Tenecteplase versus alteplase for thrombolysis in patients selected by use of perfusion imaging within 4·5 h of onset of ischaemic stroke (TASTE): a multicentre, randomised, controlled, phase 3 non-inferiority trial.

BACKGROUND: Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. METHODS: This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0-1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of -0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. FINDINGS: Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63-82), baseline National Institutes of Health Stroke Scale score of 7 (4-11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI -0·033 to 0·10], one-tailed pnon-inferiority=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [-0·02 to 0·12], one-tailed pnon-inferiority=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI -0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI -0·02 to 0·05]). INTERPRETATION: The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. FUNDING: Australian National Health Medical Research Council; Boehringer Ingelheim.

Comparison of Dual Antiplatelet Therapies for Minor, Nondisabling, Acute Ischemic Stroke: A Bayesian Network Meta-Analysis.

Importance: Dual antiplatelet therapy (DAPT) appears to be an effective treatment option for minor (nondisabling) acute ischemic stroke. This conclusion is based on trials that include both transient ischemic attack (TIA) and minor stroke; however, these 2 conditions may differ. Objective: To compare DAPT regimens specifically for minor stroke. Data Sources: PubMed was searched for randomized clinical trials published up to November 4, 2023. Search terms strategy included TIA, transient ischemic attack, minor stroke, or moderate stroke, with the filter randomized controlled trial. Unpublished data on minor stroke were sourced from authors and/or institutions. Study Selection: Trials testing DAPT within the first 24 hours of a minor stroke (defined as a National Institutes of Health Stroke Scale score ≤5) were included by consensus. Of 1508 studies screened, 6 (0.3%) initially met inclusion criteria and were reviewed. Data Extraction and Synthesis: The study was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by multiple observers. Bayesian fixed-effect network meta-analysis was conducted. Secondary analysis performed for high-risk TIA alone. Main Outcomes and Measures: Treatments were ranked using a probability measure called surface under the cumulative rank curve (SUCRA). The primary outcome was subsequent ischemic stroke at 90 days. Secondary outcomes included major hemorrhage, mortality, and hemorrhagic stroke. The number needed to treat (NNT) and number needed to harm (NNH) were obtained. Results: Five trials were included that described 28 148 patients, of whom 22 203 (78.9%) had a minor stroke. Of these, 13 995 (63.0%) were in DAPT groups and 8208 (37.0%) in aspirin (acetylsalicylic acid) groups. Aspirin and ticagrelor had a 94% probability of being the superior treatment for minor stroke (SUCRA, 0.94) for the primary outcome. Both aspirin and ticagrelor (NNT, 40; 95% CI, 31-64) and aspirin and clopidogrel (NNT, 58; 95% CI, 39-136) were superior to aspirin alone in the prevention of recurrent ischemic stroke at 90 days. Both treatments had higher rates of major hemorrhage than aspirin alone (NNH for aspirin and ticagrelor, 284; 95% CI, 108-1715 vs NNH for aspirin and clopidogrel, 330; 95% CI, 118-3430), but neither had increased risk of hemorrhagic stroke or death. For high-risk TIA, ticagrelor and aspirin had a 60% probability (SUCRA, 0.60) and clopidogrel and aspirin had a 40% probability (SUCRA 0.40) of being a superior treatment; neither was optimum, but both were superior to aspirin alone for the primary outcome. Conclusions and Relevance: These findings suggest that DAPT with aspirin and ticagrelor has higher probability of being the superior treatment among patients with minor stroke when presence of CYP2C19 loss-of-function alleles has not been excluded. For patients with TIA, the superiority of aspirin and ticagrelor vs aspirin and clopidogrel was not demonstrated.

Use of the phrase 'pyramidal weakness' within the past 100 years.

The concept of 'pyramidal weakness' denotes that neurological examination findings can be localised to the central nervous system (CNS), and implying a specific pattern of motor weakness involving upper limb extensors and lower limb flexors. However, other weakness patterns have been observed in CNS lesions. We aim to investigate the pattern of weakness observed in CNS lesions and explore the use of the phrase 'pyramidal weakness' over time. We searched Medline, PubMed, and Google Scholar up to January 1st, 2022, using keywords such as 'distal weakness,' 'upper limb flexion,' 'lower limb extension,' 'pyramidal weakness,' and related terms. The inclusion criteria were papers relating to brain or spinal cord lesions and terms inferring their presence or the description of a motor weakness pattern. We identified 117 studies since 1889, of which 29.9% of publications described weakness in upper limb extensors and lower limb flexors, and 26.5% reported distal weakness. We found an early reference to 'pyramidal weakness' in 1922 in the context of unilateral weakness in encephalitis with no description of the upper limb extensor and lower limb flexor pattern. Since 1988, 'pyramidal weakness' has become associated with weakness in upper limb extensors and lower limb flexors. The phrase 'pyramidal weakness', used in its current format, has been more frequent since the 1980s. Distal weakness and upper limb extensor and lower limb flexor weakness have been associated with CNS lesions.

What does cognitive screening reveal about early cognitive performance following endovascular clot retrieval and intravenous thrombolysis in acute ischaemic stroke?

Background Little is known regarding cognitive outcomes following treatment with endovascular clot retrieval (ECR) and intravenous tissue plasminogen activator (t-PA). We aimed to determine if there were any differences on a measure of cognitive screening between patients treated with ECR, t-PA, and those who were managed conservatively. Methods The medical records of ischaemic stroke patients admitted to Monash Medical Centre between January 2019 and December 2019 were retrospectively reviewed. Information extracted from medical records included age, sex, National Institutes of Health Stroke Scale at presentation, location of occlusion, treatment type, medical history, and cognitive screening performance measured by the Montreal Cognitive Assessment (MoCA). Results Eighty-two patients met the inclusion criteria (mean age = 66.5 ± 13.9; 49 male, 33 female). Patients treated with ECR performed significantly better on the MoCA (n = 36, 24.1 ± 4.3) compared to those who were managed conservatively (n = 26, 20.7 ± 5.5). Performance for patients treated with t-PA (n = 20, 23.9 ± 3.5) fell between the ECR and conservative management groups, but they did not significantly differ from either. Conclusion Our retrospective chart review found that ischaemic stroke patients treated with ECR appear to perform better on cognitive screening compared to patients who are managed conservatively. We also found that patients treated with ECR and t-PA appear to have similar cognitive screening performances in the acute stages following ischaemic stroke, although this finding is likely to have been impacted by group differences in stroke characteristics and may reflect the possibility that the ECR group performed better than expected based on their stroke severity.

Tranexamic acid versus placebo in individuals with intracerebral haemorrhage treated within 2 h of symptom onset (STOP-MSU): an international, double-blind, randomised, phase 2 trial.

BACKGROUND: Tranexamic acid, an antifibrinolytic agent, might attenuate haematoma growth after an intracerebral haemorrhage. We aimed to determine whether treatment with intravenous tranexamic acid within 2 h of an intracerebral haemorrhage would reduce haematoma growth compared with placebo. METHODS: STOP-MSU was an investigator-led, double-blind, randomised, phase 2 trial conducted at 24 hospitals and one mobile stroke unit in Australia, Finland, New Zealand, Taiwan, and Viet Nam. Eligible participants had acute spontaneous intracerebral haemorrhage confirmed on non-contrast CT, were aged 18 years or older, and could be treated with the investigational product within 2 h of stroke onset. Using randomly permuted blocks (block size of 4) and a concealed pre-randomised assignment procedure, participants were randomly assigned (1:1) to receive intravenous tranexamic acid (1 g over 10 min followed by 1 g over 8 h) or placebo (saline; matched dosing regimen) commencing within 2 h of symptom onset. Participants, investigators, and treating teams were masked to group assignment. The primary outcome was haematoma growth, defined as either at least 33% relative growth or at least 6 mL absolute growth on CT at 24 h (target range 18-30 h) from the baseline CT. The analysis was conducted within the estimand framework with primary analyses adhering to the intention-to-treat principle. The primary endpoint and secondary safety endpoints (mortality at days 7 and 90 and major thromboembolic events at day 90) were assessed in all participants randomly assigned to treatment groups who did not withdraw consent to use any data. This study was registered with ClinicalTrials.gov, NCT03385928, and the trial is now complete. FINDINGS: Between March 19, 2018, and Feb 27, 2023, 202 participants were recruited, of whom one withdrew consent for any data use. The remaining 201 participants were randomly assigned to either placebo (n=98) or tranexamic acid (n=103; intention-to-treat population). Median age was 66 years (IQR 55-77), and 82 (41%) were female and 119 (59%) were male; no data on race or ethnicity were collected. CT scans at baseline or follow-up were missing or of inadequate quality in three participants (one in the placebo group and two in the tranexamic acid group), and were considered missing at random. Haematoma growth occurred in 37 (38%) of 97 assessable participants in the placebo group and 43 (43%) of 101 assessable participants in the tranexamic acid group (adjusted odds ratio [aOR] 1·31 [95% CI 0·72 to 2·40], p=0·37). Major thromboembolic events occurred in one (1%) of 98 participants in the placebo group and three (3%) of 103 in the tranexamic acid group (risk difference 0·02 [95% CI -0·02 to 0·06]). By 7 days, eight (8%) participants in the placebo group and eight (8%) in the tranexamic acid group had died (aOR 1·08 [95% CI 0·35 to 3·35]) and by 90 days, 15 (15%) participants in the placebo group and 19 (18%) in the tranexamic acid group had died (aOR 1·61 [95% CI 0·65 to 3·98]). INTERPRETATION: Intravenous tranexamic acid did not reduce haematoma growth when administered within 2 h of intracerebral haemorrhage symptom onset. There were no observed effects on other imaging endpoints, functional outcome, or safety. Based on our results, tranexamic acid should not be used routinely in primary intracerebral haemorrhage, although results of ongoing phase 3 trials will add further context to these findings. FUNDING: Australian Government Medical Research Future Fund.

Ninety-Day Stroke Recurrence in Minor Stroke: Systematic Review and Meta-Analysis of Trials and Observational Studies.

BACKGROUND: Risk of recurrence after minor ischemic stroke is usually reported with transient ischemic attack. No previous meta-analysis has focused on minor ischemic stroke alone. The objective was to evaluate the pooled proportion of 90-day stroke recurrence for minor ischemic stroke, defined as a National Institutes of Health Stroke Scale severity score of ≤5. METHODS AND RESULTS: Published papers found on PubMed from 2000 to January 12, 2021, reference lists of relevant articles, and experts in the field were involved in identifying relevant studies. Randomized controlled trials and observational studies describing minor stroke cohort with reported 90-day stroke recurrence were selected by 2 independent reviewers. Altogether 14 of 432 (3.2%) studies met inclusion criteria. Multilevel random-effects meta-analysis was performed. A total of 6 randomized controlled trials and 8 observational studies totaling 45 462 patients were included. The pooled 90-day stroke recurrence was 8.6% (95% CI, 6.5-10.7), reducing by 0.60% (95% CI, 0.09-1.1; P=0.02) with each subsequent year of publication. Recurrence was lowest in dual antiplatelet trial arms (6.3%, 95% CI, 4.5-8.0) when compared with non-dual antiplatelet trial arms (7.2%, 95% CI, 4.7-9.6) and observational studies 10.6% (95% CI, 7.0-14.2). Age, hypertension, diabetes, ischemic heart disease, or known atrial fibrillation had no significant association with outcome. Defining minor stroke with a lower National Institutes of Health Stroke Scale threshold made no difference - score ≤3: 8.6% (95% CI, 6.0-11.1), score ≤4: 8.4% (95% CI, 6.1-10.6), as did excluding studies with n<500%-7.3% (95% CI, 5.5-9.0). CONCLUSIONS: The risk of recurrence after minor ischemic stroke is declining over time but remains important.

Introducing the Concept of Sanctuary Sites in Ischemic Stroke.

BACKGROUND: The topography of arterial territories has been defined using digital maps of supratentorial infarcts. Regions with a high probability of infarction (Pi) exist in the deep compartment due to a paucity of collaterals. However, less attention has been given to regions with a low Pi. METHODS: Using published digital maps, patients with cortical stroke and documented vessel occlusion were included. Infarcts from T2-weighted magnetic resonance images were segmented and registered onto a standard brain template (Montreal Neurological Institute 152). Segmented magnetic resonance images were averaged to yield the Pi at a voxel level. The overall Pi for the combined arterial territories was calculated to ensure that Pi was in the range of 0 to 1. Sanctuary sites were identified as regions with Pi <0.1. RESULTS: There were 154 patients (63% men; median age, 69 years; and interquartile range, 57-78 years). The magnetic resonance imaging scan used for segmentation was performed at a median interval of 35 (interquartile range, 3-66) days after stroke onset. Sanctuary sites were present in the frontal (gyrus rectus, the paracentral lobule, and orbitofrontal and precentral gyrus), parietal (postcentral, supramarginal, and angular gyrus, superior and inferior parietal lobule, and precuneus and posterior cingulate), and occipital cortex (cuneus, middle, and superior occipital gyrus). CONCLUSIONS: We propose that following vessel occlusion, there are cortical regions with a low Pi, which we termed sanctuary sites. The anatomic basis for this observation is the compensatory capacity of leptomeningeal collaterals.

Thrombolysis for Wake-Up Stroke Versus Non-Wake-Up Unwitnessed Stroke: EOS Individual Patient Data Meta-Analysis.

BACKGROUND: Stroke with unknown time of onset can be categorized into 2 groups; wake-up stroke (WUS) and unwitnessed stroke with an onset time unavailable for reasons other than wake-up (non-wake-up unwitnessed stroke, non-WUS). We aimed to assess potential differences in the efficacy and safety of intravenous thrombolysis (IVT) between these subgroups. METHODS: Patients with an unknown-onset stroke were evaluated using individual patient-level data of 2 randomized controlled trials (WAKE-UP [Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke], THAWS [Thrombolysis for Acute Wake-Up and Unclear-Onset Strokes With Alteplase at 0.6 mg/kg]) comparing IVT with placebo or standard treatment from the EOS (Evaluation of Unknown-Onset Stroke Thrombolysis trial) data set. A favorable outcome was prespecified as a modified Rankin Scale score of 0 to 1 at 90 days. Safety outcomes included symptomatic intracranial hemorrhage at 22 to 36 hours and 90-day mortality. The IVT effect was compared between the treatment groups in the WUS and non-WUS with multivariable logistic regression analysis. RESULTS: Six hundred thirty-four patients from 2 trials were analyzed; 542 had WUS (191 women, 272 receiving alteplase), and 92 had non-WUS (42 women, 43 receiving alteplase). Overall, no significant interaction was noted between the mode of onset and treatment effect (P value for interaction=0.796). In patients with WUS, the frequencies of favorable outcomes were 54.8% and 45.5% in the IVT and control groups, respectively (adjusted odds ratio, 1.47 [95% CI, 1.01-2.16]). Death occurred in 4.0% and 1.9%, respectively (P=0.162), and symptomatic intracranial hemorrhage in 1.8% and 0.3%, respectively (P=0.194). In patients with non-WUS, no significant difference was observed in favorable outcomes relative to the control (37.2% versus 29.2%; adjusted odds ratio, 1.76 [0.58-5.37]). One death and one symptomatic intracranial hemorrhage were reported in the IVT group, but none in the control. CONCLUSIONS: There was no difference in the effect of IVT between patients with WUS and non-WUS. IVT showed a significant benefit in patients with WUS, while there was insufficient statistical power to detect a substantial benefit in the non-WUS subgroup. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: CRD42020166903.

Asymptomatic coronary artery disease in ischaemic stroke survivors: A systematic review and meta-analysis.

BACKGROUND: Ischaemic stroke and coronary artery disease share risk factors and stroke survivors experience a high rate of cardiac events. Recent work suggests a high burden of asymptomatic coronary artery disease (CAD) in ischaemic stroke survivors. Thus, we performed this systematic review and meta-analysis to A) estimate the prevalence of CAD in ischaemic stroke survivors without known CAD and B) evaluate the association between coronary atherosclerosis and future major adverse cardiovascular events (MACE) in stroke survivors. PATIENTS AND METHODS: We conducted a systematic review and meta-analysis according to the PRISMA statement. We included studies investigating acute ischaemic stroke or transient ischaemic attack where participants underwent anatomical assessment of all coronary arteries. For objective B) we included studies that reported an association between coronary atherosclerosis and MACE. Two reviewers used the Newcastle-Ottawa Scale to assess risk of bias. We used random-effects modelling for our analyses. RESULTS: We identified 2983 studies of which 17 were included. These studies had a total of 6862 participants between 2008 and 2022. The pooled prevalence of any coronary atherosclerosis was 66.8% (95% CI 57.2%-75.1%) with substantial heterogeneity (I2 = 95.2%). The pooled prevalence of obstructive (>50%) stenosis was 29.3% with substantial heterogeneity (I2 = 91%). High-risk coronary anatomy (triple vessel disease or left main stenosis) was found in 7.0% (95% CI 4%-12%) with high heterogeneity I2 = 72%. One study examined high-risk plaques and found a prevalence of 5.9%. Five studies reported the association of coronary atherosclerosis with future MACE. The presence of obstructive CAD confers a HR of 8.0 (95% CI 1.7-37.1, p = 0.007) for future MACE. DISCUSSION AND CONCLUSIONS: Asymptomatic CAD is common in ischaemic stroke survivors. The presence and severity of asymptomatic CAD strongly associates with the risk of future MACE. Further evaluation of the benefits of routine coronary assessment in ischaemic stroke is warranted.

Estimating the cost of visiting hospital outpatient.

Objectives: This study aims to investigate the cost incurred by people travelling to the neurology outpatient clinic of a large metropolitan hospital. As outpatients are a substantial portion of a hospital's demographic, we aimed to understand the patient experience of various commuters. Methods: We conducted an observational study collecting demographic details and travel information for how people attended the neurology clinic of Monash Medical Centre. Statistical analysis was performed using R. 165 participants were randomly selected and interviewed in-person. Data were collected via an anonymous questionnaire. The study was approved by the Monash Health Human Ethics Research Committee. Results: 155 responses were included in the analysis. Patients paid an average of $A16.64 to travel to Monash Medical Centre. Drivers paid on average $A16.70 and those taking public transport paid on average $A9.64, with the maximum cost overall being $A120.00. For patients driving to hospital, parking accounted for 60% of their travel costs. The average to Monash Medical centre was 20.82 km with the maximum being 190.88 km. Distance from hospital was correlated with a higher cost of travel (p<0.001, Spearman's rank correlation coefficient=0.48). There was also an inverse association between distance from hospital and socioeconomic status (p<0.001, Spearman's rank correlation coefficient=-0.26). Conclusion: Travelling to hospital can be a costly endeavour. Driving is the most popular form of transport, but a large portion of the cost involved is hospital parking. Further research should be conducted at other tertiary centres with larger samples.

Rapid outpatient transient ischemic attack clinic and stroke service activity during the SARS-CoV-2 pandemic: a multicenter time series analysis.

Background and aim: Rapid outpatient evaluation and treatment of TIA in structured clinics have been shown to reduce stroke recurrence. It is unclear whether short-term downtrends in TIA incidence and admissions have had enduring impact on TIA clinic activity. This study aims to measure the impact of the pandemic on hospitals with rapid TIA clinics. Methods: Relevant services were identified by literature search and contacted. Three years of monthly data were requested - a baseline pre-COVID period (April 2018 to March 2020) and an intra-COVID period (April 2020 to March 2021). TIA presentations, ischemic stroke presentations, and reperfusion trends inclusive of IV thrombolysis (IVT) and endovascular thrombectomy (EVT) were recorded. Pandemic impact was measured with interrupted time series analysis, a segmented regression approach to test an effect of an intervention on a time-dependent outcome using a defined impact model. Results: Six centers provided data for a total of 6,231 TIA and 13,191 ischemic stroke presentations from Australia (52.1%), Canada (35.0%), Italy (7.6%), and England (5.4%). TIA clinic volumes remained constant during the pandemic (2.9, 95% CI -1.8 to 7.6, p = 0.24), as did ischemic stroke (2.9, 95% CI -7.8 to 1.9, p = 0.25), IVT (-14.3, 95% CI -36.7, 6.1, p < 0.01), and EVT (0, 95% CI -16.9 to 16.9, p = 0.98) counts. Proportion of ischemic strokes requiring IVT decreased from 13.2 to 11.4% (p < 0.05), but those requiring EVT did not change (16.0 to 16.7%, p = 0.33). Conclusion: This suggests that the pandemic has not had an enduring effect on TIA clinic or stroke service activity for these centers. Furthermore, the disproportionate decrease in IVT suggests that patients may be presenting outside the IVT window during the pandemic - delays in seeking treatment in this group could be the target for public health intervention.

Assessing the diagnostic accuracy of CT perfusion: a systematic review.

Background and purpose: Computed tomography perfusion (CTP) has successfully extended the time window for reperfusion therapies in ischemic stroke. However, the published perfusion parameters and thresholds vary between studies. Using Preferred Reporting Items for Systematic Reviews and Meta-Analyses of Diagnostic Test Accuracy Studies (PRISMA-DTA) guidelines, we conducted a systematic review to investigate the accuracy of parameters and thresholds for identifying core and penumbra in adult stroke patients. Methods: We searched Medline, Embase, the Cochrane Library, and reference lists of manuscripts up to April 2022 using the following terms "computed tomography perfusion," "stroke," "infarct," and "penumbra." Studies were included if they reported perfusion thresholds and undertook co-registration of CTP to reference standards. The quality of studies was assessed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool and Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. Results: A total of 24 studies were included. A meta-analysis could not be performed due to insufficient data and significant heterogeneity in the study design. When reported, the mean age was 70.2 years (SD+/-3.69), and the median NIHSS on admission was 15 (IQR 13-17). The perfusion parameter identified for the core was relative cerebral blood flow (rCBF), with a median threshold of <30% (IQR 30, 40%). However, later studies reported lower thresholds in the early time window with rapid reperfusion (median 25%, IQR 20, 30%). A total of 15 studies defined a single threshold for all brain regions irrespective of collaterals and the gray and white matter. Conclusion: A single threshold and parameter may not always accurately differentiate penumbra from core and oligemia. Further refinement of parameters is needed in the current era of reperfusion therapy.

Corrigendum: Phase I trial outcome of amnion cell therapy in patients with ischemic stroke (I-ACT).

[This corrects the article DOI: 10.3389/fnins.2023.1153231.].

Protection against brain injury after ischemic stroke by intravenous human amnion epithelial cells in combination with tissue plasminogen activator.

Background: Thrombolytic agents such as tissue plasminogen activator (tPA) are the only drug class approved to treat ischemic stroke and are usually administered within 4.5 h. However, only ~20% of ischemic stroke patients are eligible to receive the therapy. We previously demonstrated that early intravenous administration of human amnion epithelial cells (hAECs) can limit brain inflammation and infarct growth in experimental stroke. Here, we have tested whether hAECs exert cerebroprotective effects in combination with tPA in mice. Methods: Male C57Bl/6 mice were subjected to middle cerebral artery occlusion for 60 min followed by reperfusion. Immediately following reperfusion, vehicle (saline, n = 31) or tPA (10 mg/kg; n = 73) was administered intravenously. After 30 min of reperfusion, tPA-treated mice were injected intravenously with either hAECs (1×106; n = 32) or vehicle (2% human serum albumin; n = 41). A further 15 sham-operated mice were treated with vehicle (n = 7) or tPA + vehicle (n = 8). Mice were designated to be euthanised at 3, 6 or 24 h post-stroke (n = 21, 31, and 52, respectively), and brains were collected to assess infarct volume, blood-brain barrier (BBB) disruption, intracerebral bleeding and inflammatory cell content. Results: There was no mortality within 6 h of stroke onset, but a high mortality occurred in tPA + saline-treated mice between 6 h and 24 h post-stroke in comparison to mice treated with tPA + hAECs (61% vs. 27%, p = 0.04). No mortality occurred within 24 h of sham surgery in mice treated with tPA + vehicle. We focused on early infarct expansion within 6 h of stroke and found that infarction was ~50% larger in tPA + saline- than in vehicle-treated mice (23 ± 3 mm3 vs. 15 ± 2 mm3, p = 0.02) but not in mice receiving tPA + hAECs (13 ± 2 mm3, p < 0.01 vs. tPA + saline) in which intracerebral hAECs were detected. Similar to the profiles of infarct expansion, BBB disruption and intracerebral bleeding in tPA + saline-treated mice at 6 h was 50-60% greater than in vehicle-treated controls (2.6 ± 0.5 vs. 1.6 ± 0.2, p = 0.05) but not after tPA + hAECs treatment (1.7 ± 0.2, p = 0.10 vs. tPA + saline). No differences in inflammatory cell content were detected between treatment groups. Conclusion: When administered following tPA in acute stroke, hAECs improve safety and attenuate infarct growth in association with less BBB disruption and lower 24 h mortality.

Phase I trial outcome of amnion cell therapy in patients with ischemic stroke (I-ACT).

Background: We proposed a Phase I dose escalation trial to assess the safety of allogeneic human amniotic epithelial cells (hAECs) in stroke patients with a view to informing the design for a Phase II trial. Methods: The design is based on 3 + 3 dose escalation design with additional components for measuring MR signal of efficacy as well as the effect of hAECs (2-8 × 106/kg, i.v.) on preventing immunosuppression after stroke. Results: Eight patients (six males) were recruited within 24 h of ischemic stroke onset and were infused with hAECs. We were able to increase the dose of hAECs to 8 × 106 cells/kg (2 × 106/kg, n = 3; 4 × 106/kg, n = 3; 8 × 106/kg, n = 2). The mean age is 68.0 ± 10.9 (mean ± SD). The frequencies of hypertension and hyperlipidemia were 87.5%, diabetes was 37.5%, atrial fibrillation was 50%, ischemic heart disease was 37.5% and ever-smoker was 25%. Overall, baseline NIHSS was 7.5 ± 3.1, 7.8 ± 7.2 at 24 h, and 4.9 ± 5.4 at 1 week (n = 8). The modified Rankin scale at 90 days was 2.1 ± 1.2. Supplemental oxygen was given in five patients during hAEC infusion. Using pre-defined criteria, two serious adverse events occurred. One patient developed recurrent stroke and another developed pulmonary embolism whilst in rehabilitation. For the last four patients, infusion of hAECs was split across separate infusions on subsequent days to reduce the risk for fluid overload. Conclusion: Our Phase I trial demonstrates that a maximal dose of 2 × 106/kg hAECs given intravenously each day over 2 days (a total of 4 × 106/kg) is safe and optimal for use in a Phase II trial. Clinical trial registration: ClinicalTrials.gov, identifier ACTRN12618000076279P.

Effect of alteplase, benzodiazepines and beta-blocker on post-stroke pneumonia: Exploration of VISTA-Acute.

BACKGROUND: Post-stroke pneumonia is a frequent complication of stroke and is associated with high mortality. Investigators have described its associations with beta-blocker. However, there has been no evaluation of the role of recombinant tissue plasminogen activator (RTPA). We postulate that RTPA may modify the effect of stroke on pneumonia by reducing stroke disability. We explore this using data from neuroprotection trials in Virtual International Stroke Trials Archive (VISTA)-Acute. METHOD: We evaluated the impact of RTPA and other medications in random forest model. Random forest is a type of supervised ensemble tree-based machine learning method. We used the standard approach for performing random forest and partitioned the data into training (70%) and validation (30%) sets. This action enabled to the model developed on training data to be evaluated in the validation data. We borrowed idea from Coalition Game Theory on fair distribution of marginal profit (Shapley value) to determine proportional contribution of a covariate to the model. Consistent with other analysis using the VISTA-Acute data, the diagnosis of post-stroke pneumonia was based on reports of serious adverse events. RESULTS: The overall frequency of pneumonia was 10.9% (614/5652). It was present in 11.5% of the RTPA (270/2358) and 10.4% (344/3295) of the no RTPA groups. There was significant (p<0.05) imbalance in covariates (age, baseline National Institutes of Health Stroke Scale (NIHSS), diabetes, and sex). The AUC for training data was 0.70 (95% CI 0.65-0.76), validation data was 0.67 (95% CI 0.62-0.73). The Shapley value shows that baseline NIHSS (≥10) and age (≥80) made the largest contribution to the model of pneumonia while absence of benzodiazepine may protect against pneumonia. RTPA and beta-blocker had very low effect on frequency of pneumonia. CONCLUSION: In this cohort pneumonia was strongly associated with stroke severity and age whereas RTPA had a much lower effect. An intriguing finding is a possible association between benzodiazepine and pneumonia but this requires further evaluation.

Mapping topography and network of brain injury in patients with disorders of consciousness.

Background: There is a growing interest in the topography of brain regions associated with disorders of consciousness. This has caused increased research output, yielding many publications investigating the topic with varying methodologies. The objective of this study was to ascertain the topographical regions of the brain most frequently associated with disorders of consciousness. Methods: We performed a cross-sectional text-mining analysis of disorders of consciousness studies. A text mining algorithm built in the Python programming language searched documents for anatomical brain terminology. We reviewed primary PubMed studies between January 1st 2000 to 8th February 2023 for the search query "Disorders of Consciousness." The frequency of brain regions mentioned in these articles was recorded, ranked, then built into a graphical network. Subgroup analysis was performed by evaluating the impact on our results if analyses were based on abstracts, full-texts, or topic-modeled groups (non-negative matrix factorization was used to create subgroups of each collection based on their key topics). Brain terms were ranked by their frequency and concordance was measured between subgroups. Graphical analysis was performed to explore relationships between the anatomical regions mentioned. The PageRank algorithm (used by Google to list search results in order of relevance) was used to determine global importance of the regions. Results: The PubMed search yielded 24,944 abstracts and 3,780 full texts. The topic-modeled subgroups contained 2015 abstracts and 283 full texts. Text Mining across all document groups concordantly ranked the thalamus the highest (Savage score = 11.716), followed by the precuneus (Savage score = 4.983), hippocampus (Savage score = 4.483). Graphical analysis had 5 clusters with the thalamus once again having the highest PageRank score (PageRank = 0.0344). Conclusion: The thalamus, precuneus and cingulate cortex are strongly associated with disorders of consciousness, likely due to the roles they play in maintaining awareness and involvement in the default mode network, respectively. The findings also suggest that other areas of the brain like the cerebellum, cuneus, amygdala and hippocampus also share connections to consciousness should be further investigated.

Convexity subarachnoid haemorrhage: a practical guide.

Atraumatic convexity subarachnoid haemorrhage describes spontaneous bleeding into the convexities of the brain sulci without parenchymal involvement. Its many causes include reversible cerebral vasoconstriction syndrome, cerebral sinus venous thrombosis, posterior reversible encephalopathy syndrome and (in older people) cerebral amyloid angiopathy. We describe the clinical and radiological features of non-traumatic convexity subarachnoid haemorrhage with its various presentations, causes, treatments and prognoses, and use clinical vignettes to highlight important clinical points and pitfalls.

Door-in-door-out times for patients with large vessel occlusion ischaemic stroke being transferred for endovascular thrombectomy: a Victorian state-wide study.

Background: Time to reperfusion is an important predictor of outcome in ischaemic stroke from large vessel occlusion (LVO). For patients requiring endovascular thrombectomy (EVT), the transfer times from peripheral hospitals in metropolitan and regional Victoria, Australia to comprehensive stroke centres (CSCs) have not been studied. Aims: To determine transfer and journey times for patients with LVO stroke being transferred for consideration of EVT. Methods: All patients transferred for consideration of EVT to three Victorian CSCs from January 2017 to December 2018 were included. Travel times were obtained from records matched to Ambulance Victoria and the referring centre via Victorian Stroke Telemedicine or hospital medical records. Metrics of interest included door-in-door-out time (DIDO), inbound journey time and outbound journey time. Results: Data for 455 transferred patients were obtained, of which 395 (86.8%) underwent EVT. The median DIDO was 107 min (IQR 84-145) for metropolitan sites and 132 min (IQR 108-167) for regional sites. At metropolitan referring hospitals, faster DIDO was associated with use of the same ambulance crew to transport between hospitals (75 (63-90) vs 124 (99-156) min, p<0.001) and the administration of thrombolysis prior to transfer (101 (79-133) vs 115 (91-155) min, p<0.001). At regional centres, DIDO was consistently longer when patients were transported by air (160 (127-195) vs 116 (100-144) min, p<0.001). The overall door-to-door time by air was shorter than by road for sites located more than 250 km away from the CSC. Conclusion: Transfer times differ significantly for regional and metropolitan patients. A state-wide database to prospectively collect data on all interhospital transfers for EVT would be helpful for future study of optimal transport mode at regional sites and benchmarking of DIDO across the state.

Tenecteplase versus alteplase for stroke thrombolysis evaluation (TASTE): A multicentre, prospective, randomized, open-label, blinded-endpoint, controlled phase III non-inferiority trial protocol.

RATIONALE: Alteplase is the only approved thrombolytic agent for acute stroke. An alternative plasminogen activator, tenecteplase, has been previously shown to increase early biological effectiveness (reperfusion) resulting in early clinical recovery in acute stroke patients with target mismatch on perfusion imaging; however, phase III data are lacking. AIM AND HYPOTHESIS: In this study, we assess the efficacy and safety of tenecteplase compared to alteplase in acute stroke patients with target mismatch on perfusion imaging. METHODS AND DESIGN: Tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) for Stroke Thrombolysis Evaluation (TASTE) is a multicentre, prospective, randomized, open-label, blinded-endpoint (PROBE), controlled phase III non-inferiority trial (2 arms with 1:1 randomization) with an adaptive sample size re-estimation in patients with acute ischemic stroke meeting target mismatch criteria on perfusion imaging. SAMPLE SIZE ESTIMATES: Recruiting 728 patients (1:1 tenecteplase vs alteplase) would yield 90% power (two-sided alpha 0.05) to detect a treatment effect of 8% (26% modified Rankin scale (mRS) 0-1 in alteplase arm and 34% mRS 0-1 in tenecteplase arm), with an absolute non-inferiority margin of 3%. Following the pre-planned "promising zone" adaptive sample size re-estimation, the final sample size was set at 832 patients. STUDY OUTCOMES: The primary outcome measure is the proportion of patients with an mRS score of 0-1 at 3 months. Secondary outcomes include the categorical shift in mRS at 3 months; the proportion of patients with: mRS 0-2, 5-6, and 6; reduction of the National Institutes of Health Stroke Scale (NIHSS) by 8 or more points or reaching 0-1 at 24 h; symptomatic intracerebral hemorrhage within 36 h; and death. DISCUSSION: This pivotal trial will provide important data on the role of tenecteplase in acute ischemic stroke, and the use of imaging-based treatment decision-making for stroke thrombolysis. CLINICAL TRIAL PROTOCOL: Trial Registration: ACTRN12613000243718, EudraCT 2015-002657-36.