Current perspectives on the clinical management of cryptogenic stroke

ABSTRACT

Introduction

Cryptogenic stroke is a heterogeneous entity defined as an ischemic stroke for which no probable cause is identified despite thorough diagnostic evaluation. Since about a quarter of all ischemic strokes are classified as cryptogenic, it is a commonly encountered problem for providers as secondary stroke prevention is guided by stroke etiology.

Areas Covered

In this review, the authors provide an overview of stroke subtype classification schemes and diagnostic evaluation in cryptogenic stroke. They then detail putative cryptogenic stroke mechanisms, their therapeutic implications, and ongoing research. This review synthesizes the available evidence on PubMed up to December 2022.

Expert opinion

Cryptogenic stroke is an evolving concept that changes with ongoing research. Investigations are focused on improving our diagnostic capabilities and solidifying useful constructs within cryptogenic stroke that could become therapeutically targetable subgroups within an otherwise nonspecific entity. Advances in technology may help move specific proposed cryptogenic stroke mechanisms from undetermined to known source of ischemic stroke.

KEYWORDS:

• Atrial cardiopathy
• cryptogenic stroke
• embolic stroke of undetermined source
• patent foramen ovale
• stroke
• atrial fibrillation
• atherosclerosis

Article highlights

• Cryptogenic stroke is a heterogeneous entity defined as an ischemic stroke for which no probable cause is identified despite thorough diagnostic evaluation; it accounts for about 25% of all ischemic stroke.

• Cryptogenic stroke is a diagnosis of exclusion after standard stroke evaluation fails to yield a probable cause.

• Advanced diagnostic testing should be carefully geared toward the patient and clinical scenarios. If a cause is discovered, then the stroke ceases to be cryptogenic.

• The current mainstay secondary prevention for cryptogenic stroke is optimization of modifiable vascular risk factors and antiplatelet therapy, with the notable exception of possible endovascular patent foramen ovale (PFO) closure in PFO-associated stroke.

• Most proposed cryptogenic stroke mechanisms are symbolic, and thus many interventional trials have sought to test the efficacy of anticoagulation over antiplatelet therapy in cryptogenic stroke, though conclusive benefits have yet to be seen.

Declaration of Interest

MSV Elkind reports receipt of study drug in kind from the BMS-Pfizer Alliance for Eliquis and ancillary financial support from Roche, both in support of the NIH/NINDS-funded trial of apixaban versus aspirin for patients with cryptogenic stroke and atrial cardiopathy (ARCADIA trial). He is also a recipient of royalties for chapters on cryptogenic stroke published in UpToDate and is an employee of the American Heart Association. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

D Yang is supported by the National Institute of Neurological Disorders and Stroke T32NS007153.