IMPORTANCE: Cryptogenic strokes constitute approximately 40% of ischemic strokes in young adults, and most meet criteria for the embolic stroke of undetermined source (ESUS). Two randomized clinical trials, NAVIGATE ESUS and RESPECT ESUS, showed a high rate of stroke recurrence in older adults with ESUS but the prognosis and prognostic factors among younger individuals with ESUS is uncertain. OBJECTIVE: To determine rates of and factors associated with recurrent ischemic stroke and death and new-onset atrial fibrillation (AF) among young adults. DESIGN, SETTING, AND PARTICIPANTS: This multicenter longitudinal cohort study with enrollment from October 2017 to October 2019 and a mean follow-up period of 12 months ending in October 2020 included 41 stroke research centers in 13 countries. Consecutive patients 50 years and younger with a diagnosis of ESUS were included. Of 576 screened, 535 participants were enrolled after 1 withdrew consent, 41 were found to be ineligible, and 2 were excluded for other reasons. The final follow-up visit was completed by 520 patients. MAIN OUTCOMES AND MEASURES: Recurrent ischemic stroke and/or death, recurrent ischemic stroke, and prevalence of patent foramen ovale (PFO). RESULTS: The mean (SD) age of participants was 40.4 (7.3) years, and 297 (56%) participants were male. The most frequent vascular risk factors were tobacco use (240 patients [45%]), hypertension (118 patients [22%]), and dyslipidemia (109 patients [20%]). PFO was detected in 177 participants (50%) who had transthoracic echocardiograms with bubble studies. Following initial ESUS, 468 participants (88%) were receiving antiplatelet therapy, and 52 (10%) received anticoagulation. The recurrent ischemic stroke and death rate was 2.19 per 100 patient-years, and the ischemic stroke recurrence rate was 1.9 per 100 patient-years. Of the recurrent strokes, 9 (64%) were ESUS, 2 (14%) were cardioembolic, and 3 (21%) were of other determined cause. AF was detected in 15 participants (2.8%; 95% CI, 1.6-4.6). In multivariate analysis, the following were associated with recurrent ischemic stroke: history of stroke or transient ischemic attack (hazard ratio, 5.3; 95% CI, 1.8-15), presence of diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and history of coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22). CONCLUSIONS AND RELEVANCE: In this large cohort of young adult patients with ESUS, there was a relatively low rate of subsequent ischemic stroke and a low frequency of new-onset AF. Most recurrent strokes also met the criteria for ESUS, suggesting the need for future studies to improve our understanding of the underlying stroke mechanism in this population.

Department of Clinical Neurosciences University of Calgary Foothills Medical Calgary Calgary Alberta Canada

Department of Human Neurosciences Sapienza University of Rome Rome Italy

Department of Medicine Neurology McMaster University Hamilton Ontario Canada

Department of Neurolog Universitätsklinikum Würzburg Würzburg Germany

Department of Neurology and Neurological Sciences Stanford Stroke Center Stanford California

Department of Neurology Hospital de la Santa Creu i Sant Pau Barcelona Spain

Department of Neurology Sir Charles Gairdner Hospital Perth Western Australia Australia

Department of Neurology University Hospital Bern Bern Switzerland

Department of Neurosciences Western University London Ontario Canada

Department of Statistics Hamilton Health Sciences Hamilton Ontario Canada

Division of Brain Sciences Imperial College The Hammersmith Hospital London United Kingdom

Faculty of Medicine University of British Columbia Vancouver British Columbia Canada

Institute for Neurological Research FLENI Buenos Aires Argentina

International Clinical Research Center and Neurology Department St Anne's University Hospital Brno Czech Republic

Masaryk University Brno Czech Republic

Medical School Faculty of Health and Medical Sciences University of Western Australia Perth Western Australia

National Institute of Neurology La Fama Tlalpan México

Neurology Service Bichat Hospital Paris France

Population Health Research Institute Hamilton Health Sciences Hamilton Ontario Canada

Stanford Children's Health Stanford California

JAMA Neurol. 2022 May 1;79(5):444-447. doi: 10.1001/jamaneurol.2022.0058. PubMed

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