Introduction:Chronic cerebral small vessel disease (CSVD) may help distinguish different etiological mechanisms in acute lacunar stroke; this study aimed to compare vascular risk factors and stroke etiology in patients with and without CSVD. Methods:In this observational study, consecutive patients with magnetic resonance imaging (MRI)-confirmed acute lacunar stroke were included from a prospective stroke database covering the years 2015-2019. CSVD was defined as a summary small vessel disease (SVD) score ≥2 based on established MRI markers, including white matter hyperintensities, lacunes, cerebral microbleeds, and enlarged perivascular spaces. Associations between CSVD, vascular risk factors, and stroke etiology were examined using descriptive statistics and multivariable regression analysis. Results:Among 486 patients with acute lacunar stroke, 175 (36%) had CSVD. Median age was 72 years, 40.5% were female, and the median National Institutes of Health Stroke Scale (NIHSS) score on admission was 3. Patients with CSVD had a higher burden of vascular risk factors, including hypertension, previous stroke, diabetes, and atrial fibrillation, and presented with higher NIHSS scores and blood pressure on admission. A patent foramen ovale (PFO)-related stroke mechanism was less frequent in patients with CSVD (1.1% vs. 10.0%), although this association was not statistically significant in multivariable analysis (odds ratio 0.30, 95% CI 0.06-1.38). Discussion:A high SVD burden is consistent with hypertensive arteriopathy as the predominant underlying etiology, whereas minimal SVD may indicate alternative mechanisms such as PFO-related stroke. Recognition of these differences may support more tailored diagnostic evaluation and secondary prevention strategies.

Abstract Background and aims Prior oral anticoagulant (OAC) therapy in patients with atrial fibrillation (AF) and acute ischemic stroke (AIS) may influence eligibility for intravenous thrombolysis (IVT) and clinical outcomes compared with patients without prior OAC. Methods We pooled individual patient data from two national stroke registries (Switzerland, Norway). We assessed the association of prior vitamin K antagonist (VKA) or direct oral anticoagulant (DOAC) therapy versus no prior OAC with favourable functional outcome at 3 months (mRS 0-2), 3-month mortality and symptomatic intracranial haemorrhage (sICH). Among IVT-eligible patients, we evaluated the association of IVT with outcomes stratified by prior OAC status. Results 19,188 patients with AF and AIS were included (mean age 80 (SD 9.6)), 19.9% on VKAs, 23.5% on DOACs and 56.6% with noOAC, IVT rates 10.2% VKA, 6.3% DOAC, 27.5% noOAC. Compared with noOAC, neither prior VKA (adjusted odds ratio (aOR) 1.01, 95% CI 0.87-1.18) nor prior DOAC therapy (aOR 1.11, 95% CI 0.96-1.28) were associated with higher odds of favorable functional outcome. DOAC therapy was associated with lower odds of mortality (aOR 0.84, 95% CI 0.71-0.98), while VKA therapy showed a numerical trend toward lower odds of mortality (aOR 0.86, 95% CI 0.72–1.01). Among IVT-eligible patients, the association of IVT with outcome and mortality did not differ by prior OAC status. Rates of sICH were similar across groups. Conclusions In AIS patients with AF, preceding DOAC therapy was associated with lower mortality but not improved functional outcome. IVT was associated with favourable outcomes without heterogeneity across OAC types or safety concerns. Conflict of interest Elisabeth Forfang: nothing to disclose. Bernhard M Siepen: Reports research support from the Swiss Heart Foundation, the Swiss Academy of Medical Sciences and Bangerter-Rhyner-Foundation, and Inselspital Bern, Department of Teaching and Research, unrelated to the current project. Thomas R Meinel: is the global PI of the DO-IT RCT and registry. He reports research support of the Swiss National Science Foundation; research support of the Swiss Heart Foundation, Bangerter Rhyner Foundation and the Horten Foundation; research grants from Boehringer Ingelheim; consultancies for Medtronic, and Boehringer Ingelheim (fees paid to institution). Participation in an advisory board for Boehringer Ingelheim (fees paid to institution). Member of a clinical event committee (CEC) of the SWISS-AF study. Stefan Engelter: reports support of the Swiss National Science Foundation and of the Swiss Heart Foundation (unreacted to the current project). Torgeir Bruun Wyller: has received lecture honorary from NovoNordisk. Espen Saxhaug Kristoffersen: nothing to disclose. David Julian Seiffge: nothing to disclose. Ole Morten Rønning: nothing to disclose.

Abstract Background and aims Background: Hemostatic therapy for intracerebral hemorrhage (ICH) reduces haematoma expansion (HE) but increases thromboembolic events (TE). We compared their rates and clinical outcomes. Methods The TICH-2 trial assessed tranexamic acid in patients with acute sporadic ICH. In a post hoc analysis, we assessed the association between HE (absolute ≥6 mL, relative ≥33%) and TE (ischemic stroke = IS, myocardial infarction = MI, pulmonary embolism = PE, deep vein thrombosis = DVT) with mortality and good functional outcome (modified Rankin scale score 0-2) at 90 days using multivariable models calculating adjusted odds (aOR) and hazard ratios (aHR) with 95% confidence intervals (95%CI). Results Of all 2325 TICH-2 participants 570 (27,4%) had HE and 111 (4,7%) had TE (23 IS, 17 MI, 43 PE, 33 DVT); 499 (21,6%) died and 667 (28,9%) had good functional outcome. History of atrial fibrillation (aHR 2.50, 95%CI 1.06-5.88, P = 0.036) but not HE was associated with occurrence of TE. Both, HE (aHR 2.07, 95%CI 1.67-2.56, P < 0.001) and TE (aHR 1.65, 95%CI 1.09-2.51, P = 0.019) were independently associated with mortality. Both, HE (aOR 0.45, 95%CI 0.33-0.62, P < 0.001) and TE (aOR 0.41, 95%CI 0.21-0.80, P = 0.009) were independently associated with reduced good functional outcome. Assessing TE types separately, only MI (aHR 2.68, 95%CI 1.29-5.55, P = 0.008) was associated with mortality and only PE (aOR 0.13, 95%CI 0.03-0.58, P = 0.008) with reduced good functional outcome. Conclusions Occurrence of HE is 5-fold more frequent than TE in patients with ICH. Both are independently associated with increased mortality and reduced odds for good functional outcome. Conflict of interest Nothing to disclose.

Abstract Background and aims Intracerebral haemorrhage (ICH) is associated with high mortality and morbidity. While primary haemorrhage-related injury seems irreversible, the perihaemorrhagic edema (PHE) is a modifiable driver of secondary injury and an outcome predictor. However, no effective treatment of PHE exists and mechanisms linking it to functional impairment remain unclear. We aim to quantify functional connectivity (FC) between PHE and unaffected brain areas to determine if this interregional synchronization of neuronal oscillations serves as a predictive biomarker for recovery, establishing PHE as therapeutic target. Methods This single-center prospective exploratory study will enroll 30 patients with supratentorial ICH (10-80mL volume) with lobar involvement undergoing inpatient neurorehabilitation. Exclusion criteria include prior stroke, traumatic brain injury, epilepsy, or surgical bone removal. We plan 4 study Visits aligned with PHE evolution (Figure 1). High-density EEG and MRI for FC computation, alongside clinical assessments are performed at Visit 1, 2, and 4. A telephone Visit 3 and Visit 4 assess functional outcomes. The primary endpoint is clinical recovery defined as Extended Barthel Index change between Visits 1-2. Secondary endpoints include functional outcome, quality of life, and motor/ cognitive scores. Multivariable models, adjusted for clinical covariates, will be used for analyses. Results Independent funding is secured; recruitment is planned for Q2/2026. We expect FC in the PHE region to be reduced compared to the contralesional site and anticipate this will predict recovery. By clarifying this network-level interplay, this project provides the scientific foundation for future transcranial direct current stimulation interventions paving the way for active therapeutic options to improve ICH recovery. Conflict of interest G. Sökeland: supported by a National MD-PhD Fellowship from the Swiss Academy of Medical Sciences (SAMW). B. Savic: nothing to disclose in regards to the project. B. Siepen: nothing to disclose in regards to the project. M. Goedlin: nothing to disclose in regards to the project. J. Rauch: nothing to disclose in regards to the project. J. Lippert: nothing to disclose in regards to the project. F. Schuler: nothing to disclose in regards to the project. D. Seiffge: nothing to disclose in regards to the project. S. Jung: nothing to disclose in regards to the project. B. Volbers: reports personal fees from Ipsen Pharma, personal fees from CSL Behring, personal fees from AstraZeneca, non-financial support from AbbVie, personal fees from Boehringer Ingelheim GmbH, personal fees from AbbVie, grants from Bangerter Rhyner Foundation, personal fees from Athersys, Inc., personal fees from Sivantos GmbH, personal fees from Bristol-Myers Squibb GmbH & Co. KGaA, personal fees from University of Bern, outside the submitted work. Table 1 - belongs to Methods

INTRODUCTION:Covert brain infarctions (CBIs) are associated with cardiovascular risk factors (cvRFs). We aimed to evaluate the presence and therapeutic implications of modifiable cvRFs in patients with incidentally discovered CBI on routine neuroimaging. PATIENTS AND METHODS:The SILENT cohort (NCT05685069) is a prospective, multicentred European cohort recruiting patients with incidentally detected focal CBIs on routine MRI, without prior clinical stroke. Modifiable cvRFs and their control were assessed using applicable international guidelines during a dedicated outpatient visit, including a clinical examination and laboratory work-up. Associations between cvRF profiles and the number of CBIs were analysed using linear regression. RESULTS:We included 231 patients (mean age 65 years, n = 130 [56%] male) with a total of 445 CBI lesions. Most CBIs were of lacunar type (n = 226; 51%) and the most common location was the cerebellum (n = 220; 50%). One hundred and fifty (65%) patients had at least 1, 112 (49%) at least 2 and 56 (24%) at least 3 known modifiable cvRFs. Among hypertensive patients, 69 (53%) had uncontrolled hypertension; 22 (65%) of diabetics were insufficiently controlled and 74 (58%) patients with dyslipidaemia had poorly controlled low-density lipoprotein cholesterol. Therapeutic measures were made for 144 patients (62%), including antiplatelet initiation in 107 (46%) and a statin in 69 (30%). The number of cvRFs per patient was significantly associated with the number of CBIs, rate ratio 1.08 (95% Confidence Interval (CI), 1.04-1.13). CONCLUSION:In patients with incidentally discovered CBI, we found a high burden of poorly controlled cvRFs. Our findings highlight the importance and yield of a dedicated clinical and laboratory assessment of cvRFs in patients with CBIs.

BACKGROUND:Decompressive craniectomy (DC) seemed to reduce the risk of death or profound disability (modified Rankin Scale score, 5-6) after deep intracerebral hemorrhage (ICH) by an absolute 13% (95% CI, 0%-26%) in the SWITCH trial (Swiss Trial of Decompressive Craniectomy versus Best Medical Treatment of Spontaneous Supratentorial Intracerebral Hemorrhage). Whether the effect of DC differs by ICH location is unknown. METHODS:Post hoc analysis of participants with supratentorial severe deep ICH from the intention-to-treat population of the SWITCH randomized controlled trial. We categorized ICH as involving (1) the basal ganglia (BG) alone, (2) BG and the posterior limb of the internal capsule (PLIC), or (3) BG, PLIC, and thalamus. We examined the interaction between ICH location and DC's effect on primary (modified Rankin Scale score, 5-6) and secondary outcomes (death; full modified Rankin Scale score range) at 180 days using unadjusted and adjusted logistic or survival models. RESULTS:Of 197 participants comprising the trial's intention-to-treat population, 184 were available for analysis (median age, 61 years; 59 women; 91 randomized to DC plus best medical treatment; and 93 to best medical treatment). ICH involved BG alone in 26 (14%), BG+PLIC in 94 (51%), and BG+PLIC+thalamus in 64 participants (35%). The marginal risk of the primary outcome after adjustment for age, ICH severity, and volume was lower with DC by 15.6% (95% CI, -49.2% to 18.1%) in participants with ICH of BG alone, by 11.4% (-29.3% to 6.6%) in those with ICH of BG+PLIC, and by 9% (-31% to 12.9%) in those with ICH of BG+PLIC+thalamus, without evidence for treatment-by-location interaction (P=0.95). Secondary outcome analyses yielded consistent results. CONCLUSIONS:The potential benefits of DC seemed preserved regardless of the location of severe deep ICH. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT02258919.

Background and ObjectivesCerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH.MethodsWe performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013–2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses.ResultsThe SSR cohort included 1,180 patients (median age [interquartile range] 73 [62–80] years, baseline NIH Stroke Scale 6 [2–12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145–185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes.DiscussionCADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Introduction: Knowledge about uptake and workflow metrics of hyperacute treatments in patients with non-traumatic intracerebral haemorrhage (ICH) in the emergency department is scarce. Methods: Single-centre retrospective study of consecutive patients with ICH between 01/2018–08/2020. We assessed uptake and workflow metrics of acute therapies overall and according to referral mode (stroke code, transfer from other hospital, or other). Results: We enrolled 332 patients (age 73 years, IQR: 63–81 and GCS 14 points, IQR: 11–15, onset-to-admission time 284 min, IQR: 111–708 min), of whom 101 patients (35%) had lobar haematoma. Mode of referral was stroke code in 129 patients (38%), transfer from other hospital in 143 patients (43%), and arrival by other means in 60 patients (18%). Overall, 143 of 216 (66%) patients with systolic blood pressure >150 mm Hg received IV-antihypertensive treatment, and 67 of 76 (88%) on therapeutic oral anticoagulation received prothrombin complex concentrate treatment (PCC). Forty-six patients (14%) received any neurosurgical intervention within 3 h of admission. Median treatment times from admission to first IV-antihypertensive treatment were 38 min (IQR: 18–72 min) and 59 min (IQR: 37–111 min) for PCC, with significant differences according to mode of referral (p < 0.001) but not early arrival (≤6 h of onset, p = 0.92). The median time in the emergency department was 139 min (IQR: 85–220 min), and among patients with elevated blood pressure, only 44% achieved a successful control (<140 mm Hg) during ED stay. In multivariate analysis, code ICH concordant treatment was associated with significantly lower odds for in-hospital mortality (aOR 0.30, 95% CI: 0.12–0.73, p = 0.008) and non-significant trends towards better functional outcome measured using the modified Rankin scale score at 3 months (aOR for ordinal shift 0.54, 95% CI: 0.26–1.12, p = 0.097). Conclusion: Uptake of hyperacute therapies for ICH treatment in the ED is heterogeneous. Treatment delays are short, but not all patients achieve treatment targets during ED stay. Code ICH-concordant treatment may improve clinical outcomes. Further improvements seem achievable by advocating for a “code ICH” to streamline acute treatments.

Background: Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce. Aim: The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH. Methods: We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively. Results: Among 243 participants included, the median age was 80 (IQR 75–84) years, baseline hematoma volume was 9.1 (IQR 3.4–21) mL and anti-Xa activity 118 (IQR 78–222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7–16) and 4.7 (IQR 3.0–7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13–0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16–3.12, p = 0.641). Conclusion: The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.

Background We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation.Methods This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013–2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0–2) and mortality at 3 months.Results Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6–25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)).Conclusions The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Background and ObjectivesCerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH.MethodsWe performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses.ResultsThe SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes.DiscussionCADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

BACKGROUND: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non–vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH. METHODS: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis. RESULTS: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76–86]; 40% women; median hematoma volume, 11.5 [4.8–27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22–1.82]; P =0.40). There was a signal for interaction with onset-to-treatment time ( P interaction =0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37–3.04]; P =0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37–9.50]; P =0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation. CONCLUSIONS: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH. REGISTRATION: URL: https://clinicaltrials.gov ; Unique identifier: NCT02866838.

Introduction: Deep perforator arteriolopathy (DPA) causes intracerebral haemorrhage (ICH) and lacunar strokes (LS). We compare patient characteristics, MRI findings and clinical outcomes among patients with deep ICH and LS. Patients and methods: We included patients with MRI-confirmed LS or ICH in the basal ganglia, thalamus, internal capsule or brainstem from the Bernese Stroke Registry. We assessed MRI small vessel disease (SVD) markers, SVD burden score, modified Rankin Scale (mRS) and ischaemic stroke or ICH at 3months. Results: We included 716 patients, 117 patients (16.3%) with deep ICH (mean age (SD) 65.1 (15.2) years, 37.1% female) and 599 patients (83.7%) with LS (mean age (SD) 69.7 (+/- 13.6) years, 39.9% female). Compared to LS, deep ICH was associated with a higher SVD burden score (median (IQR) 2 (1-2) vs 1 (0-2)), aOR(shift) 3.19, 95%CI 2.15-4.75). Deep ICH patients had more often cerebral microbleeds (deep ICH: 71.6% vs LS: 29.2%, p<0.001, median count (IQR) 4(2-12) vs 2(1-6)) and a higher prevalence of lacunes (deep ICH: 60.5% vs LS: 27.4% p<0.001). At 3months, deep ICH was associated with higher mRS (aOR(shift) 2.16, 95%CI 1.21-3.87). Occurrence of ischaemic stroke was numerically but not significantly higher in deep ICH (4.3% vs 2.9%; p=0.51). One patient (1.1%) with ICH but none with LS suffered ICH recurrence. Discussion/Conclusion: DPA manifesting as ICH is associated with more severe MRI SVD burden and worse outcome compared to LS. The short-term risks of subsequent ischaemic stroke and recurrent ICH are similar in ICH and LS patients. This implies potential consequences for future secondary prevention strategies.

To investigate the association of different phenotypes, count, and locations of chronic covert brain infarctions (CBI) with long‐term mortality in patients with first‐ever manifest acute ischemic stroke (AIS) or transient ischemic attack (TIA). Additionally, to analyze their potential interaction with white matter hyperintensities (WMH) and predictive value in addition to established mortality scores.

BACKGROUND:A small randomized controlled trial suggested that dabigatran may be as effective as warfarin in the treatment of cerebral venous thrombosis (CVT). We aimed to compare direct oral anticoagulants (DOACs) to warfarin in a real-world CVT cohort. METHODS:This multicenter international retrospective study (United States, Europe, New Zealand) included consecutive patients with CVT treated with oral anticoagulation from January 2015 to December 2020. We abstracted demographics and CVT risk factors, hypercoagulable labs, baseline imaging data, and clinical and radiological outcomes from medical records. We used adjusted inverse probability of treatment weighted Cox-regression models to compare recurrent cerebral or systemic venous thrombosis, death, and major hemorrhage in patients treated with warfarin versus DOACs. We performed adjusted inverse probability of treatment weighted logistic regression to compare recanalization rates on follow-up imaging across the 2 treatments groups. RESULTS:Among 1025 CVT patients across 27 centers, 845 patients met our inclusion criteria. Mean age was 44.8 years, 64.7% were women; 33.0% received DOAC only, 51.8% received warfarin only, and 15.1% received both treatments at different times. During a median follow-up of 345 (interquartile range, 140-720) days, there were 5.68 recurrent venous thrombosis, 3.77 major hemorrhages, and 1.84 deaths per 100 patient-years. Among 525 patients who met recanalization analysis inclusion criteria, 36.6% had complete, 48.2% had partial, and 15.2% had no recanalization. When compared with warfarin, DOAC treatment was associated with similar risk of recurrent venous thrombosis (aHR, 0.94 [95% CI, 0.51-1.73]; P=0.84), death (aHR, 0.78 [95% CI, 0.22-2.76]; P=0.70), and rate of partial/complete recanalization (aOR, 0.92 [95% CI, 0.48-1.73]; P=0.79), but a lower risk of major hemorrhage (aHR, 0.35 [95% CI, 0.15-0.82]; P=0.02). CONCLUSIONS:In patients with CVT, treatment with DOACs was associated with similar clinical and radiographic outcomes and favorable safety profile when compared with warfarin treatment. Our findings need confirmation by large prospective or randomized studies.

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.

Background We aimed to determine the diagnostic yield of transthoracic (TTE) and transesophageal echocardiography (TEE) in patients with ischemic stroke and transient ischemic attack with established indications for direct oral anticoagulants before the index event. Methods and Results This was a retrospective cohort study of consecutive patients with preceding established indications for long‐term therapeutic direct oral anticoagulants presenting to a single comprehensive stroke center with ischemic stroke or transient ischemic attack. Choice of echocardiography modality was based on expert recommendations. The primary outcome was a composite of prespecified management‐relevant high‐risk findings adjudicated by an expert panel, based on TTE and TEE reports according to evidence‐based recommendations. Explorative analyses were performed to identify biomarkers associated with the primary outcome. Of 424 patients included (median [interquartile range] age, 78 [70–84] years; 175 [41%] women; National Institutes of Health Stroke Scale, 4 [1–12]; 67% atrial fibrillation), 292 (69%) underwent echocardiography, while 132 (31%) did not. Modality was TTE in 191 (45%) and TEE in 101 (24%). Median time from index event to echocardiography was 2 (1–3) days. TTE identified 26 of 191 (14%) patients with 35 management‐relevant pathologies. TEE identified 16 of 101(16%) patients with 20 management‐relevant pathologies. Most management‐relevant findings represented indicated coronary artery disease and valvular pathologies. In a further 3 of 191 (2%) patients with TTE and 4 of 101 (4%) patients with TEE, other relevant findings were identified. Variables associated with management‐relevant high‐risk pathologies included more severe stroke, diabetes, and laboratory biomarkers (NT‐proBNP [N‐terminal pro‐B‐type natriuretic peptide], C‐reactive protein, d‐dimer, and troponin levels). Conclusions In patients with established indications for long‐term direct oral anticoagulant therapy and stroke who received echocardiography, both TTE and TEE identified a relevant and similar proportion of management‐relevant high‐risk pathologies and predictive biomarkers could help to guide diagnostic workup in such patients.

Purpose of review Direct oral anticoagulants (DOAC) are the mainstay of anticoagulant therapy for stroke prevention in patients with nonvalvular atrial fibrillation. Persistent uncertainties remain in different areas, and this review discusses current dilemmas based on selected studies. Recent findings Optimal timing of DOAC initiation after a recent ischaemic stroke in patients with atrial fibrillation is currently unknown and subject of ongoing randomized controlled trials. Ischaemic stroke despite anticoagulant therapy in patients with atrial fibrillation is frequent, constitutes heterogeneous causes (competing stroke cause, medication error and cardioembolism despite anticoagulation) and optimal treatment is currently unknown. Thorough etiological work-up is justified. Recent randomized controlled trials found no beneficial effect of DOAC therapy in unselected patients with embolic stroke of undetermined source (ESUS). Currently ongoing trials targeting subgroup of ESUS patients with additional atrial cardiopathy will provide novel data. Cerebral mircobleeds combined in a novel risk score (MICON score) provide good predictive value to stratify the risk of intracranial haemorrhage in patients taking anticoagulants. Use of DOAC after intracerebral haemorrhage in patients with atrial fibrillation is subject of ongoing trials. Summary There are still significant uncertainties in anticoagulant management in patients with stroke. Ongoing trials will soon provide novel data to improve management of these patients.

Background This study was conducted to explore the association of different phenotypes, count, and location of chronic covert brain infarctions (CBIs) with detection of atrial fibrillation (AF) on prolonged post-stroke cardiac rhythm monitoring (PCM). Methods and Results We conducted a cohort single-center study of consecutive first-ever ischemic stroke or transient ischemic attack patients undergoing PCM between January 2015 and December 2017. We blindly rated CBI phenotypes according to established definitions and white matter hyperintensities (WMHs) according to the age-related white matter changes rating scale. We used (multiple) regression models to assess the association of the imaging biomarkers and incident AF on PCM. A total of 795 patients (median [interquartile range]) aged 69 (57-78) years, 41% women, median National Institutes of Health Stroke Scale score 2 (0-5), median PCM duration 14 (7-14) days, and AF detection in 61 patients (7.7%) were included. On univariate analysis, WMHs (per point odds ratio, 1.35 [95% CI, 1.03-1.78]) but not CBIs (odds ratio, 0.90 [95% CI, 0.52-1.56]) were associated with AF detection. Neither CBI phenotype, count, nor location were associated with AF detection. After adjustment for age, hypertension, and stroke severity, neither increasing WMHs (per point adjusted odds ratio, 0.85 [95% CI, 0.60-1.20]) nor CBIs (adjusted odds ratio, 0.60 [95% CI, 0.33-1.09]) were independently associated with AF detection. Conclusions Although WMHs and CBIs represent surrogate biomarkers of vascular risk factors, neither WMHs nor CBIs, including their phenotypes, count, and location, were independently associated with AF detection on PCM. In patients with manifest ischemic stroke or transient ischemic attack, the presence of imaging biomarkers of chronic ischemic injury does not seem promising to further refine prediction tools for AF detection on PCM.

Background: We determined the frequency of different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their association with clinical characteristics and outcomes. Methods: We analyzed data from consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014-2019). Etiology of ICH was determined according to prespecified, mutually exclusive categories. We assessed prevalence of ICH etiologies, their association with clinical characteristics, functional independence (modified Rankin Scale 0-2), mortality, recurrent ICH and ischemic stroke at 3 months. Results: We included 2584 patients (median age 72y, IQR 64-82, 46.6% female, median NIHSS 10; IQR 3-15). 2037 patients (80%) had hypertension and 553 (22.3%) were on anticoagulants. Distribution of etiologies was as follows: Hypertension (n=1216 patients; 47.1% of all / 56.3% of patients with hypertension), unknown etiology (n=542, 21.0%), antithrombotic therapy (n=225, 8.7% of all / 38% of patients on anticoagulants), cerebral amyloid angiopathy (CAA, n=211, 8.2%), macro-vascular (n=121, 4.7%), other determined etiologies (n=269, 10.4%). Patients with hypertensive ICH had significantly higher NIHSS (median 9; IQR 4-16) and blood pressure levels (median systolic 176; IQR 156-195) on admission. Patients with CAA had significantly lower NIHSS at baseline (median 5; IQR 2-12). Three month follow-up was available for 2109/2584 patients (81.6%). 820 (38.9%) were functionally independent, 658 have died (31.2%). Hypertensive ICH was associated with an increased rate of functional independence (aOR =1.42, 95%CI 1.06-1.90, p=0.02). 5.2% of patients had a cerebrovascular event within 3 months. CAA was associated with a high risk of recurrent ICH (HR 6.95, 95%CI 3.05-15.84, p<0.001). The risk of ischemic stroke (2.2%) was higher than that of ICH (1.5%) in patients with hypertensive ICH. Conclusions: In Swiss Stroke Units and Centers, one of two patients has ICH from a different cause than hypertension. The rate of functionally independent patients at 3 months seems higher than mortality. Absolute and relative risks of recurrent ICH and ischemic stroke after recent ICH differ among underlying etiologies.