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Original Investigation
March 14, 2022

Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study

Author Affiliations
  • 1Department of Medicine, Neurology, McMaster University, Hamilton, Ontario, Canada
  • 2Population Health Research Institute, Hamilton Health Sciences, Hamilton, Ontario, Canada
  • 3Department of Statistics, Hamilton Health Sciences, Hamilton, Ontario, Canada
  • 4Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia
  • 5Department of Neurology, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
  • 6Department of Neurology & Neurological Sciences, Stanford Stroke Center, Stanford, California
  • 7Stanford Children’s Health, Stanford, California
  • 8Department of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
  • 9Institute for Neurological Research-FLENI, Buenos Aires, Argentina
  • 10Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
  • 11National Institute of Neurology, La Fama, Tlalpan, México
  • 12Department of Clinical Neurosciences, University of Calgary, Foothills Medical Calgary, Calgary, Alberta, Canada
  • 13Department of Neurology, University Hospital Bern, Bern, Switzerland
  • 14International Clinical Research Center and Neurology Department, St Anne’s University Hospital, Brno, Czech Republic
  • 15Masaryk University, Brno, Czech Republic
  • 16Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
  • 17Department of Neurosciences, Western University, London, Ontario, Canada
  • 18Division of Brain Sciences, Imperial College, The Hammersmith Hospital, London, United Kingdom
  • 19Neurology Service, Bichat Hospital, Paris, France
  • 20Department of Neurolog, Universitätsklinikum Würzburg, Würzburg, Germany
JAMA Neurol. 2022;79(5):450-458. doi:10.1001/jamaneurol.2022.0048
Key Points

Question  What are the rates of recurrent ischemic stroke and new-onset atrial fibrillation (AF) in younger adults with embolic stroke of undetermined source (ESUS), and what factors are associated with these prognoses?

Findings  In this longitudinal cohort study of 535 patients, recurrent stroke risk was 1.9 per 100 patient-years. History of stroke or transient ischemic attack, diabetes, and coronary artery disease were associated with recurrence, and AF was detected in 2.8% of participants during follow-up.

Meaning  These findings suggest that young adults with ESUS may have a relatively low rate of subsequent ischemic stroke and new-onset AF compared with older adults.


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.

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    1 Comment for this article
    Do younger ESUS patients respond better to anticoagulants than to antiplatelet agents?
    J David Spence, M.D. | Stroke Prevention & Atherosclerois Research Centre, Robarts Research Institute, Western University, London, Canada
    It was disappointing that this paper did not report on the effect of anticoagulant vs. antiplatelet agents in this subgroup of younger patients with Embolic Stroke of Unknown Source (ESUS). Perhaps such an analysis is planned for a separate paper.
    Non-stenotic carotid atherosclerosis is increasingly recognized as a cause of stroke.[1]
    A major problem with the main ESUS studies of antiplatelet vs. anticoagulant was misclassification of Large Artery Atherosclerosis (LAA) as ESUS by the TOAST classification. Defining LAA by 50% stenosis misses 79% of non-stenotic LAA in our clinic population.[2] Both the SPARKLE and the Chinese (CISS) classifications[3]
    identify fewer cases as “unknown” than TOAST.
    I would expect younger patients to have less LAA, so they would likely respond better to anticoagulants than the older participants in the ESUS trials. In assessing the effects of anticoagulant vs. antiplatelet therapy in younger ESUS patients, those with known coronary artery disease should be excluded, as they are likely to have non-stenotic LAA.

    1. Kamtchum-Tatuene J, Nomani AZ, Falcione S, Munsterman D, Sykes G, Joy T, et al. Non-stenotic Carotid Plaques in Embolic Stroke of Unknown Source. Front Neurol. 2021;12:719329.
    2. Bogiatzi C, Wannarong T, McLeod AI, Heisel M, Hackam D, Spence JD. SPARKLE (Subtypes of Ischaemic Stroke Classification System), incorporating measurement of carotid plaque burden: a new validated tool for the classification of ischemic stroke subtypes. Neuroepidemiology. 2014;42(4):243-51.
    3. Zhang H, Li Z, Dai Y, Guo E, Zhang C, Wang Y. Ischaemic stroke etiological classification system: the agreement analysis of CISS, SPARKLE and TOAST. Stroke Vasc Neurol. 2019;4(3):123-8.