb impairment resolves by ≈70% within 3 months. This is known as the proportional recovery rule. Patients without CST function do not fit this rule and have worse upper limb outcomes. This study investigated resolution of motor impairment in the lower limb (LL). Methods— Patients with stroke and LL weakness were assessed 3 days and 3 months after stroke with the LL Fugl–Meyer. CST integrity was determined in a subset of patients using transcranial magnetic stimulation to test for LL motor-evoked potentials and magnetic resonance imaging to measure CST lesion load. Linear regression analyses were conducted to predict resolution of motor impairment (ΔFugl–Meyer) including factors initial impairment, motor-evoked potential status, CST lesion load, and LL therapy dose. Results— Thirty-two patients completed 3-month follow-up and recovered 74% (95% confidence interval, 60%–88%) of initial LL motor impairment. Initial impairment was the only significant predictor of resolution of motor impairment. There was no identifiable cluster of patients who did not fit the proportional recovery rule. Measures of CST integrity did not predict proportional LL recovery. Conclusions— LL impairment resolves by ≈70% within 3 months after stroke. The absence of a nonfitter group may be because of differences in the neuroanatomical organization of descending motor tracts to the upper limb and LL. Proportional recovery of the LL is not influenced by therapy dose providing further evidence that it reflects a fundamental biological process.

Objective To explore employment status, work limitations, and productivity loss after mild traumatic brain injury (TBI). Design Inception cohort study over 4 years. Setting General community. Participants Adults (N=245; >16y at the time of injury) who experienced a mild TBI and who were employed prior to their injury. Interventions Not applicable. Main Outcome Measures Details of the injury, demographic information, and preinjury employment status were collected from medical records and self-report. Symptoms and mood were assessed 1 month postinjury using the Rivermead Post-Concussion Symptom Questionnaire and the Hospital Anxiety and Depression Scale. Postinjury employment status and work productivity were assessed 4 years postinjury using the Work Limitations Questionnaire. Results Four years after mild TBI, 17.3% of participants had exited the workforce (other than for reasons of retirement or to study) or had reduced their working hours compared with preinjury. A further 15.5% reported experiencing limitations at work because of their injury. Average work productivity loss was 3.6%. The symptom of taking longer to think 1 month postinjury significantly predicted work productivity loss 4 years later (β=.47, t =3.79, P ≤.001). Conclusions Although changes in employment status and difficulties at work are likely over time, the results indicate increased unemployment rates, work limitations, and productivity loss in the longer term after a mild TBI. Identification of cognitive difficulties 1 month after TBI in working aged adults and subsequent interventions to address these difficulties are required to facilitate work productivity.

Background and Purpose— Recovery of upper-limb motor impairment after first-ever ischemic stroke is proportional to the degree of initial impairment in patients with a functional corticospinal tract (CST). This study aimed to investigate whether proportional recovery occurs in a more clinically relevant sample including patients with intracerebral hemorrhage and previous stroke. Methods— Patients with upper-limb weakness were assessed 3 days and 3 months poststroke with the Fugl–Meyer scale. Transcranial magnetic stimulation was used to test CST function, and patients were dichotomized according to the presence of motor evoked potentials in the paretic wrist extensors. Linear regression modeling of Δ Fugl–Meyer score between 3 days and 3 months was performed, with predictors including initial impairment (66 − baseline Fugl–Meyer score), age, sex, stroke type, previous stroke, comorbidities, and upper-limb therapy dose. Results— One hundred ninety-two patients were recruited, and 157 completed 3-month follow-up. Patients with a functional CST made a proportional recovery of 63% (95% confidence interval, 55%–70%) of initial motor impairment. The recovery of patients without a functional CST was not proportional to initial impairment and was reduced by greater CST damage. Conclusions— Recovery of motor impairment in patients with intact CST is proportional to initial impairment and unaffected by previous stroke, type of stroke, or upper-limb therapy dose. Novel interventions that interact with the neurobiological mechanisms of recovery are needed. The generalizability of proportional recovery is such that patients with intracerebral hemorrhage and previous stroke may usefully be included in interventional rehabilitation trials. Clinical Trial Registration— URL: http://www.anzctr.org.au . Unique identifier: ANZCTR12611000755932.

Background: Neuropsychological deficits occur in over half of the stroke survivors and are associated with the reduced functioning and a decline in quality of life. However, the trajectory of recovery and predictors of neuropsychological outcomes over the first year post stroke are poorly understood. Method: Neuropsychological performance, assessed using the CNS-Vital signs, was examined at 1 month, 6 months and 12 months after ischaemic stroke (IS) in a sample drawn from a population-based study (N = 198). Results: While mean scores across neuropsychological domains at each time-point fell in the average range, one in five individuals produced very low-range scores for verbal memory, attention and psychomotor speed. Significant improvements were seen for executive functioning, psychomotor speed and cognitive flexibility within 6 months post stroke, but no gains were noted from 6 to 12 months. Stroke-related neurological deficits and depression at baseline significantly contributed to the prediction of neuropsychological function at 12 month follow-up. Conclusions: In a significant minority of IS survivors, focal deficits are evident in psychomotor speed, verbal memory, executive functions and attention. Significant improvements in these domains were only evident in the first 6 months post stroke. Initial stroke-related neurological deficits and concurrent depression may be the best predictors of later cognitive functioning.

BACKGROUND: Stroke thrombolysis is limited by the "last-seen well" principle, which defines stroke onset time. A significant minority of stroke patients (~15%) awake with their symptoms and are by definition ineligible for thrombolysis because they were "last-seen well" at the time they went to bed implying an interval that is most often greater than three hours. METHODS: A single-centre prospective, safety study was designed to thrombolyse 20 subjects with stroke-on-awakening. Patients were eligible for inclusion if they were last seen well less than 12 hours previously, specifically including those who awoke from sleep with their stroke deficits. They had a baseline computed tomogram (CT) scan with an ASPECTS score greater than 5, no evidence of well-evolved infarction and a CT angiogram / Trans-cranial Doppler ultrasound study demonstrating an intracranial arterial occlusion. Patients fulfilled all other standard criteria for stroke thrombolysis. The primary outcome was safety defined by symptomatic ICH or death. RESULTS: Among 89 screened patients, 20 were treated with thrombolysis. Two patients (10%) died due to massive carotid territory stroke and two patients (10%) died of stroke complications. Two patients (10%) showed asymptomatic intracerebral hemorrhage (ICH) (petechial hemorrhage) and none symptomatic ICH. Reasons for exclusion were: (a) ASPECTS ≤ 5 (29); (b) well-evolved infarcts on CT (19); (c) historical mRS > 2 (17); (d) no demonstrable arterial occlusion or were too mild to warrant treatment (10). CONCLUSIONS: Patients who awake with their deficits can be safely treated with thrombolysis based upon a tissue window defined by NCCT and CTA/TCD.

The mismatch between a larger perfusion lesion and smaller diffusion lesion on magnetic resonance imaging is a validated signal of the ischemic penumbra, namely the region at risk in acute ischemic stroke that is critically hypoperfused and the target of reperfusion therapies. Clinical trials have shown strong correlations between reperfusion in mismatch patients and improved clinical outcomes. Attenuation of infarct growth is associated with reperfusion and corresponding clinical gains. Using computed tomography perfusion, the mismatch between relative cerebral blood flow or cerebral blood volume and perfusion delay is a comparable penumbral marker. Automated techniques allow rapid quantitative assessment of mismatch with thresholding to exclude benign oligemia. The penumbra is often present beyond the current 4.5-h time window, defined for the use of intravenous tPA. Treatment beyond this time point remains investigational. Although the efficacy of thrombolysis in mismatch patients requires further validation in randomized trials, there is now sufficient evidence to recommend that advanced neuroimaging of mismatch should be used for selection of delayed therapies in phase 3 trials.

Carotid endarterectomy (CEA) is an effective treatment for patients with recently symptomatic severe carotid stenosis and in selected patients with symptomatic moderate carotid stenosis. Carotid artery angioplasty and stenting (CAS) is emerging as an alternative to CEA, and randomised controlled trials suggest comparable efficacy to CEA in prevention of non-perioperative stroke. Neurovascular complications can result from both procedures, usually from thromboembolism from the operated vessel, cerebral hypoperfusion causing ischaemia and, rarely, intracerebral haemorrhage. The overall incidence of perioperative strokes complicating CEA and CAS is approximately 4% and 6%, respectively, and represents a devastating outcome that the procedure was designed to prevent. Other neurological sequelae complicating carotid revascularisation include cerebral hyperperfusion syndrome, cranial and peripheral nerve injuries, and contrast encephalopathy in patients undergoing CAS. In this review, we analyse the incidence, mechanisms and perioperative management of neurological complications for patients undergoing carotid revascularisation.

Background and Purpose— Repetitive transcranial magnetic stimulation of the primary motor cortex (M1) may improve outcomes after stroke. The aim of this study was to determine the effects of M1 theta burst stimulation (TBS) and standardized motor training on upper-limb function of patients with chronic stroke. Methods— Ten patients with chronic subcortical stroke and upper-limb impairment were recruited to this double-blind, crossover, sham-controlled study. Intermittent TBS of the ipsilesional M1, continuous TBS of the contralesional M1, and sham TBS were delivered in separate sessions in conjunction with standardized training of a precision grip task using the paretic upper limb. Results— Training after real TBS improved paretic-hand grip-lift kinetics, whereas training after sham TBS resulted in deterioration of grip-lift. Ipsilesional M1 excitability increased after intermittent TBS of the ipsilesional M1 but decreased after continuous TBS of the contralesional M1. Action Research Arm Test scores deteriorated when training followed continuous TBS of the contralesional M1, and this was correlated with reduced ipsilesional corticomotor excitability. Conclusions— Generally, TBS and training led to task-specific improvements in grip-lift. Specifically, continuous TBS of the contralesional M1 led to an overall decrement in upper-limb function, indicating that the contralesional hemisphere may play a pivotal role in recovery after stroke.

We hypothesized that pretreatment magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI) lesion volumes may have influenced clinical response to thrombolysis in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET). In 98 patients randomized to intravenous (IV) tissue plasminogen activator (tPA) or placebo 3 to 6 h after stroke onset, we examined increasing acute DWI and PWI lesion volumes (Tmax—with 2-sec delay increments), and increasing PWI/DWI mismatch ratios, on the odds of both excellent (modified Rankin Scale (mRS): 0 to 1) and poor (mRS: 5 to 6) clinical outcome. Patients with very large PWI lesions (most had internal carotid artery occlusion) had increased odds ratio (OR) of poor outcome with IV-tPA (58% versus 25% placebo; OR=4.13, P=0.032 for Tmax +2-sec volume >190 mL). Excellent outcome from tPA treatment was substantially increased in patients with DWI lesions 25 mL. In contrast, increasing mismatch ratios did not influence the odds of excellent outcome with tPA. Clinical responsiveness to IV-tPA, and stroke outcome, depends more on baseline DWI and PWI lesion volumes than the extent of perfusion–diffusion mismatch.

Background and Purpose— Reliable predictors of hemorrhagic transformation (HT) after stroke thrombolysis have not been identified. We analyzed hemorrhage in a randomized trial of tissue plasminogen activator (t-PA) vs placebo in ischemic stroke patients. We hypothesized that acute diffusion-weighted imaging (DWI) lesion volumes would be larger and blood pressures would be higher in patients with HT. Methods— HT was assessed 2 to 5 days after treatment in 97 patients. Hemorrhage was assessed by using susceptibility-weighted imaging sequences and was classified as petechial hemorrhagic infarction (HI) or parenchymal hematoma (PH). Results— PH was more frequent in t-PA– (11/49) than in placebo- (4/48) treated patients ( P =0.049). Patients with PH had larger DWI lesion volumes (63.1±56.1 mL) than did those without HT (27.6±39.0 mL, P =0.033). There were no differences in baseline systolic blood pressure (SBP) between patients with and without hemorrhage. Weighted average SBP 24 hours after treatment was higher in patients with PH (159.4±18.8 mL, P Conclusions— Pretreatment DWI lesion volume and postthrombolysis BP are both predictive of HT. Consideration should be given to excluding patients with very large baseline DWI volumes from t-PA therapy and to more stringent BP control after stroke thrombolysis.

Background and Purpose— Currently, diffusion-weighted imaging (DWI) lesion volume is the most useful magnetic resonance imaging predictor of hemorrhagic transformation (HT). Preliminary studies have suggested that very low cerebral blood volume (VLCBV) predicts HT. We compared HT prediction by VLCBV and DWI using data from the EPITHET study. Methods— Normal-percentile CBV values were calculated from the nonstroke hemisphere. Whole-brain masks with CBV thresholds of the Results— HT occurred in 44 of 91 patients. Parenchymal hematoma (PH) occurred in 13 (4 symptomatic) and asymptomatic hemorrhagic infarction (HI) in 31. The median volume of VLCBV was significantly higher in cases with PH. VLCBV predicted HT better than DWI lesion volume and thresholded apparent diffusion coefficient lesion volume in receiver operating characteristic analysis and logistic regression. A cutpoint at 2 mL VLCBV with the Conclusions— VLCBV predicted HT after thrombolysis better than did DWI or apparent diffusion coefficient volume in this large patient cohort. The advantage was greatest in patients with smaller DWI volumes. Prediction was better in patients who recanalized. If validated in an independent cohort, the addition of VLCBV to prethrombolysis decision making may reduce the incidence of HT.

Mudge S, Barber PA, Stott NS. Circuit-based rehabilitation improves gait endurance but not usual walking activity in chronic stroke: a randomized controlled trial. Objective To determine whether circuit-based rehabilitation would increase the amount and rate that individuals with stroke walk in their usual environments. Design Single-blind randomized controlled trial. Setting Rehabilitation clinic. Participants Sixty participants with a residual gait deficit at least 6 months after stroke originally enrolled in the study. Two withdrew in the initial phase, leaving 58 participants (median age, 71.5y; range, 39.0–89.0y) who were randomized to the 2 intervention groups. Interventions The exercise group had 12 sessions of clinic-based rehabilitation delivered in a circuit class designed to improve walking. The control group received a comparable duration of group social and educational classes. Main Outcome Measures Usual walking performance was assessed using the StepWatch Activity Monitor. Clinical tests were gait speed (timed 10-meter walk) and endurance (six-minute walk test [6MWT]), confidence (Activities-Based Confidence Scale), self-reported mobility (Rivermead Mobility Index [RMI]), and self-reported physical activity (Physical Activity and Disability Scale). Results Intention-to-treat analysis revealed that the exercise group showed a significantly greater distance for the 6MWT than the control group immediately after the intervention ( P =.030) but that this effect was not retained 3 months later. There were no changes in the StepWatch measures of usual walking performance for either group. The exercise and control groups had significantly different gait speed ( P =.038) and scores on the RMI ( P =.025) at the 3-month follow-up. These differences represented a greater decline in the control group compared with the exercise group for both outcome measures. Conclusions Circuit-based rehabilitation leads to improvements in gait endurance but does not change the amount or rate of walking performance in usual environments. Clinical gains made by the exercise group were lost 3 months later. Future studies should consider whether rehabilitation needs to occur in usual environments to improve walking performance.

Summary Background Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3–6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI). Methods We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3–6 h after onset of ischaemic stroke. PWI and DWI were done before and 3–5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537. Findings We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71·6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1·24 with alteplase and 1·78 with placebo (ratio 0·69, 95% CI 0·38–1·28; Student's t test p=0·239); the median relative infarct growth was 1·18 with alteplase and 1·79 with placebo (ratio 0·66, 0·36–0·92; Wilcoxon's test p=0·054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0·001), better neurological outcome (p Interpretation Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted. Funding National Health and Medical Research Council, Australia; National Stroke Foundation, Australia; Heart Foundation of Australia.

After stroke, the function of primary motor cortex (M1) between the hemispheres may become unbalanced. Techniques that promote a re-balancing of M1 excitability may prime the brain to be more responsive to rehabilitation therapies and lead to improved functional outcomes. The present study examined the effects of Active-Passive Bilateral Therapy (APBT), a putative movement-based priming strategy designed to reduce intracortical inhibition and increase excitability within the ipsilesional M1. Thirty-two patients with upper limb weakness at least 6 months after stroke were randomized to a 1-month intervention of self-directed motor practice with their affected upper limb (control group) or to APBT for 10-15 min prior to the same motor practice (APBT group). A blinded clinical rater assessed upper limb function at baseline, and immediately and 1 month after the intervention. Transcranial magnetic stimulation was used to assess M1 excitability. Immediately after the intervention, motor function of the affected upper limb improved in both groups (P < 0.005). One month after the intervention, the APBT group had better upper limb motor function than control patients (P < 0.05). The APBT group had increased ipsilesional M1 excitability (P < 0.025), increased transcallosal inhibition from ipsilesional to contralesional M1 (P < 0.01) and increased intracortical inhibition within contralesional M1 (P < 0.005). None of these changes were found in the control group. APBT produced sustained improvements in upper limb motor function in chronic stroke patients and induced specific and sustained changes in motor cortex inhibitory function. We speculate that APBT may have facilitated plastic reorganization in the brain in response to motor therapy. The utility of APBT as an adjuvant to physical therapy warrants further consideration.

Background and Purpose— For MR perfusion–diffusion (PWI-DWI) mismatch to become routine in thrombolysis patient selection, rapid and reliable assessment tools are required. We examined interrater variability in PWI/DWI volume measurements and developed a rapid assessment tool based on the Alberta Stroke Program Early CT Scores (ASPECTS) system. Methods— DWI and PWI were performed in 35 patients with stroke Results— Interobserver variability was much greater for PWI (95% limit of agreement=±72.3 mL) than for DWI (95% limit of agreement=±12.6 mL). A semiautomated PWI volume (time to peak+2 s) was therefore used to calculate mismatch volume. MR mismatch scores ≥2 predicted 20% PWI-DWI mismatch by volume with mean 78% sensitivity (range, 72% to 84%) and 88% specificity (range, 83% to 90%). There was excellent agreement on mismatch classification using MR mismatch scores between experienced raters (weighted kappa scores of 0.94) with agreement in 34 of 35 cases. Agreement was less consistent between inexperienced raters (weighted kappa=0.49, 28 of 35 cases). Conclusions— Variability in planimetric mismatch measurements arises primarily from differences in PWI volume assessment. High specificity and interrater reliability may make MR mismatch scores an ideal rapid screening tool for potential thrombolysis patients.

Background and Purpose— Stroke recurrence rates are high (20%–25%) and have not declined over past 3 decades. This study tested effectiveness of motivational interviewing (MI) for reducing stroke recurrence, measured by improving adherence to recommended medication and lifestyle changes compared with usual care. Methods— Single-blind, prospective phase III randomized controlled trial of 386 people with stroke assigned to either MI treatment (4 sessions at 28 days, 3, 6, and 9 months post stroke) or usual care; with outcomes assessed at 28 days, 3, 6, 9, and 12 months post stroke. Primary outcomes were change in systolic blood pressure and low-density lipoprotein cholesterol levels as indicators of adherence at 12 months. Secondary outcomes included self-reported adherence, new stroke, or coronary heart disease events (both fatal and nonfatal); quality of life (Short Form-36); and mood (Hospital Anxiety and Depression Scale). Results— MI did not significantly change measures of blood pressure (mean difference in change, −0.2.35 [95% confidence interval, −6.16 to 1.47]) or cholesterol (mean difference in change, −0.0.12 [95% confidence interval, −0.30 to 0.06]). However, it had positive effects on self-reported medication adherence at 6 months (1.979; 95% confidence interval, 0.98–3.98; P =0.0557) and 9 months (4.295; 95% confidence interval, 1.56–11.84; P =0.0049) post stroke. Improvement across other measures was also observed, but the differences between MI and usual care groups were not statistically significant. Conclusions— MI improved self-reported medication adherence. All other effects were nonsignificant, though in the direction of a treatment effect. Further study is required to determine whether MI leads to improvement in other important areas of functioning (eg, caregiver burden). Clinical Trial Registration— URL: http://www.anzctr.org.au . Unique identifier: ACTRN-12610000715077.

Determining whether a person with stroke has reached their full potential for recovery is difficult. While techniques such as transcranial magnetic stimulation (TMS) and MRI have some prognostic value, their role in rehabilitation is undefined. This study used TMS and MRI to determine which factors predict functional potential, defined as an individual's capacity for further functional improvement at least 6 months following stroke. We studied 21 chronic stroke patients with upper limb impairment. The functional integrity of the corticospinal tracts (CSTs) was assessed using TMS and functional MRI. The presence or absence of motor-evoked responses (MEPs) to TMS in the affected upper limb, and the lateralization of cortical activity during affected hand use were determined. The structural integrity of the CST was assessed using MRI, and diffusion tensor imaging was used to measure the asymmetry in fractional anisotropy (FA) of the internal capsules. A multiple linear regression analysis was performed, to predict both clinical score at inception and change in clinical score for 17 patients who completed a 30 day programme of motor practice with the affected upper limb. The main findings were that in patients with MEPs, meaningful gains were still possible 3 years after stroke, although the capacity for improvement declined with time. In patients without MEPs, functional potential declines with increasing CST disruption, with no meaningful gains possible if FA asymmetry exceeds a value of 0.25. This study is the first to demonstrate the complementary nature of TMS and MRI techniques in predicting functional potential in chronic stroke patients. An algorithm is proposed for the selection of individualized rehabilitation strategies, based on the prediction of functional potential. These strategies could include neuromodulation using a range of emerging techniques, to prime the motor system for a plastic response to rehabilitation.

Limited population-based data exist on differences in the incidence of major pathological stroke types and ischaemic stroke subtypes across ethnic groups. We aimed to provide such data within the large multi-ethnic population of Auckland, New Zealand.All first-ever cases of stroke (n=1423) in a population-based register in 940 000 residents (aged 15 years) in Auckland, New Zealand, for a 12-month period in 2002-2003, were classified into ischaemic stroke, primary intracerebral haemorrhage (PICH), subarachnoid haemorrhage, and undetermined stroke, according to standard definitions and results of neuroimaging/necropsy (in over 90% of cases). Ischaemic stroke was further classified into five subtypes. Ethnicity was self-identified and grouped as New Zealand (NZ)/European, Maori/Pacific, and Asian/other. Incidence rates were standardised to the WHO world population by the direct method, and differences in rates between ethnic groups expressed as rate ratios (RRs), with NZ/European as the reference group.In NZ/European people, ischaemic stroke comprised 73%, PICH 11%, and subarachnoid haemorrhage 6%, but PICH was higher in Maori/Pacific people (17%) and in Asian/other people (22%). Compared with NZ/European people, age-adjusted RRs for PICH were 2.7 (95% CI 1.8-4.0) and 2.3 (95% CI 1.4-3.7) among Maori/Pacific and Asian/other people, respectively. The corresponding RR for ischaemic stroke was greater for Maori/Pacific people (1.7 [95% CI 1.4-2.0]), particularly embolic stroke, and for Asian/other people (1.3 [95% CI 1.0-1.7]). The onset of stroke in Maori/Pacific and Asian/other people began at significantly younger ages (62 years and 64 years, respectively) than in NZ/Europeans (75 years; p0.0001). There were ethnic differences in the risk factor profiles (such as age, sex, hypertension, cardiac disease, diabetes, hypercholesterolaemia, smoking status, overweight) for the stroke types and subtypes.Compared to NZ/Europeans, Maori/Pacific and Asian/other people are at higher risk of ischaemic stroke and PICH, whereas similar rates of subarachnoid haemorrhage were evident across ethnic groups. The ethnic disparities in the rates of stroke types could be due to substantial differences found in risk factor profiles between ethnic groups. This information should be considered when planning prevention and stroke-care services in multi-ethnic communities.

There are approximately 45 000 stroke survivors in New Zealand and this number is projected to increase to 50 000 survivors, with annual costs to the health system exceeding $700 million by 2015 if no effective primary stroke prevention strategies are introduced. However, development of evidence-based stroke prevention strategies requires answering several research questions. In this article, we summarize some key research questions that are particularly pertinent to stroke prevention in New Zealand.

Background and Purpose. The authors used serial magnetic resonance perfusion-weighted imaging (PWI) and diffusionweighted imaging (DWI) to determine whether major reperfusion and the attenuation of infarct expansion are associated with improved stroke outcome. Methods. Forty-nine patients were studied with serial magnetic resonance imaging within 6 hours of stroke onset and again at 4 days (subacute studies) and 3 months (outcome studies). Two imaging parameters were examined: infarct expansion between acute and outcome studies and major reperfusion between acute and subacute studies. Results. Patients with major reperfusion (45% of those with acute PWI lesions) were more likely to have little or no disability at outcome (National Institutes of Health Stroke Scale [NIHSS] score = 4, P= .0176; Barthel Index [BI] score = 90, P= .0547)fter adjustment for baseline differences. In contrast, patients with infarct expansion (48%) were more likely to be dead or dependent at outcome (BI 2, P< .0001). These measures were used to generate sample size calculations based on hypothetical treatment effects. Therapies postulated to double the proportion of patients with major reperfusion from one third to two thirds would require 41 patients in each group (treated and untreated) to be sufficiently powered to show a difference. Interventions postulated to halve the number of patients with infarct expansion from 50% to 25% would require 66 patients in each group to show a difference. Conclusions. Infarct expansion and major reperfusion are associated with clinically meaningful changes in stroke outcome. These measures could be used as surrogate markers of outcome in late phase II proof-of-concept stroke studies designed to provide efficacy signals before embarking on large phase III studies with definitive clinical endpoints.