Comparison of echocardiographic and clinical characteristics in embolic stroke and migraine patients with patent foramen ovale.

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.

Age-related burden and characteristics of embolic stroke of undetermined source in the real world clinical practice.

Few data are available on age-related burden and characteristics of embolic stroke of undetermined source (ESUS) in the real world clinical practice. The aim of our study was to provide information about it. We retrospectively analyzed data of patients consecutively admitted to our Stroke Unit along 1 year (2017, November 1st-2018, October 31st). The etiology of ischemic stroke was defined at hospital discharge; ESUS was considered as a subset of cryptogenic stroke, and defined according to the 2014 international criteria. In the analyzed period, 306 patients, 52.3% females, mean age ± SD 77.9 ± 11.9 years, were discharged with diagnosis of ischemic stroke. Ischemic strokes of cardioembolic and lacunar origin were the most frequent subtypes: 30.1% and 29.4%, respectively. Cardioembolic strokes were particularly frequent in patients ≥ 75 years, and almost always associated with atrial fibrillation. Overall, in 80 patients (26.1%) the etiology of stroke was undetermined; in 25 (8.2%) it remained undefined because of death or severe comorbidity, making further diagnostic work-up not worthy. Cryptogenic stroke occurred in 55 patients (18%), and ESUS criteria were satisfied in 39 of them (12.7%). According to age, cryptogenic stroke was diagnosed in 21.1% (21.1% ESUS) of patients < 65 years, 24.2% (19.4% ESUS) of patients aged 65-74 years, 15.5% (9.2% ESUS) of patients ≥ 75 years. After diagnostic work-up, patent foramen ovale was most commonly associated with ESUS (17.9%), especially in patients < 65 years (62.5%); covert paroxysmal atrial fibrillation was detected in 10.5% of ESUS patients ≥ 75 years. In the real world clinical practice, the frequency of ischemic strokes of undetermined etiology, and of those satisfying ESUS criteria, is not negligible, especially in younger patients. A thorough diagnostic work-up, with an age-specific approach, is therefore necessary and of the utmost importance for the identification of stroke etiology, in order to optimize secondary stroke prevention strategies.

Non-vitamin K oral anticoagulants for secondary stroke prevention in patients with atrial fibrillation.

The aims of this article are to review the evidence regarding the use of non-vitamin K oral anticoagulants (NOACs) for secondary stroke prevention as compared to vitamin K antagonists in patients with atrial fibrillation (AF) and in patients with embolic strokes of uncertain source (ESUS), and when to initiate or resume anticoagulation after an ischaemic stroke or intracranial haemorrhage. Four large trials compared NOACs with warfarin in patients with AF. In our meta-analyses, the rate of all stroke or systemic embolism (SE) was 4.94% with NOACs vs. 5.73% with warfarin. Among the patients with AF and previous transient ischaemic attack or ischaemic stroke, the rate of haemorrhagic stroke was halved with a NOAC vs. warfarin, and the rate of major bleeding was 5.7% with a NOAC vs. 6.4% with warfarin. There was no significant difference in mortality. In a trial comparing apixaban with aspirin in patients with AF, the rate of stroke or SE was 2.4% at 1 year with apixaban vs. 9.2% at 1 year with aspirin and the rates of major bleeding were 4.1% with apixaban vs. 2.9% with aspirin. Data from registries confirmed the results from the randomized trials. Initiation or resumption of anticoagulation after ischaemic stroke or cerebral haemorrhage depends on the size and severity of stroke and the risk of recurrent bleeding. Two large trials tested the hypothesis that NOACs are more effective than 100 mg aspirin in patients with ESUS. Neither trial showed a significant benefit of the NOAC over aspirin. In the meta-analysis, the rate all stroke or SE was 4.94% with NOACs vs. 5.73% with warfarin and the rate of haemorrhagic stroke was halved with a NOAC. The four NOACs had broadly similar efficacy for the major outcomes in secondary stroke prevention.

Different Clinical Phenotypes of Embolic Stroke of Undetermined Source: A Subgroup Analysis of 86 Patients.

INTRODUCTION AND STUDY AIM: Embolic strokes of undetermined source (ESUS) represent a rather recent diagnostic entity under clinical research for relapse prevention in cryptogenic stroke patients. Despite strict diagnostic criteria, ESUS definition ignores major clinical and radiological aspects, so including heterogeneous cases and probably influencing trial results. This study researches clinically relevant phenotypes among ESUS patients. PATIENTS AND METHODS: We evaluated ESUS patients admitted at Trento Stroke Unit over a 4-year period. Vascular risk factors (RFs), neurological deficit severity, presence of potential embolic sources, and ASCOD phenotype were recorded. Ischemic lesions were categorized considering their extension in 4 groups. Subgroup comparisons by predefined differences in age, amount of RFs, history of previous stroke, deficit severity, and stroke lesion extension were done. RESULTS: ESUS cases were 86. Patients younger than 50 years old (n = 17) had a lower prevalence of RFs, left atrial enlargement, left ventricle diastolic dysfunction, a higher proportion of ASCOD score A0 (P < .05). Patients without RFs (n = 18) differed from those with greater than or equal to 3 RFs (n = 23) for a younger age and a lower prevalence of potential causes of embolism (P < .05). Patients without a previous stroke (n = 70) were younger, had a lower prevalence of RFs, left ventricle diastolic dysfunction, a higher prevalence of ASCOD score A0 (P < .05). No differences were observed comparing minor and major clinical and radiological strokes. DISCUSSION AND CONCLUSIONS: ESUS patients can be distinguished in 2 opposite phenotypes defined by a lower and a higher load of atherosclerotic pathology. They may suggest possible underlying pathogenic mechanisms and support interpretation of ongoing trials results.

Characterization of Patients with Embolic Strokes of Undetermined Source in the NAVIGATE ESUS Randomized Trial.

BACKGROUND: The New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial vs. ASA to Prevent Embolism in Embolic Stroke of Undetermined Source (NAVIGATE-ESUS) trial is a randomized phase-III trial comparing rivaroxaban versus aspirin in patients with recent ESUS. AIMS: We aimed to describe the baseline characteristics of this large ESUS cohort to explore relationships among key subgroups. METHODS: We enrolled 7213 patients at 459 sites in 31 countries. Prespecified subgroups for primary safety and efficacy analyses included age, sex, race, global region, stroke or transient ischemic attack prior to qualifying event, time to randomization, hypertension, and diabetes mellitus. RESULTS: Mean age was 66.9 ± 9.8 years; 24% were under 60 years. Older patients had more hypertension, coronary disease, and cancer. Strokes in older subjects were more frequently cortical and accompanied by radiographic evidence of prior infarction. Women comprised 38% of participants and were older than men. Patients from East Asia were oldest whereas those from Latin America were youngest. Patients in the Americas more frequently were on aspirin prior to the qualifying stroke. Acute cortical infarction was more common in the United States, Canada, and Western Europe, whereas prior radiographic infarctions were most common in East Asia. Approximately forty-five percent of subjects were enrolled within 30 days of the qualifying stroke, with earliest enrollments in Asia and Eastern Europe. CONCLUSIONS: NAVIGATE-ESUS is the largest randomized trial comparing antithrombotic strategies for secondary stroke prevention in patients with ESUS. The study population encompasses a broad array of patients across multiple continents and these subgroups provide ample opportunities for future research.

Secondary Stroke Prevention in Cryptogenic Stroke and Embolic Stroke of Undetermined Source (ESUS).

PURPOSE OF THE REVIEW: The purpose of the study was to review the literature on cryptogenic stroke and embolic stroke of undetermined stroke (ESUS). Cryptogenic stroke according to TOAST criteria is a stroke which is not due to cardiogenic embolism, small vessel disease with lacunes or large vessel disease of brain supplying arteries. In the context of secondary stroke prevention studies, cryptogenic stroke is not operationally defined. RECENT FINDINGS: The new concept of "embolic stroke of undetermined source" (ESUS) provides an operational definition. ESUS is diagnosed as a non-lacunar stroke on cerebral imaging and exclusion of large vessel atherosclerosis by CTA, MRA or ultrasound. Cardiogenic embolism is made less likely by ECG monitoring and echocardiography. At present, aspirin is used for secondary stroke prevention in patients with cryptogenic stroke. Based on the construct that ESUS might be caused by undetected atrial fibrillation or other embolic mechanisms, ongoing randomised secondary stroke prevention trials are comparing non-vitamin K oral anticoagulants (NOACs) with aspirin.

Three-Case Report of Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic stroke of undetermined source (ESUS) is a new clinical construct. It signifies that the embolus in the thromboembolic ischemic stroke is of unknown origin. The anticoagulants are usually prescribed for antithrombotic prophylaxis, but whether it is appropriate for all patients with ESUS is still unknown. METHODS AND RESULTS: In this article, we describe 3 cases of ESUS, all of whose antithrombotic therapy was antiplatelet medication, and the 3 patients had no recurrence on 3- to 7-month follow-up. CONCLUSIONS: Because there was no obvious risk factor found in these ESUS cases, the recurrence risk is difficult to evaluate, and the optimum means of secondary prevention are still unknown. Hence, many aspects warrant resolution.

Cardiac CT for intra-cardiac thrombus detection in embolic stroke of undetermined source (ESUS).

Introduction: Embolic stroke of undetermined source (ESUS) is a common medical challenge regarding secondary prevention strategy. Cardiac imaging is the cornerstone of embolic stroke workup, in an effort to diagnose high risk cardio-embolic sources. Cardiac computed tomography angiography (CCTA) is an emerging imaging modality with high diagnostic performance for intra-cardiac thrombus detection. The yield of CCTA implementation in addition to standard care in ESUS workup is unknown. Thus, the aim of this study was to assess the utility of CCTA in detecting intra-cardiac thrombi in the routine ESUS workup. Patients and methods: This is a retrospective observational analysis of ESUS cases managed in vascular neurology unit between 2019 and 2021. Within this ESUS registry, consecutive patients undergoing CCTA were included and carefully analyzed. Results: During the study period 1066 Ischemic stroke (IS) cases were treated and evaluated. 266/1066 (25%) met ESUS criteria and 129/266 (48%) underwent CCTA. Intra-cardiac thrombus was detected by CCTA in 22/129 (17%; 95% CI, 11.5%-23.5%) patients: left ventricular thrombus (LVT) in 13 (10.1%) patients, left atrial appendage (LAA) thrombus in 8 (6.2%) patients, and left atrial (LA) thrombus in 1 (0.8%) patient. Only 5/22 (23%) of these thrombi were suspected, but could not be confirmed, in trans-thoracic echocardiogram (TTE). Among CCTA-undergoing patients, 27/129 (21%; 95% CI, 14%-28%) were found to have an indication (including pulmonary embolism) for commencing anticoagulation (AC) treatment, rather than anti-platelets. In favor of CCTA implementation, 22/266 (8.2%; 95% CI, 4.9%-11.5%) patients within the entire ESUS cohort were diagnosed with intra-cardiac thrombus, otherwise missed. Conclusion: CCTA improves the detection of intra-cardiac thrombi in addition to standard care in ESUS patients. The implementation of CCTA in routine ESUS workup can change secondary prevention strategy in a considerable proportion of patients.

Vessel wall MR imaging of aortic arch, cervical carotid and intracranial arteries in patients with embolic stroke of undetermined source: A narrative review.

Despite advancements in multi-modal imaging techniques, a substantial portion of ischemic stroke patients today remain without a diagnosed etiology after conventional workup. Based on existing diagnostic criteria, these ischemic stroke patients are subcategorized into having cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS). There is growing evidence that in these patients, non-cardiogenic embolic sources, in particular non-stenosing atherosclerotic plaque, may have significant contributory roles in their ischemic strokes. Recent advancements in vessel wall MRI (VW-MRI) have enabled imaging of vessel walls beyond the degree of luminal stenosis, and allows further characterization of atherosclerotic plaque components. Using this imaging technique, we are able to identify potential imaging biomarkers of vulnerable atherosclerotic plaques such as intraplaque hemorrhage, lipid rich necrotic core, and thin or ruptured fibrous caps. This review focuses on the existing evidence on the advantages of utilizing VW-MRI in ischemic stroke patients to identify culprit plaques in key anatomical areas, namely the cervical carotid arteries, intracranial arteries, and the aortic arch. For each anatomical area, the literature on potential imaging biomarkers of vulnerable plaques on VW-MRI as well as the VW-MRI literature in ESUS and CS patients are reviewed. Future directions on further elucidating ESUS and CS by the use of VW-MRI as well as exciting emerging techniques are reviewed.

Impact of Neuroimaging Patterns for the Detection of Atrial Fibrillation by Implantable Loop Recorders in Patients With Embolic Stroke of Undetermined Source.

Objectives: Atrial fibrillation (AF) is a well-known etiology of embolic stroke of undetermined source (ESUS), although the optimal detection strategy of AF was not been fully evaluated yet. We assessed AF detection rate by implantable loop recorder (ILR) in patients with ESUS and compared the clinical characteristics and neuroimaging patterns between the patients with AF and AF-free patients. Methods: We reviewed clinical characteristics and neuroimaging patterns of consecutive patients with who were admitted to our comprehensive stroke center for ESUS and underwent ILR insertion between August 1, 2019, and January 31, 202. The inclusion criteria were (1) 18 years of age or older; (2) classified as having cryptogenic stroke extracted from the group with undetermined stroke according to ESUS International Working Group; and (3) underwent ILR insertion during or after admission due to index ischemic events. Ischemic stroke pattern was classified as (1) tiny-scattered infarction, (2) whole-territorial infarction, (3) lobar infarction and (4) multiple-territorial infarction. Interrogations of data retrieved from the ILR were performed by cardiologists in every month after the implantation. Results: In this study, 41 ESUS patients who received an ILR implantation were enrolled (mean age, 64 years; male sex, 65.9%). The rate of AF detection at 6 months was 34% (14 patients), and the mean time from ILR insertion to AF detection was 52.5 days [interquartile range (IQR), 45.0-69.5]. The median initial NIH stroke scale scores were significantly greater in patients with AF than those without AF (6.5 vs. 3.0, p = 0.019). Whole-territorial infarction pattern was significantly more frequent in patients with AF than in those without AF (64.3% vs.11.1%, p = 0.002). Conclusions: Higher covert AF detection rates within the ESUS patients were most often associated with higher NIHSS and whole-territorial infarction patterns on brain imaging.

The Relationship Between Aortic Arch Calcification and Recurrent Stroke in Patients With Embolic Stroke of Undetermined Source-A Case-Control Study.

Background: Aortic arch calcification (AoAC) is associated with plaque development and cardiovascular events. We aimed to estimate the predictive value of AoAC for stroke recurrence in patients with embolic stroke of undetermined source (ESUS). Methods: Consecutive patients with ESUS who were admitted to our center between October 2019 and October 2020 and who had a 1-year follow-up of stroke recurrence were retrospectively reviewed. According to our AoAC grading scale (AGS), AoAC was classified into four grades based on chest computed tomography (CT) findings: no visible calcification (grade 0), spotty calcification (grade 1), lamellar calcification (grade 2), and circular calcification (grade 3). Results: Of the 158 patients with ESUS (age, 62.1 ± 14.5 years; 120 men) enrolled, 24 (15.2%) had recurrent stroke within a 1-year follow-up. The Cox regression analysis showed that stroke history [hazard ratio (HR), 4.625; 95% confidence interval (CI), 1.828-11.700, p = 0.001] and AoAC (HR, 2.672; 95% CI, 1.129-6.319; p = 0.025) predicted recurrent stroke. AGS grade 1 was associated with a significantly higher risk of stroke recurrence than AGS grade 0 (HR, 5.033; 95% CI, 1.858-13.635, p = 0.001) and AGS grade 2 plus 3 (HR, 3.388; 95% CI, 1.124-10.206, p = 0.030). In patients with AoAC, receiver operating characteristic (ROC) analysis showed that AGS had a good value in predicting stroke recurrence in patients with ESUS, with an area under curve (AUC) of 0.735 (95% CI = 0.601-0.869, p = 0.005). Conclusions: Aortic arch calcification, especially spotty calcification, had a good predictive value for stroke recurrence in patients with ESUS.

Patent foramen ovale closure in India; Feasibility, challenges and mid-term outcomes.

Patent foramen ovale closure (PFO) is an underutilized therapy, and our study explored the challenges and feasibility of PFO closure in the Indian setting. Eighty patients with Embolic Stroke of Undetermined Source (ESUS) were screened by transcranial Doppler (TCD) for PFO. Twenty-nine patients underwent successful closure. High-risk features of a long tunnel, inter-atrial septal aneurysm, and large defect were present in 31%, 28%, and 59%. Transcranial Doppler had a sensitivity and specificity of 78% and 53% (p = 0.02) to detect PFO. Anticoagulation was withdrawn in 85% of patients post closure. Two patients had residual shunts at follow-up of 19 (9,34) months.

Characteristics of Clinical Symptoms, Cerebral Images and Stroke Etiology in Vertebro-Basilar Artery Fenestration-Related Infarction.

Cerebral artery fenestration is a rare variant of the vascular architecture, but its existence is well documented. The common site of fenestration is the vertebra-basilar artery and it may be found incidentally with subarachnoid hemorrhage. However, fenestration-related cerebral infarction is rare. We analyzed the clinical characteristics, stroke etiology, and image findings of fenestration-related cerebral infarction of the vertebrobasilar artery. We reviewed our hospital records and previously published reports to find cases of fenestration-related cerebral infarction. We excluded those with unknown clinical features or radiological findings. We retrieved 4 cases of fenestration-related infarction from our hospital, in which vascular change, headache, vertigo/dizziness, and dissection in stroke etiology were detected. In eight previously reported cases of fenestration-related infarction, similar vascular changes were noted, but they were mainly diagnosed as embolic stroke of undetermined source. However, based on the criteria for dissection in this study, dissection as the stroke etiology was suspected in the previously reported cases. Many hypotheses have been proposed for the development of dissection, thrombus, and aneurysms in fenestration. Although an embryological and morphological study is needed, clinicians must consider basilar artery fenestration-related infarction as a differential diagnosis and intensive non-invasive image study is recommended.