ReviewEmbolic Stroke of Undetermined Source: Current Perspectives on Diagnosis, Investigations, and Management
Section snippets
ESUS: The First Generation
ESUS as a distinct clinical construct was originally defined as having: (1) nonlacunar morphology, with either 1 cortically-based or multiple simultaneous cortical and/or subcortical strokes, or subcortical strokes ≥ 1.5 cm in diameter on computed tomography (CT) imaging and ≥ 2 cm on magnetic resonance diffusion-weighted imaging); and (2) the absence of a major-risk cardioembolic source (eg, AF, endocarditis), large artery stenosis ≥ 50%, or other known mechanism (eg, dissection, vasculitis,
Epidemiology
Earlier series have classified approximately one-sixth to one-fifth of ischemic strokes as ESUS, although rates have varied in part depending on thoroughness of diagnostic workup, and whether or not PFO was included under the study-specific definition of ESUS. A 2017 systematic review identified a 9%-25% frequency of ESUS in retrospective stroke registries.9 A review including more recent retrospective hospital- and population-based series identified proportions of 8%-28%, with a mean of 18%.10
ESUS Trials
Three first-generation secondary ESUS trials began between 2014 and 2015. In NAVIGATE ESUS rivaroxaban 15 mg daily was compared with aspirin for secondary stroke prevention in adults with ESUS aged 50 years or older.3 Criteria for ESUS were similar to the original 2014 construct report with the exception that intracranial vascular imaging was not required. (If, however, intracranial imaging was performed and a stenosis ≥ 50% in the responsible arterial territory was identified, this was an
Workup and Management of ESUS: Integrating Personalized Approaches as the Evidence Evolves
To date, the ESUS construct has evolved on multiple fronts since its initial presentation to the stroke community in 2014. First, PFO closure has been shown to have a distinct beneficial secondary prevention strategy, particularly in younger patients. Second, ESUS due to presumed cardioembolic mechanisms, including atrial cardiopathy, LV dysfunction, and untreated PFO, might possibly benefit from anticoagulation over antiplatelets for secondary prevention and might thus necessitate a distinct
Conclusions: Outstanding Questions and Future Directions
The ESUS construct has served as an important means to distinguish how secondary prevention might be personalized in the future. Time will tell as to whether the concept of “ESUS” will be a lasting concept in refining secondary prevention strategies: although nonlacunar morphology has persisted as a means to distinguish ESUS, approximately 10% of lacunar lesions are posited to be due to embolic pathology on the basis of animal models and clinical studies.113 Further, future trials might help
Funding Sources
T.S.F. is supported by a Heart and Stroke/Sauder Family Professorship of Stroke Research from the University of British Columbia and a Health Professional Investigator Award from Health Research BC.
Disclosures
T.S.F. receives in-kind study medication from Bayer Canada and has received honoraria for advisory board work for HLS Therapeutics and Roche Canada. L.A.S. receives research grants from Boehringer Ingelheim and Bayer and speaking fees/honoraria from Boehringer Ingelheim, Pfizer, Bayer, Gore, and Daiichi Sankyo. M.D.H. has received consulting fees from Sun Pharma and Brainsgate Inc. J.S.H. receives research grants and speaking fees from BMS/Pfizer and Boston Scientific, consulting fees from
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