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Background and Objectives: Assessing the risk of recurrent intracerebral hemorrhage (ICH) is of high clinical importance. MRI-based cerebral small vessel disease (SVD) markers may help establish ICH etiologic subtypes (including cryptogenic ICH) relevant for recurrence risk., Methods: We investigated the risk of recurrent ICH in a large cohort of consecutive ICH survivors with available MRI at baseline. Patients with macrovascular, structural, or other identified secondary causes (other than SVD) were excluded. Based on MRI findings, ICH etiology was defined as probable cerebral amyloid angiopathy (CAA) according to the Boston 2.0 criteria, arteriolosclerosis (nonlobar ICH and additional markers of arteriolosclerosis, absent lobar hemorrhagic lesions), mixed SVD (mixed deep and lobar hemorrhagic changes), or cryptogenic ICH (no MRI markers of SVD). Recurrent ICH was determined using electronic health records and confirmed by neuroimaging. Data from an independent multicenter cohort (CROMIS-2 ICH) were used to confirm core findings., Results: Of 443 patients with ICH (mean age 67 ± 13 years, 41% female), ICH etiology was mixed SVD in 36.7%, arteriolosclerosis in 23.6%, CAA in 23.0%, and cryptogenic ICH in 16.7%. During a median follow-up period of 5.7 years (interquartile range 2.9-10.0, 2,682 patient-years), recurrent ICH was found in 59 individual patients (13.3%). The highest recurrence rate per 100 person-years was detected in patients with CAA (8.5, 95% CI 6.1-11.7), followed by that in those with mixed SVD (1.8, 95% CI 1.1-2.9) and arteriolosclerosis (0.6, 95% CI 0.3-1.5). No recurrent ICH occurred in patients with cryptogenic ICH during 510 person-years follow-up (97.5% CI 0-0.7); this finding was confirmed in an independent cohort (CROMIS-2 ICH, n = 216), in which also there was no recurrence in patients with cryptogenic ICH. In patients with CAA, cortical superficial siderosis was the imaging feature strongest related to ICH recurrence (hazard ratio 5.7, 95% CI 2.4-13.6)., Discussion: MRI-based etiologic subtypes are helpful in determining the recurrence risk of ICH; while the highest recurrence risk was found in CAA, recurrence risk was low for arteriolosclerosis and negligible for cryptogenic ICH., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: Ischemic stroke despite a direct oral anticoagulant (DOAC) is increasingly common and portends a high risk of subsequent ischemic stroke. The efficacy and safety of antithrombotic regimens after the condition are unclear. We aimed to compare the outcomes of patients with ischemic stroke despite DOACs with and without an alternative antithrombotic regimen and determine the risk factors of recurrent ischemic stroke while on anticoagulation., Methods: In a population-based, propensity score-weighted, retrospective cohort study, we compared the clinical outcomes of DOAC-to-warfarin switch, DOAC-to-DOAC switch (DOAC switch ), or addition of antiplatelet agents, with those of unchanged DOAC regimen (DOAC same ) among patients with nonvalvular atrial fibrillation (NVAF) who developed the first ischemic stroke despite a DOAC from January 1, 2015, to December 31, 2020, in Hong Kong. The primary outcome was recurrent ischemic stroke. Secondary outcomes were intracranial hemorrhage, acute coronary syndrome, and death. We performed competing risk regression analyses to compare the clinical endpoints and determined the predictors of recurrent ischemic stroke in an unweighted multivariable logistic regression model., Results: During the 6-year study period, among 45,946 patients with AF on a DOAC as stroke prophylaxis, 2,908 patients developed ischemic stroke despite a DOAC. A total of 2,337 patients with NVAF were included in the final analyses. Compared with DOAC same , warfarin (aHR 1.96, 95% CI 1.27-3.02, p = 0.002) and DOAC switch (aHR 1.62, 95% CI 1.25-2.11, p < 0.001) were associated with an increased risk of recurrent ischemic stroke. In the DOAC same group, adjunctive antiplatelet agent was not associated with a reduced risk of recurrent ischemic stroke. Diabetes mellitus, concurrent cytochrome P450/P-glycoprotein (CYP/P-gp) modulators, and large artery atherosclerotic disease (LAD) were predictors of recurrent ischemic stroke., Discussion: In patients with NVAF with ischemic stroke despite a DOAC, the increased risk of recurrent ischemic stroke with switching to warfarin called for caution against such practice, while the increased ischemic stroke with DOAC-to-DOAC switch demands further studies. Adjunctive antiplatelet agent did not seem to reduce ischemic stroke relapse. Because diabetes mellitus, the use of CYP/P-gp modulators, and LAD were predictors of recurrent ischemic stroke, further investigations should evaluate whether strict glycemic control, DOAC level monitoring, and routine screening for carotid and intracranial atherosclerosis may reduce ischemic stroke recurrence in these patients., Classification of Evidence: This study provides Class II evidence that in patients with NVAF experiencing an ischemic stroke while being treated with a DOAC, continuing treatment with that DOAC is more effective at preventing recurrent ischemic stroke than switching to a different DOAC or to warfarin., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background and Objectives: In patients with ischemic stroke (IS) or transient ischemic attack (TIA) and cortical superficial siderosis (cSS), there are few data regarding the risk of future cerebrovascular events and also about the benefits and safety of antithrombotic drugs for secondary prevention. We investigated the associations of cSS and stroke risk in patients with recent IS or TIA., Methods: We retrospectively analyzed the Microbleeds International Collaborative Network (MICON) database. We selected patients with IS or TIA from cohorts who had MRI-assessed cSS, available data on antithrombotic treatments, recurrent cerebrovascular events (intracranial hemorrhage [ICrH], IS, or any stroke [ICrH or IS]), and mortality. We calculated incidence rates (IRs) and performed univariable and multivariable Cox regression analyses., Results: Of 12,669 patients (mean age 70.4 ± 12.3 years, 57.3% men), cSS was detected in 273 (2.2%) patients. During a mean follow-up of 24 ± 17 months, IS was more frequent than ICrH in both cSS (IR 57.1 vs 14.6 per 1,000 patient-years) and non-cSS (33.7 vs 6.3 per 1,000 patient-years) groups. Compared with the non-cSS group, cSS was associated with any stroke on multivariable analysis {IR 83 vs 42 per 1,000 patient-years, adjusted hazard ratio [HR] for cSS 1.62 (95% CI: 1.14-2.28; p = 0.006)}. This association was not significant in subgroups of patients treated with antiplatelet drugs (n = 6,554) or with anticoagulants (n = 4,044). Patients with cSS who were treated with both antiplatelet drugs and anticoagulants (n = 1,569) had a higher incidence of ICrH (IR 107.5 vs 4.9 per 1,000 patient-years, adjusted HR 13.26; 95% CI: 2.90-60.63; p = 0.001) and of any stroke (IR 198.8 vs 34.7 per 1,000 patient-years, adjusted HR 5.03; 95% CI: 2.03-12.44; p < 0.001) compared with the non-cSS group., Discussion: Patients with IS or TIA with cSS are at increased risk of stroke (ICrH or IS) during follow-up; the risk of IS exceeds that of ICrH for patients receiving antiplatelet or anticoagulant treatment alone, but the risk of ICrH exceeds that of IS in patients receiving both treatments. The findings suggest that either antiplatelet or anticoagulant treatment alone should not be avoided in patients with cSS, but combined antithrombotic therapy might be hazardous. Our findings need to be confirmed by randomized clinical trials., (© 2022 American Academy of Neurology.)

Background and Objective: We investigated the associations between the APOE genotype, intracerebral hemorrhage (ICH), and neuroimaging markers of cerebral amyloid angiopathy (CAA)., Methods: We included patients from a prospective, multicenter UK observational cohort study of patients with ICH and representative UK population controls. First, we assessed the association of the APOE genotype with ICH (compared with controls without ICH). Second, among patients with ICH, we assessed the association of APOE status with the hematoma location (lobar or deep) and brain CT markers of CAA (finger-like projections [FLP] and subarachnoid extension [SAE])., Results: We included 907 patients with ICH and 2,636 controls. The mean age was 73.2 (12.4 SD) years for ICH cases vs 69.6 (0.2 SD) for population controls; 50.3% of cases and 42.1% of controls were female. Compared with controls, any APOE ε2 allele was associated with all ICH (lobar and nonlobar) and lobar ICH on its own in the dominant model (OR 1.38, 95% CI 1.13-1.7, p = 0.002 and OR 1.50, 95% CI 1.1-2.04, p = 0.01, respectively) but not deep ICH in an age-adjusted analyses (OR 1.26, 95% CI 0.97-1.63, p = 0.08). In the cases-only analysis, the APOE ε4 allele was associated with lobar compared with deep ICH in an age-adjusted analyses (OR 1.56, 95% CI 1.1-2.2, p = 0.01). When assessing CAA markers, APOE alleles were independently associated with FLP (ε4: OR 1.74, 95% CI 1.04-2.93, p = 0.04 and ε2/ε4: 2.56, 95% CI 0.99-6.61, p = 0.05). We did not find an association between APOE alleles and SAE., Discussion: We confirmed associations between APOE alleles and ICH including lobar ICH. Our analysis shows selective associations between APOE ε2 and ε4 alleles with FLP, a CT marker of CAA. Our findings suggest that different APOE alleles might have diverging influences on individual neuroimaging biomarkers of CAA-associated ICH., (© 2022 American Academy of Neurology.)

Background and Objectives: Very poor outcome despite IV thrombolysis (IVT) and mechanical thrombectomy (MT) occurs in approximately 1 of 4 patients with ischemic stroke and is associated with a high logistic and economic burden. We aimed to develop and validate a multivariable prognostic model to identify futile recanalization therapies (FRTs) in patients undergoing those therapies., Methods: Patients from a prospectively collected observational registry of a single academic stroke center treated with MT and/or IVT were included. The data set was split into a training (N = 1,808, 80%) and internal validation (N = 453, 20%) cohort. We used gradient boosted decision tree machine learning models after k-nearest neighbor imputation of 32 variables available at admission to predict FRT defined as modified Rankin scale 5-6 at 3 months. We report feature importance, ability for discrimination, calibration, and decision curve analysis., Results: A total of 2,261 patients with a median (interquartile range) age of 75 years (64-83 years), 46% female, median NIH Stroke Scale 9 (4-17), 34% IVT alone, 41% MT alone, and 25% bridging were included. Overall, 539 (24%) had FRT, more often in MT alone (34%) as compared with IVT alone (11%). Feature importance identified clinical variables (stroke severity, age, active cancer, prestroke disability), laboratory values (glucose, C-reactive protein, creatinine), imaging biomarkers (white matter hyperintensities), and onset-to-admission time as the most important predictors. The final model was discriminatory for predicting 3-month FRT (area under the curve 0.87, 95% CI 0.87-0.88) and had good calibration (Brier 0.12, 0.11-0.12). Overall performance was moderate (F1-score 0.63 ± 0.004), and decision curve analyses suggested higher mean net benefit at lower thresholds of treatment (up to 0.8)., Conclusions: This FRT prediction model can help inform shared decision making and identify the most relevant features in the emergency setting. Although it might be particularly useful in low resource healthcare settings, incorporation of further multifaceted variables is necessary to further increase the predictive performance., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To test the hypothesis that selection by initial imaging modality (MRI vs CT) is associated with rate of futile recanalizations (FRs) after mechanical thrombectomy (MT), we assessed this association in a multicenter, retrospective observational registry (BEYOND-SWIFT [Registry for Evaluating Outcome of Acute Ischemic Stroke Patients Treated With Mechanical Thrombectomy], NCT03496064)., Methods: In 2,011 patients (49.7% female, median age 73 years [61-81]) included between 2009 and 2017, we performed univariate and multivariate analyses regarding the occurrence of FR. FRs were defined as 90-day modified Rankin Scale (mRS) score 4-6 despite successful recanalization in patients selected by MRI (n = 690) and CT (n = 1,321) with a sensitivity analysis considering only patients with mRS 5-6 as futile., Results: MRI as compared to CT resulted in similar rates of subsequent MT (adjusted odds ratio [aOR] 1.048, 95% confidence interval [CI] 0.677-1.624). Rates of FR were as follows: 571/1,489 (38%) FR mRS 4-6 including 393/1,489 (26%) FR mRS 5-6. CT-based selection was associated with increased rates of FRs compared to MRI (44% [41%-47%] vs 29% [25%-32%], p < 0.001; aOR 1.77 [95% CI 1.25-2.51]). These findings were robust in sensitivity analysis. MRI-selected patients had a delay of approximately 30 minutes in workflow metrics in real-world university comprehensive stroke centers. However, functional outcome and mortality were more favorable in patients selected by MRI compared to patients selected with CT., Conclusions: CT selection for MT was associated with an increased risk of FRs as compared to MRI selection. Efforts are needed to shorten workflow delays in MRI patients. Further research is needed to clarify the role of the initial imaging modality on FR occurrence and to develop a reliable FR prediction algorithm., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)