Safety and outcomes of different endovascular treatment techniques for anterior circulation ischaemic stroke in the elderly: data from the Imperial College Thrombectomy Registry.

BACKGROUND: Although previous studies investigated the main predictors of outcomes after endovascular thrombectomy (EVT) in patients aged 80 years and older, less is known about the impact of the procedural features on outcomes in elderly patients. The aim of this study was to investigate the influence of EVT technical procedures on the main 3-month outcomes in a population of patients aged 80 years and older. METHODS: This observational, prospective, single-centre study included consecutive patients with acute LVO ischaemic stroke of the anterior circulation. The study outcomes were functional independence at 3 months after EVT (defined as a mRS score of 0-2), successful reperfusion (mTICI ≥ 2b), incidence of haeamorrhagic transformation, and 90-day all cause of mortality. RESULTS: Our cohort included 497 patients with acute ischaemic stroke due to LVO treated with EVT. Among them, 105 (21.1%) patients were aged ≥ 80 years. In the elderly group, multivariable regression analysis showed that thromboaspiration technique vs stent-retriever was the single independent predictor of favourable post-procedural TICI score (OR = 7.65, 95%CI = 2.22-26.32, p = 0.001). CONCLUSIONS: Our study suggests that EVT for LVO stroke in the elderly could be safe. The use of thromboaspiration was associated with positive reperfusion outcome in this population. Further studies in larger series are warranted to confirm the present results and to evaluate the safety and efficacy of EVT in the elderly and oldest adults.

Outcomes of mechanical thrombectomy in acute stroke patients with atrial fibrillation detected after stroke versus known atrial fibrillation.

We aim to compare the outcomes in patients with atrial fibrillation detected after stroke (AFDAS) and their counterparts with known AF (KAF) presenting with large vessel occlusion (LVO) treated with mechanical thrombectomy (MT). This observational, prospective study included consecutive patients with acute LVO ischemic stroke of the anterior circulation with AFDAS, KAF and without AF. The primary study outcome was functional independence at 90 days after stroke. The secondary study outcomes were variation of the NIHSS score at 24 h, rate of successful reperfusion, death at 90 days and rate of immediate complications post-procedure. Overall, our cohort included 518 patients with acute ischemic stroke and LVO treated with MT, with 289 (56.8%) without a diagnosis of AF; 107 (21%) with AFDAS; 122 (22.2%) with KAF. There was no significant difference in terms of functional independence at 90 days after stroke between the three groups. Regarding the secondary study outcome, the rate of symptomatic intracranial haemorrhage (sICH) and/or parenchymal hematoma (PH) were significantly higher in the group of patients without AF (respectively, P = 0.030 and < 0.010). Logistic regression analysis showed that the subtypes of AF were not statistically significantly associated with functional independence at 90 days after stroke and with the likelihood of any ICH. Our results suggest that the subtypes of AF are not associated with clinical and safety outcomes of MT in patients with acute stroke and LVO. Further studies are needed to confirm our findings.

Outcomes of mechanical thrombectomy in orally anticoagulated patients with anterior circulation large vessel occlusion: a propensity-matched analysis of the Imperial College Thrombectomy Registry.

BACKGROUND: Mechanical thrombectomy (MT) remains an effective treatment for patients with acute ischemic stroke receiving oral anticoagulation (OAC) and large vessel occlusion (LVO). However, to date, it remains unclear whether MT is safe in patients on treatment with OAC. AIMS: In our study, we performed a propensity-matched analysis to investigate the safety and efficacy of MT in patients with acute ischemic stroke receiving anticoagulants. A propensity score method was used to target the causal inference of the observational study design. METHODS: This observational, prospective, single-centre study included consecutive patients with acute LVO ischemic stroke of the anterior circulation. Demographic, neuro-imaging and clinical data were collected and compared according to the anticoagulation status at baseline, patients on OAC vs those not on OAC. The primary study outcomes were the occurrence of any intracerebral haemorrhage (ICH) and symptomatic ICH. The secondary study outcomes were functional independence at 90 days after stroke (defined as modified Rankin Scale (mRS) scores of 0 through 2), mortality at 3 months and successful reperfusion rate according to the modified treatment in cerebral infarction (mTICI) score. RESULTS: Overall, our cohort included 573 patients with acute ischemic stroke and LVO treated with MT. After propensity score matching, 495 patients were matched (99 OAC group vs 396 no OAC group). There were no differences in terms of clinical characteristics between the two groups, except for the rate of intravenous thrombolysis less frequently given in the OAC group. There was no significant difference in terms of the rate of any ICH and symptomatic ICH between the two groups. With regards to the secondary study outcome, there was no significant difference in terms of the rate of successful recanalization post-procedure and functional independence at 3 months between the two groups. Patients in the OAC group showed a reduced mortality rate at 90 days compared to the patients with no previous use of anticoagulation (20.2% vs 21.2%, p = 0.031). Logistic regression analysis did not reveal a statistically significant influence of the anticoagulation status on the likelihood of any ICH (OR = 0.95, 95% CI = 0.46-1.97, p = 0.900) and symptomatic ICH (OR = 4.87, 95% CI = 0.64-37.1, p = 0.127). Our analysis showed also that pre-admission anticoagulant use was not associated with functional independence at 90 days after stroke (OR = 0.76, 95% CI = 0.39-1.48, p = 0.422) and rate of successful reperfusion (OR = 0.81, 95% CI = 0.38-1.72, p = 0.582). CONCLUSION: According to our findings anticoagulation status at baseline did not raise any suggestion of safety and efficacy concerns when MT treatment is provided according to the standard guidelines. Confirmation of these results in larger controlled prospective cohorts is necessary.

Endovascular Thrombectomy with or without Intravenous Thrombolysis for Anterior Circulation Large Vessel Occlusion in the Imperial College London Thrombectomy Registry.

Background and purpose. Mechanical thrombectomy (MT) is the standard of care for eligible patients with a large vessel occlusion (LVO) acute ischemic stroke. Among patients undergoing MT there has been uncertainty regarding the role of intravenous thrombolysis (IVT) and previous trials have yielded conflicting results regarding clinical outcomes. We aim to investigate clinical, reperfusion outcomes and safety of MT with or without IVT for ischemic stroke due to anterior circulation LVO. Materials and Methods. This observational, prospective, single-centre study included consecutive patients with acute LVO ischemic stroke of the anterior circulation. The primary outcomes were the rate of in-hospital mortality, symptomatic intracranial haemorrhage and functional independence (mRS 0-2 at 90 days). Results. We enrolled a total of 577 consecutive patients: 161 (27.9%) were treated with MT alone while 416 (72.1%) underwent IVT and MT. Patients with MT who were treated with IVT had lower rates of in-hospital mortality (p = 0.037), higher TICI reperfusion grades (p = 0.007), similar rates of symptomatic intracranial haemorrhage (p = 0.317) and a higher percentage of functional independence mRS (0-2) at 90 days (p = 0.022). Bridging IVT with MT compared to MT alone was independently associated with a favorable post-intervention TICI score (>2b) (OR, 1.716; 95% CI, 1.076-2.735, p = 0.023). Conclusions. Our findings suggest that combined treatment with MT and IVT is safe and results in increased reperfusion rates as compared to MT alone.

Mechanical thrombectomy in acute basilar artery stroke: a systematic review and Meta-analysis of randomized controlled trials.

BACKGROUND: The evidence for mechanical thrombectomy in acute basilar artery occlusion has until now remained inconclusive with basilar artery strokes associated with high rates of death and disability. This systematic review and meta-analysis will summarize the available evidence for the effectiveness of mechanical thrombectomy in acute basilar artery occlusion compared to best medical therapy. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials using Embase, Medline and the Cochrane Central Register of Controlled Trials (CENTRAL). We calculated risk ratios (RRs) and 95% confidence intervals (CIs) to summarize the effect estimates for each outcome. RESULTS: We performed a random effects (Mantel-Haenszel) meta-analysis of the four included randomized controlled trials comprising a total of 988 participants. We found a statistically significant improvement in the rates of those with a good functional outcome (mRS 0-3, RR 1.54, 1.16-2.06, p = 0.003) and functional independence (mRS 0-2, RR 1.69, 1.05-2.71, p = 0.03) in those who were treated with thrombectomy when compared to best medical therapy alone. Thrombectomy was associated with a higher level of sICH (RR 7.12, 2.16-23.54, p = 0.001) but this was not reflected in a higher mortality rate, conversely the mortality rate was significantly lower in the intervention group (RR 0.76, 0.65-0.89, p = 0.0004). CONCLUSIONS: Our meta-analysis of the recently presented randomized controlled studies is the first to confirm the disability and mortality benefit of mechanical thrombectomy in basilar artery stroke.

Atrial fibrillation detection using a automated electrocardiographic monitoring in a transient ischaemic attack service.

BACKGROUND: The vast majority of the transient ischaemic attacks (TIA) services in UK reported significant delays in the initiation of the routine cardiac monitoring that may result in a significant number of missed atrial fibrillation (AF) paroxysms and increased long-term risk of recurrent stroke. Automated continuous ECG monitoring (ACEM) system has shown promising results in terms of AF detection but it is unclear if ACEM improves AF detection in a rapid outpatient TIA service. OBJECTIVES: We assessed ACEM in patients with TIA with the aim to significantly reduce the delay to initiate the cardiac monitoring and to enhance the yield of AF detection in these patients. We also aimed to determine the impact of a more rapid initiation of ACEM on the 6-month risk of recurrent stroke/TIA. METHODS: This is an observational, prospective before (phase 1: 1 July to 31 December 2018) versus after (phase 2: 1 January to 30 June 2019) study of the effect of ACEM, compared with routine initiation of 24h-Holter ECG, in patients with TIA assessed in our service. RESULTS: The phase 1 (n=136) and phase 2 (n=105) cohorts did not differ with regards to age, risk factors, duration of cardiac monitoring. The rate of newly detected AF was significantly higher in phase 2 compared with phase 1 (9.52% vs 2.21%, p<0.001). The 6-month risk of recurrent stroke/TIA was significantly lower in phase 2 compared with phase 1 (7.4% vs 1%, p=0.018). CONCLUSIONS: Early initiation of ACEM improves AF detection after TIA in a rapid TIA service and is associated with a reduced risk of recurrent TIA/stroke.

Young-onset stroke complicating ulcerative colitis.

A 16-year-old girl developed a proximal occlusion of the right middle cerebral artery during a flare-up of acute ulcerative colitis. Although mechanical thrombectomy led to successful middle cerebral artery recanalisation, she required an immediate second thrombectomy due to reocclusion of the same arterial segment. She developed a second ischaemic event 7 days later despite intravenous heparin infusion, later switched to low-molecular-weight heparin, and a third event after 3 days despite the addition of aspirin. We discuss stroke risks in people with inflammatory bowel disease and the uncertainties around anticoagulation and antiplatelet regimens in such cases.

Impact of National Lockdown on the Hyperacute Stroke Care and Rapid Transient Ischaemic Attack Outpatient Service in a Comprehensive Tertiary Stroke Centre During the COVID-19 Pandemic.

Background: The COVID-19 pandemic is having major implications for stroke services worldwide. We aimed to study the impact of the national lockdown period during the COVID-19 outbreak on stroke and transient ischemic attack (TIA) care in London, UK. Methods: We retrospectively analyzed data from a quality improvement registry of consecutive patients presenting with acute ischemic stroke and TIA to the Stroke Department, Imperial College Health Care Trust London during the national lockdown period (between March 23rd and 30th June 2020). As controls, we evaluated the clinical reports and stroke quality metrics of patients presenting with stroke or TIA in the same period of 2019. Results: Between March 23rd and 30th June 2020, we documented a fall in the number of stroke admissions by 31.33% and of TIA outpatient referrals by 24.44% compared to the same period in 2019. During the lockdown, we observed a significant increase in symptom onset-to-door time in patients presenting with stroke (median = 240 vs. 160 min, p = 0.020) and TIA (median = 3 vs. 0 days, p = 0.002) and a significant reduction in the total number of patients thrombolysed [27 (11.49%) vs. 46 (16.25%, p = 0.030)]. Patients in the 2020 cohort presented with a lower median pre-stroke mRS (p = 0.015), but an increased NIHSS (p = 0.002). We registered a marked decrease in mimic diagnoses compared to the same period of 2019. Statistically significant differences were found between the COVID and pre-COVID cohorts in the time from onset to door (median 99 vs. 88 min, p = 0.026) and from onset to needle (median 148 vs. 126 min, p = 0.036) for thrombolysis whilst we did not observe any significant delay to reperfusion therapies (door-to-needle and door-to-groin puncture time). Conclusions: National lockdown in the UK due to the COVID-19 pandemic was associated with a significant decrease in acute stroke admission and TIA evaluations at our stroke center. Moreover, a lower proportion of acute stroke patients in the pandemic cohort benefited from reperfusion therapy. Further research is needed to evaluate the long-term effects of the pandemic on stroke care.

Delivering telemedicine consultations for patients with transient ischaemic attack during the COVID-19 pandemic in a comprehensive tertiary stroke centre in the United Kingdom.

BACKGROUND AND PURPOSE: The global COVID-19 pandemic led many stroke centres worldwide to shift from in-person to telemedicine consultations to assess patients with transient ischaemic attacks (TIAs). We aimed to investigate the impact of telemedicine during the COVID-19 pandemic on the management and outcome of the patients with TIA. METHODS: We retrospectively analysed data from a registry of consecutive TIA patients assessed at the Stroke Department, Imperial College Health Care Trust, London, during the national lockdown period (between March 23 2020 and 30 June 2020). As controls, we evaluated the clinical reports and stroke quality metrics of patients presenting to the TIA clinic in the same period of 2019. RESULTS: Between 23 March 2020 and 30 June 2020, 136 patients were assessed using the telemedicine TIA clinic, compared to 180 patients evaluated with face-to-face consultation in the same period in 2019. Patients' characteristics were similar in both groups. At 3 months after the TIA, there were no significant differences in the proportion of patients admitted to the hospital for recurrent TIA/stroke or any other cardiovascular cause from the 2020 period compared to the same period in 2019. CONCLUSIONS: Our analysis showed that during the pandemic, our telemedicine consultations of TIA patients were not associated with an increased 3-month rate of recurrent TIA/stroke or cardiovascular hospital admissions. More robust studies looking at this model of care will be needed to assess its long-term effects on patients and health care systems.

Impact of COVID-19 Pandemic on a Regional Stroke Thrombectomy Service in the United Kingdom.

INTRODUCTION: We examined the impact of the coronavirus disease 2019 (COVID-19) pandemic on our regional stroke thrombectomy service in the UK. METHODS: This was a single-center health service evaluation. We began testing for COVID-19 on 3 March and introduced a modified "COVID Stroke Thrombectomy Pathway" on 18 March. We analyzed the clinical, procedural and outcome data for 61 consecutive stroke thrombectomy patients between 1 January and 30 April. We compared the data for January and February ("pre-COVID," n = 33) versus March and April ("during COVID," n = 28). RESULTS: Patient demographics were similar between the 2 groups (mean age 71 ± 12.8 years, 39% female). During the COVID-19 pandemic, (a) total stroke admissions fell by 17% but the thrombectomy rate was maintained at 20% of ischemic strokes; (b) successful recanalization rate was maintained at 81%; (c) early neurological outcomes (neurological improvement following thrombectomy and inpatient mortality) were not significantly different; (d) use of general anesthesia fell significantly from 85 to 32% as intended; and (e) time intervals from onset to arrival, groin puncture, and recanalization were not significantly different, whereas internal delays for external referrals significantly improved for door-to-groin puncture (48 [interquartile range (IQR) 39-57] vs. 33 [IQR 27-44] minutes, p = 0.013) and door-to-recanalization (82.5 [IQR 61-110] vs. 60 [IQR 55-70] minutes, p = 0.018). CONCLUSION: The COVID-19 pandemic has had a negative impact on the stroke admission numbers but not stroke thrombectomy rate, successful recanalization rate, or early neurological outcome. Internal delays actually improved during the COVID-19 pandemic. Further studies should examine the effects of the COVID-19 pandemic on longer term outcome.

Antiplatelet therapy for transient ischaemic attack and minor ischaemic stroke.

Transient ischaemic attacks carry an increased risk of large ischaemic stroke in the 90 days after an event. Patients need to be seen within 24 hours in a dedicated clinic to start secondary prevention. This editorial reviews evidence for consideration of early dual antiplatelet therapy after a transient ischaemic attack.

Comparing mismatch strategies for patients being considered for ischemic stroke tenecteplase trials.

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

Reversible cerebral vasoconstriction syndrome secondary to caffeine withdrawal.

We describe a 39-year-old man who developed thunderclap headaches during a hospital admission for accidental superficial burns. His magnetic resonance brain imaging was normal expect for diffuse segmental vasoconstriction. Prior to admission, he was consuming excessive amounts of caffeine which was restarted and slowly tapered and stopped over weeks. Repeat magnetic resonance angiogram showed resolution of segmental vasoconstriction. The implications of prescribed and non-prescribed drugs on cerebral vasculature have been discussed.

Tenecteplase in ischemic stroke offers improved recanalization: Analysis of 2 trials.

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

The Impact of CT Perfusion Threshold on Predicted Viable and Nonviable Tissue Volumes in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Perfusion imaging is used for patient selection in clinical practice and trials. Postprocessing and definitions of tissue viability are nevertheless not standardized. We compared the lesion volumes generated with two well-recognized perfusion tissue definitions in a single-center phase 2 thrombolysis study. METHODS: We analyzed perfusion imaging data from the Alteplase-Tenecteplase Trial Evaluation for Stroke Thrombolysis (ATTEST) study using two popular tissue viability thresholds (ischemic core definition: (1) cerebral blood volume < 2.0 mL/100 g-1 or (2) relative cerebral blood flow < 40% that of the contralesional hemisphere and relative delay time >2 seconds; penumbra definitions: (1) mean transit time > 145% of contralesional hemisphere or (2) relative delay time < 2 seconds). We compared volumes of core and penumbra, mismatch ratio, percentage, and volume of penumbra salvaged at 24 hours. RESULTS: We included 73 (tenecteplase = 36, alteplase = 37) patients who had analyzable perfusion lesions at baseline. Significant differences were found in core volumes using the two thresholds (33 ± 37 mL vs. 26 ± 32 mL, P < .001), as was mismatch ratio (2.5 ± .9 vs. 4.2 ± 3.7, P < 0.001). The volume of penumbra salvaged at 24 hours (30 ± 19 mL vs. 35 ± 26 mL, P = .043) differed significantly, although the percentages of penumbra salvaged did not (P = .2). No difference was found between the two thrombolytic agents in the percentages of penumbra salvaged using either threshold. CONCLUSION: Two commonly used tissue definitions generated significantly different lesion volumes and mismatch ratios. Threshold selection may have significant impact on patient selection for trials or reperfusion therapies.

Impact of Computed Tomography Perfusion Imaging on the Response to Tenecteplase in Ischemic Stroke: Analysis of 2 Randomized Controlled Trials.

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

Human neural stem cells in patients with chronic ischaemic stroke (PISCES): a phase 1, first-in-man study.

BACKGROUND: 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. METHODS: 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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: ReNeuron Limited.