BACKGROUND AND AIMS:Prolonged monitoring with implantable cardiac monitors (ICMs) effectively detects subclinical atrial fibrillation (SCAF) in patients with cryptogenic stroke (CS). Understanding SCAF progression to higher burdens can affect decisions regarding oral anticoagulant (OAC) and antiarrhythmic therapies. This analysis aimed to quantify initial SCAF burden, its progression, and predictors of progression in CS patients. METHODS:This multicenter project collected demographics, stroke characteristics, and SCAF daily burden in CS patients implanted with ICM. SCAF progression was defined as an increase in daily burden from initial detection, categorized as: 5 min to 1 h, 1-6 h, 6-24 h, 24 h for < 7 days, and 24 h for ≥ 7 days. RESULTS:Of 593 patients (70.0 ± 11.3 years, 42% female, median CHA2DS2-VASc score 4.7 ± 1.4) monitored over a median of 24.6 months, 32.7% had SCAF detected. While initial SCAF daily burden was < 1 h in 38.7% of SCAF patients, 53.3% progressed to a higher SCAF daily burden, with 30.6% reaching the 24 h burden by 36 months. Higher CHA2DS2-VASc scores and stroke severity were associated with SCAF progression. OAC therapy was initiated in 91.2% patients with a maximum SCAF daily burden < 1 h, while in 98.0% of those with a maximum daily burden ≥ 1 h (p = 0.042). CONCLUSIONS:Over half of CS patients with SCAF progressed to a higher burden, and about one-third reached a 24 h SCAF daily burden. These findings highlight the importance of continuous monitoring in CS patients for early SCAF detection and personalized therapy, considering SCAF burden progression and the patient's risk profile.

Abstract Background and aims Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)–related ischemic stroke. However, patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the comparative effectiveness and safety of early versus delayed DOAC resumption after breakthrough stroke. Methods We conducted a target-trial emulation comparing early versus delayed DOAC resumption after breakthrough stroke. Treatment strategies were prespecified using severity-adapted timing rules based on baseline NIHSS scores. To emulate random treatment assignment and address immortal time bias, a cloning–censoring–weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. Results We included 833 patients (median age 81 years); 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (3.0% vs 6.6%; RR 0.44, 95% CI 0.21–0.90; RD −3.64%, 95% CI −6.40 to −0.87; HR 0.43, 95% CI 0.21–0.91). Moderate-to-severe bleeding was less frequent with early initiation. Early initiation was associated with lower all-cause and vascular mortality. Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. Conclusions In patients with breakthrough ischemic stroke, early DOAC initiation was associated with reduced recurrent ischemic events and mortality at 90 days without increased bleeding. These findings support early anticoagulation initiation in this population pending randomized trials. Conflict of interest NOTHING TO DISCLOSE

OBJECTIVE:Primary oculoleptomeningeal amyloidosis (OLMA) is a rare hereditary transthyretin (TTR) amyloidosis (ATTRv) associated with specific TTR variants. p.Arg54Gly is characterized by an ocular phenotype with vitreous opacities and chronic open-angle glaucoma. METHODS:We report for the first time the occurrence of subarachnoid hemorrhages, seizures, cardiac and skin amyloid deposits in a patient with OLMA carrying the TTR p.Arg54Gly variant. RESULTS:A 40-year-old man with a history of visual loss presented with altered mental status, right hemiplegia, and global aphasia, followed by a gradual recovery over 5 days. Brain MRI with gadolinium showed diffuse leptomeningeal enhancement and small convexity subarachnoid hemorrhagic foci. Optical coherence tomography showed spindle needle-shaped hyperreflective formations over the inner limiting membrane. Cardiac scintigraphy and skin biopsy stainings were positive. He had further neurological episodes despite Tafamidis treatment. DISCUSSION:Our case expands the phenotypic spectrum of the pathogenic p.Arg54Gly TTR gene variant, demonstrating intracranial hemorrhages, seizures with a prolonged post-ictal state, and amyloid deposits in heart and skin. OLMA may mimic various infectious, inflammatory and malignant conditions affecting the central nervous system. An accurate ophthalmological evaluation may help narrowing down broad differential diagnoses and raise the suspicion of uncommon systemic diseases.

BACKGROUND AND PURPOSE:Randomized trials support early initiation of direct oral anticoagulants (DOACs) after atrial fibrillation (AF)-related ischemic stroke, but patients with breakthrough ischemic stroke occurring despite ongoing anticoagulation have been largely under-represented. We evaluated the effectiveness and safety of early versus delayed DOAC initiation after breakthrough ischemic stroke. METHODS:We performed a target trial emulation comparing early versus delayed DOAC initiation in patients with breakthrough ischemic stroke. Treatment strategies were prespecified using severity-adapted timing thresholds based on baseline National Institutes of Health Stroke Scale (NIHSS) scores. The study population was drawn from the retrospective arm of the international, multicenter Advancing Knowledge in Ischemic Stroke Patients on Oral Anticoagulant (ASPERA) study and included patients with AF who experienced an ischemic stroke while receiving continuous anticoagulation. To emulate random assignment and avoid immortal time bias, a cloning-censoring-weighting approach with inverse probability weighting was applied. Primary outcomes were 90-day new ischemic events and moderate-to-severe bleeding. Risk ratios (RRs), absolute risk differences (RDs), and hazard ratios (HRs) were estimated using weighted regression and Cox models. RESULTS:Among 833 patients (median age = 81 years), 336 were assigned to early and 497 to delayed DOAC initiation. At 90 days, early initiation was associated with a lower risk of new ischemic events (RR = 0.44, 95% CI = 0.21-0.90; RD = -3.64%, 95% CI = -6.40 to -0.87; HR = 0.43, 95% CI = 0.21-0.91). Moderate-to-severe bleeding occurred less frequently with early initiation (RR = 0.10, 95% CI = 0.01-0.76). Early initiation was also associated with lower 90-day all-cause and vascular mortality. A Net Early Benefit Score integrating ischemic and bleeding risks was positive across all NIHSS strata. CONCLUSION:In patients with breakthrough ischemic stroke, early severity-adapted DOAC initiation was associated with lower risks of recurrent ischemic events and mortality at 90 days without an increase in major bleeding. These findings support early anticoagulation initiation in this high-risk population.

Abstract Background and aims Cognitive and neuropsychiatric sequelae following stroke are common yet frequently underrecognized, despite their major impact on functional and quality-of-life outcomes. We conducted a systematic review to quantify how often cognitive and neuropsychiatric outcomes are included as efficacy measures in randomized controlled trials of acute-phase stroke interventions. Methods ClinicalTrials.gov and World Health Organization-recognized registries were searched for interventional phase 3 trials protocols on acute ischemic or hemorrhagic stroke (January 2014-December 2024). Trials were included if the intervention occurred <72 hours of symptom onset. Data extraction was independently performed by two blinded reviewers, and descriptive statistics summarized the outcomes. Quantitative data (number and percentage of the studies employing cognitive outcomes) and qualitative findings (cognitive tools employed) were reported and tabulated. This systematic review followed the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines and was registered in PROSPERO (CRD420251048699). Results Of 4,424 screened protocols, 572 met inclusion criteria and were included. According to trial protocols, 127 studies (22.2%) planned cognitive and/or neuropsychiatric outcome measures. In all cases except for one study, they were used as secondary outcomes. In 74/127 studies (58.3%), cognitive/neuropsychiatric outcomes were limited to items within non-specific quality-of-life instruments, whereas 53/127 (41.7%) included specific cognitive/neuropsychiatric outcomes. The most frequently used cognitive tools were Montreal Cognitive Assessment (n=26) and Mini-Mental State Examination (n=13), while the most common neuropsychiatric tools were Hamilton Depression Rating Scale (n=7) and Geriatric Depression Scale (n=2). Conclusions Cognitive and neuropsychiatric domains remain underrepresented outcome measures in acute stroke trial intervention protocols. Conflict of interest All authors have nothing to disclose

BACKGROUND:Cerebral small vessel disease (SVD) is a major cause of ischemic stroke, intracerebral hemorrhage, and dementia. Despite its importance, there are few studies of its prevalence and how cerebral SVD varies across the world, different age ranges, sexes, and magnetic resonance imaging (MRI) parameters. SVD can be estimated using MRI neuroimaging markers, including white matter hyperintensities (WMHs), lacunes, cerebral microbleeds (CMBs), and perivascular spaces (PVS). AIMS:This study aimed to document the global prevalence of SVD based on population-based or large community-based MRI studies and to determine how SVD prevalence varies by region, mean age, and sex. With SVD neuroimaging markers being the standard to assess SVD prevalence, we aimed to investigate how different MRI acquisition parameters may influence its prevalence. SUMMARY OF REVIEW:In this systematic review and meta-analysis, articles were searched from the Ovid MEDLINE and EMBASE databases between 1 January 2000 and 31 March 2024, without language restrictions. Title and abstract screening, full-text review, and data extraction were performed by at least two independent reviewers. The prevalence of SVD, subject demographic information, and MRI acquisition parameters were extracted. The Risk of Bias for Non-randomized Studies tool was used. The protocol was registered on PROSPERO (CRD42022311133). Of 14,582 studies identified, 246 studies spanning 40 countries were included in the systematic review. In the meta-analysis, 85 studies (88 cohorts) from 17 regions (n = 1,562,765) were included. The quality of studies was high (mean score 7.67 out of 8, ranging between 5 and 8). The pooled prevalence of moderate-to-severe WMH was 18.9%, and the pooled mean of WMH volume was 4.4 mL. Pooled prevalences of lacunes, cerebral microbleeds (CMBs), and moderate-to-severe perivascular spaces (PVS) were 11.2%, 10.3%, and 22.6%, respectively. A lower lacune prevalence (7.3% vs 13.3%; adjusted OR (aOR) [95% confidence interval (CI)]: 0.45 [0.30-0.68]) but higher PVS prevalence (30.9% vs 19.6%; aOR [95% CI]: 12.15 [2.12-69.46]) was found in Europe compared with Asia. A higher mean age of the studies was associated with a higher prevalence of most SVD markers, except for PVS. There was an overall trend of more lacunes and CMBs in males. MRI field strength, sequence used, and slice thickness could potentially influence the reported SVD prevalence, especially for WMH volume and CMB count. There was high heterogeneity in the studies (>95%) that was not resolved by performing analyses stratified by Global Burden of Disease (GBD) regions, age groups, study design, or MRI parameters. CONCLUSION:This systematic review and meta-analysis based on large MRI studies demonstrated that SVD is a common health problem affecting about one-fifth of the adult population. SVD prevalence differs in regions separated by geographical regions. SVD prevalence is higher with increasing age. There is an overall trend of more lacunes and CMBs in males. WMH volume and CMB are SVD markers prone to the variability of MRI acquisition parameters, and a harmonised SVD scanning protocol should be used. More studies from middle- and low-income regions would benefit the estimation of a truly global prevalence of SVD.

Abstract Background and aims Oral anticoagulants (OACs), including vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs), reduce ischemic stroke risk in atrial fibrillation(AF), yet 1–2% of patients still experience breakthrough strokes annually, not fully explained only by poor adherence. Clarifying underlying mechanisms is essential to improve prevention strategies. Methods ASPERA(NCT06823466) is a multicenter ambispective study; this analysis includes the retrospective arm of AF patients with neuroimaging-confirmed ischemic stroke despite ongoing therapeutic OAC between 2020 and 2025, with collection of baseline characteristics, comorbidities, treatments, and 90-day outcomes. Results Among 1,649 patients (median age 80.4 years, 52.2% females) most were treated with DOACs (77.3%). Causal factors for breakthrough ischemic stroke included drug-to-drug interactions potentially affecting OAC efficacy (26.4%), competing etiologies (24.3%), and active cancer (4.4%). Overall, 180 (10.9%) had more than one potential cause and 724 (43.9%) of patients had at least one of those factors. Patients with almost one identifiable factor had a higher prevalence (P < 0.01) of arterial hypertension (87.3% vs 76.3%), diabetes mellitus (30.1% vs 24.3%), and dyslipidemia (58.1% vs 45.8%) and a higher rate of minor stroke (NIHSS≤5) presentation (33.8% vs 26.7%, P = 0.002) compared with those without. These patients also showed higher 90-day mortality (22.7% vs 18.4%, P = 0.032) and stroke recurrence rates (4.8% vs 2.4%, P = 0.007). Conclusions Approximately half of patients experiencing ischemic stroke despite ongoing oral anticoagulation have an identifiable mechanism that may have contributed to the event. Improved recognition and characterization of these factors may help reduce the risk of breakthrough stroke and warrant investigation in prospective studies. Conflict of interest A. Zini declares consulting and speaker fees from Bayer, Boehringer-Ingelheim, Alexion, Daiichi Sankyo, Pfizer, PIAM, and Amgen; and advisory board fees from Boehringer-Ingelheim, Daiichi Sankyo, Bayer, and AstraZeneca. L. Pantoni declares consultancy fees from Medtronic, PIAM, and Amicus. S. Sacco reports consultant fees from Novartis, Novo Nordisk, Boehringer Ingelheim, Teva, Allergan, Pfizer Canada, Abbott Canada, Lundbeck, AstraZeneca, and Eli Lilly; and compensation for other services from Novartis. The other authors have nothing to disclose.

Oral anticoagulants (OACs), including vitamin K antagonists and direct OACs, reduce stroke risk in atrial fibrillation (AF), yet breakthrough ischemic stroke still occurs in 1–2

Post-stroke cognitive impairment (PSCI) affects up to one-third of stroke survivors and is a major contributor to long-term disability and reduced quality of life. Its heterogeneous phenotype reflects the interplay of acute cerebrovascular injury with chronic vascular pathology, inflammation, blood–brain barrier dysfunction, and, in many patients, coexisting neurodegeneration. Clinical manifestations vary according to lesion location and most commonly involve executive and attentional deficits, with variable impairment of memory, language, visuospatial function, and neuropsychiatric domains. Cognitive trajectories range from partial early recovery to persistent or progressive decline.Diagnosis remains challenging because covert cerebrovascular disease and overlapping neurodegenerative processes may mimic or amplify deficits. A stepwise diagnostic strategy combining focused cognitive screening, neuropsychological assessment when indicated, and neuroimaging is therefore recommended. In many acute stroke settings, CT continues to serve as the routine first-line modality, whereas MRI allows more detailed characterization where available. Emerging adjuncts include fluid biomarkers of neuroaxonal injury, inflammation, and vascular brain injury, as well as digital and telephone-based tools that may support longitudinal monitoring in selected populations.Treatment options remain limited. Non-pharmacological interventions, including cognitive rehabilitation, physical activity, and multimodal neurorehabilitation, are central to current management, although PSCI-specific high-quality evidence is scarce. Prevention is essential and should focus on vascular risk-factor control, lifestyle modification, cognitive reserve, and social engagement.This narrative review synthesizes current evidence on the mechanisms, presentation, diagnosis, and management of PSCI and highlights priorities for harmonized care pathways and the routine integration of cognitive health into stroke care.

INTRODUCTION AND AIMS:Breakthrough ischemic stroke may occur despite ongoing oral anticoagulation (OAC) in patients with atrial fibrillation (AF). Whether infarct location influences prognosis remains unclear. We aimed to compare clinical characteristics and outcomes of posterior versus anterior circulation infarct (PCI vs ACI). METHODS:Multicentre retrospective analysis from the ASPERA cohort, including patients with AF and ischemic stroke despite continuous OAC (Feb. 2020 to Feb. 2025). Patients were classified as PCI or ACI according to infarct location. The primary outcome was a 90-day composite of recurrent ischemic stroke, myocardial infarction, or vascular death. Secondary outcomes included modified Rankin Scale (mRS) shift and all-cause mortality. Safety outcomes included 24-h hemorrhagic transformation (HT) and symptomatic intracranial hemorrhage (sICH), 90-day ICH. Inverse-probability weighting with truncation of extreme weights and additional adjustment for residual imbalance were applied. RESULTS:Among 1649 patients (mean age 78.0 ± 10.7 years; 47.8% men), 165 (10.0%) had PCI. PCI patients were more often on vitamin K antagonists and had lower stroke severity. After weighting, PCI was associated with a higher risk of the composite outcome (aHR 1.50, 95% CI 1.19-1.90; p < 0.001), vascular death (aHR 1.46, 95% CI 1.12-1.91; p = 0.005), all-cause mortality (aHR 1.85, 95% CI 1.51-2.27; p < 0.001), and worse mRS shift (aOR 1.79, 95% CI 1.51-2.13; p < 0.001). PCI was also associated with an increased risk of ICH (aHR 2.25, 95% CI 1.08-4.70; p = 0.031), whereas 24-HT and sICH were similar between groups. CONCLUSIONS:In AF patients with breakthrough stroke on OAC, PCI identifies a subgroup with worse 90-day outcomes. These findings support the prognostic relevance of infarct location.

Background Sex‐specific outcomes after breakthrough ischemic stroke on oral anticoagulation (OAC) are unexplored. We compared 90‐day outcomes by sex and explored modifiers. Methods ASPERA‐R (Advancing Knowledge in Ischemic Stroke Patients on Oral Anticoagulants retrospective cohort; NCT06823466) was an international, multicenter, retrospective study enrolling adults (aged >18 years) with breakthrough ischemic stroke on OAC for atrial fibrillation. Primary outcome was 90‐day return to baseline neurologic function (modified Rankin Scale [mRS] score 0–1 maintained if prestroke 0–1; or same/lower mRS score if prestroke ≥2). Secondary outcomes were 90‐day mRS shift, recurrent ischemic stroke/transient ischemic attack, myocardial infarction, and all‐cause and vascular death. Safety outcomes included 90‐day moderate‐to‐severe bleeding, intracranial hemorrhage, 24‐hour hemorrhagic transformation, and 24‐hour symptomatic intracranial hemorrhage. We applied inverse probability weighting and regression models to compare outcomes. Prespecified subgroup analysis tested sex‐specific interactions. Results We included 1649 patients (women, 52.2%; mean±SD age, 78.0±10.7 years). Women were older (80.2±9.6 versus 76.3±10.8 years; unweighted standardized mean difference=0.376), had higher baseline National Institutes of Health Stroke Scale score (13 [interquartile range, 9–19] versus 9 [interquartile range, 4–17]; unweighted standardized mean difference=0.227), and worse prestroke mRS score (unweighted standardized mean difference=0.237). After weighting, women were less likely to return to baseline neurologic function (35.2% versus 42.7%; adjusted risk ratio, 0.82 [95% CI, 0.71–0.96]; P =0.015), had worse mRS distribution (adjusted odds ratio, 1.17 [95% CI, 1.01–1.37]; P =0.043), and had higher recurrent ischemic stroke/transient ischemic attack (4.8% versus 2.8%; adjusted hazard ratio [HR], 1.70 [95% CI, 1.01–2.86]; P =0.045). Women showed a trend toward more moderate‐to‐severe bleeding (4.6% versus 2.8%; adjusted HR, 1.63 [95% CI, 0.96–2.72]; P =0.070). Subgroup analyses revealed significant sex interactions for OAC type, competing cause, endovascular treatment, and OAC restart. Conclusions Women had worse 90‐day outcomes than men after breakthrough ischemic stroke on OAC for atrial fibrillation, highlighting the need for sex‐aware management.

Abstract Background and aims In a cohort of patients with acute cerebrovascular events, we aimed to describe the frequency and severity of prestroke neuropsychiatric symptoms. Methods We included consecutive patients admitted to our stroke unit (April 2019 - December 2024). Prestroke NPS were screened using Neuropsychiatric Inventory questionnaire (NPI-q), an informant-based tool consisting of 12 items. Prestroke cognitive impairment was defined as an IQCODE (Informant Questionnaire for Cognitive Decline in the Elderly) score >3.3. Frequency of prestroke neuropsychiatric symptoms were reported and compared between subgroups of patients using univariate analyses. Results Of 1058 patients admitted, 864 underwent prestroke neuropsychiatric screening and were included in the study (median age 78.5 years; 54.3% male; 35.0% with prestroke cognitive impairment). Five hundred sixty-four patients (65.6%) exhibited at least one prestroke neuropsychiatric symptom; the most frequent were depression/dysphoria (33.8%), sleep disturbance (29.4%), apathy (26.5%), irritability/liability (24.8%), anxiety (23.5%). Compared to males, females had more depression (39.5% vs. 29.0%, p<0.001), less irritability (20.8% vs. 28.1%, p=0.012), more anxiety (32.9% vs. 15.6%, p<0.001). Compared to patients <80 years old, older patients had more depression/dysphoria (40.8% vs. 28.1%, p<0.001), sleep disturbance (34.1% vs. 25.5%, p=0.006), and apathy (31.8% vs. 22.2%, p<0.001). Compared to patients without cognitive decline, those with prestroke cognitive decline had more depression/dysphoria (49.3% vs. 25.4%, p<0.001), sleep disturbance (41.1% vs. 23.1%, p<0.001), apathy (51.3% vs. 13.2%, p<0.001), irritability (35.8% vs. 18.9%, p<0.001), and anxiety (31.5% vs. 19.2%, p<0.001). Conclusions Prestroke neuropsychiatric symptoms were common, especially in patients with cognitive impairment, and showed sex-specific patterns. Conflict of interest All authors have nothing to disclose

BACKGROUND:Breakthrough ischaemic stroke during oral anticoagulation (OAC) for atrial fibrillation (AF) represents a major therapeutic challenge, especially in patients with cancer, who face competing risks of thrombosis and bleeding. This study investigated the impact of cancer on 90-day outcomes after ischaemic stroke on OAC. PATIENTS AND METHODS:We analysed patients with AF who experienced ischaemic stroke while on continuous OAC enrolled in the international retrospective ASPERA-R study, comprising 35 stroke centres across 9 countries. Inverse probability weighting was applied to adjust for baseline imbalances, and weighted Cox, ordinal logistic and generalised linear models were used to estimate adjusted 90-day risks for the primary (ischaemic stroke or TIA), secondary (mRS shift, vascular/all-cause death) and safety (moderate-to-severe bleeding, ICH, 24-h haemorrhagic transformation) outcomes. RESULTS:Among 1649 included patients (mean age 78.0 ± 10.7 years; 45.8% male), 247 (15.0%) had cancer, of whom 87 (35.2%) had active cancer and 160 (64.8%) were in remission. After weighting, patients with cancer had a significantly higher 90-day risk of new ischaemic stroke or TIA (8.2% vs 2.8%; adjusted hazard ratio [aHR] 2.56; 95% CI, 1.59-4.13; P < .001) and worse 90-day mRS score distribution (adjusted odds ratio 1.29; 95% CI, 1.08-1.54; P = .005) than those without cancer. Active cancer conferred a > 4-fold higher risk of new ischaemic stroke or TIA (HR 4.48, 95% CI, 2.46-8.13; P < .001) and nearly 3-fold higher risk of moderate-to-severe bleeding (HR 2.77; 95% CI, 1.30-5.88; P = .008). Patients with cancer in remission showed increased ischaemic risk (HR 2.60; 95% CI, 1.59-5.25; P = .001) but not bleeding risk. Haematological malignancies carried a higher risk for both new ischaemic stroke or TIA (HR 3.06; 95% CI, 1.69-5.54; P = .001) and moderate-to-severe bleeding (HR 3.47, 95% CI, 1.57-7.70; P = .006) compared to solid malignancies. CONCLUSION:Cancer, particularly active and haematological malignancies, substantially worsens 90-day prognosis after breakthrough stroke on OAC, underscoring the need for refined risk stratification and tailored secondary prevention. TRIAL REGISTRATION:URL: www.clinicaltrials.gov; Unique identifier: NCT06823466.

BACKGROUND AND OBJECTIVES:Patients with atrial fibrillation (AF) who experience an ischemic stroke despite oral anticoagulation (OAC) face a high risk of recurrence and bleeding. We aimed to compare 90-day outcomes between patients with and without competing stroke etiologies after a breakthrough ischemic stroke while on OAC for AF. METHODS:ASPERA-R retrospectively enrolled adults (>18 years) with AF who experienced a breakthrough ischemic stroke, defined as either first or recurrent event, occurring on continuous OAC (last intake ≤48 hours), across 35 centers from February 2020 to February 2025. Patients' eligibility required imaging-confirmed ischemic stroke, baseline vessel imaging, and a standardized 90-day follow-up. Patients with inadequate anticoagulant dosing or poor adherence were excluded. Competing etiologies were defined as any additional mechanism coexisting with cardioembolism and plausibly contributing to the index stroke. The primary outcome was 90-day recurrent ischemic stroke; secondary outcomes included modified Rankin Scale shift, myocardial infarction, and vascular and all-cause death. Bleedings were also evaluated. We performed inverse probability weighting to balance baseline covariates and applied Cox or regression models to compare outcomes. RESULTS:Among 1,649 patients (mean age 78 years, 47.8% male), 24.3% had competing etiologies, most commonly large artery atherosclerosis (59.9%). Considering the weighted population, 90-day recurrent ischemic stroke occurred more often in those with competing etiologies (6.0% vs 2.7%; adjusted hazard ratio [aHR] 2.62, 95% CI 2.01-3.42; p < 0.001). Risk was greatest for large artery atherosclerosis and other determined causes. Competing etiologies also had worse disability distribution (adjusted odds ratio 1.30, 95% CI 1.08-1.55; p = 0.005) and higher all-cause mortality (aHR 1.58, 95% CI 1.18-2.12; p = 0.002). Moderate-to-severe bleeding was higher with competing etiologies (aHR 1.82, 95% CI 1.08-3.09; p = 0.026), whereas 24-hour hemorrhagic transformation was less frequent (adjusted risk difference -4.3%, 95% CI -7.8% to -0.7%; p = 0.020). Other outcomes did not differ. DISCUSSION:One in 4 patients with AF and breakthrough ischemic stroke on OAC had competing etiologies, most often large artery atherosclerosis. These patients showed higher risk of recurrent stroke, functional dependence, mortality, and bleeding, highlighting the need for development of individualized secondary prevention. Main study limitations include observational retrospective design and incomplete data on on-treatment anticoagulation quality. TRIAL REGISTRATION INFORMATION:ClinicalTrials.gov NCT06823466.

Background Brief and accurate tools are needed to enhance the prompt identification of cognitive disorders. This study aimed to translate and adapt two recently developed, highly accurate instruments into Italian: the Brief Assessment of Impaired Cognition (BASIC) and the BASIC Questionnaire (BASIC-Q), and to validate their diagnostic accuracy. Methods The Italian versions of BASIC and BASIC-Q were developed following a rigorous process and were validated in patient populations referred to two Italian tertiary memory clinics. Receiver operating characteristic curve analysis was used to evaluate the discriminative validity of BASIC and BASIC-Q in identifying cognitive impairment compared to specialist diagnoses. Linear regression models were used to explore the influence of traditional confounders, such as age and education. Results A total of 246 participants were recruited for the study. The BASIC and BASIC-Q assessments accurately distinguished between individuals with cognitive impairment and those with intact cognition, achieving areas under the curve of 0.96 and 0.95, respectively. The accuracy of these two tools was comparable to that of the Mini-Mental State Examination. Additionally, both instruments showed a negative association with age but were not influenced by educational level. Discussion The BASIC and BASIC-Q tools effectively identify older individuals with cognitive impairment who may need further diagnostic assessment. Their accuracy must be explored in primary care settings and among multicultural populations.

BACKGROUND AND OBJECTIVES:Contrast-associated acute kidney injury (CA-AKI) is a potentially preventable complication after exposure to iodinated contrast media. In patients undergoing endovascular thrombectomy (EVT) for acute ischemic stroke (AIS), the incidence and clinical impact are poorly characterized, and no validated prediction tool is currently available. The aim of this study was to assess the incidence and prognostic significance of CA-AKI in EVT-treated patients with AIS and to develop and validate a predictive score. METHODS:A retrospective, multicenter cohort study was conducted involving EVT-treated patients across 73 centers in 16 countries (January-December 2023). Inclusion criteria were age ≥18 years, absence of dialysis, availability of preprocedural and 48-hour postprocedural creatinine levels, and available 90-day follow-up (modified Rankin Scale [mRS] score). The primary outcome was CA-AKI, defined by KDIGO (Kidney Disease: Improving Global Outcomes criteria;creatinine increase ≥0.3 mg/dL or ≥1.5 times baseline, within 48 hours). Secondary outcomes were (1) in-hospital mortality, (2) 90-day mRS score, and (3) 90-day severe disability or death (mRS score >3). Logistic models assessing associations with outcomes accounted for within-center clustering by applying robust standard errors. CA-AKI prediction models were developed across imputed data sets using univariable selection (p < 0.20), backward elimination (p < 0.05), and coefficient-based scoring after categorization of continuous predictors, with internal validation by bootstrap to obtain optimism-adjusted estimates. RESULTS:Among 6,638 patients (median age 74 years; 48.7% male), CA-AKI occurred in 326 (4.9%) and was independently associated with in-hospital mortality (adjusted odds ratio [aOR] 2.269; 95% CI 1.615-3.190), higher 90-day mRS scores (adjusted common odds ratio 1.584; 95% CI 1.110-2.258), and 90-day severe disability or death (aOR 1.530; 95% CI 1.057-2.216). A preprocedural risk model including 12 routine clinical variables-sex, ethnicity, arterial hypertension, dyslipidemia, chronic kidney disease, antiplatelet therapy, NIH Stroke Scale score at admission, serum glucose, estimated glomerular filtration rate, hemoglobin, mean arterial pressure, and IV thrombolysis-demonstrated acceptable discrimination (area under the receiver operating characteristic curve 0.710 [95% CI 0.682-0.738]; precision-recall area under the curve 0.13 [95% CI 0.10-0.16]), good calibration (slope 0.870 [95% CI 0.759-0.928]), good overall performance (Brier score 0.045 [95% CI 0.042-0.049]). A second model that included EVT-related variables (e.g., contrast volume) showed similar performances. DISCUSSION:In this large, international cohort, CA-AKI occurred in approximately 1 in 20 EVT-treated patients with AIS and was independently associated with poor outcomes. A simple preprocedural risk score enables early identification of high-risk individuals and may support preventive strategies.

Abstract Background and aims One third of patients with acute cerebrovascular events has a prestroke cognitive impairment (preSCI). Aim of this study was to assess the impact of preSCI on length of hospitalization, functional outcome at discharge, and in-hospital mortality. Methods Consecutive patients admitted to the stroke unit from April 2019 to February 2024 were included. The Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE) was administered to caregivers. PreSCI was diagnosed if the mean IQCODE score was >3.3. In the subgroup of ischemic stroke patients, a binary logistic regression model was built with in-hospital mortality as the dependent variable. Results 809 patients were included: 45.2% women; median age 78.0 years (68.0-85.0); median NIHSS score 3.0 (1.00-8.00). An IQCODE could be obtained in 733 patients (90.6%). PreSCI was present in 235 patients (32.1%). Patients with preSCI were older (p<0.001), more often female (p=0.002), had higher rates of hypertension (p=0.002) and atrial fibrillation (p<0.001) and more severe strokes (p<0.001). At discharge, patients with preSCI had longer hospitalizations (p<0.001), higher disability (p<0.001), and a higher death rate (p<0.001). In the ischemic stroke subgroup, predictors of in-hospital mortality were stroke severity (OR 1.205, 95%CI 1.123-1.293) and preSCI (OR 3.373, 1.199-9.489]). Conclusions Our study confirms the association of preSCI with older age, female sex, and vascular risk factors. It also shows that the standardized assessment of prestroke cognitive status with the IQCODE at the time of admission to the stroke unit provides useful information about length of hospitalization, functional disability at discharge, and in-hospital mortality. Conflict of interest FM, IC, GS, AN, GM, AF, VC, FM, ES, LP: nothing to disclose

Abstract Background and aims Breakthrough ischemic stroke despite appropriate oral anticoagulant (OAC) therapy may be related to concomitant use of drugs that interact with OACs and reduce their efficacy. We assessed the prevalence and types of interacting drugs and their impact on outcomes. Methods The retrospective, multicenter ASPERA-R study consecutively included patients with breakthrough ischemic stroke despite appropriate OAC therapy. Interacting drugs were identified from the Summary of Product Characteristics. Ninety-day case-fatality, recurrent cerebral ischemic events, and major bleeding were compared between patients with and without interacting treatments using inverse probability weighting (IPW), adjusting for age, sex, and vascular risk factors. Results Among 1,649 patients (860 women, 52.2%; mean age 78.3 ± 10.4 years), 469 (28.4%) were receiving interacting drugs at stroke onset, including proton pump inhibitors (450, 27.3%), antiseizure medications (28, 1.7%), H2 inhibitors (3, 0.2%), dexamethasone (3, 0.2%), and ketoconazole (1, 0.1%). At 90 days, death occurred in 100 patients (21.3%) with interacting treatments and 234 (19.8%) without. Recurrent cerebral ischemic events occurred in 23 (4.9%) and 34 patients (2.9%), respectively, and major bleeding in 20 (4.3%) and 35 patients (3.0%). After IPW, no differences were observed in recurrent ischemic events or major bleeding, while case-fatality was slightly higher in patients receiving interacting drugs (21.0% vs 17.2%; p=0.049). Conclusions More than one-quarter of patients with breakthrough ischemic stroke despite appropriate OAC therapy were treated with potentially interacting drugs, without substantial impact on short-term clinical outcomes. Conflict of interest None

Importance:Management after an ischemic stroke occurring despite direct oral anticoagulant (DOAC) therapy for atrial fibrillation (AF) varies widely. Switching anticoagulation is common in clinical practice, although evidence supporting this strategy is limited. Objective:To evaluate whether continuation of treatment with the same DOAC was noninferior to switching oral anticoagulant therapy with respect to 90-day clinical outcomes. Design, Setting, and Participants:This multicenter registry-based cohort study with an emulated target trial design included consecutive adult patients with AF who experienced a breakthrough ischemic stroke while receiving uninterrupted DOAC therapy and resumed anticoagulation therapy thereafter. Patients were enrolled between February 2020 and February 2025, across 35 stroke centers in 9 countries in Europe and North Africa, with a standardized 90-day follow-up. The dataset was locked on September 1, 2025. A noninferiority comparison of switching vs continuation strategies was performed. Baseline confounding was addressed using inverse probability of treatment weighting (IPTW). The primary noninferiority margin was an absolute risk difference of 3.0 percentage points in 90-day net clinical benefit. Exposure:The intervention group switched to treatment with a different DOAC or vitamin K antagonist; the comparator group continued therapy with the prestroke DOAC. Main Outcomes and Measures:The primary outcome was 90-day net clinical benefit, defined as recurrent ischemic stroke and moderate to severe bleeding. Secondary outcomes included recurrent ischemic events, symptomatic intracerebral hemorrhage, moderate to severe extracranial bleeding, all-cause mortality, and vascular death. Results:Among 1006 patients included in the analysis (median age, 80.4 [IQR, 73.4-85.4] years; 503 female [50.0%] and 503 [50.0%] male), 463 (46.0%) continued the same DOAC therapy and 543 (54.0%) switched therapy. After IPTW adjustment, the 90-day net clinical benefit was 4.9% with switching and 5.1% with continuation, corresponding to a risk difference of -0.3 percentage points (90% CI, -2.7 to 2.1 percentage points), meeting the prespecified noninferiority criterion. For recurrent ischemic events and bleeding outcomes, the absolute differences were within the predefined noninferiority margins. Noninferiority was not demonstrated for all-cause or vascular mortality. Conclusions and Relevance:In patients with breakthrough ischemic stroke during DOAC therapy, switching anticoagulation treatment was not associated with clinically meaningful short-term benefit compared with continuation. These findings suggest that switching does not provide additional benefit compared with continuing treatment with the same DOAC. Randomized clinical trials are needed to identify strategies to improve secondary prevention after a breakthrough ischemic stroke.