Cause Of Cryptogenic Stroke Research Articles

Atrial Imaging and Cardiac Rhythm in Cryptogenic Embolic Stroke: The ARIES Study.

Unknown cardioembolic sources are frequent causes of cryptogenic stroke. We analyzed the risk of atrial fibrillation (AF) or high burden of ectopic atrial activity (HBEA) in patients with cryptogenic stroke, assessing atrial function and 1-year outcomes. The ARIES (Atrial Imaging and Cardiac Rhythm in Cryptogenic Embolic Stroke) study is an observational study including patients with cryptogenic stroke. We analyzed the frequency of AF and HBEA (>3000 atrial ectopic beats/day or >2 bursts or atrial tachycardia between 3 beats and ≤30 seconds) in two 30-day Holter-ECGs, comparing advanced echocardiography signs of left atrial (LA) dysfunction according to rhythm: AF, HBEA, and normal sinus rhythm. We also evaluated 1-year stroke recurrence and mortality. The study included 109 patients; 35 (32.1%) patients had AF, 27 (24.8%) HBEA, and 47 (43.1%) normal sinus rhythm. Compared with those with normal sinus rhythm, patients with AF presented higher 2-dimensional and 3-dimensional LA indexed volumes (38.8±11.2 versus 27.3±11.8 mL/m2, and 50.6±17.2 versus 34.0±15.4 mL/m2, respectively, P<0.001), lower 3-dimensional LA ejection fraction (50±14.6 versus 62.7±11.8, P=0.001), LA reservoir strain (22.0±8.6 versus 30.4±10.5, P<0.001), and LA contraction strain (10.5±8.18 versus 17.1±7.5, P<0.001), remaining significant in multivariate analysis. Patients with HBEA showed higher LA indexed volumes and lower LA reservoir strain than patients with normal sinus rhythm only in univariate analysis. There were no differences in ischemic recurrence or mortality among the groups. Patients with cryptogenic stroke showed a high incidence of AF and HBEA. AF is strongly related to LA volume, LA function, and LA reservoir and contraction strain, whereas HBEA showed milder structural changes. Advanced LA echocardiography could help patient selection for long-term ECG monitoring in suspected cardiac sources.

The Usefulness of Outpatient Cardiac Telemetry in Patients with Cryptogenic Stroke.

Introduction: Atrial fibrillation (AF), apart from non-stenotic supracardiac atherosclerosis and neoplastic disease, is the leading cause of cryptogenic stroke, including embolic stroke of un-determined source (ESUS). The aim of our study was to determine the prevalence of AF in ESUS patients based on 30-day telemetric heart rate monitoring initiated within three months after stroke onset. Another aim was to identify factors that increase the likelihood of detecting subsequent AF among ESUS patients. Material and Methods: patients with first-ever stroke classified as per the ESUS definition were eligible for this study. All patients underwent outpatient 30-day telemetric heart rate monitoring. Results: In the period between 2020 and 2022, 145 patients were included. The mean age of all qualified patients was 54; 40% of eligible patients were female. Six patients (4.14%), mostly male patients (4 vs. 2), were diagnosed with AF within the study period. In each case, the diagnosis related to a patient whose stroke occurred in the course of large vessel occlusion. Episodes of AF were detected between day 1 and 25 after starting ECG monitoring. Out of the analyzed parameters that increase the probability of, A.F.; only supraventricular extrasystoles proved to be an independent factor regarding an increased risk of AF [OR 1.046, CI 95% 1.016-1.071, p-value < 0.01]. Conclusions: The use of telemetry heart rhythm monitoring in an outpatient setting can detect AF in 4% of ESUS patients who have undergone prior diagnostic procedures for cardiogenic embolism. Supraventricular extrasystoles significantly increases the likelihood of AF detection in patients with ESUS within three months following stroke. Comorbid coronary artery disease, diabetes and hypertension, rather than a single-factor clinical burden, increase the likelihood of AF detection in older ESUS patients. ESUS in the course of large vessel occlusion is probably associated with an increased likelihood of cardiogenic embolism.

Rare causes of cryptogenic stroke

Stroke is one of the leading causes of mortality and disability in the world, which is why it is considered a key medical and social problem of modern medicine. According to international multicenter studies, ischemic stroke is the most frequent type of this condition. According to research, the pathogenetic subtype of ischemic stroke cannot be identified in a third of cases. Based on the TOAST classification, cryptogenic stroke requires exclusion of criteria for other pathogenetic subtypes. However, in clinical practice, the reasons for making this diagnosis are as follows: incomplete examination of the patient, negative test results, and identification of two or more causes. The high incidence and risk of recurrent ischemic events determines the need for a thorough diagnostic search in order to exclude rare causes and conduct reasonable secondary prophylaxis.

Paradoxical Embolism in Juveniles and Young Adults With Severe-to-Profound Sudden Sensorineural Hearing Loss.

Objective: Paradoxical embolism from right-to-left shunting is a common cause of cryptogenic stroke in the young. Circulatory ischemia of the cochlea is closely connected with severe-to-profound sudden sensorineural hearing loss. This study aimed to explore the role of paradoxical embolism in severe-to-profound sudden sensorineural hearing loss in juveniles and young adults. Methods: From August 2021 to September 2022, consecutive outpatients under 35 years of age with severe-to-profound sudden hearing loss were included in the study. Routine auditory electrophysiological testing and contrast transcranial Doppler ultrasonography (c-TCD) were conducted, and the results were retrospectively analyzed. Results: Seven patients (age: 19.4 ± 6.5 years) were enrolled, including 5 juveniles and 2 young adults. Three patients had severe deafness, and 4 patients had profound deafness. Right-to-left shunting was detected in all patients through c-TCD. Patent foramen ovale was found in 2 patients while pulmonary arteriovenous fistula was found in 1 patient through contrast transthoracic echocardiography or cardiac catheterization. No patients had precipitating factors for sudden sensorineural hearing loss, and none had abnormalities on head magnetic resonance imaging. Six patients underwent whole-exome sequencing, and no known deafness gene variant was detected. After standard treatment for 1 month, 2, 3, and 2 patients had complete, slight, and no hearing recovery, respectively. Conclusions: Paradoxical embolism is a possible cause of severe-to-profound sudden sensorineural hearing loss in juveniles and young adults. In young patients, c-TCD is an effective screening tool to detect right-to-left shunting, while contrast transthoracic echocardiography is a complementary examination to c-TCD.

Atrial imaging and cardiac Rhythm In cryptogenic Embolic Stroke: the ARIES study

Abstract Background One of the underlying causes of cryptogenic stroke is an unknown cardioembolic etiology, and the most frequent is atrial fibrillation (AF). It is not unusual to find non-sustained (&amp;lt;30 s) "microfibrillatory" atrial tachycardias (nsAT) or frequent atrial ectopic beats (AE) during the work-up but its pathological significance remains uncertain. Purpose Our aim is to analyze the risk of developing AF or nsAT in patients with cryptogenic stroke and compare their atrial function using advanced echocardiography and their clinical outcome during the follow-up. Methods The ARIES study (Atrial imaging and cardiac Rhythm In cryptogenic Embolic Stroke) is an observational, prospective study in patients admitted for recent cryptogenic stroke in a comprehensive Stroke Unit. We analyze the frequency of detecting AF and nsAT in two 30-day ECG records with a wearable device and we compare echocardiographic signs of left atrial (LA) dysfunction according to rhythm classification: AF, high-burden nsAT/AE (&amp;gt;2 nsAT/24 hours or &amp;gt;3.000 AE/24 hours respectively) and normal sinus rhythm (NSR). Finally, we evaluate stroke recurrence and mortality at 12-months and report changes in classification of stroke etiology during the follow-up. Results In total prolonged rhythm study (1st and 2nd 1-month wearable EKG), AF was found in 35 (32.1%) patients, high-burden nsAT/AE in 27 patients (24.8%) and normal rhythm was found in 47 patients (43.1%). Patients with AF compared with patients with NSR presented higher values in LA volume (69.9±21.8 vs 49.4±26.5, p&amp;lt;0.001) , LA index volume (38.8±11.2 vs 27.3±11.8 ml/m2, p&amp;lt;0.001), 3D LA index volume (50.6±17.2 vs 34.0±15.4 ml/m2, p&amp;lt;0.001), 3D-telediastolic LA volume (89.5±27.7 vs 66.8 ±31.9 ml/m2, p=0.002), 3D-telesistolic LA volume (43.6±15.3 vs 25.3±17.4 ml/m2, p &amp;lt;0.001), lower rates of LA ejection fraction (50 ±14.6 vs 62.7±11.8, p=0.001) and LA strain in reservoir (22.0±8.6 vs 30.4±10.5, p&amp;lt;0.001) and contraction (10.5±8.18 vs 17.1±7.5, p&amp;lt;0.001). After multivariable regression analysis (age, HTA and CHASDS2VASC) all the differences remained significative. High-burden nsAT/AE and NSR patients presented significant differences in LA index volume (33.4±12.4 vs 27.3±11.8 ml/m2, p=0.043) and LA strain in reservoir (26.6±12.5) vs 31.0±10.1, p=0.034) that disappeared after multivariate regression analysis. There were no significant differences in ischemic recurrence or mortality between the three groups. Conclusions In patients with cryptogenic stroke, we registered a high rate of AF and high-burden nsAT/AE. AF patients showed notable alterations in LA volume, LA function and reservoir and contraction strain, while patients with high-burden nsAT/AE showed less structural alteration in echocardiography without difference in stroke recurrence among groups.

Higher Frequency of Premature Atrial Contractions Correlates With Atrial Fibrillation Detection after Cryptogenic Stroke.

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). 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, CHADS2 score. 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. The frequency of PACs was dose-dependently associated with AF detection in patients with cryptogenic stroke.

Performance of Different Risk Scores for the Detection of Atrial Fibrillation Among Patients With Cryptogenic Stroke.

Atrial fibrillation (AF) is a frequent underlying cause of cryptogenic stroke (CS) and its detection can be increased using implantable cardiac monitoring (ICM). We sought to evaluate different risk scores and assess their diagnostic ability in identifying patients with CS with underlying AF on ICM. Patients with CS, being admitted to a single tertiary stroke center between 2017 and 2022 and receiving ICM, were prospectively evaluated. The CHA2DS2-VASc, HAVOC, Brown ESUS-AF, and C2HEST scores were calculated at baseline. The primary outcome of interest was the detection of AF, which was defined as at least 1 AF episode on ICM lasting for 2 consecutive minutes or more. The diagnostic accuracy measures and the net reclassification improvement were calculated for the 4 risk scores. Stroke recurrence was evaluated as a secondary outcome. A total of 250 patients with CS were included, and AF was detected by ICM in 20.4% (n=51) during a median monitoring period of 16 months. Patients with CS with AF detection were older compared with the rest (P=0.045). The median HAVOC, Brown ESUS-AF, and C2HEST scores were higher among the patients with AF compared with the patients without AF (all P<0.05), while the median CHA2DS2-VASc score was similar between the 2 groups. The corresponding C statistics for CHA2DS2-VASc, HAVOC, Brown ESUS-AF, and C2HEST for AF prediction were 0.576 (95% CI, 0.482-0.670), 0.612 (95% CI, 0.523-0.700), 0.666 (95% CI, 0.587-0.746), and 0.770 (95% CI, 0.699-0.839). The C2HEST score presented the highest diagnostic performance based on C statistics (P<0.05 after correction for multiple comparisons) and provided significant improvement in net reclassification for AF detection (>70%) compared with the other risk scores. Finally, stroke recurrence was documented in 5.6% of the study population, with no difference regarding the 4 risk scores between patients with and without recurrent stroke. The C2HEST score was superior to the CHA2DS2-VASc, HAVOC, and Brown ESUS-AF scores for discriminating patients with CS with underlying AF using ICM.

Clinical predictive scores for detection of sub-clinical atrial fibrillation after cryptogenic or embolic stroke of undetermined source: A brief systematic review

Subclinical atrial fibrillation (SAF) is the primary underlying cause of cryptogenic stroke (CS) or embolic stroke of undetermined source (ESUS), particularly in patients over 65 years of age. Therefore, it is strongly recommended screening for SAF in these patients. The development of tools designed to determine the priority of SAF screening is essential for optimizing the diagnostic workup. The aim of our study was to investigate the clinical predictive scores available for SAF detection in patients with CS or ESUS. We gathered data from articles published on the PubMed database from January 1, 2000, to January 31, 2023. Our search yielded eight scores for CS and three for ESUS. SAF diagnosis was established using various methods: 12-lead ECG or 24-h ECG monitoring during 1-year follow-up in three scores; 72-h non-implantable ECG monitoring in two scores; 2 or 3-week non-implantable ECG monitoring in three scores; and implantable ECG monitoring in one score. In two scores, ECG monitoring was performed using a non-implantable and/or implantable loop recorder. Overall, the rate of SAF detection was approximately 6% when using devices for monitoring lasting no more than 72 h and increased to nearly 22% employing 2 or 3-week non-implantable or implantable devices. SAF was defined differently in various scores; five scores considered any episode, even if shorter than 30 s, while six scores required episodes to last at least 30 s. Advanced age was included as a variable in 10 of 11 scores, whereas left atrial enlargement, premature atrial beats, and brain computed tomography characteristics were features in four scores. The area under the curve values of these scores ranged from 0.72 to 0.94. In conclusion, it is still challenging to put the currently available clinical scores to use due to a lack of validation. To provide more comprehensive guidance, it is essential to conduct large prospective multicenter trials in the future.

Clinical, imaging, and management features of symptomatic carotid web: Insight from CAROWEB registry.

Although carotid web (CaW) is increasingly diagnosed as a cause of cryptogenic stroke, data are still limited to monocentric small sample cohort. To broaden knowledge on symptomatic CaW, CAROWEB registry has been recently implemented. In a large cohort of symptomatic CaW patients, we described epidemiologic characteristics, admission clinical and imaging features, and the current management including the secondary preventive strategy choice made in comprehensive French Stroke Units. CAROWEB is an ongoing French observational multicenter registry enrolling consecutive CaW patients diagnosed after an ipsilateral ischemic stroke (IS) or transient ischemic attack (TIA). Submitted cases were validated by two experienced neurologist and neuroradiologist. Clinical, imaging, and management features were collected for this study. Between June 2019 and December 2021, 244 cases were submitted by 14 centers, 42 rejected, and 202 included (IS, 91.6%; TIA, 7.9%; retinal infarction, 0.5%; mean age, 50.8 ± 12.2 years; female, 62.9%; Caucasian, 47.5%; Afro-Caribbean, 20.3%). IS patients showed median (interquartile range (IQR)) admission National Institutes of Health Stroke Scale (NIHSS) score, 8 (2-15); intracranial artery occlusion, 71.8%; ipsilateral chronic cerebral infarction (CCI), 16.3%; and reperfusion treatment, 57.3%. CaW was not identified during the mechanical thrombectomy procedure in 30 of 85 (35.3%) patients. Secondary prevention was invasive in 55.6% (stenting, n = 80; surgery, n = 30). In multivariable analysis, the invasive therapeutic option was associated with ipsilateral CCI (odds ratio (OR): 4.24 (1.27-14.2), p = 0.019) and inversely associated with risk factors (OR: 0.47 (0.24-0.91), p = 0.025) and admission NIHSS score (OR: 0.93 (0.89-0.97), p = 0.001). CaW must be considered in all ethnic groups including Caucasians. Secondary prevention is heterogeneous in large French Stroke Centers. The absence of risk factors, milder severity strokes, and ipsilateral CCI were predictive variables of secondary invasive treatment. The high rate of invasive treatment suggests that medical treatment alone is deemed ineffective to avoid recurrence and emphasize the need of randomized trials.

Carotid Web: Current Understanding of Diagnosis and Treatment

The Carotid Web (CaW) is a projection of the intimal layer of the internal carotid artery on the posterior wall into the lumen, with no evidence of calcification. Its prevalence in the general population still lacks more relevant data and studies in the clinical aspect. However, there is a correlation with patients suffering from ischemic stroke, presenting a 1.2% frequency. The literature also reveals the CaW, as a cause of cryptogenic stroke (25% of cases). The CaW can cause hemodynamic changes within the vessel, predisposing to platelet aggregation and increase the chance of thromboembolism and stroke events.

Is carotid web an arterial wall dysplasia? A histological series

IntroductionDescribed for 60 years under various names, the carotid web is a suspected cause of cryptogenic stroke, especially in young patients. The web creates an intraluminal protrusion that may contribute to turbulent flow and thrombus embolization into cerebral arteries. Although the carotid web has frequently been related to arterial fibrodysplasia, its natural history and pathological description remain unclear. PatientsAmong all consecutive patients admitted to the stroke unit of Sainte-Anne Hospital and referred to the vascular surgery department from January 2015 to December 2022, we retrospectively identified 9 patients with a carotid web. The surgical specimens of the 9 patients were submitted to systematic pathological analysis. ResultsThe patients with a histologically confirmed carotid web were young (median age was 42 years), prominently women (7/9), and presenting with low cardiovascular risk. Eight patients had a stroke proven by a magnetic resonance imaging, and 1 had transient monocular amaurosis. The typical pathological lesion supporting the imaging pattern of the carotid web was a focal eccentric intimal hyperplasia forming a protruding lesion characterized by a population of vascular smooth muscle cells intermingled in an abundant, most often loose extracellular matrix. Pathologically proven thrombus was observed in 4 cases. Importantly atherosclerosis was absent. ConclusionHistological features in our 9 cases strengthen carotid web characterization as a homogeneous pattern of localized intimal hyperplasia. It is a unique entity consistent with intimal fibroplasia, distinct from medial fibromuscular dysplasia and early atherosclerosis.

P60 THE ELECTROPHYSIOLOGICAL DIAGNOSIS OF THE CRYPTOGENETIC STROKE

Abstract Introduction In the neurological field, one of the pathologies not yet fully clarified from an etiopathogenetic point of view is cryptogenic stroke. This definition applies to all those forms of stroke in which clinical–instrumental investigations have not been able to define the "primum movens". In the literature, a significant percentage of cryptogenic stroke is the result of Paroxysmal Atrial Fibrillation (FAP). Currently the recognition of asymptomatic and rapidly evolving forms of AF can be investigated with the use of implantable electrocardiographic recorders (Loop Recorder or ILR) which increase the recognition rate of AF compared to standard investigations. The Loop Recorders, monitoring the electrical activity of the heart, are automatically activated and record the event. This data, thanks to a transmission system, as well as being stored in the memory of the recorder and therefore being interrogated, is sent to a central server which in turn transmits it to the control room which stores the patient and the events remotely. Objectives To diagnose the cause of the cryptogenic Stroke through the implantation of the ILR with long–term monitoring, up to 36 months. Methods All patients admitted to the Stroke Unit with cryptogenic stroke were evaluated with the ESUS SCORE. Patients who tested positive at the administration of the score underwent Loop Recorder (ILR) implantation for prolonged cardiac monitoring in the clinical suspicion of FAP as the cause of cryptogenic stroke. The results of such monitoring were documented along with the duration of hospital cardiac monitoring. Results A total of 210 patients diagnosed with ischemic stroke or transient ischemic attack (TIA) were identified. Of the strokes, 22 (10.4%) were classified as cryptogenic. These patients underwent a Loop Recorder implant and were monitored for 12 months. 6 out of 22 patients (27.2%) were affected by atrial fibrillation and were treated with warfarin. Conclusion Continuous Loop Recorder monitoring changed the drug treatment of 27.2% of cryptogenic stroke patients due to intermittent AF detection despite no AF detection by electrocardiography and in–hospital telemetry monitoring.

Bruton Tyrosine Kinase Inhibitor Associated Cryptococcal Meningitis Manifesting as Stroke (P1-10.002)

<h3>Objective:</h3> To highlight the appearance of fungal-related stroke on MRI and to increase awareness of opportunistic CNS infection as an etiology of cryptogenic stroke in patients receiving immunomodulatory therapies <h3>Background:</h3> Over a third of strokes are cryptogenic. Identifying the etiology of stroke is a crucial step in reducing the incidence and associated morbidity and mortality of recurrent stroke. Opportunistic CNS infection is a well-documented cause of stroke. The development and increasingly widespread use of high-efficacy immunomodulatory drugs requires vigilance for opportunistic infection and associated complications in patients receiving these drugs. <h3>Design/Methods:</h3> A case report <h3>Results:</h3> A 65-year-old gentleman with Waldenstrom’s macroglobulinemia on zanubrutinib complicated by biopsy-confirmed AHL amyloidosis, which was further complicated by cardiomyopathy, nephropathy, and recurrent pleural effusions presented with encephalopathy and was found to have multifocal acute, symmetric, subcortical strokes. There was no evidence of prior strokes or chronic small vessel disease on MRI. A comprehensive stroke work-up was unremarkable, including typical vascular risk factors within goal, negative blood cultures, normal d-dimer, normal serum viscosity, no radiographic evidence of large vessel disease, and no arrhythmia on telemetry. Echocardiogram showed bi-atrial enlargement related to cardiac amyloid, but no evidence of atrial, ventricular, or perivalvular thrombus. Lumbar puncture was performed and revealed WBC 10, RBC 9, glucose 16, and protein 154. Cryptococcal antigen was positive at a titer of 1:64. Amphotericin B and flucytosine were initiated with clinical improvement over two weeks and he was transitioned to fluconazole for maintenance therapy and prophylaxis. <h3>Conclusions:</h3> This case describes a patient treated with zanubrutinib who developed cryptococcal meningitis causing multifocal acute, symmetric, subcortical strokes. Small molecule tyrosine kinase inhibitors are associated with increased relative risk of opportunistic infection, including CNS fungal infections. Opportunistic CNS infection should be considered as a potential cause of cryptogenic stroke in patient’s receiving these drugs. <b>Disclosure:</b> Dr. Perez has nothing to disclose. Mr. Morrison has nothing to disclose. The institution of Dr. Sloane has received research support from National Center for Advancing Translational Sciences of the National Institutes of Health: KL2TR001879.

Detection of Atrial Fibrillation Using Insertable Cardiac Monitors in Patients With Cryptogenic Stroke in Japan (the LOOK Study): Protocol for a Prospective Multicenter Observational Study

Paroxysmal atrial fibrillation (AF) is a probable cause of cryptogenic stroke (CS), and its detection and treatment are important for the secondary prevention of stroke. Insertable cardiac monitors (ICMs) are clinically effective in screening for AF and are superior to conventional short-term cardiac monitoring. Japanese guidelines for determining clinical indications for ICMs in CS are stricter than those in Western countries. Differences between Japanese and Western guidelines may impact the detection rate and prediction of AF via ICMs in patients with CS. Available data on Japanese patients are limited to small retrospective studies. Furthermore, additional information about AF detection, including the number of episodes, cumulative episode duration, anticoagulation initiation (type and dose of regimen and time of initiation), rate of catheter ablation, role of atrial cardiomyopathy, and stroke recurrence (time of recurrence and cause of the recurrent event), was not provided in the vast majority of previously published studies. In this study, we aim to identify the proportion and timing of AF detection and risk stratification criteria in patients with CS in real-world settings in Japan. This is a multicenter, prospective, observational study that aims to use ICMs to evaluate the proportion, timing, and characteristics of AF detection in patients diagnosed with CS. We will investigate the first detection of AF within the initial 6, 12, and 24 months of follow-up after ICM implantation. Patient characteristics, laboratory data, atrial cardiomyopathy markers, serial magnetic resonance imaging findings at baseline, 6, 12, and 24 months after ICM implantation, electrocardiogram readings, transesophageal echocardiography findings, cognitive status, stroke recurrence, and functional outcomes will be compared between patients with AF and patients without AF. Furthermore, we will obtain additional information regarding the number of AF episodes, duration of cumulative AF episodes, and time of anticoagulation initiation. Study recruitment began in February 2020, and thus far, 213 patients have provided written informed consent and are currently in the follow-up phase. The last recruited participant (May 2021) will have completed the 24-month follow-up in May 2023. The main results are expected to be submitted for publication in 2023. The findings of this study will help identify AF markers and generate a risk scoring system with a novel and superior screening algorithm for occult AF detection while identifying candidates for ICM implantation and aiding the development of diagnostic criteria for CS in Japan. UMIN Clinical Trial Registry UMIN000039809; https://tinyurl.com/3jaewe6a. DERR1-10.2196/39307.

Underlying causes of cryptogenic stroke and TIA in The Nordic Atrial Fibrillation and Stroke (NOR-FIB) Study – the importance of comprehensive clinical evaluation

BackgroundCryptogenic stroke is a heterogeneous condition, with a wide spectrum of possible underlying causes for which the optimal secondary prevention may differ substantially. Attempting a correct etiological diagnosis to reduce the stroke recurrence should be the fundamental goal of modern stroke management.MethodsProspective observational international multicenter study of cryptogenic stroke and cryptogenic transient ischemic attack (TIA) patients clinically monitored for 12 months to assign the underlying etiology. For atrial fibrillation (AF) detection continuous cardiac rhythm monitoring with insertable cardiac monitor (Reveal LINQ, Medtronic) was performed. The 12-month follow-up data for 250 of 259 initially included NOR-FIB patients were available for analysis.ResultsAfter 12 months follow-up probable stroke causes were revealed in 43% patients, while 57% still remained cryptogenic. AF and atrial flutter was most prevalent (29%). In 14% patients other possible causes were revealed (small vessel disease, large-artery atherosclerosis, hypercoagulable states, other cardioembolism). Patients remaining cryptogenic were younger (p < 0.001), had lower CHA2DS2-VASc score (p < 0.001) on admission, and lower NIHSS score (p = 0.031) and mRS (p = 0.016) at discharge. Smoking was more prevalent in patients that were still cryptogenic (p = 0.014), while dyslipidaemia was less prevalent (p = 0.044). Stroke recurrence rate was higher in the cryptogenic group compared to the group where the etiology was revealed, 7.7% vs. 2.8%, (p = 0.091).ConclusionCryptogenic stroke often indicates the inability to identify the cause in the acute phase and should be considered as a working diagnosis until efforts of diagnostic work up succeed in identifying a specific underlying etiology. Timeframe of 6-12-month follow-up may be considered as optimal.Trial registrationClinicalTrials.gov Identifier NCT02937077, EudraCT 2018-002298-23.

The Attributable Risk of Nonstenotic Cervical Carotid Plaque in Cryptogenic Embolic Stroke

Nonstenotic plaque (NSP) of a cervical artery feeding the territory of acute cerebral infarction is increasingly recognized as a cause of cryptogenic stroke. While these atherosclerotic lesions are not associated with significant luminal stenosis (&lt;50%), the probability of finding such plaque exceeds chance and is more common in parent vessels rather than vessels supplying brain regions remote from infarction. More than 20%–30% of patients with unilateral hemispheric embolic stroke of undetermined source may be attributable to cervical internal or common carotid NSP. For these patients, randomized clinical trials have not shown a significant benefit of revascularization (endarterectomy or stenting), and optimal secondary prevention strategies rely on risk factor modification and antiplatelet therapy. Heightened awareness of this subtle finding may inform second‐tier diagnostic testing recommendations for occult stroke mechanisms (eg, monitoring for paroxysmal atrial fibrillation or hypercoagulability testing). Furthermore, recognition of NSP as a culprit lesion may lead to more targeted pharmacologic strategies aimed at stabilizing plaque. Recent guidelines have also incorporated evidence of plaque vulnerability (eg, intraplaque hemorrhage or lipid‐rich necrotic core) in decision making regarding revascularization approaches. In this review, the epidemiology and management of NSP in patients with cryptogenic embolic infarction is summarized, with an emphasis on recognition of NSP such that future clinical trials can be designed to test novel interventional strategies against current medical management of embolic stroke of undetermined source.

Neuroimaging features of antiphospholipid antibody-related stroke compared with atrial fibrillation-related stroke

Recognizing the lesion pattern of antiphospholipid antibody-related stroke (aPL-stroke) may contribute to establishing the cause in patients with cryptogenic stroke. We aimed to describe the neuroimaging features of aPL-stroke compared with atrial fibrillation-related stroke (AF-stroke), a major hidden cause of cryptogenic stroke. Using a prospective stroke registry, we identified consecutive aPL- and AF-stroke patients without other potential causes of stroke. Neuroimaging features based on diffusion-weighted imaging and angiographic findings at admission were compared. A total of 56 and 333 patients were included in the aPL- and AF-stroke groups, respectively. aPL-stroke patients more often presented with single small lesions (aPL-stroke, 30.4% vs. AF-stroke, 7.5%, p < 0.001), while the predominant pattern in AF-stroke patients was large territorial lesions (26.8% vs. 56.5%, p < 0.001). aPL-stroke patients had smaller infarct volume (1.58 mL [0.45; 9.41] vs. 11.32 mL [2.82; 33.08], p < 0.001) and less experience of relevant artery occlusion (17.9% vs. 54.7%, p < 0.001). The proportion of multi-territory lesions, an embolic pattern, was similar between the two groups (28.6% vs. 22.8%, p = 0.44). In comparison only including patients with multi-territory lesions as well, aPL-stroke patients showed small lesion dominance and smaller infarct volume. Multivariate analyses showed independent associations between mild neuroimaging features (small lesion prevalence, smaller infarct volume, and absence of relevant artery occlusion) and aPL-stroke. Patterns of small lesion prevalence, small infarct volume, and absence of relevant artery occlusion were suggestive of aPL-stroke rather than AF-stroke. Cryptogenic stroke patients with such neuroimaging features may benefit from aPL testing for a precise diagnosis.

Suture-Mediated Patent Foramen Ovale Closure Using the NobleStitch EL: Results from a Hospital-Based HTA.

(1) Background: Patent foramen ovale (PFO) is a congenital abnormality present in up to 25% of the general population, and it is a relevant cause of cryptogenic stroke. We applied the hospital-based HTA model (AdHopHTA) to conduct a multidimensional assessment of NobleStitch EL, an innovative suture-mediated PFO closure device. We compared it to Amplatzer PFO Occluder (APO) to provide evidence to inform technologies’ governance in hospital settings. (2) Methods: For each AdHopHTA dimension we: systematically retrieved available evidence from the literature applying the PRISMA guidelines and then analyzed original clinical and cost data of a NobleStitch EL device at San Raffaele research hospital in Milan (Italy). The economic dimension was analyzed through activity-based costing and a cost analysis. We conducted semi-structured interviews with selected healthcare professionals to explore the organizational, legal, social, and ethical impact. (3) Results: A single study was included for the NobleStitch EL, with 10 for APO. Both literature data and original data showed comparable safety. Efficacy data analysis found that the PFO closure was at 89% for NobleStitch EL vs. 89–97% for APO. APO has a better impact on the budget and minor process costs. Consulted experts reported that the organizational impact of NobleStitch EL in the short and the long run as null, albeit a better impact under the social and the ethical aspects. (4) Conclusion: We suggest that there is inadequate evidence to conclude the relative efficacy of NobleStitch EL as compared to APO. Nevertheless, this report shows a good safety profile and higher costs for NobleStitch EL, with no organizational or legal impact. Further studies in selected population are recommended.

ESC Working Group on e-Cardiology Position Paper: accuracy and reliability of electrocardiogram monitoring in the detection of atrial fibrillation in cryptogenic stroke patients: In collaboration with the Council on Stroke, the European Heart Rhythm Association, and the Digital Health Committee.

The role of subclinical atrial fibrillation as a cause of cryptogenic stroke is unambiguously established. Long-term electrocardiogram (ECG) monitoring remains the sole method for determining its presence following a negative initial workup. This position paper of the European Society of Cardiology Working Group on e-Cardiology first presents the definition, epidemiology, and clinical impact of cryptogenic ischaemic stroke, as well as its aetiopathogenic association with occult atrial fibrillation. Then, classification methods for ischaemic stroke will be discussed, along with their value in providing meaningful guidance for further diagnostic efforts, given disappointing findings of studies based on the embolic stroke of unknown significance construct. Patient selection criteria for long-term ECG monitoring, crucial for determining pre-test probability of subclinical atrial fibrillation, will also be discussed. Subsequently, the two major classes of long-term ECG monitoring tools (non-invasive and invasive) will be presented, with a discussion of each method's pitfalls and related algorithms to improve diagnostic yield and accuracy. Although novel mobile health (mHealth) devices, including smartphones and smartwatches, have dramatically increased atrial fibrillation detection post ischaemic stroke, the latest evidence appears to favour implantable cardiac monitors as the modality of choice; however, the answer to whether they should constitute the initial diagnostic choice for all cryptogenic stroke patients remains elusive. Finally, institutional and organizational issues, such as reimbursement, responsibility for patient management, data ownership, and handling will be briefly touched upon, despite the fact that guidance remains scarce and widespread clinical application and experience are the most likely sources for definite answers.

Proteins and pathways in atrial fibrillation and atrial cardiomyopathy underlying cryptogenic stroke.

BackgroundAtrial fibrillation (AF) is one of the most prevalent causes of cryptogenic stroke. Also, apart from AF itself, structural and remodelling changes in the atria might be an underlying cause of cryptogenic stroke. We aimed to discover circulating proteins and reveal pathways altered in AF and atrial cardiomyopathy, measured by left atrial volume index (LAVI) and peak atrial longitudinal strain (PALS), in patients with cryptogenic stroke.MethodsAn aptamer array (including 1310 proteins) was measured in the blood of 20 cryptogenic stroke patients monitored during 28 days with a Holter device as a case-control study of the Crypto-AF cohort. Protein levels were compared between patients with (n = 10) and without AF (n = 10) after stroke, and the best candidates were tested in 111 patients from the same cohort (44 patients with AF and 67 without AF). In addition, in the first 20 patients, proteins were explored according to PALS and LAVI values.ResultsForty-six proteins were differentially expressed in AF cases. Of those, four proteins were tested in a larger sample size. Only DPP7, presenting lower levels in AF patients, was further validated. Fifty-seven proteins correlated with LAVI, and 270 correlated with PALS. NT-proBNP was common in all the discovery analyses performed. Interestingly, many proteins and pathways were altered in patients with low PALS.ConclusionsMultiple proteins and pathways related to AF and atrial cardiomyopathy have been revealed. The role of DPP7 as a biomarker for stroke aetiology should be further explored. Moreover, the present study may be considered hypothesis-generating.