Importance: One-third of ischemic strokes have no identifiable cause after standard evaluation. In 2014, researchers termed these embolic strokes of undetermined source (ESUS) and argued that this entity would respond to anticoagulation. Two recent randomized clinical trials have not upheld this hypothesis, leading to questions about the ESUS concept.
Observations: This article proposes that ESUS remains a useful concept, the clinical effect of which can be enhanced by considering 2 subsets defined by their likelihood of responding to anticoagulation. Recent studies indicate that some ESUS cases result from subclinical atrial fibrillation, atrial cardiopathy, unrecognized myocardial infarction, patent foramen ovale, or cancer, while other cases result from nonstenosing large-artery atherosclerosis, aortic atherosclerosis, or nonatherosclerotic vasculopathies. Evidence suggests that anticoagulation will prove superior to antiplatelet therapy for cases in the first group of causative mechanisms but not those in the second group, suggesting the need for personalized therapy.
Conclusions and relevance: Although the ESUS concept as currently constructed cannot guide treatment, efforts to better understand ESUS and develop therapies tailored to specific mechanisms are likely to help reduce the burden of stroke.