Embolic stroke of undetermined source: Gateway to a new stroke entity?

Abstract Embolic stroke of unknown source is currently thought to represent a subpopulation of cryptogenic strokes defined by its embolic stroke pattern on imaging and if after a carefully performed diagnostic evaluation, a specific, well recognized cause of stroke has not been identified. The concept was primarily established to justify and enable the conduct of the Embolic Stroke of Unknown Source (ESUS)-trials, such as RESPECT-ESUS (Randomized, Double-Blind, Evaluation in Secondary Stroke Prevention Comparing the Efficacy and Safety of the Oral Thrombin Inhibitor Dabigatran Etexilate versus Acetylsalicylic Acid in Patients with Embolic Stroke of Undetermined Source) and NAVIGATE-ESUS (New Approach Rivaroxaban Inhibition of Factor Xa in a Global Trial versus aspirin to Prevent Embolism in Embolic Stroke of Undetermined Source). With both studies having neutral results, the question arises if the embolic stroke of unknown source concept is misleading or rather a gateway for a modern understanding of stroke etiology. This review will analyze the background of the embolic stroke of unknown source concept, overview the results and the impact of the recent multicenter trials and cohort studies, and discuss the definition, etiology and diagnosis of embolic stroke of unknown source. • A novel subgroup of cryptogenic stroke with embolic infarction pattern on imaging appears without obvious cause including carotid stenosis, atrial fibrillation, cardiac disease. • Clinicians should pursue intensive diagnostic workup to identify underlying stroke cause. • Diagnostic workup will in most cases uncover underlying stroke etiology including atrial fibrillation, large-artery atherosclerotic disease, cardiac abnormalities including atrial cardiomyopathy, thrombus, patent foramen ovale, coagulation diseases, malignancies. • These measures have the potential to reduce the rate of cryptogenic stroke.