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.).

Trial of Thrombectomy 6 to 24 Hours after Stroke Due to Basilar-Artery Occlusion.

BACKGROUND: The effects and risks of endovascular thrombectomy 6 to 24 hours after stroke onset due to basilar-artery occlusion have not been extensively studied. METHODS: In a trial conducted over a 5-year period in China, we randomly assigned, in a 1:1 ratio, patients with basilar-artery stroke who presented between 6 to 24 hours after symptom onset to receive either medical therapy plus thrombectomy or medical therapy only (control). The original primary outcome, a score of 0 to 4 on the modified Rankin scale (range, 0 to 6, with a score of 0 indicating no disability, 4 moderately severe disability, and 6 death) at 90 days, was changed to a good functional status (a modified Rankin scale score of 0 to 3, with a score of 3 indicating moderate disability). Primary safety outcomes were symptomatic intracranial hemorrhage at 24 hours and 90-day mortality. RESULTS: A total of 217 patients (110 in the thrombectomy group and 107 in the control group) were included in the analysis; randomization occurred at a median of 663 minutes after symptom onset. Enrollment was halted at a prespecified interim analysis because of the superiority of thrombectomy. Thrombolysis was used in 14% of the patients in the thrombectomy group and in 21% of those in the control group. A modified Rankin scale score of 0 to 3 (primary outcome) occurred in 51 patients (46%) in the thrombectomy group and in 26 (24%) in the control group (adjusted rate ratio, 1.81; 95% confidence interval [CI], 1.26 to 2.60; P<0.001). The results for the original primary outcome of a modified Rankin scale score of 0 to 4 were 55% and 43%, respectively (adjusted rate ratio, 1.21; 95% CI, 0.95 to 1.54). Symptomatic intracranial hemorrhage occurred in 6 of 102 patients (6%) in the thrombectomy group and in 1 of 88 (1%) in the control group (risk ratio, 5.18; 95% CI, 0.64 to 42.18). Mortality at 90 days was 31% in the thrombectomy group and 42% in the control group (adjusted risk ratio, 0.75; 95% CI, 0.54 to 1.04). Procedural complications occurred in 11% of the patients who underwent thrombectomy. CONCLUSIONS: Among patients with stroke due to basilar-artery occlusion who presented 6 to 24 hours after symptom onset, thrombectomy led to a higher percentage with good functional status at 90 days than medical therapy but was associated with procedural complications and more cerebral hemorrhages. (Funded by the Chinese National Ministry of Science and Technology; BAOCHE ClinicalTrials.gov number, NCT02737189.).

Mode of Onset Modifies the Effect of Time to Endovascular Reperfusion on Clinical Outcomes after Acute Ischemic Stroke: An Analysis of the DAWN Trial.

OBJECTIVE: We aimed to assess the impact of time to endovascular thrombectomy (EVT) on clinical outcomes in the DAWN trial, while also exploring the potential effect modification of mode of stroke onset on this relationship. METHODS: The association between every 1-h treatment delay with 90-day functional independence (modified Rankin Scale [mRS] score 0-2), symptomatic intracranial hemorrhage, and 90-day mortality was explored in the overall population and in three modes of onset subgroups (wake-up vs. witnessed vs. unwitnessed). RESULTS: Out of the 205 patients, 98 (47.8%) and 107 (52.2%) presented in the 6 to 12 hours and 12 to 24 hours time window, respectively. Considering all three modes of onset together, there was no statistically significant association between time last seen well to randomization with either functional independence or mortality at 90 days in either the endovascular thrombectomy (mRS 0-2 1-hour delay OR 1.07; 95% CI 0.93-1.24; mRS 6 OR 0.84; 95% CI 0.65-1.03) or medical management (mRS 0-2 1-hour delay OR 0.98; 95% CI 0.80-1.14; mRS 6 1-hour delay OR 0.94; 95% CI 0.79-1.09) groups. Moreover, there was no significant interaction between treatment effect and time (p = 0.439 and p = 0.421 for mRS 0-2 and 6, respectively). However, within the thrombectomy group, the models that tested the association between time last seen well to successful reperfusion (modified Treatment in Cerebral Infarction ≥2b) and 90-day functional independence showed a significant interaction with mode of presentation (p = 0.013). This appeared to be driven by a nominally positive slope for both witnessed and unwitnessed strokes versus a significantly (p = 0.018) negative slope in wake-up patients. There was no association between treatment times and symptomatic intracranial hemorrhage. INTERPRETATION: Mode of onset modifies the effect of time to reperfusion on thrombectomy outcomes, and should be considered when exploring different treatment paradigms in the extended window. ANN NEUROL 2024;96:356-364.

Rescue Therapy for Failed Mechanical Thrombectomy in Acute Ischemic Stroke: A Pooled Analysis of the Society of Vascular and Interventional Neurology Registry.

OBJECTIVE: We aimed to evaluate the association between rescue therapy (RT) and functional outcomes compared to medical management (MM) in patients presenting after failed mechanical thrombectomy (MT). METHODS: This cross-sectional study utilized prospectively collected and maintained data from the Society of Vascular and Interventional Neurology Registry, spanning from 2011 to 2021. The cohort comprised patients with large vessel occlusions (LVOs) with failed MT. The primary outcome was the shift in the degree of disability, as gauged by the modified Rankin Scale (mRS) at 90 days. Additional outcomes included functional independence (90-day mRS score of 0-2), symptomatic intracranial hemorrhage (sICH), and 90-day mortality. RESULTS: Of a total of 7,018 patients, 958 presented failed MT and were included in the analysis. The RT group comprised 407 (42.4%) patients, and the MM group consisted of 551 (57.5%) patients. After adjusting for confounders, the RT group showed a favorable shift in the overall 90-day mRS distribution (adjusted common odds ratio = 1.79, 95% confidence interval [CI] = 1.32-2.45, p < 0.001) and higher rates of functional independence (RT: 28.8% vs MM: 15.7%, adjusted odds ratio [aOR] = 1.93, 95% CI = 1.21-3.07, p = 0.005) compared to the MM group. RT also showed lower rates of sICH (RT: 3.8% vs MM: 9.1%, aOR = 0.52, 95% CI = 0.28-0.97, p = 0.039) and 90-day mortality (RT: 33.4% vs MM: 45.5%, aOR = 0.61, 95% CI = 0.42-0.89, p = 0.009). INTERPRETATION: Our findings advocate for the utilization of RT as a potential treatment strategy for cases of LVO resistant to first-line MT techniques. Prospective studies are warranted to validate these observations and optimize the endovascular approach for failed MT patients. ANN NEUROL 2024;96:343-355.

Recent Translational Research Models of Intracranial Atherosclerotic Disease.

Intracranial atherosclerotic disease (ICAD) is a leading cause of ischemic stroke worldwide. However, research on the pathophysiology of ICAD is scarce due to the relative inaccessibility of histology samples and the lack of comprehensive experimental models. As a result, much of the current understanding of ICAD relies on research on extracranial atherosclerosis. This approach is problematic as intracranial and extracranial arteries are anatomically, structurally, physiologically, and metabolically distinct, indicating that intracranial and extracranial atherosclerosis likely develop through different biologic pathways. The current standard of care for ICAD treatment relies predominantly on therapeutics developed to treat extracranial atherosclerosis and is insufficient given the alarmingly high risk of stroke. To provide a definitive treatment for the disease, a deeper understanding of the pathophysiology underlying ICAD is specifically required. True mechanistic understanding of disease pathogenesis is only possible using robust experimental models. In this review, we aim to identify the advantages and limitations of the existing in vivo and in vitro models of ICAD and basic atherosclerotic processes, which may be used to inform better models of ICAD in the future and drive new therapeutic strategies to reduce stroke risk.

Magnesium and Hematoma Expansion in Intracerebral Hemorrhage: A FAST-MAG Randomized Trial Analysis.

BACKGROUND: Observational studies suggest that magnesium may have hemostatic effects. FAST-MAG (Field Administration of Stroke Therapy-Magnesium) was a pragmatic clinical trial of magnesium sulfate administered prehospital for acute clinical stroke syndromes and included patients with intracerebral hemorrhage. Exploratory secondary analysis by the treatment group found no reduction in hematoma expansion (HE) associated with magnesium treatment in intracerebral hemorrhage but did not consider serum magnesium levels achieved. We analyzed FAST-MAG intracerebral hemorrhage data for associations between serum magnesium level, HE, and early neurological deterioration, accounting for groupwise biases. METHODS: HE was defined as hematoma volume increase ≥3 mL within 24 hours and early neurological deterioration as ≥1-point Glasgow Coma Scale decline from arrival to hospital day 4. Comparing treatment and placebo groups confirmed biased availability of neuroimaging data. Therefore, HE and neurological deterioration were analyzed and stratified by treatment and placebo groups using univariate tests and adjusted logistic regression. RESULTS: Spontaneous intracerebral hemorrhage was present in 381 patients. Placebo patients had fewer serial neuroimaging studies available (123 [65.4%] versus 145 [75.1%]; P=0.038). Necessary data were available in 104 magnesium- and 85 placebo-treated patients (age, 64.9 [13.0] years; 67.7% male). In the magnesium group, higher magnesium level was associated with less HE (adjusted odds ratio, 0.64 per mg/dL [95% CI, 0.42-0.93]) and less neurological deterioration (adjusted odds ratio, 0.54 per mg/dL [95% CI, 0.33-0.82]). In the placebo group, magnesium level was not associated with either HE or neurological deterioration. CONCLUSIONS: Magnesium may exhibit a hemostatic effect that was only observable in the FAST-MAG magnesium treatment group. Equipoise should be maintained, and specific trials are needed. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00059332.

ARISE I Consensus Review on the Management of Intracranial Aneurysms.

BACKGROUND: Intracranial aneurysms (IAs) remain a challenging neurological diagnosis associated with significant morbidity and mortality. There is a plethora of microsurgical and endovascular techniques for the treatment of both ruptured and unruptured aneurysms. There is no definitive consensus as to the best treatment option for this cerebrovascular pathology. The Aneurysm, Arteriovenous Malformation, and Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts discussed best practices and the most promising approaches to improve the management of brain aneurysms. METHODS: A group of experts from academia, industry, and federal regulators convened to discuss updated clinical trials, scientific research on preclinical system models, management options, screening and monitoring, and promising novel device technologies, aiming to improve the outcomes of patients with IA. RESULTS: Aneurysm, Arteriovenous Malformation, and Chronic Subdural Hematoma Roundtable Discussion With Industry and Stroke Experts suggested the incorporation of artificial intelligence to capture sequential aneurysm growth, identify predictors of rupture, and predict the risk of rupture to guide treatment options. The consensus strongly recommended nationwide systemic data collection of unruptured IA radiographic images for the analysis and development of machine learning algorithms for rupture risk. The consensus supported centers of excellence for preclinical multicenter trials in areas such as genetics, cellular composition, and radiogenomics. Optical coherence tomography and magnetic resonance imaging contrast-enhanced 3T vessel wall imaging are promising technologies; however, more data are needed to define their role in IA management. Ruptured aneurysms are best managed at large volume centers, which should include comprehensive patient management with expertise in microsurgery, endovascular surgery, neurology, and neurocritical care. CONCLUSIONS: Clinical and preclinical studies and scientific research on IA should engage high-volume centers and be conducted in multicenter collaborative efforts. The future of IA diagnosis and monitoring could be enhanced by the incorporation of artificial intelligence and national radiographic and biologic registries. A collaborative effort between academic centers, government regulators, and the device industry is paramount for the adequate management of IA and the advancement of the field.

Association of Incident Stroke Risk With an IL-18-Centered Inflammatory Network Biomarker Composite.

BACKGROUND: A coordinated network of circulating inflammatory molecules centered on the pleotropic pro-atherogenic cytokine interleukin-18 (IL-18) is linked to cerebral small vessel disease. We sought to validate the association of this inflammatory biomarker network with incident stroke risk, cognitive impairment, and imaging metrics in a sample of the Framingham Offspring Cohort. METHODS: Using available baseline measurements of serum levels of IL-18, GDF (growth and differentiation factor)-15, soluble form of receptor for advanced glycation end products, myeloperoxidase, and MCP-1 (monocyte chemoattractant protein-1) from Exam 7 of the Framingham Offspring Cohort (1998-2001), we constructed a population-normalized, equally weighted log-transformed mean Z-score value representing the average level of each serum analyte to create an inflammatory composite score (ICS5). Multivariable regression models were used to determine the association of ICS5 with incident stroke, brain magnetic resonance imaging features, and cognitive testing performance. RESULTS: We found a significant association between ICS5 score and increased risk for incident all-cause stroke (hazard ratio, 1.48 [95% CI, 1.05-2.08]; P=0.024) and ischemic stroke (hazard ratio, 1.51 [95% CI, 1.03-2.21]; P=0.033) in the Exam 7 cohort of 2201 subjects (mean age 62±9 years; 54% female) aged 45+ years with an all-cause incident stroke rate of 6.1% (135/2201) and ischemic stroke rate of 4.9% (108/2201). ICS5 and its component serum markers are all associated with the Framingham Stroke Risk Profile score (ß±SE, 0.19±0.02; P<0.0001). In addition, we found a significant inverse association of ICS5 with a global cognitive score, derived from a principal components analysis of the neuropsychological battery used in the Framingham cohort (-0.08±0.03; P=0.019). No association of ICS5 with magnetic resonance imaging metrics of cerebral small vessel disease was observed. CONCLUSIONS: Circulating serum levels of inflammatory biomarkers centered on IL-18 are associated with an increased risk of stroke and cognitive impairment in the Framingham Offspring Cohort. Linking specific inflammatory pathways to cerebral small vessel disease may enhance individualized quantitative risk assessment for future stroke and vascular cognitive impairment.

Predicting Functional Outcome Using 24-Hour Post-Treatment Characteristics: Application of Machine Learning Algorithms in the STRATIS Registry.

FOR SOCIAL MEDIA: @AliciaCastongu2, @FazalZaidi9, @oozaidat, @Mouhammad_Jumaa OBJECTIVE: Machine learning (ML) algorithms have emerged as powerful predictive tools in the field stroke. Here, we examine the predictive accuracy of ML models for predicting functional outcomes using 24-hour post-treatment characteristics in the Systematic Evaluation of Patients Treated With Neurothrombectomy Devices for Acute Ischemic Stroke (STRATIS) Registry. METHODS: ML models, adaptive boost, random forest (RF), classification and regression trees (CART), C5.0 decision tree (C5.0), support vector machine (SVM), least absolute shrinkage and selection operator (LASSO), and logistic regression (LR), and traditional LR models were used to predict 90-day functional outcome (modified Rankin Scale score 0-2). Twenty-four-hour National Institutes of Health Stroke Scale (NIHSS) was examined as a continuous or dichotomous variable in all models. Model accuracy was assessed using the area under characteristic curve (AUC). RESULTS: The 24-hour NIHSS score was a top-predictor of functional outcome in all models. ML models using the continuous 24-hour NIHSS scored showed moderate-to-good predictive performance (range mean AUC: 0.76-0.92); however, RF (AUC: 0.92 ± 0.028) outperformed all ML models, except LASSO (AUC: 0.89 ± 0.023, p = 0.0958). Importantly, RF demonstrated a significantly higher predictive value than LR (AUC: 0.87 ± 0.031, p = 0.048) and traditional LR (AUC: 85 ± 0.06, p = 0.035) when using the 24-hour continuous NIHSS score. Predictive accuracy was similar between the 24-hour NIHSS score dichotomous and continuous ML models. INTERPRETATION: In this substudy, we found similar predictive accuracy for functional outcome when using the 24-hour NIHSS score as a continuous or dichotomous variable in ML models. ML models had moderate-to-good predictive accuracy, with RF outperforming LR models. External validation of these ML models is warranted. ANN NEUROL 2023;93:40-49.

Value of intravenous alteplase before thrombectomy among patients with tandem lesions and emergent carotid artery stenting: A subgroup analysis of the SWIFT DIRECT trial.

BACKGROUND AND PURPOSE: The value of intravenous thrombolysis (IVT) in eligible tandem lesion patients undergoing endovascular treatment (EVT) is unknown. We investigated treatment effect heterogeneity of EVT + IVT versus EVT-only in tandem lesion patients. Additional analyses were performed for patients undergoing emergent internal carotid artery (ICA) stenting. METHODS: SWIFT DIRECT randomized IVT-eligible patients to either EVT + IVT or EVT-only. Primary outcome was 90-day functional independence (modified Rankin Scale score 0-2) after the index event. Secondary endpoints were reperfusion success, 24 h intracranial hemorrhage rate, and 90-day all-cause mortality. Interaction models were fitted for all predefined outcomes. RESULTS: Among 408 included patients, 63 (15.4%) had a tandem lesion and 33 (52.4%) received IVT. In patients with tandem lesions, 20 had undergone emergent ICA stenting (EVT + IVT: 9/33, 27.3%; EVT: 11/30, 36.7%). Tandem lesion did not show treatment effect modification of IVT on rates of functional independence (tandem lesion EVT + IVT vs. EVT: 63.6% vs. 46.7%, non-tandem lesion EVT + IVT vs. EVT: 65.6% vs. 58.2%; p for interaction = 0.77). IVT also did not increase the risk of intracranial hemorrhage  among tandem lesion patients (tandem lesion EVT + IVT vs. EVT: 34.4% vs. 46.7%, non-tandem lesion EVT + IVT vs. EVT: 33.5% vs. 26.3%; p for interaction = 0.15). No heterogeneity was noted for other endpoints (p for interaction > 0.05). CONCLUSIONS: No treatment effect heterogeneity of EVT + IVT versus EVT-only was observed among tandem lesion patients. Administering IVT in patients with anticipated emergent ICA stenting seems safe, and the latter should not be a factor to consider when deciding to administer IVT before EVT.

Brain imaging prior to thrombectomy in the late window of large vessel occlusion ischemic stroke: a systematic review and meta-analysis.

PURPOSE: Optimal imaging modalities to select patients for endovascular thrombectomy (EVT) in the late window of acute ischemic stroke due to large vessel occlusions (AIS-LVO) are not known. We conducted a systematic review comparing outcomes of patients selected by non-contrast computed tomography (NCCT)/CT angiography (CTA) vs. those selected by CT perfusion (CTP) or magnetic resonance imaging (MRI) for EVT in these patients. METHODS: We searched PUBMED, EMBASE, and the Cochrane Library from January 1, 2000, to July 15, 2023, to identify studies comparing outcomes of patients selected for EVT by NCCT/CTA vs. CTP or MRI in the late time window for AIS-LVO. Primary outcome was independence (mRS 0-2) at 90 days or discharge. Secondary outcomes were symptomatic intracranial hemorrhage (sICH) and mortality. We pooled data across studies based on an inverse variance method. RESULTS: Six cohort studies with 4208 patients were included. Pooled results showed no significant difference in the rate of independence at 90 days or discharge (RR 0.96, 95% CI 0.88-1.03) and sICH (RR 1.26, 0.85-1.86) between patients selected by NCCT/CTA vs. CTP or MRI for EVT in the late window of AIS-LVO. However, patients selected by NCCT/CTA vs. CTP or MRI for EVT were associated with a higher risk of mortality (RR 1.21, 1.06-1.39). CONCLUSION: For AIS-LVO in the late window, patients selected by NCCT/CTA compared with those selected by CTP or MRI for EVT might have a comparable rate of functional independence and sICH. Baseline NCCT/CTA may triage AIS-LVO in the late window.

Cerebral venous sinus thrombosis associated with cancer: analysis of the ACTION-CVT study.

Nearly one fifth of patients with venous thromboembolism (VTE) have cancer. When both of these conditions occur, especially in cases of cerebral vein thrombosis (CVT), patient management is often challenging. The aim of this study was to compare the characteristics and event courses in patients affected by CVT with and without cancer. Consecutive patients with CVT from the ACTION-CVT cohort study were included if cancer status was reported. Risk factors as well as the clinical and radiological characteristics of patients were compared. Univariable and multivariable analyses were performed to assess variables associated with cancer. Kaplan-Meier method and log-rank test, logistic regression analysis, and propensity score matching were used to investigate any association between cancer-related CVT and study outcomes (primary outcome at 3-months: recurrent VTE or major hemorrhage; recurrent VTE; major hemorrhage; recanalization status; all-cause-death). Overall, 1,023 patients with CVT were included, of which 6.5% had cancer. Older age (adjusted odds ratio [aOR] 1.28 per decade increase; 95% confidence interval [CI] 1.08-1.52) and absence of headache (aOR 0.47; 95% CI 0.27-0.84) were independently associated with cancer. Patients with cancer had a higher risk of recurrent VTE or major hemorrhage (aOR 3.87; 95% CI 2.09-7.16), all-cause-death (aOR 7.56 95% CI 3.24-17.64), and major hemorrhage (aOR 3.70 95% CI 1.76-7.80). Recanalization rates, partial or complete, was not significantly different. CVT patients with cancer were more likely to be older, have no referred headache, and have worse outcomes compared to CVT patients without cancer.

Reperfusion Injury Is Associated With Poor Outcome in Patients With Recanalization After Thrombectomy.

BACKGROUND: The existence of cerebral reperfusion injury in human beings remains controversial. Thus, we aimed to explore the presence of reperfusion injury in acute ischemic stroke patients with recanalization after mechanical thrombectomy and analyzed its impact on neurological outcome. METHODS: We reviewed our prospectively collected database CIPPIS (Comparison Influence to Prognosis of CTP and MRP in AIS Patients, NCT03367286), and enrolled anterior circulation large artery occlusion patients with recanalization after mechanical thrombectomy who underwent (1) computed tomography (CT) perfusion on admission and immediately after recanalization to determine reperfusion region, and (2) CT and/or magnetic resonance imaging (MRI) immediately and 24 hours after recanalization to determine lesion areas. The expansion of lesion between recanalization and 24 hours within reperfusion region was potentially caused by reperfusion, thus termed as radiological observed reperfusion injury (RORI). Based on the imaging modality immediately after recanalization, RORI was further divided into RORICT and RORIMRI. We first included a small cohort who had performed both CT and MRI immediately after recanalization to validate the consistency between RORICT and RORIMRI (Study 1). Then the association with RORICT and poor outcome, defined as 3-month modified Rankin Scale score of 3 to 6, was explored in a larger cohort (Study 2). RESULTS: Study 1 included 23 patients and good consistency was found between RORICT and RORIMRI (intraclass correlation=0.97, P<0.001). Among 226 patients included in Study 2, a total of 106 (46.9%) were identified with RORI. The ratio of RORI to reperfusion region was 30.1 (16.2, 51.0)% and was independently associated with poor outcome (odds ratio=1.55 per 10% [95% CI' 1.30-1.84]; P<0.001). CONCLUSIONS: Our findings suggested that RORI was relatively frequent in stroke patients with recanalization after mechanical thrombectomy and associated with poor outcome despite successful recanalization. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03367286.

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.

Consensus Recommendations for Standardized Data Elements, Scales, and Time Segmentations in Studies of Human Circadian/Diurnal Biology and Stroke.

Increasing evidence indicates that circadian and diurnal rhythms robustly influence stroke onset, mechanism, progression, recovery, and response to therapy in human patients. Pioneering initial investigations yielded important insights but were often single-center series, used basic imaging approaches, and used conflicting definitions of key data elements, including what constitutes daytime versus nighttime. Contemporary methodologic advances in human neurovascular investigation have the potential to substantially increase understanding, including the use of large multicenter and national data registries, detailed clinical trial data sets, analysis guided by individual patient chronotype, and multimodal computed tomographic and magnetic resonance imaging. To fully harness the power of these approaches to enhance pathophysiologic knowledge, an important foundational step is to develop standardized definitions and coding guides for data collection, permitting rapid aggregation of data acquired in different studies, and ensuring a common framework for analysis. To meet this need, the Leducq Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA) convened a Consensus Statement Working Group of leading international researchers in cerebrovascular and circadian/diurnal biology. Using an iterative, mixed-methods process, the working group developed 79 data standards, including 48 common data elements (23 new and 25 modified/unmodified from existing common data elements), 14 intervals for time-anchored analyses of different granularity, and 7 formal, validated scales. This portfolio of standardized data structures is now available to assist researchers in the design, implementation, aggregation, and interpretation of clinical, imaging, and population research related to the influence of human circadian/diurnal biology upon ischemic and hemorrhagic stroke.

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.

Thrombectomy for Stroke in the Public Health Care System of Brazil.

BACKGROUND: Randomized trials involving patients with stroke have established that outcomes are improved with the use of thrombectomy for large-vessel occlusion. These trials were performed in high-resource countries and have had limited effects on medical practice in low- and middle-income countries. METHODS: We studied the safety and efficacy of thrombectomy in the public health system of Brazil. In 12 public hospitals, patients with a proximal intracranial occlusion in the anterior circulation that could be treated within 8 hours after the onset of stroke symptoms were randomly assigned in a 1:1 ratio to receive standard care plus mechanical thrombectomy (thrombectomy group) or standard care alone (control group). The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. RESULTS: A total of 300 patients were enrolled, including 79 who had undergone thrombectomy during an open-label roll-in period. Approximately 70% in the two groups received intravenous alteplase. The trial was stopped early because of efficacy when 221 of a planned 690 patients had undergone randomization (111 to the thrombectomy group and 110 to the control group). The common odds ratio for a better distribution of scores on the modified Rankin scale at 90 days was 2.28 (95% confidence interval [CI], 1.41 to 3.69; P = 0.001), favoring thrombectomy. The percentage of patients with a score on the modified Rankin scale of 0 to 2, signifying an absence of or minor neurologic deficit, was 35.1% in the thrombectomy group and 20.0% in the control group (difference, 15.1 percentage points; 95% CI, 2.6 to 27.6). Asymptomatic intracranial hemorrhage occurred in 51.4% of the patients in the thrombectomy group and 24.5% of those in the control group; symptomatic intracranial hemorrhage occurred in 4.5% of the patients in each group. CONCLUSIONS: In this randomized trial conducted in the public health care system of Brazil, endovascular treatment within 8 hours after the onset of stroke symptoms in conjunction with standard care resulted in better functional outcomes at 90 days than standard care alone. (Funded by the Brazilian Ministry of Health; RESILIENT ClinicalTrials.gov number, NCT02216643.).

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.

High-resolution magnetic resonance imaging of acute intracranial artery thrombus.

BACKGROUND AND PURPOSE: The development of high-resolution magnetic resonance imaging (HR-MRI) has enabled submillimeter-level evaluation of intracranial artery plaque and luminal thrombus. We sought to investigate the value of HR-MRI in assessing the pathogenesis of acute intracranial artery thrombus. METHODS: We examined the presence of intracranial thrombus on three-dimensional T1-weighted HR-MRI in acute ischemic stroke patients with intracranial artery occlusion on magnetic resonance angiography. We defined two thrombus-related HR-MRI features (peri-thrombus plaque and distal residual flow beyond the thrombus) and analyzed their association with potential embolic sources. RESULTS: Luminal thrombus and a shrunken artery without luminal thrombus were detected in 162 (96.4%) and six (3.6%) of 168 patients with intracranial artery occlusion, respectively. Among 111 patients with culprit major artery thrombus, peri-thrombus plaques were observed in 46.8% and distal residual flow beyond the thrombus in 64.0%. Patients with peri-thrombus plaque had a higher prevalence of diabetes (44.2% vs. 25.4%; p = 0.037), a lower prevalence of potential sources of cardioembolism (0% vs. 16.9%; p = 0.002), and a nonsignificantly lower prevalence of potential embolic sources from extracranial arteries (9.6% vs. 20.3%; p = 0.186) than those without. Patients with distal residual flow beyond the thrombus had a lower prevalence of potential sources of cardioembolism (1.4% vs. 22.5%; p < 0.001) and smaller infarct volumes (5.0 [1.4-12.7] mL vs. 16.6 [2.4-94.6] mL; p = 0.012) than those without. CONCLUSIONS: Our study showed that HR-MRI helps clarify the pathogenesis of acute intracranial artery thrombus. The presence of peri-thrombus plaque and distal residual flow beyond the thrombus favor the stroke mechanism of atherosclerosis rather than cardioembolism.

Impact of genetic polymorphisms on the risk of epilepsy amongst patients with acute brain injury: A systematic review.

BACKGROUND AND PURPOSE: The genetics of late seizure or epilepsy secondary to traumatic brain injury (TBI) or stroke are poorly understood. We undertook a systematic review to test the association of single-nucleotide polymorphisms (SNPs) with the risk of post-traumatic epilepsy (PTE) and post-stroke epilepsy (PSE). METHODS: We followed methods from our prespecified protocol on PROSPERO to identify indexed articles for this systematic review. We collated the association statistics from the included articles to assess the association of SNPs with the risk of epilepsy amongst TBI or stroke patients. We assessed study quality using the Q-Genie tool. We report odds ratios (OR) and hazard ratios with 95% confidence intervals (CIs). RESULTS: The literature search yielded 420 articles. We included 16 studies in our systematic review, of which seven were of poor quality. We examined published data on 127 SNPs from 32 genes identified in PTE and PSE patients. Eleven SNPs were associated with a significantly increased risk of PTE. Three SNPs, TRMP6 rs2274924, ALDH2 rs671, and CD40 -1C/T, were significantly associated with an increased risk of PSE, while two, AT1R rs12721273 and rs55707609, were significantly associated with reduced risk. The meta-analysis for the association of the APOE ɛ4 with PTE was nonsignificant (OR 1.8, CI 0.6-5.6). CONCLUSIONS: The current evidence on the association of genetic polymorphisms in epilepsy secondary to TBI or stroke is of low quality and lacks validation. A collaborative effort to pool genetic data linked to epileptogenesis in stroke and TBI patients is warranted.