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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.

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.

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.

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.

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.

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.

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.

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.

Why the US Center for Medicare and Medicaid Services Should Not Extend Reimbursement Indications for Carotid Artery Angioplasty/Stenting

Contains fulltext : 167926.PDF (Publisher’s version ) (Open Access) BACKGROUND: Rates of acute intracerebral hemorrhage (ICH) increase in winter months but the magnitude of risk is unknown. We aimed to quantify the association of ambient temperature with the risk of ICH in the Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT2) participants on an hourly timescale. METHODS: INTERACT2 was an international, open, blinded endpoint, randomized controlled trial of patients with spontaneous ICH (

Background: This study aimed at identifying the determinants and prognostic significance of a sedimentation level (fluid-blood level) in the hematoma among patients with acute intracerebral hemorrhage (ICH) who participated in the main Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Methods: Post-hoc analysis of the INTERACT2 dataset, a randomized controlled trial of patients with acute ICH with elevated systolic blood pressure (SBP), randomly assigned to intensive (target SBP Results: Of 2,065 participants, 19 (1%) had sedimentation level on baseline CT, which was independently associated with warfarin use (p = 0.006) and lobar ICH (p = 0.025). Sedimentation level was also associated with death or major disability at 90-day in both crude (84 vs. 53%; p = 0.014) and multivariable analyses adjusted for age, gender, Chinese region, warfarin use, baseline National Institutes of Health Stroke Scale score, onset to CT time, volume and location of ICH, intraventricular extension, and randomized intensive BP lowering (OR 3.94, 95% CI 1.01-15.37; p = 0.049). Conclusions: The presence of hematoma sedimentation level on baseline CT is associated with warfarin use and lobar location of ICH, and predicts a worse outcome. Although uncommon, sedimentation level is an easily detectable prognostic factor in acute ICH.

Lacunar infarction accounts for approximately one quarter of all ischemic strokes but can be difficult to diagnose on noncontrast CT and clinical grounds.1 Diffusion-weighted imaging MRI has traditionally been considered the optimal modality for imaging confirmation1 but can be difficult to obtain acutely. CT perfusion has been increasingly used in hyperacute stroke and has shown promise in improving detection of lacunar infarcts.2 We present 4 patients in whom CT perfusion was performed using a 320-slice scanner (Aquilion ONE Vision, Toshiba, Japan) and Ultravist 370 (iopromide, Bayer, Switzerland) injected at 4 mL/s for 50 mL. Multiplanar reconstruction of perfusion data was performed using commercially available software (Vitrea 6.6.2036.1, Vital Images, Minnetonka, MN). Time from stroke onset to CT perfusion is presented in the table.

Intracerebral hemorrhage (ICH) remains a common and deadly form of stroke, with virtually no greatly effective treatments aside from supportive and stroke unit care. Several surgical and medical therapies have been studied, but nothing has yet been found that greatly changes the pathophysiology. To achieve this, there will need to be substantial changes in treatment strategies. This article will focus on refinements to existing strategies and consider new approaches to the management of ICH. It will draw parallels with ischemic stroke treatments, and define the idea of ‘interventional therapy’ for ICH. It is suggested that reducing hematoma expansion could be compared with salvage of the ischemic penumbra, as a potential target for interventional ICH treatments. The concept of different time windows for the application of therapies according to the pathophysiology will be discussed. Finally, some novel treatment strategies are proposed, including an endovascular approach and ‘external, stereotactic cautery’, as future possibilities.

Background: Conflicting data exist of an association between off-hour (weekend, holiday, or night-time) hospital admission and adverse outcome in intracerebral hemorrhage (ICH). We determined the association between off-hour admissions and poor clinical outcome, and of any differential effect of early intensive blood pressure (BP) lowering treatment between off- and on-hour admissions, among participants of the Intensive BP Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Methods: Subsidiary analysis of INTERACT2, a multinational, multicenter, clinical trial of patients with spontaneous ICH with elevated systolic BP, randomly assigned to intensive (target systolic BP Results: Of 2,794 patients with information on the primary outcome, 1,770 (63%) were admitted to study centers during off-hours. Off-hour admission was not associated with risk of poor outcome at 90 days (53% off-hour vs. 55% on-hour; p = 0.49), even after adjustment for comorbid risk factors (odds ratio 0.92; 95% CI 0.76-1.12). Consistency exists in the effects of intensive BP lowering between off- and on-hour admission (p = 0.85 for homogeneity). Conclusions: Off-hour admission was not associated with increased risks of death or major disability among trial protocol participants with acute ICH. Intensive BP lowering can provide similar treatment effect irrespective of admission hours.

The distribution of some cholecystokinin (CCK) systems in the rat brain is reviewed focusing on mesencephalic dopamine neurones which coexpress CCK and, in particular, on cortico-striatal CCK neurones which probably have glutamate as their co-transmitter. Functional studies based on the effect of several CCKB antagonists on phencyclidine-induced motility suggest that CCK is involved in locomotor behaviour causing inhibition in phencyclidine-treated habituated rats. In contrast, in unhabituated rats CCK stimulates exploratory behaviour. These effects may be related to the cortico-striatal CCK/glutamatergic pathway. Moreover, these studies provide evidence for endogenous release of a neuropeptide with behavioural consequences.

Background and Purpose— Severe atherosclerosis in the aortic arch is associated with a high risk of recurrent vascular events, but the optimal antithrombotic strategy is unclear. Methods— This prospective randomized controlled, open-labeled trial, with blinded end point evaluation (PROBE design) tested superiority of aspirin 75 to 150 mg/d plus clopidogrel 75 mg/d (A+C) over warfarin therapy (international normalized ratio 2–3) in patients with ischemic stroke, transient ischemic attack, or peripheral embolism with plaque in the thoracic aorta >4 mm and no other identified embolic source. The primary end point included cerebral infarction, myocardial infarction, peripheral embolism, vascular death, or intracranial hemorrhage. Follow-up visits occurred at 1 month and then every 4 months post randomization. Results— The trial was stopped after 349 patients were randomized during a period of 8 years and 3 months. After a median follow-up of 3.4 years, the primary end point occurred in 7.6% (13/172) and 11.3% (20/177) of patients on A+C and on warfarin, respectively (log-rank, P =0.2). The adjusted hazard ratio was 0.76 (95% confidence interval, 0.36–1.61; P =0.5). Major hemorrhages including intracranial hemorrhages occurred in 4 and 6 patients in the A+C and warfarin groups, respectively. Vascular deaths occurred in 0 patients in A+C arm compared with 6 (3.4%) patients in the warfarin arm (log-rank, P =0.013). Time in therapeutic range (67% of the time for international normalized ratio 2–3) analysis by tertiles showed no significant differences across groups. Conclusions— Because of lack of power, this trial was inconclusive and results should be taken as hypothesis generating. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00235248.

Liberal proceduralism and religious orthodoxy have long battled across a range of controversies in U. S. education policy. An important setting for these controversies has been the promulgation by courts in recent decades of a robust notion of students' rights. A victory for liberal proceduralism, students' rights has in turn contributed greatly to a religious orthodox backlash against public schooling manifest along a number of fronts, such as support for vouchers, home schooling, and other withdrawal initiatives. This article examines the ideological sources of this dynamic and whether liberalism in general is able to meet the resulting challenge to its core ideals.

The very idea of public schooling is currently under sustained challenge from an array of groups with sectarian social, political, religious, and cultural agendas. Some of these challenges come in the form of policy initiatives such as school vouchers, charter schools, "parents' rights" movements, and the rise of home schooling and other forms of nonpublic schooling. In the face of this momentum, the democratic state must continually find ways to balance individual parental and community rights against the public interest. But the state cannot bend over backward to meet every demand and, in particular, those of fanatics, whose agendas include commandeering educational institutions or opting out of "the system" altogether. By providing a conceptual framework for identifying and assessing fanaticism, and then by making the case that in a democracy fanatics should not be allowed to run schools of any kind, this article seeks to establish an outer boundary for what forms of school initiatives ought to be perm...

Why Calls for More Routine Carotid Stenting Are Currently Inappropriate An International, Multispecialty, Expert Review and Position Statement

Objective To report the number of participants needed to recruit per baby born to trial staff during AVERT, a large international trial on acute stroke, and to describe trial management consequences. Design Retrospective observational analysis. Setting 56 acute stroke hospitals in eight countries. Participants 1074 trial physiotherapists, nurses, and other clinicians. Outcome measures Number of babies born during trial recruitment per trial participant recruited. Results With 198 site recruitment years and 2104 patients recruited during AVERT, 120 babies were born to trial staff. Births led to an estimated 10% loss in time to achieve recruitment. Parental leave was linked to six trial site closures. The number of participants needed to recruit per baby born was 17.5 (95% confidence interval 14.7 to 21.0); additional trial costs associated with each birth were estimated at 5736 Australian dollars on average. Conclusion The staff absences registered in AVERT owing to parental leave led to delayed trial recruitment and increased costs, and should be considered by trial investigators when planning research and estimating budgets. However, the celebration of new life became a highlight of the annual AVERT collaborators’ meetings and helped maintain a cohesive collaborative group. Trial registration Australian New Zealand Clinical Trials Registry no 12606000185561. Disclaimer Participation in a rehabilitation trial does not guarantee successful reproductive activity.

Objective To compare systemic arterial inflammation in subjects with recent ischaemic stroke or TIA and controls with prior cerebrovascular disease. Methods Systemic arterial inflammation was prospectively measured by 18 F-fluorodeoxygluose positron emission tomography in 11 cases with recent ischaemic stroke or TIA, and 11 sex matched controls with prior cerebrovascular disease. Results Hot spots (both carotid and non-carotid) of localised 18 FDG uptake were found in more than half of all patients with either recent ( n =6) or prior ( n =8) cerebrovascular disease. There was no significant difference in the total number of hotspots, or hotspots at specific sites, in cases compared with controls. Mean standard uptake values (SUV) were similar in the carotid arteries and aorta of cases and controls, and showed a trend toward higher values in the femoral arteries of the controls (median 1.8; IQR 1.6–2.2) compared to cases (median 1.5; IQR 1.4–1.7). Conclusion Arterial inflammation was common, and appeared similar, in patients with recent stroke/TIA, and controls with stroke/TIA more than two years previously.

To the Editor: We read with interest the systematic review of the validity of the ACBD system by Giles et al,1 a clinically important topic. Pooled validation is an important step toward establishing the use of a clinical prediction rule. Given its potential to influence organization of services and acute management protocols for transient ischemic attack, this analysis deserves careful consideration. The authors conclude that the pooled area under the curve (AUC) of 0.72 is indicative of “good predictive value.” First, the AUC is only a global pretest measure of test performance and not a measure of posttest predictive value that can be applied to an …

Background Acute ischaemic stroke is associated with alteration in systemic markers of vascular function. We measured forearm vascular function (using forearm flow mediated dilatation) to clarify whether recent acute ischaemic stroke/TIA is associated with impaired systemic vascular function. Methods Prospective case control study enrolling 17 patients with recent acute ischaemic stroke/TIA and 17 sex matched controls with stroke more than two years previously. Forearm vascular function was measured using flow medicated dilatation (FMD). Results Flow mediated dilatation was 6.0 ± 1.1% in acute stroke/TIA patients and 4.7 ± 1.0% among control subjects (p = 0.18). The mean paired difference in FMD between subjects with recent acute stroke and controls was 1.25% (95% CI -0.65, 3.14; p = 0.18). Endothelium independent dilatation was measured in six pairs of participants and was similar in acute stroke/TIA patients (22.6 ± 4.3%) and control subjects (19.1 ± 2.6%; p = 0.43). Conclusions Despite the small size of this study, these data indicate that recent acute stroke is not necessarily associated with a clinically important reduction in FMD.

The bottom line Stroke is increasingly common and often fatal or disabling.1 The absence of a definitive diagnostic test for stroke and the potential for emergency interventions to restore brain perfusion,2 improve survival free of handicap, and minimise early recurrent stroke3 mean that doctors need to be able to diagnose acute stroke rapidly and accurately. Stroke is not consistently defined in clinical practice, clinical research, and public health. Traditionally, stroke has been defined clinically by the abrupt onset of symptoms of focal neurological dysfunction that last more than 24 hours (or lead to earlier death) and are caused by acute vascular injury to part of the brain.4 The vascular causes include inadequate blood supply to part of the brain or spinal cord (ischaemic stroke, arterial or venous) and spontaneous haemorrhage into part of the brain (primary intracerebral haemorrhage) or over …