Ischemic Stroke Of Undetermined Cause Research Articles

Abstract TP249: A Real World Study of PFO Closure in Young Patients With Ischemic Stroke

Introduction: Over the past decade, the concept of Patent Foreman Ovale (PFO)-related stroke has been evolving. Current guidelines recommend PFO closure in young patients who had a non-lacunar ischemic stroke of undetermined cause and related to a high-risk PFO. Whereas there remains a discrepancy in patient selection for PFO closure among providers and institutions in real-world practice. The retrospective study comprehensively examined patient characteristics, clinical assessments, and outcomes among young stroke patients who underwent PFO closure to gauge the current clinical process in selecting PFO candidates. Methods: Adult ischemic stroke patients (age >18) who underwent PFO closure from 1/2018 to 12/2022 at the single center were identified from the cardiology PFO closure database. Patients were characterized into PFO-Associated Stroke Causal Likelihood (PASCAL)-probable; PASCAL-possible, and PASCAL-unlikely categories for comparison. Descriptive statistics was conducted due to the small sample size. Results: The mean age of qualified 78 patients was 47 years old when receiving PFO closure; the majority were males (64%) and Caucasians (75%). High risk PFO was identified in 55% of patients, and 63% of patients had high Risk of Paradoxical Embolism score ≥7. The patients were determined as PASCAL- probable (53%); PASCAL-possible (33%), and PASCAL-unlikely (15%), respectively. Among all the patients, the rate of successful device implantation was 96.0%, rate of closure related adverse events were 15.8% with post closure atrial fibrillation rate of 7.9%. Compared to PASCAL possible and unlikely patients, PASCAL-probable patients had the highest rate of successful device implantation and the lowest closure-related adverse events rate, including post-procedure atrial fibrillation. During a median follow-up of 3.4 years after PFO closure, three patients (one PASCAL-unlikely and two PASCAL-possible) had a recurrent stroke. Conclusions: The findings of real-world data confirmed that PASCAL-probable patient most likely benefit from PFO closure with the least procedure-related adverse events.

Atrial fibrillation detected with outpatient cardiac rhythm monitoring in patients with ischemic stroke or TIA of undetermined cause

ObjectivesGuidelines advise cardiac rhythm monitoring for 3 up to 30 days for detecting atrial fibrillation (AF) in patients with ischemic stroke of undetermined cause. However, the optimal monitoring duration is unknown. We aimed to determine the AF detection rate during 7-day outpatient cardiac rhythm monitoring in this patient group. MethodsParticipants from a large tertiary hospital in a prospective observational study (ATTEST) underwent outpatient cardiac rhythm monitoring after a negative standard diagnostic evaluation (i.e., 12-lead electrocardiogram and in-hospital telemetry). Primary outcome was the rate of newly detected AF. ResultsWe examined 373 patients [age: 67.8±11.6 years; women: 166(44.5%); stroke: 278(74.5%)]. Median monitoring duration was 7 days (Inter Quartile Range (IQR) 7-7), performed after median of 36 days (IQR 27-47). AF was newly detected in 17(4.6%) patients, 5.4% of patients with ischemic stroke and 2.1% of patients with TIA. 53% of AF was detected on day-1, after day-3 73% of new AF was found. First AF episodes were detected up to day-7. Diabetes and increasing age were independent predictors of new AF. ConclusionAfter ischemic stroke or TIA of undetermined cause, 7-day outpatient cardiac rhythm monitoring detected new AF in 4.6%. Patients with AF had significantly more cardiovascular risk factors. Although about 50% of first AF episodes occurred during the first day of monitoring, new AF was detected up to day-7, implying that the recommended minimum of 3 days cardiac rhythm monitoring after ischemic stroke of undetermined cause is insufficient. Subsequent long-term rhythm monitoring should be considered in selected patients.

Incidence, characteristics and outcomes in patients with embolic stroke of undetermined source: A population-based study

Embolic stroke of undetermined source (ESUS) represents a subgroup of cryptogenic ischemic stroke (CS) distinguished by high probability of an underlying embolic mechanism. There are scarce population-based data regarding the incidence, characteristics and outcomes of ESUS. Consecutive patients included with first-ever ischemic stroke of undetermined cause in the previously published population-based Evros Stroke Registry were further subdivided into ESUS and non-ESUS CS. Crude and adjusted [according to the European Standard Population (ESP), WHO and Segi population] incidence rates (IR) for ESUS and non-ESUS CS were calculated. Baseline characteristics, admission stroke severity (assessed using NIHSS-score), stroke recurrence and functional outcomes [determined by modified Rankin Scale (mRS) scores], were recorded during the 1-year follow-up period. We identified 21 and 242 cases with ESUS (8% of CS) and non-ESUS CS. The crude and ESP-adjusted IR for ESUS were 17.5 (95%CI: 10–25) and 16.6 (95%CI: 10–24) per 100,000 person-years. Patients with ESUS were younger (p < .001) and had lower median admission NIHSS-scores (p < .001). Functional outcomes were more favorable in ESUS at 28, 90 and 365 days. ESUS was independently (p = .033) associated with lower admission NIHSS-scores (unstandardized linear regression coefficient: -13.34;95%CI: -23.34, −3.35) on multiple linear regression models. ESUS was not related to 1-year stroke recurrence, mortality and functional improvement on multivariable analyses. In conclusion we found that ESUS cases represented 8% of CS patients in this population-based study. Despite the fact that ESUS was independently related to lower admission stroke severity, there was no association of ESUS with long-term outcomes.

Abstract TP199: Incidence, Characteristics and Outcomes in Patients With Embolic Stroke of Undetermined Source: A Population-based Study

Introduction: Embolic stroke of undetermined source (ESUS) represents a subgroup of cryptogenic ischemic stroke (CS) distinguished by high probability of an underlying embolic mechanism. There are scarce population-based data regarding the incidence, characteristics and outcomes of ESUS. Methods: Consecutive patients included with first-ever ischemic stroke of undetermined cause in the previously published population-based Evros Stroke Registry were further subdivided into ESUS and non-ESUS CS. Crude and adjusted [according to the European Standard Population (ESP), WHO and Segi population] incidence rates (IR) for ESUS and non-ESUS CS were calculated. Baseline characteristics, admission stroke severity (assessed using NIHSS-score), stroke recurrence and functional outcomes [determined by modified Rankin Scale (mRS) scores], were recorded during the 1-year follow-up period. Results: We identified 21 and 242 cases with ESUS (8% of CS) and non-ESUS CS. The crude and ESP-adjusted IR for ESUS were 17.5 (95%CI: 10-25) and 16.6 (95%CI: 10-24) per 100,000 person-years. Patients with ESUS were younger [median age 68 years (IQR:61-75) vs. 79 years (IQR:73-83); p&lt;0.001] and had lower median admission NIHSS-scores [4 points (IQR:2-8) vs. 8 points (IQR:5-16); p&lt;0.001]. Functional outcomes were more favorable in ESUS at 28 [median mRS-score: 2 (IQR:1-3) vs. 4 (IQR:3-6)], 90 [median mRS-score: 1 (IQR:0-2) vs. 4 (IQR:2-6)] and 365 days [median mRS-score: 1 (IQR:0-2) vs. 5 (IQR:2-6)]. ESUS was independently (p=0.033) associated with lower admission NIHSS-scores (unstandardized linear regression coefficient: -13.34;95%CI: -23.34, -3.35) on multiple linear regression models. ESUS was not related to 1-year stroke recurrence (HR: 0.22, 95%CI: 0.01-4.06), mortality (HR: 0.25, 95%CI: 0.02-4.36) and functional improvement (1-point shift in mRS-scores; cOR: 1.47, 95%CI: 0.59-3.70) on multivariable analyses. Conclusions: ESUS cases represented 8% of CS patients in this population-based study. Despite the fact that ESUS was independently related to lower admission stroke severity, there was no association of ESUS with long-term outcomes.

Genetically Determined FXI (Factor XI) Levels and Risk of Stroke.

Background and Purpose- FXI (factor XI) is involved in thrombus propagation and stabilization. It is unknown whether lower FXI levels have a protective effect on risk of ischemic stroke (IS) or myocardial infarction. This study investigated the effect of genetically determined FXI levels on risk of IS, myocardial infarction, and intracerebral hemorrhage. Methods- Two-sample Mendelian randomization analysis was performed. Instruments and genetic association estimates for FXI levels were obtained from a genome-wide association study of 16 169 individuals. Genetic association estimates for IS and its etiological subtypes were obtained from a study of 16 851 cases and 32 473 controls. For myocardial infarction, estimates were obtained from a study of 43 676 cases and 123 504 controls and for intracerebral hemorrhage from a study of 1545 cases and 1481 controls. Results- After applying a Bonferroni correction for multiple testing, the Mendelian randomization analysis supported a causal effect of higher, genetically determined FXI levels on risk of any IS (odds ratio [OR] per 1-unit increase in natural logarithm-transformed FXI levels, 2.54; 95% CI, 1.68-3.84; P=1×10-5) but not myocardial infarction (OR, 1.01; 95% CI, 0.76-1.34; P=0.94) or intracerebral hemorrhage (OR, 1.81; 95% CI, 0.44-7.38; P=0.41). Examining IS subtypes, the main results supported an effect of higher, genetically determined FXI levels on risk of cardioembolism (OR, 4.23; 95% CI, 1.94-9.19; P=3×10-4) and IS of undetermined cause (OR, 3.44; 95% CI, 1.79-6.60; P=2×10-4) but not large artery atherosclerosis (OR, 2.73; 95% CI, 1.15-6.45; P=0.02) or small artery occlusion (OR, 1.19; 95% CI, 0.50-2.82; P=0.69). However, the statistically significant result for IS of undetermined cause was not replicated in all sensitivity analyses. Conclusions- We find Mendelian randomization evidence supporting FXI as a possible target to reduce risk of the cardioembolic subtype of IS.

Long-Term Outcomes of Patent Foramen Ovale Closure or Medical Therapy after Stroke

BackgroundWhether closure of a patent foramen ovale reduces the risk of recurrence of ischemic stroke in patients who have had a cryptogenic ischemic stroke is unknown.MethodsIn a multicenter, randomized, open-label trial, with blinded adjudication of end-point events, we randomly assigned patients 18 to 60 years of age who had a patent foramen ovale (PFO) and had had a cryptogenic ischemic stroke to undergo closure of the PFO (PFO closure group) or to receive medical therapy alone (aspirin, warfarin, clopidogrel, or aspirin combined with extended-release dipyridamole; medical-therapy group). The primary efficacy end point was a composite of recurrent nonfatal ischemic stroke, fatal ischemic stroke, or early death after randomization. The results of the analysis of the primary outcome from the original trial period have been reported previously; the current analysis of data from the extended follow-up period was considered to be exploratory.ResultsWe enrolled 980 patients (mean age, 45.9 years) at 69 sites. Patients were followed for a median of 5.9 years. Treatment exposure in the two groups was unequal (3141 patient-years in the PFO closure group vs. 2669 patient-years in the medical-therapy group), owing to a higher dropout rate in the medical-therapy group. In the intention-to-treat population, recurrent ischemic stroke occurred in 18 patients in the PFO closure group and in 28 patients in the medical-therapy group, resulting in rates of 0.58 events per 100 patient-years and 1.07 events per 100 patient-years, respectively (hazard ratio with PFO closure vs. medical therapy, 0.55; 95% confidence interval [CI], 0.31 to 0.999; P=0.046 by the log-rank test). Recurrent ischemic stroke of undetermined cause occurred in 10 patients in the PFO closure group and in 23 patients in the medical-therapy group (hazard ratio, 0.38; 95% CI, 0.18 to 0.79; P=0.007). Venous thromboembolism (which comprised events of pulmonary embolism and deep-vein thrombosis) was more common in the PFO closure group than in the medical-therapy group.ConclusionsAmong adults who had had a cryptogenic ischemic stroke, closure of a PFO was associated with a lower rate of recurrent ischemic strokes than medical therapy alone during extended follow-up. (Funded by St. Jude Medical; RESPECT ClinicalTrials.gov number, NCT00465270.)

Thrombus Histology Suggests Cardioembolic Cause in Cryptogenic Stroke.

Ischemic stroke of undetermined cause is a major health issue because of its high frequency and clinical relevance. Histopathologic analysis of human thrombi, retrieved from stroke patients with large-vessel occlusion during mechanical thrombectomy, may provide information about underlying pathologies. This study examines the relationship between stroke causes and histological clot composition to identify specific patterns that might help to distinguish causes of cryptogenic stroke. Thrombi of 145 consecutive stroke patients with large-vessel occlusion were collected during intracranial mechanical recanalization. The hematoxylin and eosin-stained specimens were quantitatively analyzed in terms of the relative fractions of the main constituents (red and white blood cells and fibrin/platelets). These data, along with additional clinical and interventional parameters, were compared for different stroke subtypes, as defined by the international Trial of Org 10172 in Acute Stroke Treatment criteria. The composition of thrombi from cardioembolic and noncardioembolic stroke patients differed significantly for all main thrombus components. Cardioembolic thrombi had higher proportions of fibrin/platelets (P=0.009), less erythrocytes (P=0.003), and more leucocytes (P=0.035) than noncardioembolic thrombi. Cryptogenic strokes showed strong overlap with cardioembolic strokes but not with noncardioembolic strokes, in terms of both thrombus histology and interventional and clinical outcome parameters. Quantitative evaluation of thrombus composition may help to distinguish between different stroke causes. Our findings support the notion that the majority of cryptogenic strokes are cardioembolic.

A male Fabry disease patient treated with intravenous thrombolysis for acute ischemic stroke

The use of intravenous thrombolytic therapy for acute ischemic stroke is associated with improved outcomes. Fabry disease is an X-linked glycosphingolipid storage disease with vascular endothelial deposits. Affected males with the classic phenotype develop renal, cardiac, and cerebrovascular disease and die prematurely. However, Fabry disease is rare in young men with first ischemic stroke of undetermined cause. We report a 38-year-old man with acute aphasia and a left M2 segment of the middle cerebral artery thrombus with no recanalization who was finally diagnosed with Fabry disease after left ventricular hypertrophy of undetermined cause had been identified. A gene test revealed a R227X mutation typical of Fabry disease with the classical phenotype. To our knowledge our patient is the first reported male Fabry patient who was given intravenous thrombolytic therapy and the first reported Fabry patient who received intravenous thrombolytic therapy between 3 and 4.5hours of the symptom onset. Despite favorable prognostic indicators on admission imaging, our patient suffered a significant stroke and had an unfavorable clinical outcome. Fortunately, the episode was not complicated by intracranial hemorrhage. Further studies are needed to evaluate the efficacy and safety of intravenous thrombolytic therapy in treating patients with Fabry disease and acute ischemic stroke.

Coexisting Large and Small Vessel Disease in Patients with Ischemic Stroke of Undetermined Cause

Background and Purpose: Large artery atherosclerosis (LAA) and small vessel disease (SVD) share common risk factors for stroke. We aimed at investigating the association of SVD with cerebral LAA as well as with atherosclerosis in patients with stroke likely to originate from aortic plaques. Methods: We investigated 71 consecutive patients (48 men, mean age 64.2 ± 13 years) with ischemic stroke of undetermined cause according to the ASCO classification, who received ECG-triggered CT angiography for best available atherosclerotic plaque detection in the aorta. Results: Aortic atherosclerotic plaques were detected in 54 patients (76.1%). The presence of SVD significantly correlated with the presence of aortic plaques (p < 0.001), as well as LAA (p < 0.001) and risk factors such as arterial hypertension (p = 0.032) and diabetes mellitus (p = 0.017). Conclusions: Aortic plaques are common in patients with stroke of undetermined cause. If so, SVD and LAA are often coexisting, which demonstrates the close link of macro- and microangiopathy, at least in cases of severe risk factors of atherosclerosis.

Heart and vessel pathology underlying brain infarction in 142 stroke patients

This study was designed to determine the histopathological characteristics of cardiac and vascular lesions responsible for various subtypes of ischemic stroke. Postmortem pathological examination was performed on 142 patients who died within 30 days of the onset of ischemic stroke in the National Cardiovascular Center, Osaka, Japan. The numbers of cases with autopsy-proven diagnoses of atherothrombotic, cardioembolic, and lacunar strokes, ischemic stroke of other determined causes, and ischemic stroke of undetermined cause were 17, 107, 2, 12, and 4, respectively. Thrombi that developed at the culprit plaques of the cerebral arteries were responsible for atherothrombotic stroke. In 70% of the cases with cardioembolic stroke, the presence of thrombi as potential embolic sources were confirmed in the heart or, in some cases, in the venous circulation of patients with patent foramen ovale and tetralogy of Fallot. In most atherothrombotic strokes, fibrin- and platelet-rich thrombi of various thicknesses develop at the culprit plaques of the cerebral arteries, which are finally occluded with fibrin- and red-cell-rich thrombi (red thrombi). In most cardioembolic strokes, red thrombi generated in the heart or peripheral veins are dislodged to embolize the cerebral arteries.