Direct oral anticoagulants in embolic stroke of undetermined source: an updated meta-analysis.

The efficacy and safety of direct oral anticoagulants (DOAC) in patients with embolic stroke of undetermined source (ESUS) remains unclear. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCT) comparing DOACs versus aspirin in patients with ESUS. Risk ratios (RR) and 95% confidence intervals (CI) were computed for binary endpoints. Four RCTs comprising 13,970 patients were included. Compared with aspirin, DOACs showed no significant reduction of recurrent stroke (RR 0.95; 95% CI 0.84-1.09; p = 0.50; I2 = 0%), ischemic stroke or systemic embolism (RR 0.97; 95% CI 0.80-1.17; p = 0.72; I2 = 0%), ischemic stroke (RR 0.92; 95% CI 0.79-1.06; p = 0.23; I2 = 0%), and all-cause mortality (RR 1.11; 95% CI 0.87-1.42; p = 0.39; I2 = 0%). DOACs increased the risk of clinically relevant non-major bleeding (CRNB) (RR 1.52; 95% CI 1.20-1.93; p < 0.01; I2 = 7%) compared with aspirin, while no significant difference was observed in major bleeding between groups (RR 1.57; 95% CI 0.87-2.83; p = 0.14; I2 = 63%). In a subanalysis of patients with non-major risk factors for cardioembolism, there is no difference in recurrent stroke (RR 0.98; 95% CI 0.67-1.42; p = 0.90; I2 = 0%), all-cause mortality (RR 1.24; 95% CI 0.58-2.66; p = 0.57; I2 = 0%), and major bleeding (RR 1.00, 95% CI 0.32-3.08; p = 1.00; I2 = 0%) between groups. In patients with ESUS, DOACs did not reduce the risk of recurrent stroke, ischemic stroke or systemic embolism, or all-cause mortality. Although there was a significant increase in clinically relevant non-major bleeding, major bleeding was similar between DOACs and aspirin.

Left atrial strain, embolic stroke of undetermined source, and atrial fibrillation detection.

BACKGROUND: Atrial cardiopathy is a proposed mechanism of embolic stroke of undetermined source (ESUS). Left atrial (LA) strain may identify early atrial cardiopathy prior to structural changes. We aim to study the associations between LA strain, ESUS, and atrial fibrillation (AF) detection in ESUS. METHODS: The study population included patients with ESUS and noncardioembolic (NCE) stroke presenting to the Rhode Island Hospital Stroke Center between January 2016 and June 2017 who underwent transthoracic echocardiography. Speckle tracking echocardiography (STE) was used to measure the three phases of LA strain (reservoir, conduit, and contractile). Binary logistic regression analysis was performed to determine the associations between LA strain and stroke subtype (ESUS vs. NCE) as well as follow-up detection of AF in ESUS patients. RESULTS: We identified 656 patients, 307 with ESUS and 349 with NCE. In binary logistic regression, the lowest tertiles of LA reservoir (adjusted OR 1.944, 95% CI 1.266-2.986, p = .002), contractile (aOR 1.568, 95% CI 1.035-2.374, p = .034), and conduit strain (aOR 2.288, 95% CI 1.448-3.613, p = .001) were more likely to be significantly associated with ESUS compared to NCE stroke. Among all ESUS patients, the lowest tertiles of LA reservoir strain (OR 2.534, 95% CI 1.029-6.236, p = .043), contractile strain (OR 2.828, 95% CI 1.158-6.903, p = .022), and conduit strain (OR 2.614, 95% CI 1.003-6.815, p = .049) were significantly associated with subsequent detection of AF. CONCLUSION: Reduced LA strain is associated with ESUS occurrence and AF detection in ESUS patients. Therefore, quantification of LA strain in ESUS patients may improve risk stratification and guide secondary prevention strategies.

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.

Effectiveness of statins on outcomes of patients with Embolic Stroke of Undetermined Source (ESUS).

BACKGROUND: Statins are highly recommended as a secondary prevention strategy after a stroke. Embolic Stroke of Undetermined Source (ESUS) accounts for up to one fifth of cases of ischemic stroke. There is a lack of studies investigating the effectiveness of statins in this subgroup of patients. METHODS: We designed a longitudinal cohort study involving patients properly diagnosed with ESUS. Data about statin therapy included information about the time of initiation of the treatment, pre-stroke statin use, statin withdrawal, and the type and dosage of the statin prescribed. Patients were followed for 48 months after the index stroke. The primary endpoints included stroke recurrence, major cardiovascular events, and death from all causes. The secondary endpoint was the functional outcome, assessed in a standardized and systematic way using the modified Rankin Scale (mRS). RESULTS: Patients who were not taking any statin after ESUS have significantly increased odds of stroke recurrence (OR = 3.29, 95% CI 1.27 - 8.55) or presenting the composite outcome of stroke recurrence, major cardiovascular events, and death (OR = 3.70, 95% CI 1.44 - 9.50) in the multivariate analysis. No statin therapy was directly associated with the functional outcome as well (OR = 3.32, 95% CI = 1.58 - 6.96). The early initiation of the statin therapy was estimated to reduce the risk of a second stroke and the composite outcome by 89% and 87%. CONCLUSIONS: Our pioneering study provides evidence that patients with ESUS may benefit from statin therapy, especially if prescribed early and at higher dosages.

Non-stenosing carotid artery plaques in embolic stroke of undetermined source: a retrospective analysis.

BACKGROUND: We aim to identify the association between high-risk carotid plaques and their laterality to stroke in ESUS patient population. We also discuss recurrent stroke events and their laterality to the index stroke. METHODS: This was a retrospective study. We reviewed data for patients with ESUS between June 20, 2016, and June 20, 2021. Using computed tomography angiography, we analyzed plaque features that are associated with ESUS, and then, we identified the recurrent stroke events and characterized lateralization to the index stroke. RESULTS: Out of 1779 patients with cryptogenic ischemic stroke, we included 152 patients who met the criteria for ESUS. High-risk plaque features were found more often ipsilateral to the stroke side when compared contralaterally: plaque ulceration (19.08% vs 5.26%, p < .0001), plaque thickness > 3 mm (19.08% vs 7.24%, p = 0.001), and plaque length > 1 cm (13.16% vs 5.92%, p = 0.0218). There was also a significant difference in plaque component in which both components (soft and calcified) and only soft plaques were more prevalent ipsilaterally (42.76% vs 23.68% and 17.76% vs 9.21%, respectively, p < .0001). Of the 152 patients, 17 patients were found to have a recurrent stroke event, and 47% (n = 8) had an ipsilateral stroke to the index event. Moreover, stroke was bilateral in 41% of the patients (n = 7), and contralateral in 12% (n = 2). CONCLUSION: High-risk plaque features studied here were more prevalent ipsilaterally to the stroke side in ESUS than contralaterally. Multicenter studies are needed to form precise prediction models and scoring systems to help guide treatment, i.e., choice of medical therapy and/or revascularization.

Echocardiography in cardioembolic stroke prevention.

Stroke is a leading cause of mortality and disability, and cardiac embolism accounts for one-third of all ischaemic strokes. Thirty per cent of strokes are cryptogenic. In this setting, echocardiography is essential in the diagnosis, treatment, and prevention of embolic stroke of undetermined source since it is a widely available, safe, and inexpensive tool. Transthoracic echocardiography and transoesophageal echocardiography, furthermore, are proven to change therapeutic management leading to initiation of anti-coagulation, anti-microbial therapy, patent foramen ovale (PFO) closure, or cardiac tumour resection. The most common cardioembolic sources include left atrial appendage thrombus, left ventricular thrombus, vegetations in endocarditis, paradoxical embolization in PFO, prosthesis thrombosis, and intracardiac tumours. Although the presence of a cardioembolic source only represents a risk factor for an ischaemic stroke, it could not assure the certain or the unique cause of the event. The purpose of this review is to underline the importance of echocardiography and overview the main sources of cardiac embolism and the echocardiographic features.

Atrial cardiomyopathy: Diagnosis, clinical implications and unresolved issues in anticoagulation therapy.

Atrial cardiomyopathy (AC) is an evolving pathophysiological entity that has expanded our understanding regarding the atrium and its role in arrhythmogenesis and cardiac thromboembolism. The pathological myocardium in AC promotes arrhythmogenesis through mechanical dysfunction (hypocontractility, fibrosis), adverse alterations of the endothelium and secretion of prothrombotic factors (IL-6, IL-8, TNF-a). 'Red flags', indicative of AC, can be recognized either non-invasively by electrocardiography, echocardiography and cardiac magnetic resonance imaging or invasively by high-density electroanatomical mapping as low bipolar voltage areas of the affected myocardium. Signs of AC have been strongly associated with an increased risk of ischemic stroke, even embolic strokes of undetermined source, regardless of the coexistence of atrial fibrillation (AF). The underlying existence of AC has been negatively correlated with the success rate of catheter ablation of AF. The clinical value of AC is the provision of a novel pathway regarding the potential mechanisms of cerebrovascular events of cardiac thromboembolic origin. In addition, AC may serve as a risk stratification tool to predict the long-term responders of AF catheter ablation.

Prevalence of high-risk aortic arch atherosclerosis features on computed tomography angiography in embolic stroke of undetermined source.

INTRODUCTION: Embolic stroke of undetermined source (ESUS) comprises a heterogenous group. There is a need to further identify etiologies within this group to guide management strategies. We examined the prevalence of aortic arch atherosclerosis (AAA) on CT angiography (CTA) in patients with embolic stroke of undetermined source (ESUS) to characterize high-risk plaque features. METHODS: All patients from two prospective multicenter acute ischemic stroke studies (INTERRSeCT and PRove-IT) were included if the CTA adequately imaged the proximal aortic arch and the stroke etiology was recorded. Three readers blinded to stroke etiology analyzed the following AAA plaque features on baseline CTA at the time of stroke: 1) thickness in millimetres (mm); 2) morphology (none, smooth, ulcerated, or protruding); 3) location within the aortic arch (proximal, transverse, or distal); and 4) calcification (none, single small, multiple small, single large, or diffuse extensive). RESULTS: We included 1063 patients, of which 293 (27.6%) had ESUS (mean age 67.5 years; 46.4% men; median NIHSS 12; 80.6% large vessel occlusion). Mean AAA thickness was significantly larger in ESUS patients (3.8 mm) compared to non-ESUS patients (3.0 mm; p<0.0001) and to a subgroup of patients with large artery atherosclerosis (2.9 mm; p=0.003). ESUS patients had a significantly higher proportion of ulcerated or protruding plaques (17.4% vs 10.3%; risk ratio 1.7, 95% C.I. 1.2-2.4, p=0.002). The location of AAA in the ESUS group was the ascending aorta in 37.9%, transverse arch in 42.3%, and descending aorta in 84.6%. Although AAA was mostly located in the distal aortic arch, ulcerated or protruding plaques were least common in the distal arch (p=0.002). There was no difference between ESUS and non-ESUS patients in plaque location (p=0.23) or calcification grade (p=0.092). CONCLUSION: ESUS patients in our study had thicker AAA and a higher prevalence of ulcerated or protruding plaques located more proximally within the aortic arch. High-risk plaque features may suggest a causal role of AAA in the ESUS population with visible intracranial occlusions.

Management of Patients with Embolic Stroke of Unknown Source: Interpreting the Evidence in the Light of Clinical Judgement.

PURPOSE OF REVIEW: To assess the validity of the belief that anticoagulation is not beneficial in patients with embolic stroke of unknown source (ESUS), and to asssess the benefits and safety of direct-acting oral anticoagulants (DOACs). RECENT FINDINGS: The failure of randomized trials to show benefit of anticoagulation in ESUS is probably due to misclassification of large artery atherosclerosis (LAA) as ESUS, as defined by a stenosis ≥ 50%. There are important differences among DOACs. There are a number of problems with dabigatran, and rivaroxaban and edoxaban are not suitable for once-daily dosing. Recent evidence from real-world practice indicates that apixaban is more effective and safer than rivaroxaban. Plaque burden should be included in the definition of LAA. Patients in whom a cardioembolic source is strongly suspected should be anticoagulated; antiplatelet agents are not significantly safer than DOACs, and are not effective in cardioembolic stroke.

Coexisting of aortic arch atheroma and atrial fibrillation for short-term recurrence and poor functional outcome in acute stroke.

BACKGROUND AND PURPOSE: Multiple embolic sources are sometimes observed simultaneously in patients with embolic stroke. The present study investigated the effects of coexisting aortic arch atheroma ≥ 4 mm thick and atrial fibrillation (AF) on short-term stroke recurrence and functional outcome. METHODS: Transesophageal echocardiography (TEE) was performed in consecutive embolic stroke patients, and 395 patients were classified into 4 groups according to the presence of aortic arch atheroma ≥ 4 mm thick and AF: AF - /ARCH - group, AF + /ARCH - group, AF - /ARCH + group, and AF + /ARCH + group. In accordance with these 4 groups, we evaluated stroke recurrence and all-cause death for 3 months after stroke onset, and also evaluated the 3-month functional outcome using the modified Rankin scale (mRS). RESULTS: Among the 128 AF patients, 39.1% also had aortic arch atheroma ≥ 4 mm thick. Of the 395 enrolled cases, the AF + /ARCH + group showed the highest frequencies of stroke recurrence and all-cause death during 3 months after onset. On multivariate analysis, stroke recurrence or all-cause death during 3 months after onset was relatively more frequent in the AF + /ARCH + group than in the AF + /ARCH - group (OR, 2.34; 95% CI, 0.82-6.69; p = 0.11), but that was not statistically significant, and poor functional outcome (mRS score 3-6) at 3 months was significantly more frequent in the AF + /ARCH + group than in the AF + /ARCH - group (OR, 2.59; 95% CI, 1.08-6.24; p = 0.0339). CONCLUSIONS: Aortic arch atheroma concomitant with AF is not rare and appears associated with increased risks of stroke recurrence and poor functional outcome.

Ischaemic stroke in the absence of documented atrial fibrillation: is there who could benefit from anticoagulant therapy?

About 25% of ischaemic strokes are of cryptogenic origin and a significant proportion of them has a certain embolic nature, and for these patients the term embolic stroke of undetermined source (ESUS) has been coined. In the absence of subclinical atrial fibrillation (AF) identifiable through prolonged electrocardiogram monitoring, atrial cardiomyopathy, demonstrable through non-invasive cardiac imaging, aortic plaques and heart failure with preserved sinus rhythm, have been recognized among the potential causes of ESUS. In patients with ESUS, randomized clinical trials performed so far have failed to demonstrate a benefit of therapy with direct oral anticoagulants (DOACs). However, it is possible that in patients in whom the presence of atrial cardiomyopathy is ascertained there may be a benefit of anticoagulant therapy in secondary prevention after ESUS. In patients with aortic plaques associated with a thrombotic component and in those with heart failure and preserved sinus rhythm in the absence of AF but with a high congestive heart failure, hypertension age, diabetes, stroke, vascular disease (CHA2DS2-VASc) score, the decision on anticoagulant therapy with DOACs could be made in the individual patient even in the absence of evidence from clinical trials.

Rivaroxaban versus aspirin on functional and cognitive outcomes after embolic stroke of undetermined source: NAVIGATE ESUS trial.

BACKGROUND: The effect of interventions on functional impairment is an important outcome in stroke prevention trials and should be considered as an adjunct to counting discrete events. In the NAVIGATE-ESUS trial, 7213 patients with recent embolic strokes of undetermined source were randomized to rivaroxaban (15 mg once daily) or aspirin (100 mg daily). After 11 months there was no effect on the prevention of recurrent stroke. AIMS: To determine the effect of rivaroxaban compared to aspirin on functional and cognitive outcomes. METHODS: Function and cognition were measured at baseline, 1 year, and study end using the Standard Assessment of Global Everyday Activities (SAGEA), a 15-item scale assessing cognitive, instrumental, and basic activities of daily living as well as mobility, and the Montreal Cognitive Assessment (MoCA). Changes in scores were calculated by subtracting either study end or 1-year scores from baseline, and differences in distributions were compared using the Mann-Whitney U test. SAGEA and MoCA scores were also correlated with recurrent stroke. RESULTS: Follow-up SAGEA scores were available in 6378 (88%) participants. There was no difference in change in function for those allocated to rivaroxaban compared to aspirin (Mann-Whitney U test, p = 0.8), with both distributions having a median (25p,75p) change of 0 (-2,1). Overall, more of those who experienced a recurrent stroke (n=247; mostly minor ischemic), reported functional difficulty at study end versus entry, compared with those who did not (51% versus 30%, chi-square test, p< 0.001), and this was consistent across global regions. There was no difference in the change in cognition by treatment group, nor were recurrent strokes associated with a change in cognition. CONCLUSIONS: Rivaroxaban, compared to aspirin, was not associated with changes in functional or cognitive status in patients with recent ESUS. The SAGEA scale detected changes in functional status associated with recurrent strokes in an international stroke population.

Ipsilateral Carotid Plaque Presence is Inversely Associated with Patent Foramen Ovale in Cryptogenic Stroke: A Multicenter CohortStudy.

BACKGROUND: Embolic stroke of undetermined source (ESUS) accounts for up to 20% of all strokes. Potential contributors to ESUS include patent foramen ovale (PFO) and non-stenotic plaque (<50%, NSP) of the ipsilateral internal carotid artery (ICA). To better differentiate these as unique mechanisms, we explored the prevalence of each in a multicenter observational cohort. METHODS: A retrospective multicenter cohort of consecutive patients with ESUS was queried (2015-2021). Patients with unilateral, anterior circulation ESUS who had a computed tomography angiography neck scan and a transthoracic echocardiogram (TTE) and/or transesophageal echocardiogram (TEE) with adequate visualization of a PFO were included. Patients with prior carotid stent, endarterectomy or alternative etiologies were excluded from the study. Descriptive statistics were used to characterize patients with and without PFO, with multivariable logistic regression used to predict the presence of a PFO based on clinicoradiographic factors as well as degree of luminal stenosis and ipsilateral plaque thickness >3mm, based on previously published thresholds of clinical relevance. RESULTS: Of the 234 included patients with unilateral anterior ESUS and adequate TTE or TEE, 17 (7.3%) had a PFO and 64 (27.4%) had ≥3mm of ipsilateral ICA plaque. Patients with PFO had significantly less NSP and less ipsilateral cervical ICA stenosis (0% [IQR 0-0%] vs. 0% [IQR 0-50%], p=0.03; Table). After adjustment for all predictors of PFO in multivariable regression (p<0.1: Hispanic ethnicity and ipsilateral plaque thickness), ipsilateral NSP was independently associated with a 62% lower odds of harboring a PFO (ORadj per 1cm of plaque 0.48, 95%CI 0.25-0.94). No patients with a PFO had ≥3mm of ipsilateral ICA plaque. CONCLUSION: Ipsilateral NSP is more common in ESUS patients without a PFO. While this study is limited by the small PFO event rate, it supports the notion that NSP and PFO may be independent contributors to ESUS.

Functional Abilities of an International Post-Stroke Population: Standard Assessment of Global Everyday Activities (SAGEA) Scale.

BACKGROUND AND OBJECTIVES: Function is an important outcome after stroke; traditional assessments may not capture functional deficits important to patients. We examined the validity of the Standard Assessment of Global Everyday Activities (SAGEA), a patient-reported outcome that assesses activities important to patients and for use in international clinical trials. METHODS: The NAVIGATE-ESUS trial evaluated rivaroxaban compared to aspirin in preventing recurrent stroke in 7213 participants. The Modified Rankin Scale (mRS), the National Institutes of Health Stroke Scale (NIHSS), and the SAGEA were collected at entry. Chi square tests were used to compare proportions and Spearman rank correlations were used to compare between measures. SAGEA was compared to the Modified Frailty Index (MFI) and the occurrence of infarct to examine criterion validity RESULTS: Participants were 67 years, 2/3 were male, and at baseline 30% had no disability and 58% had slight disability according to mRS scores. SAGEA was weakly correlated with the mRS (r=0.37), the NIHSS (r=0.29) and the MFI (r=0.30). Of the 2154 with an mRS score of 0, 61% reported difficulty on the SAGEA. The largest discrepancies between SAGEA and other measures were because of cognitive functional deficits detected by the SAGEA that were not identified on other assessments. A larger number of MRI identified infarcts (acute and covert) were associated with a higher SAGEA score (p=0.007). CONCLUSIONS: The SAGEA is a simple, globally applicable measure of cognitive and functional abilities that identifies issues that other commonly used assessments of disability and function do not capture.

Interventional compared with medical management of symptomatic carotid web: A systematic review.

BACKGROUND: Carotid web (CaW) is non-atheromatous, shelf-like intraluminal projection, generally affecting the posterolateral wall of the proximal internal carotid artery, and associated with embolic stroke, particularly in younger patients without traditional stroke risk factors. Treatment options for symptomatic CaWs include interventional therapy with carotid endarterectomy or carotid stenting versus medical therapy with antiplatelet or anticoagulants. As safety and efficacy of these approaches have been incompletely delineated in small-to-moderate case series, we performed a systematic review of outcomes with interventional and medical management. METHODS: Systematic literature search was conducted and data analyzed per PRISMA guidelines (Preferred Reporting Items for Systemic Reviews and Meta-Analyses) from January 2000 to October 2021 using the search strategy: "Carotid web" OR "Carotid shelf" OR "Web vessels" OR "Intraluminal web". Patient-level demographics, stroke risk factors, technical procedure details, medical and interventional management strategies were abstracted across 15 series. All data were analyzed using descriptive statistics. RESULTS: Among a total of symptomatic 282 CaW patients across 14 series, age was 49.5 (44-55.7) years, 61.7% were women, and 76.6% were black. Traditional stroke risk factors were less frequent than the other stroke causes, including hypertension in 28.6%, hyperlipidemia 14.6%, DM 7.0%, and smoking 19.8%. Thrombus adherent to CaW was detected on initial imaging in 16.2%. Among 289 symptomatic CaWs across 15 series, interventional management was pursued in 151 (52.2%), carotid artery stenting in 87, and carotid endarterectomy in 64; medical management was pursued in 138 (47.8%), including antiplatelet therapy in 80.4% and anticoagulants in 11.6%. Interventional and medical patients were similar in baseline characteristics. The reported time from index stroke to carotid revascularization was median 14 days (IQR 9.5-44). In the interventional group, no periprocedural mortality was noted, major periprocedural complications occurred in 1/151 (0.5%), and no recurrent ischemic events were observed over follow-up range of 3-60 months. In the medical group, over a follow-up of 2-55 months, the recurrence cerebral ischemia rate was 26.8%. CONCLUSION: Cumulative evidence from multiple series suggests that carotid revascularization is a safe and effective option for preventing recurrent ischemic events in patients with symptomatic carotid webs.

From cryptogenic to ESUS: Toward precision medicine?

Cryptogenic infarctions are infarctions without a defined cause, despite a complete work-up. They differ from infarctions of undetermined causes, which may involve overlapping causes or an incomplete investigation. It is also different from uncommon heritable and non-heritable causes. The term embolic stroke of undetermined source (ESUS) proposed in 2014 is defined as a non-lacunar brain infarct without proximal arterial stenosis or cardioembolic sources. The major advantage of this definition compared to cryptogenic definition is the proposition of a specific work-up. In a general population, frequent potential sources of embolism in patients with ESUS have been suggested since a long time and include: patent foramen ovale (PFO), covert atrial fibrillation (AF), complex aortic arch atheroma, large vessel atheroma with stenosis<50%, carotid web, atrial cardiomyopathy, thrombophilia associated with cancer. It took almost 30 years to show, in patients under 60 with a cryptogenic stroke and a PFO, that PFO occlusion was superior to medical treatment alone for recurrent stroke. PFO under 60 is therefore no longer a cryptogenic cause of infarction. The concept of cryptogenic stroke and its refinement in ESUS have been fruitful for the identification of PFO associated as a cause. Covert AF can be detected by different techniques but its risk significance for recurrent stroke might be different from the simple electrocardiographic detection of AF. With the development of direct oral anticoagulants (DOAs), randomized studies in patients with ESUS, were run for stroke prevention but no difference was observed between patients treated by DOA compared to aspirin. These studies showed however the heterogeneity of ESUS patients. Further ESUS classification should be considered as a tool to identify homogeneous groups. We propose to further split the ESUS group into different subgroups: ESU-PFO>60-year-old, ESUS-ATH with stenosis<50%, ESUS-AF (covert AF & atrial cardiomyopathy), ESUS-cancer and others. Precision medicine is the ability to make targeted healthcare decisions based on the specific risks of individual patients. One preliminary stage is therefore to identify homogeneous groups suitable in the future for new therapeutic trials and, at the end, for new specific treatments.

Prognostic impact of renal dysfunction on embolic stroke of undetermined source-Role beyond CHA2 DS2 -VASc score: Results from Taiwan Stroke Registry.

BACKGROUND AND PURPOSE: The CHA2 DS2 -VASc score has immense prognostic value in patients with embolic stroke of undetermined source (ESUS). We aimed to determine the usefulness of advanced renal dysfunction and its addition to the CHA2 DS2 -VASc score in improving predictive accuracy. METHODS: In total, 3775 ESUS patients were enrolled from a nationwide hospital-based prospective study. Advanced renal dysfunction was defined as estimated glomerular filtration rate <30 ml/min per 1.73 m2 or patients under dialysis. Clinical outcomes included recurrent stroke and 1-year all-cause mortality. Poor functional outcome was defined as a modified Rankin Scale >2 at first-, third-, and sixth-month post-stroke. The renal (R)-CHA2 DS2 -VASc score was derived by including advanced renal dysfunction in the CHA2 DS2 -VASc score. Risk stratification improvement after including advanced renal dysfunction was assessed using C statistic, integrated discrimination improvement (IDI), and category-free net reclassification index (NRI). RESULTS: After adjusting for confounding factors and CHA2 DS2 -VASc score, advanced renal dysfunction showed significant associations with all-cause mortality (HR: 2.88, 95% CI: 1.92-4.34) and poor functional outcome at third- (OR: 2.69, 95% CI: 1.47-4.94) and sixth-month post-stroke (OR: 2.67, 95% CI: 1.47-4.83). IDI and NRI showed that incorporating advanced renal dysfunction significantly improved risk discrimination over the original CHA2 DS2 -VASc score. R-CHA2 DS2 -VASc score ≥2 increased risk by 1.94-fold (95% CI: 1.15-3.27) for all-cause mortality, and ≥4 increased risk by 1.62-fold (95% CI: 1.05-2.50) of poor functional outcome at third-month post-stroke and by 1.81-fold (95% CI: 1.19-2.75) at sixth-month post-stroke. CONCLUSIONS: Advanced renal dysfunction was significantly associated with clinical and functional outcomes in ESUS patients and may improve prognostic impact of the CHA2 DS2 -VASc score.

Routine surveillance of pelvic and lower extremity deep vein thrombosis in stroke patients with patent foramen ovale.

Patent foramen ovale (PFO) is a potential conduit for paradoxical embolization to the systemic atrial circulation of a thrombus originating in the venous system. In a selected group of subjects, the prevalence of deep vein thrombosis (DVT) was assessed. Subjects were identified if they underwent magnetic resonance venography (MRV) pelvis and lower extremity doppler (LE-VDU) for assessment of DVT with PFO. The primary outcome measure was to report the number of patients with paradoxical embolization as their suspected etiology of stroke due to the presence of DVT, which then will be considered as determined stroke. Others with determined stroke diagnosis were reported using Treatment of Acute Stroke Trial (TOAST) criteria. At discharge, those without etiology of their stroke were grouped under embolic stroke of undetermined source (ESUS). We further analyzed the prevalence of DVT by age group, ≤ 60 years vs > 60 years to describe if the prevalence is higher with younger age and to evaluate if higher Risk of Paradoxical Embolism (ROPE) score will have higher number of DVTs compared to lower ROPE scores. Of the 293, 19 (7%) were strokes due to paradoxical embolism. At discharge, determined stroke were 54% vs ESUS were 46%. The overall prevalence of DVT was 19 (7%); MRV-pelvis 13 (4%), and LE-VDU was 9 (3%). No significant difference was noted using both modalities. However, in multivariable regression analysis, a trend suggested an association between pelvic thrombi and high ROPE score as the etiology of stroke; OR 3.56 (0.98, 12.93); p = 0.054. Detection of DVT was not associated with PFO, high ROPE scores or young age. Our data indicate an over-reliance of testing for DVT, particularly MRV pelvis with contrast, in patients with PFO. Clinical studies are needed to identify other factors predictive of DVT in patients with ischemic stroke and PFO.

Prevalence and predictors of atrial fibrillation in patients with embolic stroke of undetermined source: a real-life single-center retrospective study.

INTRODUCTION: Up to one-third of ischemic strokes remained cryptogenic despite extensive investigations. Atrial fibrillation may be detected in a significant proportion of patients with embolic stroke of undetermined source, particularly after the introduction of implantable loop recorder in clinical practice. METHODS: We retrospectively included all the consecutive patients with embolic stroke of undetermined source referred to our units in the period November 2013 to December 2018 and in which an implantable loop recorder was positioned within 6 months from stroke event. Prevalence and predictors of atrial fibrillation were investigated. RESULTS: One hundred thirty-eight patients with embolic stroke of undetermined source fulfilling inclusion criteria were identified. The crude prevalence of atrial fibrillation at the end of observation period was of 45.7%. Incidence rates at 6, 12, 18, 24, and 36 months resulted, respectively, 31.8% (95% CI, 30.4-46.7), 38.0% (95% CI, 30.4-46.9), 42.6% (95% CI, 34.5-51.6), 46.6% (95% CI, 38.2-55.8), and 50.4% (95% CI, 41.6-59.9). On multivariate analysis, only excessive supraventricular electric activity and left atrial enlargement resulted to be significant predictors of atrial fibrillation (p = 0.037 and p < 0.0001, respectively). CONCLUSIONS: Atrial fibrillation may be detected in a relevant proportion (up to 50%) of patients with embolic stroke of undetermined source if a careful and extensive diagnostic work-up is employed. Excessive supraventricular electric activity and left atrial enlargement are significant predictors of the occurrence of atrial fibrillation in these patients.

Diagnosis and Treatment for embolic stroke of undetermined source: Consensus statement from the Taiwan stroke society and Taiwan society of cardiology.

Cryptogenic stroke comprises about one-quarter of ischemic strokes with high recurrence rate; however, studies specifically investigating the features and treatment of this stroke subtype are rare. The concept of 'embolic stroke of undetermined source' (ESUS) may facilitate the development of a standardized approach to diagnose cryptogenic stroke and improve clinical trials. Since recent large randomized control trials failed to demonstrate a reduction in stroke recurrence with anticoagulants, anti-platelet agents remain the first-line treatment for ESUS patients. Nevertheless, patients with high risk of stroke recurrence (e.g., those with repeated embolic infarcts despite aspirin treatment) require a more extensive survey of stroke etiology, including cardiac imaging and prolonged cardiac rhythm monitoring. Anticoagulant treatments may still benefit some subgroups of high-risk ESUS patients, such as those with multiple infarcts at different arterial territories without aortic atheroma, the elderly, or patients with high CHA2D2-VASc or HOVAC scores, atrial cardiopathy or patent foramen ovale. Several important ESUS clinical trials are ongoing, and the results are anticipated. With rapid progress in our understanding of ESUS pathophysiology, new subcategorizations of ESUS and assignment of optimal treatments for each ESUS subgroup are expected in the near future.