Review
Embolic Stroke of Undetermined Source: Current Perspectives on Diagnosis, Investigations, and Management

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Abstract

In 2014, Hart et al. introduced the concept of “embolic stroke of undetermined source” (ESUS) to the clinical-research stroke community. The hypothesis underlying the development of the ESUS construct was that this potentially heterogenous group of stroke mechanisms were largely thromboembolic, and would thus benefit from anticoagulation over antiplatelet for secondary prevention. Since then, 2 large clinical trials have shown that, to date, there is not a clear uniform antithrombotic strategy for secondary prevention after ESUS as it was originally broadly defined. However, this work has yielded valuable information about the patient phenotypes that experience ESUS strokes, as well as hypothesis-generating substudies that have given rise to the next generation of secondary prevention trials aimed at more personalized approaches for different suspected mechanisms of embolic stroke. In parallel with the evolution of ESUS, several studies aimed at screening for atrial fibrillation in the secondary stroke prevention population have generated additional questions about the mechanistic relevance of atrial fibrillation detected after stroke, and how this should inform poststroke workup, and secondary prevention strategies. Herein, we provide a synthesis of the current understanding surrounding the patient phenotypes that experience ESUS strokes, and previous, ongoing, and anticipated clinical trials that will guide earlier and later secondary prevention strategies and poststroke cardiac investigations.

Résumé

En 2014, Hart et ses collaborateurs ont introduit le concept d’« accident vasculaire cérébral embolique de source indéterminée » (embolic stroke of undetermined source ou ESUS) dans le domaine de la recherche clinique sur les accidents vasculaires cérébraux (AVC). Selon l’hypothèse sous-tendant le concept, l’ESUS était probablement attribuable à des mécanismes hétérogènes essentiellement thromboemboliques. Conséquemment, un traitement anticoagulant paraissait préférable à un traitement antiplaquettaire en prévention secondaire de cette forme d’AVC. Depuis lors, deux essais cliniques de grande envergure ont montré qu’il n’existe à ce jour aucune stratégie antithrombotique claire et cohérente en matière de prévention secondaire de l’ESUS, au sens large de la définition princeps. Néanmoins, les travaux effectués ont fourni de précieux renseignements sur les phénotypes des patients qui subissent un ESUS. Ils ont aussi donné lieu à des sous-études permettant de formuler des hypothèses qui sont à l’origine de la prochaine génération d’essais en prévention secondaire axés sur des approches plus personnalisées des différents mécanismes présumés de l’AVC embolique. Parallèlement à l’évolution du concept d’ESUS, plusieurs études centrées sur le dépistage de la fibrillation auriculaire en contexte de prévention secondaire des AVC ont soulevé d’autres questions sur l’importance de la fibrillation auriculaire détectée après un AVC relativement aux mécanismes en jeu et sur sa portée au regard du bilan post-AVC et des stratégies de prévention secondaire. Nous présentons ici une synthèse de la compréhension actuelle des phénotypes des patients qui subissent un ESUS. Nous résumons aussi les essais cliniques passés, en cours et à venir qui orienteront les stratégies de prévention secondaire et les investigations cardiaques post-AVC à court et à plus long terme.

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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