Differences in research methodology have hampered the optimization of Computer Tomography Perfusion (CTP) for identification of the ischemic core. We aim to optimize CTP core identification using a ...novel benchmarking tool. The benchmarking tool consists of an imaging library and a statistical analysis algorithm to evaluate the performance of CTP. The tool was used to optimize and evaluate an in-house developed CTP-software algorithm. Imaging data of 103 acute stroke patients were included in the benchmarking tool. Median time from stroke onset to CT was 185 min (IQR 180-238), and the median time between completion of CT and start of MRI was 36 min (IQR 25-79). Volumetric accuracy of the CTP-ROIs was optimal at an rCBF threshold of <38%; at this threshold, the mean difference was 0.3 ml (SD 19.8 ml), the mean absolute difference was 14.3 (SD 13.7) ml, and CTP was 67% sensitive and 87% specific for identification of DWI positive tissue voxels. The benchmarking tool can play an important role in optimizing CTP software as it provides investigators with a novel method to directly compare the performance of alternative CTP software packages.
Revascularization after endovascular therapy for acute ischemic stroke is measured by the Thrombolysis In Cerebral Infarction (TICI) scale, yet variability exists in scale definitions. We examined ...the degree of reperfusion with the expanded TICI (eTICI) scale and association with outcomes in the HERMES collaboration of recent endovascular trials.
The HERMES Imaging Core, blind to all other data, evaluated angiography after endovascular therapy in HERMES. A battery of TICI scores (mTICI, TICI, TICI2C) was used to define reperfusion of the initial target occlusion defined by non-invasive imaging and conventional angiography.
Angiography of 801 subjects was available, including 797 defined by non-invasive imaging (154 internal carotid artery (ICA), 583 M1, 60 M2) and 748 by conventional angiography (195 ICA, 459 M1, 94 M2). Among 729 subjects in whom the reperfusion grade could be established, using eTICI (3=100%, 2C=90-99%, 2b67=67-89%, 2b50=50-66%) of the conventional angiography target occlusion, there were 63 eTICI 3 (9%), 166 eTICI 2c (23%), 218 eTICI 2b67 (30%), 103 eTICI 2b50 (14%), 100 eTICI 2a (14%), 19 eTICI 1 (3%), and 60 eTICI 0 (8%). Modified Rankin Scale shift analyses from baseline to 90 days showed that increasing TICI grades were linked with better outcomes, with significant distinctions between TICI 0/1 versus 2a (p=0.028), 2a versus 2b50 (p=0.017), and 2b50 versus 2b67 (p=0.014).
The benefit of endovascular therapy in HERMES was strongly associated with increasing degrees of reperfusion defined by eTICI. The eTICI metric identified meaningful distinctions in clinical outcomes and may be used in future studies and routine practice.
This review summarizes the current state of knowledge regarding the use of imaging to guide stroke treatment. Brain imaging plays a central role in the diagnosis of stroke and identification of the ...mechanism of stroke, which is relevant to acute treatment, prognosis, and secondary prevention. The chief potential modalities are computed tomography (CT) and magnetic resonance imaging (MRI). Currently, most imaging occurs in hospital but mobile stroke units have expanded CT brain imaging into the prehospital field. The proven therapies for ischemic stroke are based on achieving reperfusion and the DAWN and DEFUSE 3 trials have now firmly established a need for imaging selection based on estimated ischemic core volume to guide reperfusion decisions in patients beyond 6 h of stroke onset. However, data also indicate that estimated ischemic core volume, in conjunction with patient factors and expected time delay to reperfusion, forms one of the most useful prognostic assessments that could alter decision-making for patients within 6 h. Current trials are also investigating agents that aim to achieve neuroprotection, reduction in edema or prevention of hemorrhagic transformation. Imaging may play a role in identifying patients likely to benefit from this next generation of interventions for stroke patients.
Despite years of basic research and pioneering clinical work, ischemic stroke remains a major public health concern. Prior STAIR (Stroke Treatment Academic Industry Roundtable) conferences identified ...both failures of clinical trial design and failures in preclinical assessment in developing putative ischemic stroke treatments. At STAIR XI, participants in workshop no. 1 Top Priorities for Neuroprotection sought to redefine the neuroprotection paradigm and given the paucity of evidence underlying preclinical assessment, offer consensus-based recommendations. STAIR proposes the term brain cytoprotection or cerebroprotection to replace the term neuroprotection when the intention of an investigation is to demonstrate that a new, candidate treatment benefits the entire brain. Although "time is still brain," tissue imaging techniques have been developed to identify patients with both predicted core injury and penumbral, salvageable brain tissue, regardless of time after stroke symptom onset. STAIR XI workshop participants called this imaging approach a tissue window to select patients for recanalization. Elements of the neurovascular unit show differential vulnerability evolving over differing time scales in different brain regions. STAIR proposes the term target window to suggest therapies that target the different elements of the neurovascular unit at different times. Based on contemporary principles of rigor and transparency, the workshop updated, revised, and enhanced the STAIR preclinical recommendations for developing new treatments in 2 phases: an exploratory qualification phase and a definitive validation phase. For new, putative treatments, investigators should carefully characterize the mechanism of action, the pharmacokinetics/pharmacodynamics, demonstrate target engagement, and confirm penetration through the blood-brain barrier. Before clinical trials, testing of candidate molecules in stroke models could proceed in a comprehensive manner using animals of both sexes and to include significant variables such as age and comorbid conditions. Comprehensive preclinical assessment might include multicenter, collaborative testing, for example, network trials. In the absence of a proven cerebroprotective agent to use as a gold standard, however, it remains speculative whether such comprehensive preclinical assessment can effectively predict clinical outcome.
Diffusion-weighted imaging (DWI) is commonly used to assess irreversibly infarcted tissue but its accuracy is challenged by reports of diffusion lesion reversal (DLR). We investigated the frequency ...and implications for mismatch classification of DLR using imaging from the EPITHET (Echoplanar Imaging Thrombolytic Evaluation Trial) and DEFUSE (Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution) studies. In 119 patients (83 treated with IV tissue plasminogen activator), follow-up images were coregistered to acute diffusion images and the lesions manually outlined to their maximal visual extent in diffusion space. Diffusion lesion reversal was defined as voxels of acute diffusion lesion that corresponded to normal brain at follow-up (i.e., final infarct, leukoaraiosis, and cerebrospinal fluid (CSF) voxels were excluded from consideration). The appearance of DLR was visually checked for artifacts, the volume calculated, and the impact of adjusting baseline diffusion lesion volume for DLR volume on perfusion-diffusion mismatch analyzed. Median DLR volume reduced from 4.4 to 1.5 mL after excluding CSF/leukoaraiosis. Visual inspection verified 8/119 (6.7%) with true DLR, median volume 2.33 mL. Subtracting DLR from acute diffusion volume altered perfusion—diffusion mismatch (Tmax>6 seconds, ratio>1.2) in 3/119 (2.5%) patients. Diffusion lesion reversal between baseline and 3 to 6 hours DWI was also uncommon (7/65, 11%) and often transient. Clinically relevant DLR is uncommon and rarely alters perfusion—diffusion mismatch. The acute diffusion lesion is generally a reliable signature of the infarct core.
Alteplase has been the mainstay of thrombolytic treatment since the National Institutes of Neurological Disorders and Stroke trial was published in 1995. Over recent years, several trials have ...investigated alternative thrombolytic agents. Tenecteplase, a genetically engineered mutant tissue plasminogen activator, has a longer half-life, allowing single intravenous bolus administration without infusion, is more fibrin specific, produces less systemic depletion of circulating fibrinogen, and is more resistant to plasminogen activator inhibitor compared to alteplase. Tenecteplase is established as the first-line intravenous thrombolytic drug for myocardial infarction, where it has been shown to achieve comparable reperfusion with reduced risk of systemic bleeding in comparison to alteplase. We review the literature on tenecteplase for the treatment of acute ischemic stroke, with a focus on the major completed and ongoing trials. Overall, tenecteplase shows promise for treatment of acute ischemic stroke, both in populations currently eligible for alteplase and also in groups not currently treated with thrombolysis.
Rationale:
While thrombolysis is standard of care for patients with acute ischemic stroke (AIS) within 4.5 h of symptom onset, the benefit of tenecteplase beyond this time window is less certain.
...Aim:
The TIMELESS trial (NCT03785678) aims to determine if treatment with tenecteplase increases the proportion of good clinical outcomes among patients with stroke due to a large vessel occlusion who present beyond 4.5 h after symptom onset.
Sample size estimates:
A total of 456 patients will provide ⩾90% power to detect differences in the distribution of modified Rankin Scale scores at Day 90 at the two-sided 0.049 significance level.
Methods and design:
TIMELESS is a Phase III, double-blind, randomized, placebo-controlled trial of tenecteplase with or without endovascular thrombectomy in patients with AIS and evidence of salvageable tissue via imaging who present within the 4.5- to 24-h time window with an internal carotid artery (ICA) or middle cerebral artery (MCA) (M1/M2) occlusion.
Study outcomes:
The primary efficacy objective of tenecteplase compared with placebo will be evaluated with ordinal modified Rankin Scale scores at Day 90. Safety will be evaluated via incidence of symptomatic intracranial hemorrhage, incidence and severity of adverse events, and mortality rate.
Discussion:
Results from TIMELESS will contribute to understanding of the safety and efficacy of tenecteplase administered 4.5–24 h following symptom onset for patients with an ICA or MCA occlusion.
ObjectivesThe threat of a pandemic, over and above the disease itself, may have significant and broad effects on a healthcare system. We aimed to describe the impact of the SARS-CoV-2 pandemic ...(during a relatively low transmission period) and associated societal restrictions on presentations, admissions and outpatient visits.DesignWe compared hospital activity in 2020 with the preceding 5 years, 2015–2019, using a retrospective cohort study design.SettingQuaternary hospital in Melbourne, Australia.ParticipantsEmergency department presentations, hospital admissions and outpatient visits from 1 January 2015 to 30 June 2020, n=896 934 episodes of care.InterventionIn Australia, the initial peak COVID-19 phase was March–April.Primary and secondary outcome measuresSeparate linear regression models were fitted to estimate the impact of the pandemic on the number, type and severity of emergency presentations, hospital admissions and outpatient visits.ResultsDuring the peak COVID-19 phase (March and April 2020), there were marked reductions in emergency presentations (10 389 observed vs 14 678 expected; 29% reduction; p<0.05) and hospital admissions (5972 observed vs 8368 expected; 28% reduction; p<0.05). Stroke (114 observed vs 177 expected; 35% reduction; p<0.05) and trauma (1336 observed vs 1764 expected; 24% reduction; p<0.05) presentations decreased; acute myocardial infarctions were unchanged. There was an increase in the proportion of hospital admissions requiring intensive care (7.0% observed vs 6.0% expected; p<0.05) or resulting in death (2.2% observed vs 1.5% expected; p<0.05). Outpatient attendances remained similar (30 267 observed vs 31 980 expected; 5% reduction; not significant) but telephone/telehealth consultations increased from 2.5% to 45% (p<0.05) of total consultations.ConclusionsAlthough case numbers of COVID-19 were relatively low in Australia during the first 6 months of 2020, the impact on hospital activity was profound.
A decade on from the first positive thrombectomy trials, hyperacute therapies for ischemic stroke continue to rapidly advance. Effective treatments remain limited to reperfusion, although several ...cytoprotective approaches continue to be investigated. Intravenous fibrinolytics are now demonstrated to be beneficial up to 24 h in patients selected using perfusion imaging, but their role in patients with non-disabling symptoms appears very limited. Tenecteplase is superior to alteplase in meta-analysis of the latest trials, and adjuvant thrombolytics are an area of active investigation. Endovascular thrombectomy is beneficial in a wide range of anterior and posterior circulation large vessel occlusions up to 24 h after onset with the more distal occlusions, mild presentations, and >24 h window being the main frontiers to be tested in ongoing trials. Imaging parameters are prognostic but appear not to modify the relative treatment benefit of thrombectomy versus standard medical care. Therefore, deciding who not to treat with thrombectomy is a key clinical challenge that requires careful but rapid integration of clinical, imaging, and patient preference considerations. Systems of care to accelerate delivery of these highly effective therapies will maximize benefits for the greatest number of patients with stroke.
Internationally, Mobile Stroke Unit (MSU) ambulances have changed pre-hospital acute stroke care delivery. MSU clinical and cost-effectiveness studies are emerging, but little is known about ...important factors for achieving sustainability of this innovative model of care.
Mixed-methods study from the Melbourne MSU (operational since November 2017) process evaluation. Participant purposive sampling included clinical, operational and executive/management representatives from Ambulance Victoria (AV) (emergency medical service provider), the MSU clinical team, and receiving hospitals. Sustainability was defined as ongoing MSU operations, including MSU workforce and future model considerations. Theoretically-based on-line survey with Unified Theory of Acceptance and Use of Technology (UTAUT), Self Determination Theory (SDT, Intrinsic Motivation), and open-text questions targeting barriers and benefits was administered (June-September 2019). Individual/group interviews were conducted, eliciting improvement suggestions and requirements for ongoing use. Descriptive and regression analyses (quantitative data) and directed content and thematic analysis (open text and interview data) were conducted.
There were 135 surveys completed. Identifying that the MSU was beneficial to daily work (β=0.61), not experiencing pressure/tension about working on the MSU (β=0.17) and thinking they did well working within the team model (β=0.17) were significantly associated with wanting to continue working within the MSU model R
=0.76; F(15, 60)=12.76,
<.001. Experiences varied between those on the MSU team and those working with the MSU. Advantages were identified for patients (better, faster care) and clinicians (interdisciplinary learning). Disadvantages included challenges integrating into established systems, and establishing working relationships. Themes identified from 35 interviews were MSU team composition, MSU vehicle design and layout, personnel recruitment and rostering, communication improvements between organisations, telemedicine options, MSU operations and dispatch specificity.
Important factors affecting the sustainability of the MSU model of stroke care emerged. A cohesive team approach, with identifiable benefits and good communication between participating organisations is important for clinical and operational sustainability.
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