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Background: Endovascular thrombectomy (EVT) access in remote areas is limited. Preliminary data suggest that long distance transfers for EVT may be beneficial; however, the magnitude and best imaging strategy at the referring center remains uncertain. We hypothesized that patients transferred >300 miles would benefit from EVT, achieving rates of functional independence (modified Rankin Scale [mRS] score of 0–2) at 3 months similar to those patients treated at the comprehensive stroke center in the randomized EVT extended window trials and that the selection of patients with computed tomography perfusion (CTP) at the referring site would be associated with ordinal shift toward better outcomes on the mRS. Methods: This is a retrospective analysis of patients transferred from 31 referring hospitals >300 miles (measured by the most direct road distance) to 9 comprehensive stroke centers in Australia and New Zealand for EVT consideration (April 2016 through May 2021). Results: There were 131 patients; the median age was 64 [53–74] years and the median baseline National Institutes of Health Stroke Scale score was 16 [12–22]. At baseline, 79 patients (60.3%) had noncontrast CT+CT angiography, 52 (39.7%) also had CTP. At the comprehensive stroke center, 114 (87%) patients underwent cerebral angiography, and 96 (73.3%) proceeded to EVT. At 3 months, 62 patients (48.4%) had an mRS score of 0 to 2 and 81 (63.3%) mRS score of 0 to 3. CTP selection at the referring site was not associated with better ordinal scores on the mRS at 3 months (mRS median of 2 [1–3] versus 3 [1–6] in the patients selected with noncontrast CT+CT angiography, P =0.1). Nevertheless, patients selected with CTP were less likely to have an mRS score of 5 to 6 (odds ratio 0.03 [0.01–0.19]; P Conclusions: In selected patients transferred >300 miles, there was a benefit for EVT, with outcomes similar to those treated in the comprehensive stroke center in the EVT extended window trials. Remote hospital CTP selection was not associated with ordinal mRS improvement, but was associated with fewer very poor 3-month outcomes.

Introduction Infection after stroke is associated with unfavorable outcome. Randomized controlled studies did not show benefit of preventive antibiotics in stroke but lacked power for subgroup analyses. Aim of this study is to assess whether preventive antibiotic therapy after stroke improves functional outcome for specific patient groups in an individual patient data meta-analysis. Patients and methods We searched MEDLINE (1946–7 May 2021), Embase (1947–7 May 2021), CENTRAL (17th September 2021), trial registries, cross-checked references and contacted researchers for randomized controlled trials of preventive antibiotic therapy versus placebo or standard care in ischemic or hemorrhagic stroke patients. Meta-analysis was performed by a one-step and two-step approach. Primary outcome was functional outcome adjusted for age and stroke severity. Secondary outcomes were infections and mortality. Results 4197 patients from nine trials were included. Preventive antibiotic therapy was not associated with a shift in functional outcome (mRS) at 3 months (OR1.13, 95%CI 0.98–1.31) or unfavorable functional outcome (mRS 3–6) (OR0.85, 95%CI 0.60–1.19). Preventive antibiotics did not improve functional outcome in pre-defined subgroups (age, stroke severity, timing and type of antibiotic therapy, pneumonia prediction scores, dysphagia, type of stroke, and type of trial). Preventive antibiotics reduced infections (276/2066 (13.4%) in the preventive antibiotic group vs. 417/2059 (20.3%) in the control group, OR 0.60, 95% CI 0.51–0.71, p < 0.001), but not pneumonia (191/2066 (9.2%) in the preventive antibiotic group vs. 205/2061 (9.9%) in the control group (OR 0.92 (0.75–1.14), p = 0.450). Discussion and conclusion Preventive antibiotic therapy did not benefit any subgroup of patients with acute stroke and currently cannot be recommended.

Background and Purpose: The AFFINITY trial (Assessment of Fluoxetine in Stroke Recovery) reported that oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. After trial medication was ceased at 6 months, survivors were followed to 12 months post-randomization. This preplanned secondary analysis aimed to determine any sustained or delayed effects of fluoxetine at 12 months post-randomization. Methods: AFFINITY was a randomized, parallel-group, double-blind, placebo-controlled trial in adults (n=1280) with a clinical diagnosis of stroke in the previous 2 to 15 days and persisting neurological deficit who were recruited at 43 hospital stroke units in Australia (n=29), New Zealand (4), and Vietnam (10) between 2013 and 2019. Participants were randomized to oral fluoxetine 20 mg once daily (n=642) or matching placebo (n=638) for 6 months and followed until 12 months after randomization. The primary outcome was function, measured by the modified Rankin Scale, at 6 months. Secondary outcomes for these analyses included measures of the modified Rankin Scale, mood, cognition, overall health status, fatigue, health-related quality of life, and safety at 12 months. Results: Adherence to trial medication was for a mean 167 (SD 48) days and similar between randomized groups. At 12 months, the distribution of modified Rankin Scale categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio, 0.93 [95% CI, 0.76–1.14]; P =0.46). Compared with placebo, patients allocated fluoxetine had fewer recurrent ischemic strokes (14 [2.18%] versus 29 [4.55%]; P =0.02), and no longer had significantly more falls (27 [4.21%] versus 15 [2.35%]; P =0.08), bone fractures (23 [3.58%] versus 11 [1.72%]; P =0.05), or seizures (11 [1.71%] versus 8 [1.25%]; P =0.64) at 12 months. Conclusions: Fluoxetine 20 mg daily for 6 months after acute stroke had no delayed or sustained effect on functional outcome, falls, bone fractures, or seizures at 12 months poststroke. The lower rate of recurrent ischemic stroke in the fluoxetine group is most likely a chance finding. Registration: URL: http://www.anzctr.org.au/ ; Unique identifier: ACTRN12611000774921.

INTRODUCTION Patients with ischaemic stroke due to large vessel occlusion (LVO) can be treated successfully with mechanical thrombectomy (MT) and/or intravenous thrombolysis. In the landmark trials, MT was only performed for those with no functional disability prior to stroke (mRS 0-2). There are limited data available regarding clinical outcomes for patients with pre-stroke moderate disability (mRS ≥ 3). The aims of this study were to analyse the clinical outcomes and financial implications in regard to accommodation costs of performing MT in patients with pre-stroke mRS = 3. METHODS An observational cohort study was performed of 802 patients with anterior circulation LVO ischaemic stroke who underwent MT between October 2016 and January 2020 at three tertiary hospitals. Patient demographics, premorbid mRS, stroke and interventional data, 90-day mRS and accommodation situation were recorded. RESULTS Eighty-two patients with anterior circulation LVO ischaemic stroke were pre-stroke mRS 3. 38% had a good clinical outcome, as defined by mRS 3 at 90 days. Mortality rate was 38%. The majority of patients presented from home (83%) and greater than one third of those returned home during the 90 days post treatment. 81% of patients had no increase in accommodation cost at 90 days. CONCLUSION Patients with pre-stroke moderate disability may benefit from MT if they are appropriately selected. This may result in fewer patients requiring nursing home placement and less financial burden on the public health system, indicating significant savings are possible.

Poly-arginine peptides R18 and R18D have previously been demonstrated to be neuroprotective in ischaemic stroke models. Here we examined the proteolytic stability and efficacy of R18 and R18D in reducing infarct core growth and preserving the ischaemic penumbra following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. R18 (300 or 1000 nmol/kg), R18D (300 nmol/kg) or saline were administered intravenously 10 min after MCAO induced using a filament. Serial perfusion and diffusion-weighted MRI imaging was performed to measure changes in the infarct core and penumbra from time points between 45- and 225-min post-occlusion. Repeated measures analyses of infarct growth and penumbral tissue size were evaluated using generalised linear mixed models (GLMMs). R18D (300 nmol/kg) was most effective in slowing infarct core growth (46.8 mm3 reduction; p

Background: Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population.Methods: AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921.Findings: Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [Interpretation: Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke.Funding: National Health and Medical Research Council of Australia.

Stroke is a debilitating condition that impairs one's ability to live independently while also greatly decreasing one's quality of life. For these reasons, stroke rehabilitation is important. Engagement is a crucial part of rehabilitation, increasing a stroke survivor's recovery rate and the positive outcomes of their rehabilitation. For this reason, virtual reality (VR) has been widely used to gamify stroke rehabilitation to support engagement. Given that VR and the serious games that form its basis may not necessarily be engaging in themselves, ensuring that their design is engaging is important. This chapter discusses 39 principles that may be useful for engaging stroke survivors with VR-based rehabilitation post-stroke. This chapter then discusses a subset of the game design principles that are likely to engage stroke survivors with VR designed for upper limb rehabilitation post-stroke.

Background Seizures may be a feature of SMART (stroke-like migraine attacks after radiation therapy) syndrome but their role in the pathophysiology and clinical presentation is unclear. Method The clinical and investigation findings in a series of adult patients with SMART syndrome presenting primarily with seizures were reviewed. Results Four patients with SMART syndrome presenting with seizures were identified (mean age 51 years). Mean time from radiation therapy to SMART syndrome was 22.5 years (range 15-32 years). Indications for radiation were primary brain tumour (three patients) and haematological malignancy (one patient). Two patients had a history of seizures prior to SMART syndrome. Three patients had headaches at presentation. All patients presented with focal impaired awareness seizures with motor features. One patient had refractory non-convulsive status epilepticus requiring intravenous anaesthesia. Three patients had persistent negative motor deficits, associated with ongoing electrographic seizures with no clinical correlate, only identified on repeated EEGs or continuous EEG (cEEG). All patients failed initial anti-seizure medications (ASM), requiring a mean of five ASMs for seizure control. All patients had enhancing cortical MRI changes consistent with SMART syndrome that corresponded to the clinical deficit and ictal changes on EEG. At follow-up all patients improved but had persistent neurological deficits. Conclusion SMART syndrome presents with seizures and less frequently status epilepticus and may be the basis for the associated clinical features and radiologic abnormalities. Judicious use of EEG and where necessary CEEG to identify non-convulsive seizures should be considered in patients with SMART syndrome presenting with prolonged neurological deficits.

Background and Purpose: Conditions associated with frailty are common in people experiencing stroke and may explain differences in outcomes. We assessed associations between a published, generic frailty risk score, derived from administrative data, and patient outcomes following stroke/transient ischemic attack; and its accuracy for stroke in predicting mortality compared with other measures of clinical status using coded data. Methods: Patient-level data from the Australian Stroke Clinical Registry (2009–2013) were linked with hospital admissions data. We used International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes with a 5-year look-back period to calculate the Hospital Frailty Risk Score (termed Frailty Score hereafter) and summarized results into 4 groups: no-risk (0), low-risk (1–5), intermediate-risk (5–15), and high-risk (>15). Multilevel models, accounting for hospital clustering, were used to assess associations between the Frailty Score and outcomes, including mortality (Cox regression) and readmissions up to 90 days, prolonged acute length of stay (>20 days; logistic regression), and health-related quality of life at 90 to 180 days (quantile regression). The performance of the Frailty Score was then compared with the Charlson and Elixhauser Indices using multiple tests (eg, C statistics) for predicting 30-day mortality. Models were adjusted for covariates including sociodemographics and stroke-related factors. Results: Among 15 468 adult patients, 15% died ≤90 days. The frailty scores were 9% no risk; 23% low, 45% intermediate, and 22% high. A 1-point increase in frailty (continuous variable) was associated with greater length of stay (OR adjusted , 1.05 [95% CI, 1.04 to 1.06), 90-day mortality (HR adjusted , 1.04 [95% CI, 1.03 to 1.05]), readmissions (OR adjusted , 1.02 [95% CI, 1.02 to 1.03]; and worse health-related quality of life (median difference, −0.010 [95% CI −0.012 to −0.010]). Adjusting for the Frailty Score provided a slightly better explanation of 30-day mortality (eg, larger C statistics) compared with other indices. Conclusions: Greater frailty was associated with worse outcomes following stroke/transient ischemic attack. The Frailty Score provides equivalent precision compared with the Charlson and Elixhauser indices for assessing risk-adjusted outcomes following stroke/transient ischemic attack.

This personal viewpoint, written by a neurologist with Parkinson disease (PD), is to provide a patient's perspective, to accompany the clinical perspective in this issue of the Intenal Medicine Journal entitled 'Approach to the patient with early stage Parkinson disease'. The aim is to provide a personal insight into the numerous issues surrounding early diagnosis and management of PD, from the position of being a physician patient.

This study examined the nature and characteristics of sleep-disordered breathing, including obstructive sleep apnea and central sleep apnea, in patients with post-stroke dysphagia, to determine the demographic, anthropometric and clinical variables that were associated with sleep-disordered breathing. Thirty-nine patients diagnosed with acute stroke (28 males and 11 females with a mean age of 72.3 ± 10.0 years) underwent overnight polysomnography (within 3.9 ± 1.6 days after admission). Sleep-disordered breathing was described by the apnea-hypopnea index and its obstructive and central components by the obstructive apnea-hypopnea index and central apnea-hypopnea index, respectively. Severity of dysphagia was assessed using the Mann Assessment of Swallowing Ability score. Severity of stroke and functional dependence were assessed by the National Institute of Health Stroke Scale and the modified Barthel index, respectively. Most of the cohort (87%) had moderate-to-severe dysphagia (Mann Assessment of Swallowing Ability of 143.2 ± 19.9). Sleep-disordered breathing (apnea-hypopnea index ≥ 5 events/hr) was present in 38 participants (97%) with a mean apnea-hypopnea index of 37.5 ± 24.4 events/hr. Sleep-disordered breathing was predominantly obstructive in nature, with a mean obstructive apnea-hypopnea index and central apnea-hypopnea index of 19.6 ± 15.7 and 11.4 ± 17.6 events/hr, respectively. Multivariate linear regression analyses showed that the apnea-hypopnea index was associated with sex (p = .0001), body mass index (p = .029) and the modified Barthel index (p = .006); the obstructive apnea-hypopnea index was associated with the Mann Assessment of Swallowing Ability (p = .006), sex (p = .004) and body mass index (p = .015) and had a nonlinear relationship with the modified Barthel index (p = .019); and the central apnea-hypopnea index was associated with sex (p = .027) and the modified Barthel index (p = .019). The present study showed that dysphagia severity was associated with obstructive sleep apnea severity and this association was independent of sex, modified Barthel index and body mass index. However, stroke-induced dysphagia was not associated with central sleep apnea or overall sleep-disordered breathing.

I could feel Parkinson’s disease creeping up on me, so when I finally summoned up the courage to have a colleague assess me and make the diagnosis, it was of no surprise; in fact, it was almost a relief. In my mid-30s, I had taken up long-distance running, mainly to shed the weight I’d stacked on during training and fellowship years. About 10 years later, I developed a gait disturbance, manifesting as an exercise-induced dystonia in my leg. Initially, it appeared only after running a significant distance, but gradually it became more problematic, eventually leading me to stop participating in competitive events. My leg would spasm, twist and generally tighten up. I knew it was dystonia but told others it was just cramp or a ‘hip problem’; that was easier than explaining what this could become.1 I was otherwise fine and made a concerted effort to keep fit and to continue exercise as best I could. I also abandoned plans to reduce my caffeine intake given the possibility of this being neuroprotective in Parkinson’s disease. Sadly, my sense of olfaction became impaired, …

Poly-arginine peptide-18 (R18) is neuroprotective in different rodent middle cerebral artery occlusion (MCAO) stroke models. In this study, we examined whether R18 treatment could reduce ischemic brain injury and improve functional outcome in a nonhuman primate (NHP) stroke model. A stroke was induced in male cynomolgus macaques by MCAO distal to the orbitofrontal branch of the MCA through a right pterional craniotomy, using a 5-mm titanium aneurysm clip for 90 min. R18 (1000 nmol/kg) or saline vehicle was administered intravenously 60 min after the onset of MCAO. Magnetic resonance imaging (MRI; perfusion-weighted imaging, diffusion-weighted imaging, or T2-weighted imaging) of the brain was performed 15 min, 24 h, and 28 days post-MCAO, and neurological outcome was assessed using the NHP stroke scale (NHPSS). Experimental endpoint was 28 days post-MCAO, treatments were randomized, and all procedures were performed blinded to treatment status. R18 treatment reduced infarct lesion volume by up to 65.2% and 69.7% at 24 h and 28 days poststroke, respectively. Based on NHPSS scores, R18-treated animals displayed reduced functional deficits. This study confirms the effectiveness of R18 in reducing the severity of ischemic brain injury and improving functional outcomes after stroke in a NHP model, and provides further support for its clinical development as a stroke neuroprotective therapeutic. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s13311-019-00809-1) contains supplementary material, which is available to authorized users.

Background and Purpose— Readmissions after stroke are common and appear to be associated with comorbidities or disability-related characteristics. In this study, we aimed to determine the patient and health-system level factors associated with all-cause and unplanned hospital readmission within 90 days after acute stroke or transient ischemic attack (TIA) in Australia. Methods— We used person-level linkages between data from the Australian Stroke Clinical Registry (2009–2013), hospital admissions data and national death registrations from 4 Australian states. Time to first readmission (all-cause or unplanned) for discharged patients was examined within 30, 90, and 365 days, using competing risks regression to account for deaths postdischarge. Covariates included age, stroke severity (ability to walk on admission), stroke type, admissions before stroke/TIA and the Charlson Comorbidity Index (derived from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision , [Australian modified] coded hospital data in the preceding 5 years). Results— Among the 13 594 patients discharged following stroke/TIA (45% female; 65% ischemic stroke; 11% intracerebral hemorrhage; 4% undetermined stroke; and 20% TIA), 25% had an all-cause readmission and 15% had an unplanned readmission within 90 days. In multivariable analyses, the factors independently associated with a greater risk of unplanned readmission within 90 days were being female (subhazard ratio, 1.13 [95% CI, 1.03–1.24]), greater Charlson Comorbidity Index scores (subhazard ratio, 1.11 [95% CI, 1.09–1.12]) and having an admission ≤90 days before the index event (subhazard ratio, 1.85 [95% CI, 1.59–2.15]). Compared with being discharged to rehabilitation or aged care, those who were discharged directly home were more likely to have an unplanned readmission within 90 days (subhazard ratio, 1.44 [95% CI, 1.33–1.55]). These factors were similar for readmissions within 30 and 365 days. Conclusions— Apart from comorbidities and patient-level characteristics, readmissions after stroke/TIA were associated with discharge destination. Greater support for transition to home after stroke/TIA may be needed to reduce unplanned readmissions.

Engagement with one's rehabilitation is crucial for stroke survivors. Serious games utilising desktop Virtual Reality could be used in rehabilitation to increase stroke survivors' engagement. This paper discusses the results of a user experience case study that was conducted with six stroke survivors to determine which game design principles are or would be important for engaging them with a desktop VR serious games designed for the upper limb rehabilitation. The results of our study showed the game design principles that warrant further investigation are awareness, feedback, interactivity, flow and challenge; and also important to a great extent are attention, involvement, motivation, effort, clear instructions, usability, interest, psychological absorption, purpose and a first-person view.

El texto completo de este trabajo no está disponible en el Repositorio Académico UPC por restricciones de la casa editorial donde ha sido publicado. Background: Various randomized-controlled clinical trials (RCTs) have investigated the neuroprotective role of minocycline in acute ischemic stroke (AIS) or acute intracerebral hemorrhage (ICH) patients. We sought to consolidate and investigate the efficacy and safety of minocycline in patients with acute stroke. Methods: Literature search spanned through November 30, 2017 across major databases to identify all RCTs that reported following efficacy outcomes among acute stroke patients treated with minocycline vs. placebo: National Institute of Health Stroke Scale (NIHSS), Barthel Index (BI), and modified Rankin Scale (mRS) scores. Additional safety, neuroimaging and biochemical endpoints were extracted. We pooled mean differences (MD) and risk ratios (RR) from RCTs using random-effects models. Results: We identified 7 RCTs comprising a total of 426 patients. Of these, additional unpublished data was obtained on contacting corresponding authors of 5 RCTs. In pooled analysis, minocycline demonstrated a favorable trend towards 3-month functional independence (mRS-scores of 0–2) (RR = 1.31; 95% CI 0.98–1.74, p = 0.06) and 3-month BI (MD = 6.92; 95% CI − 0.92, 14.75; p = 0.08). In AIS subgroup, minocycline was associated with higher rates of 3-month mRS-scores of 0–2 (RR = 1.59; 95% CI 1.19–2.12, p = 0.002; I2 = 58%) and 3-month BI (MD = 12.37; 95% CI 5.60, 19.14, p = 0.0003; I2 = 47%), whereas reduced the 3-month NIHSS (MD − 2.84; 95% CI − 5.55, − 0.13; p = 0.04; I2 = 86%). Minocycline administration was not associated with an increased risk of mortality, recurrent stroke, myocardial infarction and hemorrhagic conversion. Conclusions: Although data is limited, minocycline demonstrated efficacy and seems a promising neuroprotective agent in acute stroke patients, especially in AIS subgroup. Further RCTs are needed to evaluate the efficacy and safety of minocycline among ICH patients. Revisión por pares Revisión por pares

Background and Purpose: Endovascular thrombectomy (EVT) improves the functional outcome when added to best medical therapy, including alteplase, in patients with acute ischaemic stroke secondary to large vessel occlusion (LVO) in the anterior circulation. However, the evidence for EVT in alteplase-ineligible patients is less compelling. It is also uncertain whether alteplase is necessary in patients with successful recanalization by EVT, as the treatment effect of EVT may be so powerful that bridging alteplase may not add to efficacy and may compromise safety by increasing bleeding risks. We aimed to survey the proportion of patients suitable for EVT who are alteplase-ineligible and to compare the safety and effectiveness of standard care of acute large artery ischaemic stroke by EVT plus thrombolysis with that of EVT alone in a tertiary hospital clinical stroke service. Methods: We performed a retrospective analysis of acute ischaemic stroke patients treated with EVT at our centre between October 2013 and April 2016, based on a registry with prospective and consecutive patient collection. Individual patient records were retrieved for review. Significant early neurological improvement was defined as a NIHSS score of 0–1, or a decrease from baseline of ≤8, at 24 h after stroke onset. Results: Fifty patients with acute ischaemic stroke secondary to LVO in the anterior circulation received EVT in this period, of whom 21 (42%) received concurrent alteplase and 29 (58%) EVT alone. The 2 groups had similar baseline characteristics and similar outcomes. Significant neurological improvement at 24 h occurred in 47.6% of the patients with EVT and bridging alteplase and in 51.7% of the patients with EVT alone (p = 0.774). Mortality during acute hospitalization was 20% for the bridging alteplase group versus 7.1% for EVT alone (p = 0.184). Intracranial haemorrhage rates were 14.3% for bridging alteplase versus 20.7% for EVT alone (p = 0.716). Local complications, groin haematoma (23.8 vs. 10.3%) and groin pseudoaneurysms (4.8 vs. 0%) (p = 0.170), were not significantly different. Conclusion: Our study highlights the relatively large proportion of patients suitable for EVT who have a contraindication to alteplase and raises the hypothesis that adding alteplase to successful EVT may not be necessary to optimize functional outcome. The results are consistent with observational data from other endovascular centres and support a randomised controlled trial of EVT versus EVT with bridging alteplase.

We examined the efficacy of R18 in a transient MCAO model and compared its effectiveness to the well-characterized neuroprotective NA-1 peptide. R18 and NA-1 peptides were administered intravenously (30, 100, 300, 1000nmol/kg), 60min after the onset of 90min of MCAO. Infarct volume, cerebral swelling and functional outcomes (neurological score, adhesive tape and rota-rod) were measured 24h after MCAO. R18 reduced total infarct volume by 35.1% (p=0.008), 24.8% (p=0.059), 12.2% and 9.6% for the respective 1000 to 30nmol/kg doses, while the corresponding doses of NA-1 reduced lesion volume by 26.1% (p=0.047), 16.6%, 16.5% and 7%, respectively. R18 also reduced hemisphere swelling by between 46.1% (1000 and 300nmol/kg; p=0.009) and 24.4% (100nmol/kg; p=0.066), while NA-1 reduced swelling by 25.7% (1000nmol/kg; p=0.054). In addition, several R18 and NA-1 treatment groups displayed a significant improvement in at least one parameter of the adhesive tape test. These results confirm the neuroprotective properties of R18, and suggest that the peptide is a more effective neuroprotective agent than NA-1. This provides strong justification for the continuing development of R18 as a neuroprotective treatment for stroke.

Aims: We have previously demonstrated that the poly-arginine peptides R18 and R18D are neuroprotective at 24 hours following intraluminal middle cerebral artery occlusion (MCAO) in the rat. Therefore, using an independent laboratory we examined the ability of R18 and R18D to improve functional outcomes after endothelin-1 (ET-1) induced MCAO in rats over 56 days post-stroke. Methods: Peptides were administered intravenously at 100, 300 or 1000 nmol/kg, 60 minutes after ET-1 induced MCAO. Multiple forelimb placing tests and horizontal ladder tests were performed post-stroke, and the neuroprotective peptide NA-1 (TAT-NR2Bpc), which is being assessed in Phase 3 clinical stroke trials, was used as a benchmark. Results: R18 (300 and 1000nmol/kg, respectively) was the most effective peptide to improve functional outcomes, followed by R18D (300 and 1000 nmol/kg, respectively), and NA-1 (300 and 100 nmol/kg, respectively). Furthermore, R18 at 300 and 1000 nmol/kg was the most effective treatment to restore pre-stroke animal body weight (post-stroke day 4 versus day 7 for saline, and days 5-7 for all other treatments), while R18 and R18D at 300 and 1000 nmol/kg, but not NA-1 also significantly reduced the number of animals requiring special care (hand feeding) 48 hours after stroke. Conclusion: In conclusion, this study confirms that R18 and R18D can improve long-term functional outcomes after stroke, and given the superior effectiveness of R18 over NA-1 in the present, as well as in our previous studies, justifies further evaluation in a non-human primate stroke model and in a clinical stroke trial.

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

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.

CT perfusion is increasingly utilised in hyperacute stroke to facilitate diagnosis and patient selection for reperfusion therapies. This review article demonstrates eight examples of how CT perfusion can be used to diagnose stroke mimics and small volume infarcts, which can be easily missed on non-contrast CT, and to suggest the presence of an ischaemic penumbra. Radiologists involved in stroke management must understand the importance of rapid imaging acquisition and be confident in the prospective interpretation of this powerful diagnostic tool as we move into a new era of hyperacute stroke care.

We have previously demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties, with poly-arginine peptide R18 identified as being highly effective at reducing infarct volume following middle cerebral artery occlusion (MCAO) in the Sprague Dawley rat. Since peptides synthesised using D-isoform amino acids have greater stability than L-isoform peptides due to increased resistance to proteolytic degradation, they represent potentially more effective peptide therapeutics. Therefore we compared the neuroprotective efficacy of R18 and its D-enantiomer R18D following permanent MCAO in the Wistar rat. Furthermore, as increased peptide stability may also increase peptide toxicity, we examined the effects of R18 and R18D on cultured cortical neurons, astrocytes, brain endothelial cells (bEND.3), and embryonic kidney cells (HEK293) following a 10-minute or 24-hour peptide exposure duration. The in vivo studies demonstrated that R18D resulted in a greater reduction in mean infarct volume compared to R18 (33%, p = 0.004 vs 12%, p = 0.27) after intravenous administration at 300 nmol/kg 30 minutes after MCAO. Both R18D and R18 reduced cerebral hemisphere swelling to a comparable degree (27%, p = 0.03 and 30%, p = 0.02), and improved neurological assessment scores (1.5, p = 0.02 and 2, p = 0.058 vs 3 for vehicle). No abnormal histological findings specific to peptide treatments were observed in hematoxylin and eosin stained sections of kidney, liver, spleen, lung and heart. In vitro studies demonstrated that R18 and R18D were most toxic to neurons, followed by astrocytes, HEK293 and bEND.3 cells, but only at high concentrations and/or following 24-hour exposure. These findings further highlight the neuroprotective properties of poly-arginine peptides, and indicate that R18D at the dose examined is more potent than R18 in Wistar rats, and justify continued investigation of the R18 peptide as a novel neuroprotective agent for stroke.

Item does not contain fulltext OBJECTIVES: To investigate the effects of intensive blood pressure (BP) lowering according to baseline BP levels and optimal achieved BP levels in patients with acute intracerebral hemorrhage (ICH). METHODS: INTERACT2 was an open, blinded endpoint, randomized controlled trial in 2,839 patients with ICH within 6 hours of onset and elevated systolic BP (SBP) (150-220 mm Hg) who were allocated to receive intensive (target SBP /=190 mm Hg (p homogeneity = 0.790). Analyses of achieved BP showed linear increases in the risk of physical dysfunction for achieved SBP above 130 mm Hg for both hyperacute (1-24 hours) and acute (2-7 days) phases while modest increases were also observed for achieved SBP below 130 mm Hg. CONCLUSIONS: Intensive BP lowering appears beneficial across a wide range of baseline SBP levels, and target SBP level of 130-139 mm Hg is likely to provide maximum benefit in acute ICH. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that the effect of intensive BP lowering on physical function is not influenced by baseline BP.

Game-based technologies have been widely used as part of stroke rehabilitation. The Neuromender system utilises game-based technologies and consists of serious games that are designed and developed for the purpose of rehabilitation of stroke survivors. In this paper, one of the modules in the Neuromender system which is the “upper limb” module is described and tested for its usability. The upper limb module primarily focuses on the rehabilitation of the upper body extremities of stroke survivors. An experimental study is designed to test the usability of the upper limb module. Various metrics including the optimal distance between the 3D depth sensor device and the survivor, the optimal position of the 3D depth sensor with respect to the survivor, and the response time of the gestures made by the survivors based on their distance to the sensor are evaluated. At the end of the experiments, the optimal distance and optimal position for the survivors to utilise the upper limb module is determined.

Following positive results with the poly-arginine peptide R18 when administered intravenously 30 or 60min after permanent and/or transient middle cerebral artery occlusion (MCAO; 90min) in the rat, we examined the effectiveness of the peptide when administered 2h after MCAO. R18 was administered intravenously (1000nmol/kg via jugular vein) after permanent MCAO or a transient 3-h MCAO or when administered intra-arterially (100nmol/kg via internal carotid artery) immediately after reperfusion following a transient 2-h MCAO. In the transient MCAO studies, the neuroprotective NA-1 peptide was used as a positive control. Infarct volume, cerebral edema and functional outcomes were measured 24h after MCAO. Following permanent or transient MCAO, neither R18 nor NA-1 significantly reduced infarct volume. However, following permanent MCAO, R18 appeared to reduce cerebral edema (p=0.006), whereas following a transient 3-h MCAO, R18 improved the time to remove adhesive tape (p=0.04) without significantly affecting cerebral edema. There was also a trend (p=0.07) towards improved rota-rod performance with R18 in both permanent and transient 3-h MCAO. Following a transient 2-h MCAO, R18 had no significant effects on cerebral edema or neurological score but did lessen the extent of weight loss. Overall, while R18 had no effect on infarct volume, the peptide reduced cerebral edema after permanent MCAO, and improved some functional outcomes after transient MCAO.

Background Cationic arginine-rich peptides (CARPs) have demonstrated neuroprotective and/or behavioural efficacy in ischemic and hemorrhagic stroke and traumatic brain injury models. Therefore, in this study we investigated the safety and neuroprotective efficacy of the CARPs poly-arginine-18 (R18; 18-mer of arginine) and its D-enantiomer R18D given in the acute bleeding phase in an intracerebral hemorrhage (ICH) model. Methods One hundred and fifty-eight male Sprague-Dawley rats received collagenase-induced ICH. Study 1 examined various doses of R18D (30, 100, 300, or 1000 nmol/kg) or R18 (100, 300, 1000 nmol/kg) administered intravenously 30 minutes post-collagenase injection on hemorrhage volume 24 hours after ICH. Study 2 examined R18D (single intravenous dose) or R18 (single intravenous dose, plus 6 daily intraperitoneal doses) at 300 or 1000 nmol/kg commencing 30 minutes post-collagenase injection on behavioural outcomes (Montoya staircase test, and horizontal ladder test) in the chronic post-ICH period. A histological assessment of tissue loss was assessed using a Nissl stain at 28 days after ICH. Results When administered during ongoing bleeding, neither R18 or R18D exacerbated hematoma volume or worsened functional deficits. Lesion volume assessment at 28 days post-ICH was not reduced by the peptides; however, animals treated with the lower R18D 300 nmol/kg dose, but not with the higher 1000 nmol/kg dose, demonstrated a statistically increased lesion size compared to saline treated animals. Conclusion Overall, both R18 and R18D appeared to be safe when administered during a period of ongoing bleeding following ICH. Neither peptide appears to have any statistically significant effect in reducing lesion volume or improving functional recovery after ICH. Additional studies are required to further assess dose efficacy and safety in pre-clinical ICH studies.

David Blacker speaks to Simi Thankaraj, Assistant Commissioning Editor David Blacker was born in Bunbury, Western Australia, and studied medicine at the University of Western Australia (Perth, Australia), graduating in 1991. He undertook physician and neurology specialist training in Perth. He developed an interest in acute stroke therapies early in his career, and was involved with cases treated with intra-arterial techniques in the mid-1990s. Like many young Australian neurologists, he then undertook 2 years of fellowship training at the Mayo Clinic (MN, USA). There, Blacker was mentored by Professors Bob Brown and Eelco Wijdicks, and further developed interests in stroke and acute hospital-based neurology. His return to Australia in 2003 coincided with the approval of tissue plasminogen activator as a stroke therapy. He helped establish the acute stroke team at Sir Charles Gairdner Hospital (Perth, Australia), and has continued to work on the development of stroke services locally, and across the geoprahically enormous state of Western Australia ever since. In his role as a Clinical Associate Professor of Neurology at the University of Western Australia, he is actively involved in teaching, and has a wide range of research interests mainly in acute stroke, but also in neurorehabilitation. In this interview, he shares some thoughts on the future of stroke treatment and research.

Background and Purpose— Minocycline, in animal models and 2 small randomized controlled human trials, is a promising neuroprotective agent in acute stroke. We analyzed the efficacy and safety of intravenous minocycline in acute ischemic and hemorrhagic stroke. Methods— A multicenter prospective randomized open-label blinded end point evaluation pilot study of minocycline 100 mg administered intravenously, commenced within 24 hours of onset of stroke, and continued 12 hourly for a total of 5 doses, versus no minocycline. All participants received routine stroke care. Primary end point was survival free of handicap (modified Rankin Scale, ≤2) at day 90. Results— Ninety-five participants were randomized; 47 to minocycline and 48 to no minocycline. In the intention-to-treat population, 29 of 47 (65.9%) allocated minocycline survived free of handicap compared with 33 of 48 (70.2%) allocated no minocycline (rate ratio, 0.94; 95% confidence interval, 0.71–1.25 and odds ratio, 0.73; 95% CI, 0.31–1.71). A meta-analysis of the 3 human trials suggests minocycline may increase the odds of handicap-free survival by 3-fold (odds ratio, 2.99; 95% CI, 1.74–5.16) but there was substantial heterogeneity among the trials. Conclusions— In this pilot study of a small sample of acute stroke patients, intravenous minocycline was safe but not efficacious. The study was not powered to identify reliably or exclude a modest but clinically important treatment effect of minocycline. Larger trials would improve the precision of the estimates of any treatment effect of minocycline. Clinical Trial Registration— URL: http://www.anzctr.org.au . Unique identifier: ACTRN12612000237886.

We have demonstrated that arginine-rich and poly-arginine peptides possess potent neuroprotective properties with arginine content and peptide positive charge being particularly critical for neuroprotective efficacy. In addition, the presence of other amino acids within arginine-rich peptides, as well as chemical modifications, peptide length and cell-penetrating properties also influence the level of neuroprotection. Against this background, we have examined the neuroprotective efficacy of arginine-rich protamine peptides, a cyclic (R12-c) poly-arginine peptide and a R22 poly-arginine peptide, as well as arginine peptides containing tryptophan or other amino acids (phenylalanine, tyrosine, glycine or leucine) in in vitro glutamic acid excitotoxicity and in vivo rat permanent middle cerebral artery occlusion models of stroke. In vitro studies demonstrated that protamine and poly-arginine peptides (R12-c, R22) were neuroprotective. Arginine-tryptophan-containing peptides were highly neuroprotective, with R12W8a being the most potent arginine-rich peptide identified in our laboratory. Peptides containing phenylalanine or tyrosine substituted in place of tryptophan in R12W8a were also highly neuroprotective, whereas leucine, and in particular glycine substitutions, decreased peptide efficacy. In vivo studies with protamine administered intravenously at 1000 nmol/kg 30 min after MCAO significantly reduced infarct volume and cerebral oedema by 22.5 and 38.6%, respectively. The R12W8a peptide was highly toxic when administered intravenously at 300 or 100 nmol/kg and ineffective at reducing infarct volume when administered at 30 nmol/kg 30 min after MCAO, unlike R18 (30 nmol/kg), which significantly reduced infarct volume by 20.4%. However, both R12W8a and R18 significantly reduced cerebral oedema by 19.8 and 42.2%, respectively. Protamine, R12W8a and R18 also reduced neuronal glutamic acid-induced calcium influx. These findings further highlight the neuroprotective properties of arginine-rich peptides and support the view that they represent a new class of neuroprotective agent.

The prognosis in acute spontaneous intracerebral hemorrhage (ICH) is related to hematoma volume, where30 mL is commonly used to define large ICH as a threshold for neurosurgical decompression but without clear supporting evidence.To determine the factors associated with large ICH and neurosurgical intervention among participants of the Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trials (INTERACT).We performed pooled analysis of the pilot INTERACT1 (n = 404) and main INTERACT2 (n = 2839) studies of ICH patients (6 h of onset) with elevated systolic blood pressure (SBP, 150-220 mm Hg) who were randomized to intensive (target SBP140 mm Hg) or contemporaneous guideline-recommended (target SBP180 mm Hg) management. Neurosurgical intervention data were collected at 7 d postrandomization. Multivariable logistic regression was used to determine associations.There were 372 (13%) patients with large ICH volume (30 mL), which was associated with nonresiding in China, nondiabetic status, severe neurological deficit (National Institutes of Health stroke scale [NIHSS] score ≥ 15), lobar location, intraventricular hemorrhage extension, raised leucocyte count, and hyponatremia. Significant predictors of those patients who underwent surgery (226 of 3233 patients overall; 83 of 372 patients with large ICH) were younger age, severe neurological deficit (lower Glasgow coma scale score, and NIHSS score ≥ 15), baseline ICH volume30 mL, and intraventricular hemorrhage.Early identification of severe ICH, based on age and clinical and imaging parameters, may facilitate neurosurgery and intensive monitoring of patients.