Explore the vast range of titles available.

CTX0E03 is an immortalised human neural stem-cell line from which a drug product (CTX-DP) was developed for allogeneic therapy. Dose-dependent improvement in sensorimotor function in rats implanted with CTX-DP 4 weeks after middle cerebral artery occlusion stroke prompted investigation of the safety and tolerability of this treatment in stroke patients. We did an open-label, single-site, dose-escalation study. Men aged 60 years or older with stable disability (National Institutes of Health Stroke Scale [NIHSS] score ≥6 and modified Rankin Scale score 2–4) 6–60 months after ischaemic stroke were implanted with single doses of 2 million, 5 million, 10 million, or 20 million cells by stereotactic ipsilateral putamen injection. Clinical and brain imaging data were collected over 2 years. The primary endpoint was safety (adverse events and neurological change). This trial is registered with ClinicalTrials.gov, number NCT01151124. 13 men were recruited between September, 2010, and January, 2013, of whom 11 (mean age 69 years, range 60–82) received CTX-DP. Median NIHSS score before implantation was 7 (IQR 6–8) and the mean time from stroke was 29 (SD 14) months. Three men had subcortical infarcts only and seven had right-hemisphere infarcts. No immunological or cell-related adverse events were seen. Other adverse events were related to the procedure or comorbidities. Hyperintensity around the injection tracts on T2-weighted fluid-attenuation inversion recovery MRI was seen in five patients. At 2 years, improvement in NIHSS score ranged from 0 to 5 (median 2) points. Single intracerebral doses of CTX-DP up to 20 million cells induced no adverse events and were associated with improved neurological function. Our observations support further investigation of CTX-DP in stroke patients. ReNeuron Limited.

BackgroundHuman neural stem cell implantation may offer improved recovery from stroke. We investigated the feasibility of intracerebral implantation of the allogeneic human neural stem cell line CTX0E03 in the subacute—chronic recovery phase of stroke and potential measures of therapeutic response in a multicentre study.MethodsWe undertook a prospective, multicentre, single-arm, open-label study in adults aged >40 years with significant upper limb motor deficits 2–13 months after ischaemic stroke. 20 million cells were implanted by stereotaxic injection to the putamen ipsilateral to the cerebral infarct. The primary outcome was improvement by 2 or more points on the Action Research Arm Test (ARAT) subtest 2 at 3 months after implantation.FindingsTwenty-three patients underwent cell implantation at eight UK hospitals a median of 7 months after stroke. One of 23 participants improved by the prespecified ARAT subtest level at 3 months, and three participants at 6 and 12 months. Improvement in ARAT was seen only in those with residual upper limb movement at baseline. Transient procedural adverse effects were seen, but no cell-related adverse events occurred up to 12 months of follow-up. Two deaths were unrelated to trial procedures.InterpretationAdministration of human neural stem cells by intracerebral implantation is feasible in a multicentre study. Improvements in upper limb function occurred at 3, 6 and 12 months, but not in those with absent upper limb movement at baseline, suggesting a possible target population for future controlled trials.FundingReNeuron, Innovate UK (application no 32074-222145).Trial registration numberEudraCT Number: 2012-003482-18

In most countries, alteplase given within 4·5 h of onset is the only approved medical treatment for acute ischaemic stroke. The newer thrombolytic drug tenecteplase has been investigated in one randomised trial up to 3 h after stroke and in another trial up to 6 h after stroke in patients selected by advanced neuroimaging. In the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST), we aimed to assess the efficacy and safety of tenecteplase versus alteplase within 4·5 h of stroke onset in a population not selected on the basis of advanced neuroimaging, and to use imaging biomarkers to inform the design of a definitive phase 3 clinical trial. In this single-centre, phase 2, prospective, randomised, open-label, blinded end-point evaluation study, adults with supratentorial ischaemic stroke eligible for intravenous thrombolysis within 4·5 h of onset were recruited from The Institute of Neurological Sciences, Glasgow, Scotland. Patients were randomly assigned (1:1) to receive tenecteplase 0·25 mg/kg (maximum 25 mg) or alteplase 0·9 mg/kg (maximum 90 mg). Treatment allocation used a mixed randomisation and minimisation algorithm including age and National Institutes of Health Stroke Scale score, generated by an independent statistician. Patients were not informed of treatment allocation; treating clinicians were aware of allocation but those assessing the primary outcome were not. Imaging comprised baseline CT, CT perfusion, and CT angiography; and CT plus CT angiography at 24–48 h. The primary endpoint was percentage of penumbra salvaged (CT perfusion-defined penumbra volume at baseline minus CT infarct volume at 24–48 h). Analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT01472926. Between Jan 1, 2012, and Sept 7, 2013, 355 patients were screened, of whom 157 were eligible for intravenous thrombolysis, and 104 patients were enrolled. 52 were assigned to the alteplase group and 52 to tenecteplase. Of 71 patients (35 assigned tenecteplase and 36 assigned alteplase) contributing to the primary endpoint, no significant differences were noted for percentage of penumbral salvaged (68% [SD 28] for the tenecteplase group vs 68% [23] for the alteplase group; mean difference 1·3% [95% CI −9·6 to 12·1]; p=0·81). Neither incidence of symptomatic intracerebral haemorrhage (by SITS-MOST definition, 1/52 [2%] tenecteplase vs 2/51 [4%] alteplase, p=0·55; by ECASS II definition, 3/52 [6%] vs 4/51 [8%], p=0·59) nor total intracerebral haemorrhage events (8/52 [15%] vs 14/51 [29%], p=0·091) differed significantly. The incidence of serious adverse events did not differ between groups (32 in the tenecteplase group, three considered probably or definitely related to drug treatment; 16 in the alteplase group, five were considered drug-related). Neurological and radiological outcomes did not differ between the tenecteplase and alteplase groups. Evaluation of tenecteplase in larger trials of patients with acute stroke seems warranted. The Stroke Association.

Acute ischaemic stroke is a major public health priority and will become increasingly relevant to neurologists of the future. The cornerstone of effective stroke care continues to be timely reperfusion treatment. This requires early recognition of symptoms by the public and first responders, triage to an appropriate stroke centre and efficient assessment and investigation by the attending stroke team. The aim of treatment is to achieve recanalisation and reperfusion of the ischaemic penumbra with intravenous thrombolysis and/or endovascular thrombectomy in appropriately selected patients. All patients should be admitted directly to an acute stroke unit for close monitoring for early neurological deterioration and prevention of secondary complications. Prompt investigation of the mechanism of stroke allows patients to start appropriate secondary preventative treatment. Future objectives include improving accessibility to endovascular thrombectomy, using advanced imaging to extend therapeutic windows and developing neuroprotective agents to prevent secondary neuronal damage.

Among patients with stroke of unknown onset, thrombolytic treatment is withheld. In this randomized trial, such patients who had evidence of infarction on MRI but no FLAIR signal had a significantly better functional outcome with alteplase than with placebo.

With fewer than 2000 patients in all completed thrombectomy trials, few subgroup analyses will have statistical validity, so many questions will probably remain unanswered. Because it seems unlikely that randomisation to best medical therapy alone within the first 6 h after stroke onset will be feasible in any future trial, the current dataset might be all of the randomised data that we will ever have, and questions around generalisability could persist--a situation reminiscent of that after the first positive trials of intravenous thrombolysis for stroke 20 years ago.

Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography. In a systematic review of OVID MEDLINE—with additional hand-searching of relevant studies' bibliographies— from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5–24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known. Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56–76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36–0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46–11·60; p<0·0001), antiplatelet use (1·68, 1·06–2·66; p=0·026), and anticoagulant use (3·48, 1·96–6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75–0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95–6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03–0·07). In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials. UK Medical Research Council and British Heart Foundation.

The likelihood of disability-free recovery after acute ischemic stroke is significantly improved by reperfusion either by intravenous thrombolytic drug treatment or with endovascular mechanical thrombectomy in selected cases. The use of intravenous thrombolysis is limited by the short treatment window and you need to assess individual balance of benefit and risk of symptomatic intracranial haemorrhage. Benefit is greater for shorter onset-to-reperfusion time intervals, requiring optimisation of pre-hospital and in-hospital pathways. Symptomatic haemorrhage is more likely with more severe strokes, but a greater proportion of patients are left free of disability than suffer a treatment-related haemorrhage at all levels of severity. Extracranial haemorrhage and orolingual angioedema are less common complications. Endovascular mechanical thrombectomy can be used in selected patients with imaging-proven large artery occlusion. Successful therapy depends on well-organised services that can deliver treatment within a short time window at centres with adequate expertise to perform the procedure.