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Background and Aims: The putative association between serum 25-hydroxyvitamin D concentration [25(OH)D] and the risk of cardioembolic stroke (CES) has been examined in observational studies, which indicate controversial findings. We performed Mendelian randomization (MR) analysis to determine the causal relationship of serum 25(OH)D with the risk of CES., Methods and Results: The summary statistics dataset on the genetic variants related to 25(OH)D was used from the published GWAS of European descent participants in the UK Biobank, including 417,580 subjects, yielding 143 independent loci in 112 1-Mb regions. GWAS summary data of CES was obtained from GIGASTROKE Consortium, which included European individuals (10,804 cases, 1,234,808 controls). Our results unveiled a causal relationship between 25(OH)D and CES using IVW [OR = 0.82, 95% CI: 0.67-0.98, p = 0.037]. Horizontal pleiotropy was not seen [MR-Egger intercept = 0.001; p = 0.792], suggesting an absence of horizontal pleiotropy. Cochrane's Q [Q = 78.71, p-value = 0.924], Rucker's Q [Q = 78.64, p-value = 0.913], and I 2  = 0.0% (95% CI: 0.0%, 24.6%) statistic suggested no heterogeneity. This result remained consistent using different MR methods and sensitivity analyses, including Maximum likelihood [OR = 0.82, 95%CI: 0.67-0.98, p-value = 0.036], Constrained maximum likelihood [OR = 0.76, 95%CI: 0.64-0.90, p-value = 0.002], Debiased inverse-variance weighted [OR = 0.82, 95%CI: 0.68-0.99, p-value = 0.002], MR-PRESSO [OR = 0.82, 95%CI 0.77-0.87, p-value = 0.022], RAPS [OR = 0.82, 95%CI 0.67-0.98, p-value = 0.038], MR-Lasso [OR = 0.82, 95%CI 0.68-0.99, p-value = 0.037]., Conclusion: Our MR analysis provides suggestive evidence that increased 25(OH)D levels may play a protective role in the development of cardioembolic stroke. Determining the role of 25(OH)D in stroke subtypes has important clinical and public health implications., Competing Interests: Declaration of competing interest All authors declare that they have no conflicts of interest., (Copyright © 2024 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Objective: This paper presents a rare case of subacute bacterial endocarditis (SBE) following a herpes zoster (HZ) episode, with no prior records found in the existing literature., Patient Information: Specifically, we describe a case of a 76-year-old female whose diagnosis of SBE was hindered by the concurrent manifestation of HZ symptoms, which had emerged 3 weeks before the onset of SBE indicators., Follow-Up and Outcomes: This delay in diagnosis resulted in profound complications, including a cerebrovascular accident and significant mitral valve destruction., Discussion: HZ episodes have not conventionally been linked in the medical literature to the occurrence of SBE. Nonetheless, it is noteworthy that HZ infections have been associated with the development of other consequential bacterial infections, such as pneumonia and necrotizing fasciitis.This case underscores the necessity for medical practitioners to recognize the possibility of HZ symptoms obscuring indications of critical underlying conditions and infections. The implications of this report highlight the significance of maintaining heightened vigilance for signs of other severe infections when managing patients presenting with HZ symptoms., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Methamphetamine use has emerged as a major risk factor for cardiovascular and cerebrovascular disease in young adults. The aim of this study was to investigate a possible association of methamphetamine use with cardioembolic stroke., Methods and Results: We performed a retrospective study of patients with acute ischemic stroke admitted at our medical center between 2019 and 2022. All patients were screened for methamphetamine use and cardiomyopathy, defined as left ventricular ejection fraction ≤45%. Among 938 consecutive patients, 46 (4.9%) were identified as using methamphetamine. Compared with the nonmethamphetamine group (n=892), the methamphetamine group was significantly younger (52.8±9.6 versus 69.7±15.2 years; P <0.001), included more men (78.3% versus 52.8%; P <0.001), and had a significantly higher rate of cardiomyopathy (30.4% versus 14.0%; P <0.01). They were also less likely to have a history of atrial fibrillation (8.7% versus 33.4%; P <0.01) or hyperlipidemia (28.3% versus 51.7%; P <0.01). Compared with patients with cardiomyopathy without methamphetamine use, the patients with cardiomyopathy with methamphetamine use had significantly lower left ventricular ejection fraction (26.0±9.59% versus 32.47±9.52%; P <0.01) but better functional outcome at 3 months, likely attributable to significantly younger age and fewer comorbidities. In the logistic regression model of clinical variables, methamphetamine-associated cardiomyopathy was found to be significantly associated with cardioembolic stroke (odds ratio, 1.79 [95% CI, 1.04-3.06]; P <0.05)., Conclusions: We demonstrate that methamphetamine use is significantly associated with cardiomyopathy and cardioembolic stroke in young adults.

Background: Covert atrial fibrillation (AF) is a major cause of cryptogenic stroke. This study investigated whether a dose-dependent relationship exists between the frequency of premature atrial contractions (PACs) and AF detection in patients with cryptogenic stroke using an insertable cardiac monitor (ICM)., Methods: We enrolled consecutive patients with cryptogenic stroke who underwent ICM implantation between October 2016 and September 2020 at 8 stroke centers in Japan. Patients were divided into 3 groups according to the PAC count on 24-hour Holter ECG: ≤200 (group L), >200 to ≤500 (group M), and >500 (group H). We defined a high AF burden as above the median of the cumulative duration of AF episodes during the entire monitoring period. We evaluated the association of the frequency of PACs with AF detection using log-rank trend test and Cox proportional hazard model and with high AF burden using logistic regression model, adjusting for age, sex, CHADS 2 score., Results: Of 417 patients, we analyzed 381 patients with Holter ECG and ICM data. The median age was 70 (interquartile range, 59.5-76.5), 246 patients (65%) were males, and the median duration of ICM recording was 605 days (interquartile range, 397-827 days). The rate of new AF detected by ICM was higher in groups with more frequent PAC (15.5%/y in group L [n=277] versus 44.0%/y in group M [n=42] versus 71.4%/y in group H [n=62]; log-rank trend P <0.01). Compared with group L, the adjusted hazard ratios for AF detection in groups M and H were 2.11 (95% CI, 1.24-3.58) and 3.23 (95% CI, 2.07-5.04), respectively, and the adjusted odds ratio for high AF burden in groups M and H were 2.57 (95% CI, 1.14-5.74) and 4.25 (2.14-8.47), respectively., Conclusions: The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke., Competing Interests: Disclosures Dr Todo reports lecture fees from Pfizer, Bristol-Myers Squibb, Daiichi-Sankyo, Bayer, Medtronic, Abbott, and Otsuka Pharmaceutical. Dr Doijiri reports lecture fees from Medtronic, Abbott, Biotronic, Daiichi Sankyo, Bristol-Myers Squibb, and Bayer. Dr Yamazaki reports lecture fees from Medtronic, Abbott, Daiichi Sankyo, Bristol-Myers Squibb, and Bayer. Dr Iwata reports lecture fees from Daiichi-Sankyo, and Medtronic. Dr Sonoda reports lecture fees from Medtronic, Abbott, and Daiichi-Sankyo. Dr Koge reports lecture fees from Medtronic. Dr Koga reports honoraria from Daiichi-Sankyo and research support from Daiichi-Sankyo. Dr Nagata reports lecture fees from Otsuka Pharmaceutical, Daiichi-Sankyo, Eli Lilly, and Amgen. Dr Ueno reports research funds from Bristol-Myers Squibb. Dr Yamagami reports lecture fees from Medtronic, Abbott, Daiichi-Sankyo, Bristol-Myers Squibb, and Bayer, and grant support from Bristol-Myers Squibb. Dr Gon reports lecture fees from Eisai, Kyowa Kirin, and Pfizer. The other authors report no conflicts.

Background and Purpose: Ischemic stroke is a heterogeneous disease with various etiologies. The current subtyping process is complicated, time-consuming, and costly. Metabolite-based biomarkers have the potential to improve classification and deliver optimal treatments. We here aimed to identify novel, targeted metabolomics-based biomarkers to discriminate between large-artery atherosclerosis (LAA) and cardioembolic (CE) stroke., Methods: We acquired serum samples and clinical data from a hospital-based acute stroke registry (ischemic stroke within 3 days from symptom onset). We included 346 participants (169 LAA, 147 CE, and 30 healthy older adults) and divided them into training and test sets. Targeted metabolomic analysis was performed using quantitative and quality-controlled liquid chromatography with tandem mass spectrometry. A multivariate regression model using metabolomic signatures was created that could independently distinguish between LAA and CE strokes., Results: The training set (n = 193) identified metabolomic signatures that were different in patients with LAA and CE strokes. Six metabolomic biomarkers, i.e., lysine, serine, threonine, kynurenine, putrescine, and lysophosphatidylcholine acyl C16:0, could discriminate between LAA and CE stroke after adjusting for sex, age, body mass index, stroke severity, and comorbidities. The enhanced diagnostic power of key metabolite combinations for discriminating between LAA and CE stroke was validated using the test set (n = 123)., Conclusions: We observed significant differences in metabolite profiles in LAA and CE strokes. Targeted metabolomics may provide enhanced diagnostic yield for stroke subtypes. The pathophysiological pathways of the identified metabolites should be explored in future studies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Previous studies suggest an association between schizophrenia and stroke, but no studies have investigated stroke subtypes. We examined potential causal associations between schizophrenia and a range of atherosclerotic, embolic, and hemorrhagic stroke outcomes., Methods and Results: Two-sample Mendelian randomization analyses were conducted. The summary-level data (restricted to European ancestry) were obtained for schizophrenia and stroke: ischemic stroke, large-artery stroke, small-vessel stroke, cardioembolic stroke, and intracerebral hemorrhage. The associations between schizophrenia and each outcome were analyzed by an inverse variance weighting method primarily and Mendelian randomization Egger, weighted median, and weighted mode subsequently. The presence of pleiotropy was also tested by Cochran Q statistic, I index, and Mendelian randomization Egger intercept with scatter and funnel plots. We found associations between schizophrenia and cardioembolic stroke (odds ratio [OR], 1.070 [95% CI, 1.023-1.119]) and intracerebral hemorrhage (OR, 1.089 [95% CI, 1.005-1.180]) using inverse variance weighting. Little evidence of associations with the other stroke subtypes was found. Different Mendelian randomization methods corroborated the association with cardioembolic stroke but not intracerebral hemorrhage.2 index, and Mendelian randomization Egger intercept with scatter and funnel plots. We found associations between schizophrenia and cardioembolic stroke (odds ratio [OR], 1.070 [95% CI, 1.023-1.119]) and intracerebral hemorrhage (OR, 1.089 [95% CI, 1.005-1.180]) using inverse variance weighting. Little evidence of associations with the other stroke subtypes was found. Different Mendelian randomization methods corroborated the association with cardioembolic stroke but not intracerebral hemorrhage., Conclusions: We have provided evidence of a potentially causal association between schizophrenia and cardioembolic stroke. Our findings suggest that cardiac evaluation should be considered for those with schizophrenia.

Background: In patients with acute cardiogenic cerebral embolism, a residual thrombus may still be present in the cardiac cavity even after reperfusion therapy. We aimed to investigate the occurrence of a residual cardiac thrombus in cardioembolic stroke after reperfusion therapy and analyze its impact on clinical outcome., Methods and Results: We enrolled patients with cardioembolic stroke from our prospectively collected database who underwent 2-phase cardiac computed tomography within 7 days after reperfusion therapy. Residual cardiac thrombus was defined as a filling defect on both early- and late-phase images, whereas circulatory stasis was defined as a filling defect only on the early-phase images in the left atrial appendage. The primary outcome was a poor clinical outcome (modified Rankin Scale score, 3-6) at 90 days. The secondary outcome was a composite end point event (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke) at 90 days. A total of 303 patients were included, of whom 94 (31.0%) had a residual cardiac thrombus. Binary logistic regression analysis showed that the presence of a residual cardiac thrombus was associated with a poor clinical outcome (odds ratio, 1.951 [95% CI, 1.027-3.707]; P =0.041) but not circulatory stasis in the left atrial appendage (odds ratio, 1.096 [95% CI, 0.542-2.217]; P =0.798). Furthermore, there was no correlation between a residual cardiac thrombus and the composite end point event (30.0% versus 31.1%; P =1.000)., Conclusions: Residual cardiac thrombus occurs in approximately one-third of patients with cardioembolic stroke after reperfusion therapy and is often indicative of a poor clinical outcome.

Background: Intravenous injection of alteplase, a recombinant tPA (tissue-type plasminogen activator) as a thrombolytic agent has revolutionized ischemic stroke management. However, tPA is a more complex enzyme than expected, being for instance able to promote thrombolysis, but at the same time, also able to influence neuronal survival and to affect the integrity of the blood-brain barrier. Accordingly, the respective impact of endogenous tPA expressed/present in the brain parenchyma versus in the circulation during stroke remains debated., Methods: To address this issue, we used mice with constitutive deletion of tPA (tPA Null [tPA-deficient mice]) or conditional deletion of endothelial tPA (VECad [vascular endothelial-Cadherin-Cre-recombinase]-Cre ∆tPA ). We also developed parabioses between tPA Null and wild-type mice (tPA WT ), anticipating that a tPA WT donor would restore levels of tPA to normal ones, in the circulation but not in the brain parenchyma of a tPA Null recipient. Stroke outcomes were investigated by magnetic resonance imaging in a thrombo-embolic or a thrombotic stroke model, induced by local thrombin injection or FeCl 3 application on the endothelium, respectively., Results: First, our data show that endothelial tPA, released into the circulation after stroke onset, plays an overall beneficial role following thrombo-embolic stroke. Accordingly, after 24 hours, tPA Null /tPA Null parabionts displayed less spontaneous recanalization and reperfusion and larger infarcts compared with tPA WT /tPA WT littermates. However, when associated to tPA WT littermates, tPA Null mice had similar perfusion deficits, but less severe brain infarcts. In the thrombotic stroke model, homo- and hetero-typic parabionts did not differ in the extent of brain damages and did not differentially recanalize and reperfuse., Conclusions: Together, our data reveal that during thromboembolic stroke, endogenous circulating tPA from endothelial cells sustains a spontaneous recanalization and reperfusion of the tissue, thus, limiting the extension of ischemic lesions. In this context, the impact of endogenous parenchymal tPA is limited., Competing Interests: Disclosures None.

Background: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset., Methods and results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis., Conclusions: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Background and Objectives: Risk of readmission after stroke differs by stroke (sub)type and etiology, with higher risks reported for hemorrhagic stroke and cardioembolic stroke. We examined the risk and cause of first readmission by stroke subtype over the years post incident stroke., Methods: Atherosclerosis Risk in Communities (ARIC) study participants (n = 1,412) with first-ever stroke were followed up for all-cause readmission after incident stroke. Risk of first readmission was examined by stroke subtypes (cardioembolic, thrombotic/lacunar, and hemorrhagic [intracerebral and subarachnoid]) using Cox and Fine-Gray proportional hazards models, adjusting for sociodemographic and cardiometabolic risk factors., Results: Among 1,412 participants (mean [SD] age 72.4 [9.3] years, 52.1% women, 35.3% Black), 1,143 hospitalizations occurred over 41,849 person-months. Overall, 81% of participants were hospitalized over a maximum of 26.6 years of follow-up (83% of participants with thrombotic/lacunar stroke, 77% of participants with cardioembolic stroke, and 78% of participants with hemorrhagic stroke). Primary cardiovascular and cerebrovascular diagnoses were reported for half of readmissions. Over the entire follow-up period, compared with cardioembolic stroke, readmission risk was lower for thrombotic/lacunar stroke (hazard ratio [HR] 0.82, 95% CI 0.71-0.95) and hemorrhagic stroke (HR 0.74, 95% CI 0.58-0.93) in adjusted Cox proportional hazards models. By contrast, there was no statistically significant difference among subtypes when adjusting for atrial fibrillation and competing risk of death. Compared with cardioembolic stroke, thrombotic/lacunar stroke was associated with lower readmission risk within 1 month (HR 0.66, 95% CI 0.46-0.93) and during 1 month-1 year (HR 0.78, 95% CI 0.62-0.97), and hemorrhagic stroke was associated with lower risk during 1 month-1 year (HR 0.60, 95% CI 0.41-0.87). There was no significant difference between subtypes in readmission risk during later periods., Discussion: Over 26 years of follow-up, 81% of stroke participants experienced a readmission. Cardiovascular and cerebrovascular diagnoses at readmission were most common across stroke subtypes. Though cardioembolic stroke has previously been reported to confer higher risk of readmission, in this study, the readmission risk was not statistically significantly different between stroke subtypes or over different periods when accounting for the competing risk of death.

Background: Embolic stroke of unknown source (ESUS) accounts for 1 in 6 ischemic strokes. Current guidelines do not recommend routine cardiac magnetic resonance (CMR) imaging in ESUS, and beyond the identification of cardioembolic sources, there are no data assessing new clinical findings from CMR in ESUS. This study aimed to assess the prevalence of new cardiac and noncardiac findings and to determine their impact on clinical care in patients with ESUS., Methods and Results: In this prospective, multicenter, observational study, CMR imaging was performed within 3 months of ESUS. All scans were reported according to standard clinical practice. A new clinical finding was defined as one not previously identified through prior clinical evaluation. A clinically significant finding was defined as one resulting in further investigation, follow-up, or treatment. A change in patient care was defined as initiation of medical, interventional, surgical, or palliative care. From 102 patients recruited, 96 underwent CMR imaging. One or more new clinical findings were observed in 59 patients (61%). New findings were clinically significant in 48 (81%) of these patients. Of 40 patients with a new clinically significant cardiac finding, 21 (53%) experienced a change in care (medical therapy, n=15; interventional/surgical procedure, n=6). In 12 patients with a new clinically significant extracardiac finding, 6 (50%) experienced a change in care (medical therapy, n=4; palliative care, n=2)., Conclusions: CMR imaging identifies new clinically significant cardiac and noncardiac findings in half of patients with recent ESUS. Advanced cardiovascular screening should be considered in patients with ESUS., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04555538.

Competing Interests: Disclosures None.

Background: This single-center observational study aimed to compare the echocardiographic and clinical features in patients diagnosed with migraine and embolic stroke of undetermined source (ESUS) who presented with a known patent foramen ovale (PFO)., Methods: Two-dimensional and color Doppler images were obtained using various transthoracic echocardiography views for both migraine and ESUS patients. Suspected PFO cases underwent further assessment through contrast echocardiography and transesophageal echocardiography (TEE). High-risk PFO characteristics were evaluated using TEE, and the Risk of Paradoxical Embolism (RoPe) score was calculated., Results: The study included 310 participants (age range: 18-60, 73.2% female), with 43.5% diagnosed with migraine and 56.5% with ESUS. Common comorbidities included diabetes (26.1%). High-velocity shunting through the interatrial septum was observed in 35.5% of patients. ESUS patients were older, with higher rates of diabetes and hypertension, while active smoking was more prevalent among migraine patients. Basic echocardiographic parameters were mostly similar, except for elevated pulmonary artery systolic pressure in ESUS. ESUS patients exhibited a greater occurrence of large microbubble passage through the interatrial septum and longer PFO lengths compared to migraine patients. However, the RoPe and High-risk PFO scores were similar between the groups., Conclusions: ESUS patients, characterized by older age and higher rates of diabetes and hypertension, demonstrated increased pulmonary artery pressure, more significant microbubble crossings, and longer PFO lengths. Conversely, migraine patients had a higher prevalence of active smoking. Despite differing clinical profiles, the risk scores for PFO-related embolic events were comparable between the groups. These findings underscore potential distinctions between ESUS and migraine patients with PFO and their implications for management strategies., (© 2024 Wiley Periodicals LLC.)

LT3001 is a novel synthetic small molecule with thrombolytic and free radical scavenging activities. In this study, we tested the effects of LT3001 as a potential alternative thrombolytic in focal embolic ischemic stroke rat model. Stroked rats received intravenous injection of 10 mg/kg LT3001 or tPA at 1.5, 3, or 4.5 h after stroke, respectively, and the outcomes were measured at different time points after stroke by performing multi-parametric MRI, 2,3,5-triphenyltetrazolium chloride (TTC) staining, and modified neurological severity score. Lastly, we assessed the effect of LT3001 on the tPA activity in vitro, the international normalized ratio (INR), and the serum levels of active tPA and plasminogen activator inhibitor-1 (PAI-1). LT3001 treated at 1.5 h after stroke is neuroprotective by reducing the CBF lesion size and lowering diffusion and T2 lesion size measured by MRI, which is consistent with the reduction in TTC-stained infarction. When treated at 3 h after stroke, LT3001 had significantly better therapeutic effects regarding reduction of infarct size, swelling rate, and hemorrhagic transformation compared to tPA. When treated at 4.5 h after stroke, tPA, but not LT3001, significantly increased brain swelling and intracerebral hemorrhagic transformation. Lastly, LT3001 did not interfere with tPA activity in vitro, or significantly alter the INR and serum levels of active tPA and PAI-1 in vivo. Our data suggests that LT3001 is neuroprotective in focal embolic stroke rat model. It might have thrombolytic property, not interfere with tPA/PAI-1 activity, and cause less risk of hemorrhagic transformation compared to the conventional tPA. Taken together, LT3001 might be developed as a novel therapy for treating thrombotic ischemic stroke., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Stroke is a major cause of morbidity, mortality, and disability. The American Heart Association/American Stroke Association recently published updated guidelines on secondary stroke prevention. In these rounds, 2 vascular neurologists use the case of Mr. S, a 75-year-old man with a history of 2 strokes, to discuss and debate questions in the guideline concerning intensity of atrial fibrillation monitoring in embolic stroke of undetermined source, diagnosis and management of moderate symptomatic carotid stenosis, and therapeutic strategies for recurrent embolic stroke of undetermined source in the setting of guideline-concordant therapy., Competing Interests: Disclosures: All relevant financial relationships have been mitigated. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-3136.

We report an elderly woman with vascular risk factors and recurrent cardioembolic strokes in whom the stroke aetiology was finally ascertained to be a calcified amorphous tumour of the heart after repeated negative investigations for embolic aetiology over 2 years. This report discusses the clinical and imaging characteristics of calcified amorphous tumours of the heart with emphasis of recent advances in cardiac imaging., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Primary stroke prevention in non-valvular atrial fibrillation (NVAF) is primarily with non-vitamin K oral anticoagulant (NOAC) therapy. However, 20-36% of ischaemic strokes seem to occur in patients with atrial fibrillation while already on anticoagulation. We present a case of an ischaemic stroke in an elderly female in her 70s with medical history significant for hypertension and NVAF. She had a CHA2DS2-VASc score of 3 and was on apixaban for thromboprophylaxis. She presented with neurological deficits consistent with a left middle cerebral artery stroke, confirmed via head imaging; the most likely stroke aetiology was determined to be cardioembolic in the setting of NVAF. She was treated with continuation of her apixaban at the same dosage She displayed improved function, although with residual expressive aphasia at her 2-month neurology follow-up. Cardioembolic ischaemic stroke in NVAF despite current NOAC therapy does not have current management guidelines., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives : Acute ischemic cardioembolic stroke (CS) is a clinical condition with a high risk of death, and can lead to dependence, recurrence, and dementia. Materials and Methods : In this study, we evaluated gender differences and female-specific clinical data and early outcomes in 602 women diagnosed with CS from a total of 4600 consecutive acute stroke patients in a single-center hospital stroke registry over 24 years. A comparative analysis was performed in women and men in terms of demographics, cerebrovascular risk factors, clinical data, and early outcomes. Results : In a multivariate analysis, age, hypertension, valvular heart disease, obesity, and internal capsule location were independent variables associated with CS in women. The overall in-hospital mortality rate was similar, but the group of women had a greater presence of neurological deficits and a higher percentage of severe limitation at hospital discharge. After the multivariate analysis, age, altered consciousness, limb weakness, and neurological, respiratory, gastrointestinal, renal, cardiac and peripheral vascular complications were independent predictors related to early mortality in women. Conclusions : Women with CS showed a differential demographic and clinical profile and worse early outcomes than men. Advanced age, impaired consciousness, and medical complications were predictors of stroke severity in women with CS.

BACKGROUND: Rivaroxaban and dabigatran were not superior to aspirin in trials of patients with embolic stroke of undetermined source (ESUS). It is unknown whether apixaban is superior to aspirin in patients with ESUS and known risk factors for cardioembolism. METHODS: We conducted a multicenter, randomized, open-label, blinded-outcome trial of apixaban (5 mg twice daily) compared with aspirin (100 mg once daily) initiated within 28 days after ESUS in patients with at least one predictive factor for atrial fibrillation or a patent foramen ovale. Cardiac monitoring was mandatory, and aspirin treatment was switched to apixaban in case of atrial fibrillation detection. The primary outcome was any new ischemic lesion on brain magnetic resonance imaging (MRI) during 12-month follow-up. Secondary outcomes included major and clinically relevant nonmajor bleeding. RESULTS: A total of 352 patients were randomly assigned to receive apixaban (178 patients) or aspirin (174 patients) at a median of 8 days after ESUS. At 12-month follow-up, MRI follow-up was available in 325 participants (92.3%). New ischemic lesions occurred in 23 of 169 (13.6%) participants in the apixaban group and in 25 of 156 (16.0%) participants in the aspirin group (adjusted odds ratio, 0.79; 95% confidence interval, 0.42 to 1.48; P=0.57). Major and clinically relevant nonmajor bleeding occurred in five and seven participants, respectively (1-year cumulative incidences, 2.9 and 4.2; hazard ratio, 0.68; 95% confidence interval, 0.22 to 2.16). Serious adverse event rates were 43.9 per 100 person-years in those given apixaban and 45.7 per 100 person-years in those given aspirin. The Apixaban for the Treatment of Embolic Stroke of Undetermined Source trial was terminated after a prespecified interim analysis as a result of futility. CONCLUSIONS: Apixaban treatment was not superior to cardiac monitoring-guided aspirin in preventing new ischemic lesions in an enriched ESUS population. (Funded by Bristol-Myers Squibb and Medtronic Europe; ClinicalTrials.gov number, NCT02427126.)

Introduction: The intricate relationship between Chagas disease and ischemic stroke remains unclear. Limited evidence exists concerning secondary prophylaxis, etiological diagnosis, and stroke-related determinants. This study aims to discern factors linked to stroke in Chagas disease by contrasting patients with and without a history of ischemic stroke., Methods: Retrospective data from all outpatient Chagas disease patients from two Brazilian hospitals - one Chagas center and one stroke clinic - were examined. Descriptive analyses were conducted to identify stroke-associated factors. Variables were compared between patients with and without ischemic stroke history., Results: Among 678 subjects, 72 had experienced stroke. Univariate associations with stroke included male gender, heart failure, prior or ongoing alcoholism, electrocardiographic features (non-sinus rhythm, left bundle branch, right bundle branch block, left anterosuperior fascicular block, atrial fibrillation), as well as echocardiographic findings indicative of reduced left ventricular ejection fraction and segmental abnormalities. After logistic regression (multivariate analysis), congestive heart failure, right bundle branch block, left anterosuperior divisional block, and atrial fibrillation retained independent associations., Conclusion: In this study, cardiac involvement emerged as the predominant factor correlated with stroke in Chagas disease. While atherosclerosis-related risk factors were prevalent, their influence on ischemic stroke in Chagas disease appeared limited., Competing Interests: Declaration of Competing Interest None of the authors report conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Carotid web (CaWeb) is a rare form of fibromuscular dysplasia that can produce embolic stroke. Misdiagnosis of symptomatic CaWeb as "cryptogenic stroke" or "embolic stroke of unknown source" is common and can lead to recurrent, catastrophic neurologic events. Reports of CaWeb in the literature are scarce, and their natural history is poorly understood. Appropriate management remains controversial., Methods: CaWeb was defined as a single, shelf-like, linear projection in the posterolateral carotid bulb causing a filling defect on computed tomography angiography (CTA) or cerebral angiography. Cases of symptomatic CaWeb at a single institution with a high-volume stroke center were identified through collaborative evaluation by vascular neurologists and vascular surgeons., Results: Fifty-two patients with symptomatic CaWeb were identified during a 6-year period (2016-2022). Average age was 49 years (range, 29-73 years), 35 of 52 (67%) were African American, and 18 of 52 (35%) were African American women under age 50. Patients initially presented with stroke (47/52; 90%) or transient ischemic attack (5/52; 10%). Stenosis was <50% in 49 of 52 patients (94%) based on NASCET criteria, and 0 of 52 (0%) CaWebs were identified with carotid duplex. Definitive diagnosis was made by CTA examined in multiple planes or cerebral angiography examined in a lateral projection to adequately assess the posterolateral carotid bulb, where 52 of 52 (100%) of CaWebs were seen. Early in our institutional experience, 10 of 52 patients (19%) with symptomatic CaWeb were managed initially with dual antiplatelet and statin therapy or systemic anticoagulation; all suffered ipsilateral recurrent stroke at an average interval of 43 months (range, 1-89 months), and five were left with permanent deficits. Definitive treatment included carotid endarterectomy in 27 of 50 (56%) or carotid stenting in 23 of 50 (46%). Two strokes were irrecoverable, and intervention was deferred. Web-associated thrombus was observed in 20 of 50 (40%) on angiography or grossly upon carotid exploration. Average interval from initial stroke to intervention was 39 days. After an average follow-up of 38 months, there was no reported postintervention stroke or mortality., Conclusions: To our knowledge, this is the largest single-institution analysis of symptomatic CaWeb yet reported. Our series demonstrates that carotid duplex is inadequate for diagnosis, and that medical management is unacceptable for symptomatic CaWeb. Recurrent stroke occurred in all patients managed early in our experience with medical therapy alone. We have since adopted an aggressive interventional approach in cases of symptomatic CaWeb, with no postoperative stroke reported over an average follow-up of 38 months. In younger patients presenting with cryptogenic stroke, especially African American women, detailed review of lateral cerebral angiography or multi-planar, fine-cut CTA images is required to accurately rule out or diagnose CaWeb and avoid recurrent neurologic events., Competing Interests: Disclosures None., (Copyright © 2023 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: Cerebral arterial gas embolism (CAGE) occurs when air or medical gas enters the systemic circulation during invasive procedures and lodges in the cerebral vasculature. Non-contrast computer tomography (CT) may not always show intracerebral gas. CT perfusion (CTP) might be a useful adjunct for diagnosing CAGE in these patients., Methods: This is a retrospective single-center cohort study. We included patients who were diagnosed with iatrogenic CAGE and underwent CTP within 24 h after onset of symptoms between January 2016 and October 2022. All imaging studies were evaluated by two independent radiologists. CTP studies were scored semi-quantitatively for perfusion abnormalities (normal, minimal, moderate, severe) in the following parameters: cerebral blood flow, cerebral blood volume, time-to-drain and time-to-maximum., Results: Among 27 patient admitted with iatrogenic CAGE, 15 patients underwent CTP within the designated timeframe and were included for imaging analysis. CTP showed perfusion deficits in all patients except one. The affected areas on CTP scans were in general located bilaterally and frontoparietally. The typical pattern of CTP abnormalities in these areas was hypoperfusion with an increased time-to-drain and time-to-maximum, and a corresponding minimal decrease in cerebral blood flow. Cerebral blood volume was mostly unaffected., Conclusion: CTP may show specific perfusion defects in patients with a clinical diagnosis of CAGE. This suggests that CTP may be supportive in diagnosing CAGE in cases where no intracerebral gas is seen on non-contrast CT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Patients with atrial fibrillation-related stroke (AF-stroke) are prone to developing rapid ventricular response (RVR). We investigated whether RVR is associated with initial stroke severity, early neurological deterioration (END) and poor outcome at 3 months., Methods: We reviewed patients who had AF-stroke between January 2017 and March 2022. RVR was defined as having heart rate &gt;100 beats per minute on initial electrocardiogram. Neurological deficit was evaluated with National Institutes of Health Stroke Scale (NIHSS) score at admission. END was defined as increase of ≥2 in total NIHSS score or ≥1 in motor NIHSS score within first 72 h. Functional outcome was score on modified Rankin Scale at 3 months. Mediation analysis was performed to examine potential causal chain in which initial stroke severity may mediate relationship between RVR and functional outcome., Results: We studied 568 AF-stroke patients, among whom 86 (15.1%) had RVR. Patients with RVR had higher initial NIHSS score (p &lt; 0.001) and poor outcome at 3 months (p = 0.004) than those without RVR. The presence of RVR [adjusted odds ratio (aOR) = 2.13; p = 0.013] was associated with initial stroke severity, but not with END and functional outcome. Otherwise, initial stroke severity [aOR = 1.27; p = &lt;0.001] was significantly associated with functional outcome. Initial stroke severity as a mediator explained 58% of relationship between RVR and poor outcome at 3 months., Conclusion: In patients with AF-stroke, RVR was independently associated with initial stroke severity but not with END and functional outcome. Initial stroke severity mediated considerable proportion of association between RVR and functional outcome., (© 2023 S. Karger AG, Basel.)

Objective: Understanding the lateralization factors, including the anatomic and hemodynamic mechanisms, is essential for diagnosing cardio-embolic stroke. This study aims to investigate the elements, for the first time together, that could affect the laterality of stroke., Methods: We performed a monocentric retrospective case-control study based on prospective registries of acute ischemic stroke patients in the comprehensive stroke center of the RWTH University hospital of Aachen for three years (June 2018-June 2021). We enrolled 222 patients with cardioembolic stroke (136 left stroke and 86 right stroke) admitted for first-ever acute ischemic stroke with unilateral large vessel occlusion of the anterior circulation. The peak systolic velocity (PSV) asymmetry of middle cerebral artery (MCA) was assessed by doppler as well as internal carotid artery (ICA) angle, aortic arch (AA) branching pattern and anatomy were assessed by CT-Angiography., Results: We found that the increasing left ICA angle (p = 0.047), presence of bovine type AA anatomy (p = 0.041) as well as slow PSV of the right MCA with a value of >15% than left (p = 0.005) were the predictors for left stroke lateralization, while the latter was an independent predictor for the left stroke (OR=3.341 [1.415-7.887]). Inter-Rater Reliability ranged from moderate to perfect agreement., Conclusion: The predictors for left stroke lateralization include the higher values of left ICA angle, presence of the bovine type AA and the slow right MCA PSV., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

A 45-year-old man suffered multiple cerebral infarctions in the vertebrobasilar artery territory, followed by second stroke against conservative treatment. Radiological examinations revealed intra-arterial defect in left persistent 1st intersegmental artery (PFIA) at C1 level, suggesting mural thrombus, and mechanical compression of left PFIA at the level with head rotation to the right clearly revealed by reconstructed 3-dimensional radiological images, but no findings of atlantoaxial instability. One month after the second stroke, posterior fixation was performed. Postoperative course was uneventful without subsequent stroke for 24 months. This unique case demonstrated that PFIA might associate with cerebral stroke as a clinical condition of bow hunter's stroke even in middle age. Reconstructed 3-dimensional radiological images might be useful for clear demonstration of the pathophysiology in this complex clinical entity.

Objective: The scope of this paper is to review the subtypes of transient ischemic attack (TIA) and minor stroke (mS) in which a surgical treatment is needed, discussing the importance and the timing of a multidisciplinary approach, in order to achieve an optimized management and prevent major strokes or other critical complications., Materials and Methods: The keywords "transient ischemic attack," "minor stroke," "surgical treatment," "vascular surgery," "heart surgery," "neurosurgery," and "multidisciplinary" were searched using MEDLINE, EMBASE, and Scopus. Relevant search results were discussed by the authors for references inclusion., Results: Notwithstanding that best medical therapy is usually the first choice for the most part of cases, there are specific but recurrent etiologies that must be properly recognized because of a potential surgical approach, even in urgency. In fact, symptomatic carotid stenosis, or particular cases of hemodynamic cerebrovascular events, should be promptly referred to vascular surgeon, since increasing evidences highlighted a benefit from an early artery revascularization. In addition, beyond arrhythmic causes, cardioembolic events due to bacterial endocarditis and atrial myxoma should be quickly diagnosed, possibly in emergency department, because they are a presumptive urgency for heart surgery. In addition to the above-mentioned conditions, in patients suffering from vertebrobasilar TIA or mS, clinicians should keep in mind the Bow Hunter disease, because surgical artery decompression can represent the only suitable treatment in selected cases., Conclusions: TIA and mS require a multidisciplinary in order to discuss therapeutic options, comparing risks and benefits and determining the best timing for an optimized management., (© 2023. Fondazione Società Italiana di Neurologia.)

Age and sex have effect on atherosclerosis. This study aimed to investigate their effect on non-stenotic intracranial atherosclerotic plaque (NIAP) in embolic stroke of undetermined source (ESUS) using high-resolution magnetic resonance imaging (HR-MRI). We retrospectively recruited consecutive ESUS patients who underwent intracranial HR-MRI to assess the plaque characteristics (remodeling index [RI], plaque burden [PB], fibrous cap [FC], discontinuity of plaque surface [DPS], intraplaque hemorrhage [IPH] and complicated plaque [CP]). We divided patients into three groups (< 60 years, 60-74 years, ≥ 75 years). 155 patients with ipsilateral NIAP were found from 243 ESUS patients, with 106 men (68.39%) and 49 women (31.61%). In total population or age group under 60 years, there were no significant differences in plaque characteristics between men and women (all p > 0.05). In age group of 60-74 years, men were associated with higher PB (66.27 ± 9.17% vs 60.91 ± 8.86%, p = 0.017) and RI (1.174 vs 1.156, p = 0.019), higher prevalence of DPS (82.50% vs 60.00%, p = 0.036) and complicated plaque (85.00% vs 63.33%, p = 0.036). For subjects ≥ 75 years old, PB were significantly higher in twomen vs men (68.85 ± 6.14% vs 62.62 ± 7.36%, p = 0.040). In addition, the probability for PB upper (≥ median PB), RI upper (≥ median RI) and vulnerable plaque increased as age increased, and its predictive power for index ESUS was higher in men than women. This study identified age-dependent sex differences in NIAP characteristics of ESUS patients, which will help us clarify their etiology., (© 2023. The Author(s).)

Parkinson's disease (PD) and cardio-cerebrovascular diseases are related, according to earlier studies, but these studies have some controversy. Our aim was to assess the impact of PD on cardiocerebrovascular diseases using a Mendelian randomization (MR) method. The data for PD were single nucleotide polymorphisms (SNPs) from a publicly available genome-wide association study (GWAS) dataset containing data on 482,730 individuals. And the outcome SNPs data is were derived from five different GWAS datasets. The basic method for MR analysis was the inverse variance weighted (IVW) approach. We use the weighted median method and the MR-Egger method to supplement the MR analysis conclusion. Finally, We used Cochran's Q test to test heterogeneity, MR-PRESSO method and leave-one-out analysis method to perform sensitivity analysis. We used ratio ratios (OR) to assess the strength of the association between exposure and outcome, and 95% confidence intervals (CI) to show the reliability of the results. Our findings imply that PD is linked to a higher occurrence of coronary artery disease (CAD) (OR = 1.055, 95% CI 1.020-1.091, P = 0.001), stroke (OR = 1.039, 95% CI 1.007-1.072, P = 0.014). IVW analyses for stroke's subgroups of ischemic stroke (IS) and 95% CI 1.007-1.072, P = 0.014). IVW analyses for stroke's subgroups of ischemic stroke (IS) and cardioembolic stroke (CES) also yielded positive results, respectively (OR = 1.043, 95% CI 1.008-1.079, P = 0.013), (OR = 1.076, 95% CI 1.008-1.149, P = 0.026). There is no evidence of a relationship between PD and other cardio-cerebrovascular diseases. Additionally, sensitivity analysis revealed reliable outcomes. Our MR study analysis that PD is related with an elevated risk of CAD, stroke, IS, and CES., (© 2023. The Author(s).)

A woman in her 70s was admitted for acute, painless vision loss in the left eye. Examination showed cherry red spot in the macula and plaque in the nasal vessels, consistent with central retinal artery occlusion. MRI orbits revealed multifocal subclinical acute infarcts in the right middle cerebral artery (MCA) territory and bilateral cerebella. Transthoracic echocardiogram showed calcification of the anterolateral papillary muscle. Further characterisation with cardiac MRI elucidated caseous 'toothpaste-like' calcification of the muscle complex. Stroke workup was otherwise unremarkable. The patient underwent hyperbaric treatment with mild improvement. Anticoagulation and surgical intervention were deferred due to known risks and unknown benefit for calcific emboli. The patient was continued on her home dual anti-platelet therapy (DAPT) and discharged with a loop monitor. Caseous calcification of the papillary muscle (CCPM) may be a risk factor for cardioembolic stroke. Further discussions on medical and surgical guidelines for CCPM would be beneficial for stroke prevention., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Methods: We performed a hospital-based prospective cohort study with 1,317 enrolled participants. We compared patients and healthy volunteers according to the main demographic, anthropometric parameters, stroke risk factors, comorbidities, and data of clinical and instrumental examination. In order to balance the study and the control groups for age and sex, the propensity score matching was performed. In order to generate the overall predictive model, a multivariate analysis was performed using the binary logistic regression method., Results: The following predictors of ESUS were identified in current study: arterial hypertension (AH); increased heart rate and pulmonary arterial systolic pressure (PASP); the presence of conduction disturbance; the enlargement of left, right atrium, and left ventricle end-systolic length; increased intima-media thickness (IMT) in right and left common carotid artery (CCA); lowered Montreal Cognitive Assessment (MoСA) cognitive scale score; the presence of subcortical microbleeds; central brain atrophy; the larger size of third ventricle; and the higher medial temporal lobe atrophy (MTA) score. The following risk factors were included in the final predictive model: the presence of AH ( p < 0.0005; OR = 12.98 (95% CI: 4.53-37.21)) and PASP ( p =0.018; OR = 1.13 (95% CI: 1.02-1.25)) and male sex ( p =0.046; OR = 2.771 (95% CI: 1.017-7.555)). The Nagelkerke's pseudo-R-squared value was 0.404 and the significance of the Hosmer-Lemeshow test was 0.733, which indicate the goodness of the final logistic regression model., Conclusions: We propose that AH and its consequences are the main predictors of ESUS. The results of this study emphasize the importance of AH control for primary and secondary prevention of ESUS., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2023 Alexander B. Berdalin et al.)

Recent research has shed light on the culpability of LA (left atrial) abnormality, in the form of atrial cardiopathy, as an independent risk factor for the development of atrial fibrillation, LA thrombus and subsequent stroke. The aim of this study was to measure LA electromechanical dissociation (EMD), LA volumes, P-wave dispersion (PWD) and P-wave terminal force in V1 (PTFV1) as markers of atrial cardiopathy in patients with ESUS (embolic stroke of undetermined source), to determine whether atrial cardiopathy is an integral part in the causal pathway of ESUS. 28 patients presenting with ischemic stroke and fulfilling the criteria for ESUS were enrolled into this cross-sectional, observational study along with a control group of 28 age- and gender-matched apparently healthy individuals. On ECG, PWD and PTFV1 were measured. On echocardiography, LA EMD and LA volumes were recorded. Increased PWD (34.14 ± 9.89 ms vs. 27.32 ± 8.95 ms; p = 0.01), atrial EMD (73.32 ± 16.31 ms vs. 63.63 ± 13.59 ms; p = 0.02) and LA volumes were observed in patients with ESUS as compared to controls. A significant correlation was also found between these parameters (p < 0.01). According to the results of our study, PWD, atrial EMD and LA volumes may be novel predictors for ESUS. Our results support the notion that atrial cardiopathy is a distinct mechanism of thrombosis in ESUS patients. Further research is required to clarify its function in the causation of stroke, ESUS in particular., (© 2023. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Liver cirrhosis is a confirmed risk factor for poor prognosis of stroke; however, the contribution of clinically inapparent liver fibrosis to cardioembolic stroke (CES) and its outcomes are poorly understood. This study aimed to investigate the associations between liver fibrosis-measured by the Fibrosis-4 (FIB-4) score-and stroke severity and short-term clinical outcomes of patients with acute CES due to nonvalvular atrial fibrillation (NVAF). A total of 522 patients were followed for a median of 90 days. We calculated the FIB-4 score and defined liver fibrosis as follows: likely advanced fibrosis (FIB-4 > 3.25), indeterminate advanced fibrosis (FIB-4, 1.45-3.25), and unlikely advanced fibrosis (FIB-4 < 1.45). Logistic regression analysis and Cox regression analysis were used to investigate the relations between the FIB-4 score and stroke severity, major disability at discharge, and all-cause mortality. Among these 522 acute CES patients with NVAF, the mean FIB-4 score (2.28) on admission reflected intermediate fibrosis, whereas liver enzymes were largely normal. In multivariate regression analysis, patients with advanced liver fibrosis were more likely to have a higher risk of severe stroke (OR = 2.21, 95% CI 1.04-3.54), major disability at discharge (OR = 4.59, 95% CI 1.88-11.18), and all-cause mortality (HR = 1.25, 95% CI 1.10-1.56) than their counterparts. Regarding sex, these associations were stronger in males but not significant in females. In patients with acute CES due to NVAF, advanced liver fibrosis is associated with severe stroke, major disability, and all-cause death. Our findings indicate that early screening and management of liver fibrosis may decrease stroke severity and risk of death in patients with NVAF, especially for male patients. Consequently, FIB-4 > 3.25 of male patients should receive ultrasound elastography to further determine the degree of liver fibrosis., (© 2023. The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI).)

Background: Right to left shunt (RLS), including patent foramen ovale, is a recognized risk factor for stroke. RLS/patent foramen ovale diagnosis is made by transthoracic echocardiography (TTE), which is insensitive, transesophageal echocardiography, which is invasive, and transcranial Doppler (TCD), which is noninvasive and accurate but scarce., Methods: We conducted a prospective, single-arm device clinical trial of robot-assisted TCD (raTCD) versus TTE for RLS diagnosis at 6 clinical sites in patients who presented with an event suspicious for embolic cerebrovascular ischemia from October 6, 2020 to October 20, 2021. raTCD was performed with standard TCD bubble study technique. TTE bubble study was performed per local standards. The primary outcome was rate of RLS detection by raTCD versus TTE., Results: A total of 154 patients were enrolled, 129 evaluable (intent to scan) and 121 subjects had complete data per protocol. In the intent to scan cohort, mean age was 60±15 years, 47% were women, and all qualifying events were diagnosed as ischemic stroke or transient ischemic attack. raTCD was positive for RLS in 82 subjects (64%) and TTE was positive in 26 (20%; absolute difference 43.4% [95% CI, 35.2%-52.0%]; P <0.001). On prespecified secondary analysis, large RLS was detected by raTCD in 35 subjects (27%) versus 13 (10%) by TTE (absolute difference 17.0% [95% CI, 11.5%-24.5%]; P <0.001). There were no serious adverse events., Conclusions: raTCD was safe and ≈3 times more likely to diagnose RLS than TTE. TTE completely missed or underdiagnosed two thirds of large shunts diagnosed by raTCD. The raTCD device, used by health professionals with no prior TCD training, may allow providers to achieve the known sensitivity of TCD for RLS and patent foramen ovale detection without the need for an experienced operator to perform the test. Pending confirmatory studies, TCD appears to be the superior screen for RLS compared with TTE (funded by NeuraSignal)., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT04604015., Competing Interests: Disclosures Drs Alexandrov, Rubin, Tsivgoulis, and Volpi have received payment as consultants to the study sponsor. C. Douville has received travel support from the study sponsor. The other authors report no conflicts.

Background: Observational studies have found an increased risk of stroke in patients with spondyloarthritis, but the results are susceptible to reverse causality and confounders. Therefore, the study aimed to further explore the association between spondyloarthritis and different subtypes of stroke by using a two sample Mendelian randomization (MR) analysis., Methods: Genetic instrumental variables for spondyloarthritis were identified using summary level data from a genome-wide association study involving 201,581 people. Summary statistics from the Multiancestry Genome-wide Association Study of Stroke Consortium were used to obtain genetic data on stroke. There was no sample overlap between the exposure and outcome datasets. Inverse-variance weighted was considered the primary MR method for causal analysis. Heterogeneity, pleiotropy and sensitivity analyses were performed to ensure robustness, and single nucleotide polymorphism (SNP) with potential confounders was further screened in the PhenoScanner database to better evaluate the stability of our study., Results: One SNP (rs1065045) was excluded due to schizophrenia. After excluding SNP (rs1065045), results of the second MR analysis were slightly different from the first, which were considered as the final result: a significant positive causality between spondyloarthritis and cardioembolic stroke (OR=1.296, 95% CI:1.094-1.534, p =0.003); a possible positive causality between spondyloarthritis and any stroke (OR=1.082, 95% CI:1.016-1.152, p =0.013)/any ischemic stroke (OR=1.086, 95% CI:1.013-1.163, p=0.020); no significant/possible causality between spondyloarthritis and small vessel stroke (OR=1.168, 95% CI:0.993-1.375, p =0.061). Insufficient power may be one possible reason why a causality was not observed between spondyloarthritis in our study., Conclusions: This study suggests that the possible causative effects of spondyloarthritis predicted by genetics on stroke may be limited to any stroke, any ischemic stroke, and cardioembolic stroke, especially the last., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Yu, Huo, Mei, Zhao and Zhu.)

Background Chitinase-3 like protein 1 (CHI3L1, YKL-40) was reported to be implicated in the development of ischemic stroke, but whether the association between them was causal remained unclear. We conducted a 2-sample Mendelian randomization study to explore the associations of genetically determined plasma YKL-40 with ischemic stroke and its subtypes (large artery stroke, small vessel stroke, and cardioembolic stroke). Methods and Results Based on genome-wide association study data of 3394 European-descent individuals, we selected 13 single-nucleotide polymorphisms associated with plasma YKL-40 as genetic instruments. Summary data about ischemic stroke and its subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium, involving 34 217 ischemic stroke cases and 406 111 controls of European ancestry. We used the inverse-variance weighted method followed by a series of sensitivity analyses to assess the causal associations of plasma YKL-40 with ischemic stroke and its subtypes. The primary analysis showed that genetically determined high YKL-40 levels were associated with increased risks of large artery stroke (odds ratio [OR], 1.08 [95% CI, 1.04-1.12]; P =1.73×10 -4 ) and small vessel stroke (OR, 1.05 [95% CI, 1.01-1.09]; P =7.96×10 -3 ) but not with ischemic stroke or cardioembolic stroke. Sensitivity analyses further confirmed these associations, and Mendelian randomization-Egger indicated no evidence of genetic pleiotropy. In addition, supplementary analysis based on the summary data from the Olink proximity extension assay cardiovascular I (Olink CVD-I) panel showed that high YKL-40 levels were positively associated with the risks of large artery stroke (OR, 1.15 [95% CI, 1.08-1.22]; P =4.16×10 -6 ) but not with small vessel stroke. Conclusions Genetically determined high plasma YKL-40 levels were causal associated with increased risks of large artery stroke.

Objective: Leukoaraiosis and other brain MRI-assessed parameters were shown to be associated with recurrent stroke in this population. We aimed to develop an MRI-based predictive tool for risk stratification of ESUS patients., Methods: We retrospectively assessed consecutive patients who were diagnosed with ESUS and underwent brain MRI and performed a multivariable analysis with the outcome of recurrent stroke/TIA. Based on the coefficient of each covariate, we generated an integer-based point scoring system. The discrimination and calibration of the score were assessed using the area under the receiver operator characteristic curve, net reclassification improvement, integrated discrimination improvement, calibration curve, and decision curve analysis. Also, we compared the new score with a previously published score (ALM score)., Results: Among 176 patients followed for an overall period of 902.3 patient-years (median of 74 months), there were 39 recurrent ischemic stroke/TIAs (4.32 per 100 patient-years). Fazekas score (HR: 1.26, 95% CI: 1.03-1.54), enlarged perivascular space (EPVS) (HR: 2.76, 95% CI: 1.12-6.17), NIHSS at admission (HR: 1.11, 95% CI: 1.02-1.18), and infarct subtypes (HR: 2.88, 95% CI: 1.34-6.17) were associated with recurrent stroke/TIA. Accordingly, a score (FENS score) was developed with AUC-ROC values of 0.863, 0.788, and 0.858 for 1, 3, and 5 years, respectively. These were significantly better than the AUC-ROC of ALM score (0.635, 0.695, and 0.705, respectively). The FENS score exhibited better calibration and discrimination ability than the ALM score (Hosmer-Lemeshow test χ 2 : 4.402, p = 0.819)., Conclusion: The MRI-based FENS score can provide excellent predictive performance for recurrent stroke/TIA and may assist in risk stratification of ESUS patients., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

We aimed to analyse whether patients with ischaemic stroke (IS) occurring within eight days after the onset of COVID-19 (IS-COV) are associated with a specific aetiology of IS. We used SUPERGNOVA to identify genome regions that correlate between the IS-COV cohort (73 IS-COV cases vs. 701 population controls) and different aetiological subtypes. Polygenic risk scores (PRSs) for each subtype were generated and tested in the IS-COV cohort using PRSice-2 and PLINK to find genetic associations. Both analyses used the IS-COV cohort and GWAS from MEGASTROKE (67,162 stroke patients vs. 454,450 population controls), GIGASTROKE (110,182 vs. 1,503,898), and the NINDS Stroke Genetics Network (16,851 vs. 32,473). Three genomic regions were associated ( p -value < 0.05) with large artery atherosclerosis (LAA) and cardioembolic stroke (CES). We found four loci targeting the genes PITX2 (rs10033464, IS-COV beta = 0.04, p -value = 2.3 × 10 -2 , se = 0.02), previously associated with CES, HS6ST1 (rs4662630, IS-COV beta = -0.04, p -value = 1.3 × 10 -3 , se = 0.01), TMEM132E (rs12941838 IS-COV beta = 0.05, p -value = 3.6 × 10 -4 , se = 0.01), and RFFL (rs797989 IS-COV beta = 0.03, p -value = 1.0 × 10 -2 , se = 0.01). A statistically significant PRS was observed for LAA. Our results suggest that IS-COV cases are genetically similar to LAA and CES subtypes. Larger cohorts are needed to assess if the genetic factors in IS-COV cases are shared with the general population or specific to viral infection.

Background High plasma prekallikrein was reported to be associated with increased risks of stroke, but the causality for these associations remains unclear. We aimed to investigate the associations of genetically predicted plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, 3 ischemic stroke subtypes, and intracerebral hemorrhage (ICH) using a 2-sample Mendelian randomization approach. Methods and Results Seven independent prekallikrein-related single-nucleotide polymorphisms were identified as genetic instruments for prekallikrein based on a genome-wide association study with 1000 European individuals. The summary statistics for all-cause stroke, ischemic stroke, and ischemic stroke subtypes were obtained from the Multiancestry Genome-wide Association Study of Stroke Consortium with 40 585 cases and 406 111 controls of European ancestry. The summary statistics for ICH were obtained from the ISGC (International Stroke Genetics Consortium) with 1545 ICH cases and 1481 controls of European ancestry. In the main analysis, the inverse-variance weighted method was applied to estimate the associations of plasma prekallikrein concentrations with all-cause stroke, ischemic stroke, ischemic stroke subtypes, and ICH. Genetically predicted high plasma prekallikrein levels were significantly associated with elevated risks of all-cause stroke (odds ratio [OR] per SD increase, 1.04 [95% CI, 1.02-1.06]; P =5.44×10 -5 ), ischemic stroke (OR per SD increase, 1.05 [95% CI, 1.03-1.07]; P =1.42×10 -5 ), cardioembolic stroke (OR per SD increase, 1.08 [95% CI, 1.03-1.12]; P =3.75×10 -4 ), and small vessel stroke (OR per SD increase, 1.11 [95% CI, 1.06-1.17]; P =3.02×10 -5 ). However, no significant associations were observed for genetically predicted prekallikrein concentrations with large artery stroke and ICH. Conclusions This Mendelian randomization study found that genetically predicted high plasma prekallikrein concentrations were associated with increased risks of all-cause stroke, ischemic stroke, cardioembolic stroke, and small vessel stroke, indicating that prekallikrein might have a critical role in the development of stroke.

Introduction: Cryptogenic stroke constitutes 25% of all ischemic strokes, of which 20-30% are due to atrial fibrillation (AF). With the aim of increasing the detection rate, implantable long-term monitoring devices have emerged. The study of the profile of the ideal candidate subsidiary to such monitoring would provide a better understanding of the mechanisms underlying this subtype of stroke., Objective: To determine which variables are related and can predict the detection of silent AF in patients with cryptogenic stroke., Patients and Methods: This is a longitudinal cohort with recruitment from March 2017 to May 2022. They are patients with an implantable monitoring device and cryptogenic stroke with a minimum monitoring of one year., Results: The total number of patients included was 73, with a mean age of 58.8 years, 56.2% were male. AF was detected in 21 patients (28.8%). The most frequent cardiovascular risk factors were hypertension (47.9%) and dyslipidemia (45.2%). The most frequent topography was cortical (52%). Regarding the echocardiographic parameters, 22% had a dilated left atrium, 19% had a patent foramen ovale, and 22% had high-density supraventricular tachycardia (>1%) on Holter monitoring. In the multivariate analysis, the only variable that predicts AF is the presence of high-density supraventricular tachycardia, with an area under the curve of 0.726 (CI 0.57-0.87, p=0.04), sensitivity of 47.6%, specificity of 97.5%, positive predictive value of 90.9%, negative predictive value of 78.8%, and accuracy of 80.9%., Conclusions: The presence of high-density supraventricular tachycardia can be indicative for predicting silent AF. No other variables have been observed that allow us to predict detection of AF in these patients., (Copyright © 2023 Elsevier España, S.L.U. All rights reserved.)

Background and Aims: Atrial fibrillation (AF) is the most important cause of embolic stroke of undetermined source (ESUS). Implantable loop recorder (ILR) demonstrated the highest sensitivity for detecting it. This register was created to confirm the high prevalence of AF in patients after ESUS and to verify possible benefits on clinical outcomes such as TIA (Transient Ischaemic Attack)/stroke recurrence and death using ILR., Methods: A total of 278 patients admitted to "Molinette" Hospital in Stroke Unit department between 2011 and 2016, diagnosed with ESUS, underwent ILR implantation if they had at least one risk factor for AF. A total of 165 patients admitted to other departments in the same center for the same pathology, without ILR, represent the control group. We used propensity score to select 132 patients from each group (matching age, sex, CHADS-VASC, and HAS-BLEED baseline characteristics)., Results: The detection rate of AF episodes was significantly higher in the ILR group (p < 0.001). No significant protective role of ILR for clinical endpoints was found on univariate analysis, although a trend towards significance has been pointed for the composite outcome of death and ischemic events recurrence (OR 0.52, CI 0.26-1.04, p = 0.06). A protective role of ILR was found for deaths (OR 0.4, CI 0.17-0.94, p 0.03) and for the composite outcome (OR 0.41, CI 0.19-0.87, p 0.02) on multivariate analysis in the best subsets., Conclusion: With our statistical models, we identified a significant clinical benefit from ILR monitoring, evidenced by a trend of less death and TIA/stroke recurrence and relevant ILR protection for prediction of TIA/stroke recurrence.

Competing Interests: Disclosures None.

Competing Interests: None

Design: Mendelian randomization study., Case Selection: Using a Mendelian randomization framework, the causal relationship between periodontitis [chronic periodontitis (CP) and aggressive periodontitis (AgP)] and ischemic stroke and its subtypes [cardioembolic (CE) stroke, large artery atherosclerosis (LAA), and small vessel occlusion (SVO)], were studied., Data Analysis: Data from three large databanks, namely, UK Biobank, genome-wide association study of European ancestry, and MEGASTROKE consortium of European ancestry were used to obtain genetic variant information of CP, AgP, and ischemic stroke, respectively. UK Biobank contributed 950 cases of CP and 455,398 controls. Genome-wide association study of European ancestry contributed 851 AgP cases and 6836 controls. MEGASTROKE consortium of European ancestry contributed 34,217 cases of ischemic stroke and its subtypes and 406,111 controls. Statistical tests including inverse variant weighted method and sensitivity analyses were performed to analyse the causal inference and to verify the strength of the results., Results: A total of 15 single nucleotide polymorphisms (SNPs) for CP was obtained as genetic instruments. No causal inference of CP on ischemic stroke was found. Among the ischemic stroke subtypes, with the exception of CE stroke, no significant causal inference of CP on LAA or SVO was found. A total of 9 single nucleotide polymorphisms (SNPs) for AgP was obtained as genetic instruments. No causal inference of AgP on ischemic stroke and its subtypes were found., Conclusions: Neither CP nor AgP was found to have a causal inference on ischemic stroke and most of its subtypes. A probable causal effect of CP on CE stroke was noted., (© 2023. The Author(s).)