Embolic Stroke of Undetermined Source: CRM, August 2025 Review Finds Cardiovascular Diagnostic Uncertainty

These findings were published in August 2025, in Cardiovascular Revascularization Medicine.

The Clinical Burden of Diagnostic Uncertainty

ESUS is defined as a non-lacunar stroke confirmed by neuroimaging—such as Computed Tomography (CT) or Magnetic Resonance Imaging (MRI)—in the absence of significant atherosclerosis or identifiable cardioembolic sources. Because the underlying pathophysiology is often unclear, patients and clinicians face considerable uncertainty regarding optimal treatment. Research indicates that the annualized recurrence rate for these strokes can reach 4% to 5%, which is notably higher than other types of cryptogenic strokes. This condition frequently affects younger populations and has a higher prevalence in females, who may experience less complete reperfusion during acute treatment.

Diagnostic and Pathophysiological Overview

The evaluation of ESUS requires a multidisciplinary collaboration between neurology, cardiology, and hematology to navigate various potential etiologies. Key areas of investigation include carotid atheroembolism, where complex plaques may cause embolic events even without severe luminal stenosis. Additionally, cardiac pathologies such as Left Atrial (LA) cardiopathy and Left Ventricular (LV) dysfunction—specifically an Ejection Fraction (EF) below 30%—are significant contributors. The review also emphasizes the role of occult malignancy, noting that approximately 50% of strokes related to cancer are initially labeled as ESUS. Prolonged cardiac monitoring using devices such as a Holter monitor remains essential for detecting subclinical Atrial Fibrillation (AF) or Atrial High-Rate Episodes (AHRE). Detecting these rhythm disorders often necessitates a shift from antiplatelet therapy to oral anticoagulation (OAC). Other diagnostic tools include a transthoracic echocardiogram (TTE) or transesophageal echocardiogram (TEE) to exclude a patent foramen ovale (PFO) or cardiac thrombi.

The key findings from the review include:

• ESUS accounts for approximately 17% of all ischemic strokes, highlighting its prevalence in clinical practice.

• The annualized stroke recurrence rate is estimated at 4% to 5%, which is higher than other cryptogenic stroke types.

• Atrial High-Rate Episodes (AHRE) lasting more than 24 hours are associated with an increased risk of systemic embolism, though the use of OAC in these cases must be balanced against bleeding risks.

• LA fibrosis is significantly more prevalent in ESUS patients than in those without the condition, serving as a potential surrogate marker for atrial disease.

Clinical Relevance and Targeted Prevention

For practicing physicians, the review underscores that ESUS management must shift from empiric treatment toward a pathophysiology-directed approach. While Dual Antiplatelet Therapy (DAPT)—typically involving aspirin and clopidogrel—is standard for initial secondary prevention, clinicians should escalate diagnostic diligence using prolonged cardiac monitoring and advanced neurovascular imaging. The lack of a "one-size-fits-all" strategy means that shared decision-making is vital, especially regarding the use of OAC in the absence of documented AF. Ultimately, aggressive risk factor modification, including blood pressure and lipid control, remains the cornerstone of long-term care for patients with diagnostic uncertainty.

Reference

Rao A, Rahman H, Bhatia H, et al. Embolic stroke of undetermined source: A cardiovascular approach to diagnostic uncertainty. Cardiovascular Revascularization Medicine. 2026;83:84–89.