Tenecteplase for Stroke at 4.5 to 24 Hours with Perfusion-Imaging Selection.

BACKGROUND: Thrombolytic agents, including tenecteplase, are generally used within 4.5 hours after the onset of stroke symptoms. Information on whether tenecteplase confers benefit beyond 4.5 hours is limited. METHODS: We conducted a multicenter, double-blind, randomized, placebo-controlled trial involving patients with ischemic stroke to compare tenecteplase (0.25 mg per kilogram of body weight, up to 25 mg) with placebo administered 4.5 to 24 hours after the time that the patient was last known to be well. Patients had to have evidence of occlusion of the middle cerebral artery or internal carotid artery and salvageable tissue as determined on perfusion imaging. The primary outcome was the ordinal score on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability and a score of 6 indicating death) at day 90. Safety outcomes included death and symptomatic intracranial hemorrhage. RESULTS: The trial enrolled 458 patients, 77.3% of whom subsequently underwent thrombectomy; 228 patients were assigned to receive tenecteplase, and 230 to receive placebo. The median time between the time the patient was last known to be well and randomization was approximately 12 hours in the tenecteplase group and approximately 13 hours in the placebo group. The median score on the modified Rankin scale at 90 days was 3 in each group. The adjusted common odds ratio for the distribution of scores on the modified Rankin scale at 90 days for tenecteplase as compared with placebo was 1.13 (95% confidence interval, 0.82 to 1.57; P = 0.45). In the safety population, mortality at 90 days was 19.7% in the tenecteplase group and 18.2% in the placebo group, and the incidence of symptomatic intracranial hemorrhage was 3.2% and 2.3%, respectively. CONCLUSIONS: Tenecteplase therapy that was initiated 4.5 to 24 hours after stroke onset in patients with occlusions of the middle cerebral artery or internal carotid artery, most of whom had undergone endovascular thrombectomy, did not result in better clinical outcomes than those with placebo. The incidence of symptomatic intracerebral hemorrhage was similar in the two groups. (Funded by Genentech; TIMELESS ClinicalTrials.gov number, NCT03785678.).

Endovascular thrombectomy plus medical care versus medical care alone for large ischaemic stroke: 1-year outcomes of the SELECT2 trial.

BACKGROUND: Multiple randomised trials have shown efficacy and safety of endovascular thrombectomy in patients with large ischaemic stroke. The aim of this study was to evaluate long-term (ie, at 1 year) evidence of benefit of thrombectomy for these patients. METHODS: SELECT2 was a phase 3, open-label, international, randomised controlled trial with blinded endpoint assessment, conducted at 31 hospitals in the USA, Canada, Spain, Switzerland, Australia, and New Zealand. Patients aged 18-85 years with ischaemic stroke due to proximal occlusion of the internal carotid artery or of the first segment of the middle cerebral artery, showing large ischaemic core on non-contrast CT (Alberta Stroke Program Early Computed Tomographic Score of 3-5 [range 0-10, with lower values indicating larger infarctions]) or measuring 50 mL or more on CT perfusion and MRI, were randomly assigned, within 24 h of ischaemic stroke onset, to thrombectomy plus medical care or to medical care alone. The primary outcome for this analysis was the ordinal modified Rankin Scale (range 0-6, with higher scores indicating greater disability) at 1-year follow-up in an intention-to-treat population. The trial is registered at ClinicalTrials.gov (NCT03876457) and is completed. FINDINGS: The trial was terminated early for efficacy at the 90-day follow-up after 352 patients had been randomly assigned (178 to thrombectomy and 174 to medical care only) between Oct 11, 2019, and Sept 9, 2022. Thrombectomy significantly improved the 1-year modified Rankin Scale score distribution versus medical care alone (Wilcoxon-Mann-Whitney probability of superiority 0·59 [95% CI 0·53-0·64]; p=0·0019; generalised odds ratio 1·43 [95% CI 1·14-1·78]). At the 1-year follow-up, 77 (45%) of 170 patients receiving thrombectomy had died, compared with 83 (52%) of 159 patients receiving medical care only (1-year mortality relative risk 0·89 [95% CI 0·71-1·11]). INTERPRETATION: In patients with ischaemic stroke due to a proximal occlusion and large core, thrombectomy plus medical care provided a significant functional outcome benefit compared with medical care alone at 1-year follow-up. FUNDING: Stryker Neurovascular.

Arterial Recanalization During Interhospital Transfer for Thrombectomy.

BACKGROUND: Patients with acute ischemic stroke harboring a large vessel occlusion admitted to nonendovascular-capable centers often require interhospital transfer for thrombectomy. We evaluated the incidence and predictors of arterial recanalization during transfer, as well as the relationship between interhospital recanalization and clinical outcomes. METHODS: We analyzed data from 2 cohorts of patients with an anterior circulation large vessel occlusion transferred for consideration of thrombectomy to a comprehensive center, with arterial imaging at the referring hospital and on comprehensive stroke center arrival. Interhospital recanalization was determined by comparison of the baseline and posttransfer arterial imaging and was defined as revised arterial occlusive lesion (rAOL) score 2b to 3. Pretransfer variables independently associated with interhospital recanalization were studied using multivariable logistic regression analysis. RESULTS: Of the 520 included patients (Montpellier, France, n=237; Stanford, United States, n=283), 111 (21%) experienced interhospital recanalization (partial [rAOL=2b] in 77% and complete [rAOL=3] in 23%). Pretransfer variables independently associated with recanalization were intravenous thrombolysis (adjusted odds ratio, 6.8 [95% CI, 4.0-11.6]), more distal occlusions (intracranial carotid occlusion as reference: adjusted odds ratio, 2.0 [95% CI, 0.9-4.5] for proximal first segment of the middle cerebral artery, 5.1 [95% CI, 2.3-11.5] for distal first segment of the middle cerebral artery, and 5.0 [95% CI, 2.1-11.8] for second segment of the middle cerebral artery), and smaller clot burden (clot burden score 0-4 as reference: adjusted odds ratio, 3.4 [95% CI, 1.5-7.6] for 5-7 and 5.6 [95% CI, 2.4-12.7] for 8-9). Recanalization on arrival at the comprehensive center was associated with less interhospital infarct growth (rAOL, 0-2a: 11.6 mL; rAOL, 2b: 2.2 mL; rAOL, 3: 0.6 mL; Ptrend<0.001) and greater interhospital National Institutes of Health Stroke Scale score improvement (0 versus -5 versus -6; Ptrend<0.001). Interhospital recanalization was associated with reduced 3-month disability (adjusted common odds ratio, 2.51 [95% CI, 1.68-3.77]) with greater benefit from complete than partial recanalization. CONCLUSIONS: Recanalization is frequently observed during interhospital transfer for thrombectomy and is strongly associated with favorable outcomes, even when partial. Broadening thrombolysis indications in primary centers, and developing therapies that increase recanalization during transfer, will likely improve clinical outcomes.

Determinants of Infarct Core Growth During Inter-hospital Transfer for Thrombectomy.

OBJECTIVE: Patients with acute ischemic stroke harboring a large vessel occlusion who present to primary stroke centers often require inter-hospital transfer for thrombectomy. We aimed to determine clinical and imaging factors independently associated with fast infarct growth (IG) during inter-hospital transfer. METHODS: We retrospectively analyzed data from acute stroke patients with a large vessel occlusion transferred for thrombectomy from a primary stroke center to one of three French comprehensive stroke centers, with an MRI obtained at both the primary and comprehensive center before thrombectomy. Inter-hospital IG rate was defined as the difference in infarct volumes on diffusion-weighted imaging between the primary and comprehensive center, divided by the delay between the two MRI scans. The primary outcome was identification of fast progressors, defined as IG rate ≥5 mL/hour. The hypoperfusion intensity ratio (HIR), a surrogate marker of collateral blood flow, was automatically measured on perfusion imaging. RESULTS: A total of 233 patients were included, of whom 27% patients were fast progressors. The percentage of fast progressors was 3% among patients with HIR < 0.40 and 71% among those with HIR ≥ 0.40. In multivariable analysis, fast progression was independently associated with HIR, intracranial carotid artery occlusion, and exclusively deep infarct location at the primary center (C-statistic = 0.95; 95% confidence interval [CI], 0.93-0.98). IG rate was independently associated with good functional outcome (adjusted OR = 0.91; 95% CI, 0.83-0.99; P = 0.037). INTERPRETATION: Our findings show that a HIR > 0.40 is a powerful indicator of fast inter-hospital IG. These results have implication for neuroprotection trial design, as well as informing triage decisions at primary stroke centers. ANN NEUROL 2023;93:1117-1129.

Infarct Core Growth During Interhospital Transfer For Thrombectomy Is Faster At Night.

BACKGROUND: Preclinical stroke models have recently reported faster infarct growth (IG) when ischemia was induced during daytime. Considering the inverse rest-activity cycles of rodents and humans, faster IG during the nighttime has been hypothesized in humans. METHODS: We retrospectively evaluated acute ischemic stroke patients with a large vessel occlusion transferred from a primary to 1 of 3 French comprehensive stroke center, with magnetic resonance imaging obtained at both centers before thrombectomy. Interhospital IG rate was calculated as the difference in infarct volumes on the 2 diffusion-weighted imaging, divided by the time elapsed between the 2 magnetic resonance imaging. IG rate was compared between patients transferred during daytime (7:00-22:59) and nighttime (23:00-06:59) in multivariable analysis adjusting for occlusion site, National Institutes of Health Stroke Scale score, infarct topography, and collateral status. RESULTS: Out of the 329 patients screened, 225 patients were included. Interhospital transfer occurred during nighttime in 31 (14%) patients and daytime in 194 (86%). Median interhospital IG was faster when occurring at night (4.3 mL/h; interquartile range, 1.2-9.5) as compared to the day (1.4 mL/h; interquartile range, 0.4-3.5; P<0.001). In multivariable analysis, nighttime transfer remained independently associated with IG rate (P<0.05). CONCLUSIONS: Interhospital IG appeared faster in patients transferred at night. This has potential implications for the design of neuroprotection trials and acute stroke workflow.

Hypoperfusion Intensity Ratio Is Correlated With the Risk of Parenchymal Hematoma After Endovascular Stroke Treatment.

BACKGROUND: Parenchymal hematoma (PH) is a major complication after endovascular treatment (EVT) for ischemic stroke. The hypoperfusion intensity ratio (HIR) represents a perfusion parameter reflecting arterial collateralization and cerebral microperfusion in ischemic brain tissue. We hypothesized that HIR correlates with the risk of PH after EVT. METHODS: Retrospective multicenter cohort study of patients with large vessel occlusion who underwent EVT between 2013 and 2021 at one of the 2 comprehensive stroke centers (University Medical Center Hamburg-Eppendorf, Germany and Stanford University School of Medicine, CA). HIR was automatically calculated on computed tomography perfusion studies as the ratio of brain volume with time-to-max (Tmax) delay >10 s over volume with Tmax >6 s. Reperfusion hemorrhages were assessed according to the Heidelberg Bleeding Classification. Primary outcome was PH occurrence (PH+) or absence (PH-) on follow-up imaging. Secondary outcome was good clinical outcome defined as a 90-day modified Rankin Scale score of 0 to 2. RESULTS: A total of 624 patients met the inclusion criteria. We observed PH in 91 (14.6%) patients after EVT. PH+ patients had higher HIR on admission compared with PH- patients (median, 0.6 versus 0.4; P<0.001). In multivariable regression, higher admission blood glucose (adjusted odds ratio [aOR], 1.08 [95% CI, 1.04-1.13]; P<0.001), extensive baseline infarct defined as Alberta Stroke Program Early CT Score ≤5 (aOR, 2.48 [1.37-4.42]; P=0.002), and higher HIR (aOR, 1.22 [1.09-1.38]; P<0.001) were independent determinants of PH after EVT. Both higher HIR (aOR, 0.83 [0.75-0.92]; P<0.001) and PH on follow-up imaging (aOR, 0.39 [0.18-0.80]; P=0.013) were independently associated with lower odds of achieving good clinical outcome. CONCLUSIONS: Poorer (higher) HIR on admission perfusion imaging was strongly associated with PH occurrence after EVT. HIR as a surrogate for cerebral microperfusion might reflect tissue vulnerability for reperfusion hemorrhages. This automated and quickly available perfusion parameter might help to assess the need for intensive medical care after EVT.

Semiautomated Detection of Early Infarct Signs on Noncontrast CT Improves Interrater Agreement.

BACKGROUND: Acute ischemic infarct identification on noncontrast computed tomography (NCCT) is highly variable between raters. A semiautomated method for segmentation of acute ischemic lesions on NCCT may improve interrater reliability. METHODS: Patients with successful endovascular reperfusion from the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) were included. We created relative NCCT (rNCCT) color-gradient overlays by comparing the density of a voxel on NCCT to the homologous region in the contralateral hemisphere. Regions with a relative hypodensity of at least 5% were visualized. We coregistered baseline and follow-up images. Two neuroradiologists and 6 nonradiologists segmented the acute ischemic lesion on the baseline scans with 2 methods: (1) manually outlining hypodense regions on the NCCT (unassisted segmentation) and (2) manually excluding areas deemed outside of the ischemic lesion on the rNCCT color map (rNCCT-assisted segmentation). Voxelwise interrater agreement was quantified using the Dice similarity coefficient and volumetric agreement between raters with the detection index (DI), defined as the true positive volume minus the false positive volume. RESULTS: From a total of 92, we included 61 patients. Median age was 59 (64-77), and 57% were female. Stroke onset was known in 39%. Onset to NCCT was median, 8.5 hours (7-11) and median 10 hours (8.4-11.5) in patients with known and unknown onset, respectively. Compared with unassisted NCCT segmentation, rNCCT-assisted segmentation increased the Dice similarity coefficient by >50% for neuroradiologists (Dice similarity coefficient, 0.38 versus 0.83; P<0.001) and nonradiologists (Dice similarity coefficient, 0.14 versus 0.84; P<0.001), and improved the DI among nonradiologists (mean improvement, 5.8 mL [95% CI, 3.1-8.5] mL, P<0.001) but not among neuroradiologists. CONCLUSIONS: The high variability of manual segmentations of the acute ischemic lesion on NCCT is greatly reduced using semiautomated rNCCT. The rNCCT map may therefore aid acute infarct detection and provide more reliable infarct estimates for clinicians with less experience.

Functional Outcome Prediction in Acute Ischemic Stroke Using a Fused Imaging and Clinical Deep Learning Model.

BACKGROUND: Predicting long-term clinical outcome based on the early acute ischemic stroke information is valuable for prognostication, resource management, clinical trials, and patient expectations. Current methods require subjective decisions about which imaging features to assess and may require time-consuming postprocessing. This study's goal was to predict ordinal 90-day modified Rankin Scale (mRS) score in acute ischemic stroke patients by fusing a Deep Learning model of diffusion-weighted imaging images and clinical information from the acute period. METHODS: A total of 640 acute ischemic stroke patients who underwent magnetic resonance imaging within 1 to 7 days poststroke and had 90-day mRS follow-up data were randomly divided into 70% (n=448) for model training, 15% (n=96) for validation, and 15% (n=96) for internal testing. Additionally, external testing on a cohort from Lausanne University Hospital (n=280) was performed to further evaluate model generalization. Accuracy for ordinal mRS, accuracy within ±1 mRS category, mean absolute prediction error, and determination of unfavorable outcome (mRS score >2) were evaluated for clinical only, imaging only, and 2 fused clinical-imaging models. RESULTS: The fused models demonstrated superior performance in predicting ordinal mRS score and unfavorable outcome in both internal and external test cohorts when compared with the clinical and imaging models. For the internal test cohort, the top fused model had the highest area under the curve of 0.92 for unfavorable outcome prediction and the lowest mean absolute error (0.96 [95% CI, 0.77-1.16]), with the highest proportion of mRS score predictions within ±1 category (79% [95% CI, 71%-88%]). On the external Lausanne University Hospital cohort, the best fused model had an area under the curve of 0.90 for unfavorable outcome prediction and outperformed other models with an mean absolute error of 0.90 (95% CI, 0.79-1.01), and the highest percentage of mRS score predictions within ±1 category (83% [95% CI, 78%-87%]). CONCLUSIONS: A Deep Learning-based imaging model fused with clinical variables can be used to predict 90-day stroke outcome with reduced subjectivity and user burden.

Priorities for Advancements in Neuroimaging in the Diagnostic Workup of Acute Stroke.

STAIR XII (12th Stroke Treatment Academy Industry Roundtable) included a workshop to discuss the priorities for advancements in neuroimaging in the diagnostic workup of acute ischemic stroke. The workshop brought together representatives from academia, industry, and government. The participants identified 10 critical areas of priority for the advancement of acute stroke imaging. These include enhancing imaging capabilities at primary and comprehensive stroke centers, refining the analysis and characterization of clots, establishing imaging criteria that can predict the response to reperfusion, optimizing the Thrombolysis in Cerebral Infarction scale, predicting first-pass reperfusion outcomes, improving imaging techniques post-reperfusion therapy, detecting early ischemia on noncontrast computed tomography, enhancing cone beam computed tomography, advancing mobile stroke units, and leveraging high-resolution vessel wall imaging to gain deeper insights into pathology. Imaging in acute ischemic stroke treatment has advanced significantly, but important challenges remain that need to be addressed. A combined effort from academic investigators, industry, and regulators is needed to improve imaging technologies and, ultimately, patient outcomes.

Using Epidemiological Data to Inform Clinical Trial Feasibility Assessments: A Case Study.

BACKGROUND: Clinical trial enrollment and completion is challenging, with nearly half of all trials not being completed or not completed on time. In 2014, the National Institutes of Health StrokeNet in collaboration with stroke epidemiologists from GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) began providing proposed clinical trials with formal trial feasibility assessments. Herein, we describe the process of prospective feasibility analyses using epidemiological data that can be used to improve enrollment and increase the likelihood a trial is completed. METHODS: In 2014, DEFUSE 3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke 3) trialists, National Institutes of Health StrokeNet, and stroke epidemiologists from GCNKSS collaborated to evaluate the initial inclusion/exclusion criteria for the DEFUSE 3 study. Trial criteria were discussed and an assessment was completed to evaluate the percent of the stroke population that might be eligible for the study. The DEFUSE 3 trial was stopped early with the publication of DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct), and the Wilcoxon rank-sum statistic was used to analyze whether the trial would have been stopped had the proposed changes not been made, following the DEFUSE 3 statistical analysis plan. RESULTS: After initial epidemiological analysis, 2.4% of patients with acute stroke in the GCNKSS population would have been predicted to be eligible for the study. After discussion with primary investigators and modifying 4 key exclusion criteria (upper limit of age increased to 90 years, baseline modified Rankin Scale broadened to 0-2, time since last well expanded to 16 hours, and decreased lower limit of National Institutes of Health Stroke Scale score to <6), the number predicted to be eligible for the trial increased to 4%. At the time of trial conclusion, 57% of the enrolled patients qualified only by the modified criteria, and the trial was stopped at an interim analysis that demonstrated efficacy. We estimated that the Wilcoxon rank-sum value for the unadjusted predicted enrollment would not have crossed the threshold for efficacy and the trial not stopped. CONCLUSIONS: Objectively assessing trial inclusion/exclusion criteria using a population-based resource in a collaborative and iterative process including epidemiologists can lead to improved recruitment and can increase the likelihood of successful trial completion.

Thrombectomy for anterior circulation stroke beyond 6 h from time last known well (AURORA): a systematic review and individual patient data meta-analysis.

BACKGROUND: Trials examining the benefit of thrombectomy in anterior circulation proximal large vessel occlusion stroke have enrolled patients considered to have salvageable brain tissue, who were randomly assigned beyond 6 h and (depending on study protocol) up to 24 h from time last seen well. We aimed to estimate the benefit of thrombectomy overall and in prespecified subgroups through individual patient data meta-analysis. METHODS: We did a systematic review and individual patient data meta-analysis between Jan 1, 2010, and March 1, 2021, of randomised controlled trials of endovascular stroke therapy. In the Analysis Of Pooled Data From Randomized Studies Of Thrombectomy More Than 6 Hours After Last Known Well (AURORA) collaboration, the primary outcome was disability on the modified Rankin Scale (mRS) at 90 days, analysed by ordinal logistic regression. Key safety outcomes were symptomatic intracerebral haemorrhage and mortality within 90 days. FINDINGS: Patient level data from 505 individuals (n=266 intervention, n=239 control; mean age 68·6 years [SD 13·7], 259 [51·3%] women) were included from six trials that met inclusion criteria of 17 screened published randomised trials. Primary outcome analysis showed a benefit of thrombectomy with an unadjusted common odds ratio (OR) of 2·42 (95% CI 1·76-3·33; p<0·0001) and an adjusted common OR (for age, gender, baseline stroke severity, extent of infarction on baseline head CT, and time from onset to random assignment) of 2·54 (1·83-3·54; p<0·0001). Thrombectomy was associated with higher rates of independence in activities of daily living (mRS 0-2) than best medical therapy alone (122 [45·9%] of 266 vs 46 [19·3%] of 238; p<0·0001). No significant difference between intervention and control groups was found when analysing either 90-day mortality (44 [16·5%] of 266 vs 46 [19·3%] of 238) or symptomatic intracerebral haemorrhage (14 [5·3%] of 266 vs eight [3·3%] of 239). No heterogeneity of treatment effect was noted across subgroups defined by age, gender, baseline stroke severity, vessel occlusion site, baseline Alberta Stroke Program Early CT Score, and mode of presentation; treatment effect was stronger in patients randomly assigned within 12-24 h (common OR 5·86 [95% CI 3·14-10·94]) than those randomly assigned within 6-12 h (1·76 [1·18-2·62]; pinteraction=0·0087). INTERPRETATION: These findings strengthen the evidence for benefit of endovascular thrombectomy in patients with evidence of reversible cerebral ischaemia across the 6-24 h time window and are relevant to clinical practice. Our findings suggest that in these patients, thrombectomy should not be withheld on the basis of mode of presentation or of the point in time of presentation within the 6-24 h time window. FUNDING: Stryker Neurovascular.

Predicting Hypoperfusion Lesion and Target Mismatch in Stroke from Diffusion-weighted MRI Using Deep Learning.

Background Perfusion imaging is important to identify a target mismatch in stroke but requires contrast agents and postprocessing software. Purpose To use a deep learning model to predict the hypoperfusion lesion in stroke and identify patients with a target mismatch profile from diffusion-weighted imaging (DWI) and clinical information alone, using perfusion MRI as the reference standard. Materials and Methods Imaging data sets of patients with acute ischemic stroke with baseline perfusion MRI and DWI were retrospectively reviewed from multicenter data available from 2008 to 2019 (Imaging Collaterals in Acute Stroke, Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution 2, and University of California, Los Angeles stroke registry). For perfusion MRI, rapid processing of perfusion and diffusion software automatically segmented the hypoperfusion lesion (time to maximum, ≥6 seconds) and ischemic core (apparent diffusion coefficient [ADC], ≤620 × 10-6 mm2/sec). A three-dimensional U-Net deep learning model was trained using baseline DWI, ADC, National Institutes of Health Stroke Scale score, and stroke symptom sidedness as inputs, with the union of hypoperfusion and ischemic core segmentation serving as the ground truth. Model performance was evaluated using the Dice score coefficient (DSC). Target mismatch classification based on the model was compared with that of the clinical-DWI mismatch approach defined by the DAWN trial by using the McNemar test. Results Overall, 413 patients (mean age, 67 years ± 15 [SD]; 207 men) were included for model development and primary analysis using fivefold cross-validation (247, 83, and 83 patients in the training, validation, and test sets, respectively, for each fold). The model predicted the hypoperfusion lesion with a median DSC of 0.61 (IQR, 0.45-0.71). The model identified patients with target mismatch with a sensitivity of 90% (254 of 283; 95% CI: 86, 93) and specificity of 77% (100 of 130; 95% CI: 69, 83) compared with the clinical-DWI mismatch sensitivity of 50% (140 of 281; 95% CI: 44, 56) and specificity of 89% (116 of 130; 95% CI: 83, 94) (P < .001 for all). Conclusion A three-dimensional U-Net deep learning model predicted the hypoperfusion lesion from diffusion-weighted imaging (DWI) and clinical information and identified patients with a target mismatch profile with higher sensitivity than the clinical-DWI mismatch approach. ClinicalTrials.gov registration nos. NCT02225730, NCT01349946, NCT02586415 © RSNA, 2022 Supplemental material is available for this article. See also the editorial by Kallmes and Rabinstein in this issue.

Benefit of Intravenous Alteplase before Thrombectomy Depends on ASPECTS.

PURPOSE: Baseline variables could be used to guide the administration of additional intravenous alteplase (IVT) before mechanical thrombectomy (MT). The aim of this study was to determine how baseline imaging and demographic parameters modify the effect of IVT on clinical outcomes in patients with ischemic stroke due to large vessel occlusion. METHODS: Multicenter retrospective cohort study of ischemic stroke patients triaged by multimodal-CT undergoing MT treatment after direct admission to an MT-eligible center. Inverse-probability weighting analysis (IPW) was used to assess the treatment effect of IVT adjusted for baseline variables. Multivariable logistic regression analysis with IPW-weighting and interaction terms for IVT was performed to predict functional independence (mRS 0-2 at 90-days). RESULTS: 720 patients were included, of which 366 (51%) received IVT. In IPW, the treatment effect of IVT on outcome (mRS 0-2) distinctively varied according to the ASPECTS subgroup (ASPECTS 9-10: +15%, ASPECTS 6-8: +7%, ASPECTS <6: -11%). In multivariable logistic regression analysis, IVT was independently associated with functional independence (aOR: 1.57, 95% CI: 1.16-2.14, p = 0.003) and the interaction term was significant for ASPECTS and IVT revealing that IVT was only significantly associated with better outcomes in patients with higher ASPECTS. No other significant baseline variable interaction terms were identified. INTERPRETATION: ASPECTS was the only baseline variable that showed a significant interaction with IVT for outcome prediction. Use of IVT prior to MT in patients with an ASPECTS of <6 was not associated with a treatment benefit and should be considered carefully. ANN NEUROL 2022;92:588-595.

Machine learning models of plasma proteomic data predict mood in chronic stroke and tie it to aberrant peripheral immune responses.

Post-stroke depression is common, long-lasting and associated with severe morbidity and death, but mechanisms are not well-understood. We used a broad proteomics panel and developed a machine learning algorithm to determine whether plasma protein data can predict mood in people with chronic stroke, and to identify proteins and pathways associated with mood. We used Olink to measure 1,196 plasma proteins in 85 participants aged 25 and older who were between 5 months and 9 years after ischemic stroke. Mood was assessed with the Stroke Impact Scale mood questionnaire (SIS3). Machine learning multivariable regression models were constructed to estimate SIS3 using proteomics data, age, and time since stroke. We also dichotomized participants into better mood (SIS3 > 63) or worse mood (SIS3 ≤ 63) and analyzed candidate proteins. Machine learning models verified that there is indeed a relationship between plasma proteomic data and mood in chronic stroke, with the most accurate prediction of mood occurring when we add age and time since stroke. At the individual protein level, no single protein or set of proteins predicts mood. But by using univariate analyses of the proteins most highly associated with mood we produced a model of chronic post-stroke depression. We utilized the fact that this list contained many proteins that are also implicated in major depression. Also, over 80% of immune proteins that correlate with mood were higher with worse mood, implicating a broadly overactive immune system in chronic post-stroke depression. Finally, we used a comprehensive literature review of major depression and acute post-stroke depression. We propose that in chronic post-stroke depression there is over-activation of the immune response that then triggers changes in serotonin activity and neuronal plasticity leading to depressed mood.

Unfavorable cerebral venous outflow is associated with futile recanalization in acute ischemic stroke patients.

BACKGROUND AND PURPOSE: Mechanical thrombectomy (MT) has proven to be the standard of care for patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO). However, high revascularization rates do not necessarily result in favorable functional outcomes. We aimed to investigate imaging biomarkers associated with futile recanalization, defined as unfavorable functional outcome despite successful recanalization in AIS-LVO patients. METHODS: A retrospective multicenter cohort study was made of AIS-LVO patients treated by MT. Successful recanalization was defined as modified Thrombolysis in Cerebral Infarction score of 2b-3. A modified Rankin Scale score of 3-6 at 90 days was defined as unfavorable functional outcome. Cortical Vein Opacification Score (COVES) was used to assess venous outflow (VO), and the Tan scale was utilized to determine pial arterial collaterals on admission computed tomography angiography (CTA). Unfavorable VO was defined as COVES ≤ 2. Multivariable regression analysis was performed to investigate vascular imaging factors associated with futile recanalization. RESULTS: Among 539 patients in whom successful recanalization was achieved, unfavorable functional outcome was observed in 59% of patients. Fifty-eight percent of patients had unfavorable VO, and 31% exhibited poor pial arterial collaterals. In multivariable regression, unfavorable VO was a strong predictor (adjusted odds ratio = 4.79, 95% confidence interval = 2.48-9.23) of unfavorable functional outcome despite successful recanalization. CONCLUSIONS: We observe that unfavorable VO on admission CTA is a strong predictor of unfavorable functional outcomes despite successful vessel recanalization in AIS-LVO patients. Assessment of VO profiles could help as a pretreatment imaging biomarker to determine patients at risk for futile recanalization.

Daily Vibrotactile Stimulation Exhibits Equal or Greater Spasticity Relief Than Botulinum Toxin in Stroke.

OBJECTIVE: To test the feasibility and efficacy of the VibroTactile Stimulation (VTS) Glove, a wearable device that provides VTS to the impaired limb to reduce spastic hypertonia. DESIGN: Prospective 2-arm intervention study-including 1 group of patients who use Botulinum toxin (BTX-A) for spasticity and 1 group of patients who do not use BTX-A. SETTING: Participants were recruited through rehabilitation and neurology clinics. PARTICIPANTS: Patients with chronic stroke (N=20; mean age=54 years, mean time since stroke=6.9 years). Patients who were previously receiving the standard of care (BTX-A injection) were eligible to participate and started the intervention 12 weeks after their last injection. INTERVENTION: Participants were instructed to use the VTS Glove for 3 hours daily, at home or during everyday activities, for 8 weeks. MAIN OUTCOME MEASURES: Spasticity was assessed with the Modified Ashworth Scale and the Modified Tardieu Scale at baseline and then at 2-week intervals for 12 weeks. Primary outcomes were the difference from baseline and at week 8 (end of VTS Glove use) and week 12 (4 weeks after stopping VTS Glove use). Patients who were receiving BTX-A were also assessed during the 12 weeks preceding the start of VTS Glove use to monitor the effect of BTX-A on spastic hypertonia. Range of motion and participant feedback were also studied. RESULTS: A clinically meaningful difference in spastic hypertonia was found during and after daily VTS Glove use. Modified Ashworth and Modified Tardieu scores were reduced by an average of 0.9 (P=.0014) and 0.7 (P=.0003), respectively, at week 8 of daily VTS Glove use, and by 1.1 (P=.00025) and 0.9 (P=.0001), respectively, 1 month after stopping VTS Glove use. For participants who used BTX-A, 6 out of 11 showed greater change in Modified Ashworth ratings during VTS Glove use (mean=-1.8 vs mean=-1.6 with BTX-A) and 8 out of 11 showed their lowest level of symptoms during VTS Glove use (vs BTX-A). CONCLUSIONS: Daily stimulation from the VTS Glove provides relief of spasticity and hypertonia. For more than half of the participants who had regularly used BTX-A, the VTS Glove provided equal or greater symptom relief.

Cerebral perfusion imaging predicts final infarct volume after basilar artery thrombectomy.

OBJECTIVES: Cerebral perfusion imaging may be used to identify the ischemic core in acute ischemic stroke (AIS) patients with a large vessel occlusion of the anterior circulation; however, perfusion parameters that predict the ischemic core in AIS patients with a basilar artery occlusion (BAO) are poorly described. We determined which cerebral perfusion parameters best predict the ischemic core after successful endovascular thrombectomy (EVT) in BAO patients. MATERIALS AND METHODS: We performed multicenter retrospective study of BAO patients with perfusion imaging before EVT and a DWI after successful EVT. The ischemic core was defined as regions on CTP, which were co-registered to the final DWI infarct. Various time-to-maximum (Tmax) and cerebral blood flow (CBF) thresholds were compared to final infarct volume to determine the best predictor of the final infarct. RESULTS: 28 patients were included in the analysis for this study. Tmax >8s (r2: 0.56; median absolute error, 16.0 mL) and Tmax >10s (r2: 0.73; median absolute error, 11.3 mL) showed the strongest agreement between the pre-EVT CTP study and the final DWI. CBF <38% (r2: 0.76; median absolute error, 8.2 mL) and CBF <34% (r2: 0.76; median absolute error, 9.1 mL) also correlated well with final infarct volume on DWI. CONCLUSIONS: Pre-EVT CT perfusion imaging is useful to predict the final ischemic infarct volume in BAO patients. Tmax >8s and Tmax >10s were the strongest predictors of the post-EVT final infarct volume.

Elevated Hypoperfusion Intensity Ratio (HIR) observed in patients with a large vessel occlusion (LVO) presenting in the evening.

BACKGROUND: Circadian variability has been implicated in timing of stroke onset, yet the full impact of underlying biological rhythms on acute stroke perfusion patterns is not known. We aimed to describe the relationship between time of stroke onset and perfusion profiles in patients with large vessel occlusion (LVO). METHODS: A retrospective observational study was conducted using prospective registries of four stroke centers across North America and Europe with systematic use of perfusion imaging in clinical care. Included patients had stroke due to ICA, M1 or M2 occlusion and baseline perfusion imaging performed within 24h from last-seen-well (LSW). Stroke onset was divided into eight hour intervals: (1) Night: 23:00-6:59, (2) Day: 7:00-14:59, (3) Evening: 15:00-22:59. Core volume was estimated on CT perfusion (rCBF <30%) or DWI-MRI (ADC <620) and the collateral circulation was estimated with the Hypoperfusion Intensity Ratio (HIR = [Tmax>10s]/[Tmax>6s]). Non-parametric testing was conducted using SPSS to account for the non-normalized dependent variables. RESULTS: A total of 1506 cases were included (median age 74.9 years, IQR 63.0-84.0). Median NIHSS, core volumes, and HIR were 14.0 (IQR 8.0-20.0), 13.0mL (IQR 0.0-42.0), and 0.4 (IQR 0.2-0.6) respectively. Most strokes occurred during the Day (n = 666, 44.2%), compared to Night (n = 360, 23.9%), and Evening (n = 480, 31.9%). HIR was highest, indicating worse collaterals, in the Evening compared to the other timepoints (p = 0.006). Controlling for age and time to imaging, Evening strokes had significantly higher HIR compared to Day (p = 0.013). CONCLUSION: Our retrospective analysis suggests that HIR is significantly higher in the evening, indicating poorer collateral activation which may lead to larger core volumes in these patients.

Larger ischemic cores and poor collaterals among large vessel occlusions presenting in the late evening.

BACKGROUND: Components critical to cerebral perfusion have been noted to oscillate over a 24-h cycle. We previously reported that ischemic core volume has a diurnal relationship with stroke onset time when examined as dichotomized epochs (i.e. Day, Evening, Night) in a cohort of over 1,500 large vessel occlusion (LVO) patients. In this follow-up analysis, our goal was to explore if there is a sinusoidal relationship between ischemic core, collateral status (as measured by HIR), and stroke onset time. METHODS: We retrospectively examined collection of LVO patients with baseline perfusion imaging performed within 24 h of stroke onset from four international comprehensive stroke centers. Both ischemic core volume and HIR, were utilized as the primary radiographic parameters. To evaluate for differences in these parameters over a continuous 24-h cycle, we conducted a sinusoidal regression analysis after linearly regressing out the confounders age and time to imaging. RESULTS: A total of 1506 LVO cases were included, with a median ischemic core volume of 13.0 cc (IQR: 0.0-42.0) and median HIR of 0.4 (IQR: 0.2-0.6). Ischemic core volume varied by stroke onset time in the unadjusted (p = 0.001) and adjusted (p = 0.003) sinusoidal regression analysis with a peak in core volume around 7:45PM. HIR similarly varied by stroke onset time in the unadjusted (p = 0.004) and adjusted (p = 0.002) models with a peak in HIR values at around 8:18PM. CONCLUSION: The results suggest that critical factors to the development of the ischemic core vary by stroke onset time and peak around 8PM. When placed in the context of prior studies, strongly suggest a diurnal component to the development of the ischemic core.

Intravenous tPA (Tissue-Type Plasminogen Activator) Correlates With Favorable Venous Outflow Profiles in Acute Ischemic Stroke.

BACKGROUND: Intravenous tPA (tissue-type plasminogen activator) is often administered before endovascular thrombectomy (EVT). Recent studies have questioned whether tPA is necessary given the high rates of arterial recanalization achieved by EVT, but whether tPA impacts venous outflow (VO) is unknown. We investigated whether tPA improves VO profiles on baseline computed tomography (CT) angiography (CTA) images before EVT. METHODS: Retrospective multicenter cohort study of patients with acute ischemic stroke due to large vessel occlusion undergoing EVT triage. Included patients underwent CT, CTA, and CT perfusion before EVT. VO profiles were determined by opacification of the vein of Labbé, sphenoparietal sinus, and superficial middle cerebral vein on CTA as 0, not visible; 1, moderate opacification; and 2, full. Pial arterial collaterals were graded on CTA, and tissue-level collaterals were assessed on CT perfusion using the hypoperfusion intensity ratio. Clinical and demographic data were determined from the electronic medical record. Using multivariable regression analysis, we determined the correlation between tPA administration and favorable VO profiles. RESULTS: Seven hundred seventeen patients met inclusion criteria. Three hundred sixty-five patients received tPA (tPA+), while 352 patients were not treated with tPA (tPA-). Fewer tPA+ patients had atrial fibrillation (n=128 [35%] versus n=156 [44%]; P=0.012) and anticoagulants/antiplatelet treatment before acute ischemic stroke due to large vessel occlusion onset (n=130 [36%] versus n=178 [52%]; P<0.001) compared with tPA- patients. One hundred eighty-five patients (51%) in the tPA+ and 100 patients (28%) in the tPA- group exhibited favorable VO (P<0.001). Multivariable regression analysis showed that tPA administration was a strong independent predictor of favorable VO profiles (OR, 2.6 [95% CI, 1.7-4.0]; P<0.001) after control for favorable pial arterial CTA collaterals, favorable tissue-level collaterals on CT perfusion, age, presentation National Institutes of Health Stroke Scale, antiplatelet/anticoagulant treatment, history of atrial fibrillation and time from symptom onset to imaging. CONCLUSIONS: In patients with acute ischemic stroke due to large vessel occlusion undergoing thrombectomy triage, tPA administration was strongly associated with the presence of favorable VO profiles.