Perera KS, et al. Young ESUS Investigators. Evaluating Rates of Recurrent Ischemic Stroke Among Young Adults With Embolic Stroke of Undetermined Source: The Young ESUS Longitudinal Cohort Study. JAMA Neurol. 2022 Mar 14. PMID: 35285869
Background: Embolic stroke of undetermined source (ESUS) is defined as ischemic stroke(s) that is non-lacunar in nature and without any identified major cardioembolic etiology. In younger adults (<50 years of age), ESUS can comprise up to 40 percent of ischemic stroke cases. Silent atrial fibrillation (AF) has been postulated to be an etiology of ESUS, but this is not certain as other etiologies have also been implicated.
Methods: Young ESUS was an international prospective longitudinal cohort study conducted in 41 centers in 13 different countries from October 2017 to October 2019.
Inclusion criteria: Young adults £50 years of age with non-lacunar, non-cardioembolic stroke (no known atrial fibrillation, LV thrombus, or mechanical valve) who had non-stenotic extracranial arteries (<50% stenosis) and no other cause of stroke found. At least 24 hours of cardiac monitoring without evidence of AF was also required.
Outcomes measured: Patients were followed up at 6, 12, 18 months, and/or at the end of the study via a telephone interview which assessed the following questions: was the patient was alive; did they have a recurrent ischemic stroke; and had atrial fibrillation been diagnosed in the interim. To determine predictors of recurrent stroke, the authors considered prior stroke or transient ischemic attack (TIA), current or previous tobacco use, age, diabetes, hypertension, presence of a patent foramen ovale (PFO), and aspirin use prior to the index event. The primary outcome was recurrent ischemic stroke or death. Candidate predictors from univariable analyses were included in the multivariable modified Poisson regression model.
Results: Of 576 patients screened, 535 were enrolled. The mean age was 40.4 years with 56% of patients being male; 6.5% were Asian, 7.5% Black, 13.8% Hispanic, and 70.8% White. The primary outcome of ischemic stroke or death occurred in 16 patients (14 recurrent strokes, 2 deaths). It is important to note that of the 14 recurrent strokes, 5 were subsequently diagnosed with other etiologies (e.g., dissection, aortic valve mass, etc.). Therefore, only 9 recurrent strokes were truly diagnosed as ESUS. Atrial fibrillation was detected in 15 patients (2.8%) and 1 additional patient also had atrial fibrillation detected via loop recorder at 18 months follow-up. Using multivariable analysis, a prior history of stroke or TIA (hazard ratio, 5.3; 95% CI, 1.8-15), diabetes (hazard ratio, 4.4; 95% CI, 1.5-13), and coronary artery disease (hazard ratio, 10; 95% CI, 4.8-22) were associated with recurrent stroke.
Commentary: The key finding of this study was that the rate of recurrent strokes classified as ESUS in young patients was low. Most patients with recurrent stroke had no embolic source identified.
The Young ESUS longitudinal cohort study had some limitations. First, 8% of patients were excluded for not having intracranial imaging, and it is unclear how this could have affected the results. Additionally, there was no requirement for patients to have long-term monitoring for atrial fibrillation, which makes it challenging to ascertain how many cases of atrial fibrillation might have been missed and how this would have affected outcome. In comparison, although screening for atrial fibrillation in older patients with elevated stroke risk did result in more cases detected in the LOOP study, it did not reduce time to first stroke1. Similarly, transesophageal echocardiography (TEE) was not required for inclusion in the study, which likely led to some PFOs being missed; however, according to the results, the presence of PFO was not associated with recurrent strokes. Other potential stroke risk factors such as atrial cardiopathy may also contribute to stroke risk in younger patients, and the ongoing ARCADIA trial2 may be ale to provide further insights into this possibility. Finally, because this study’s cohort comprised patients who were 71% White, its results may not be applicable to a more diverse population. Therefore, further studies are needed to help elucidate stroke mechanisms in young patients with ESUS, as it is unclear whether treatments that have failed to show a benefit in prior studies across all ESUS patients (RESPECT-ESUS3 and NAVIGATE-ESUS4) may have utility in a younger subgroup.
- Svendsen, et al. Implantable loop recorder detection of atrial fibrillation to prevent stroke (The LOOP Study): a randomised controlled trial. Lancet. 2021 Oct 23;398(10310):1507-1516
- Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source.N Engl J Med. (2018) 378:2191–201
- Diener HC, Sacco RL, Donald Easton J, Granger CB, Bernstein RA, Uchiyama S, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source.N Engl J Med. (2019) 380:1906–17
- Kamel H, Longstreth WT, Tirschwell DL, Kronmal RA, Broderick JP, Palesch YY, et al. The AtRial cardiopathy and antithrombotic drugs in prevention after cryptogenic stroke randomized trial: rationale and methods.Int J Stroke. (2019) 14:207–14
Bilal Butt, MD
Assistant Professor of Neurology
Department of Neurology
University of Maryland School of Medicine