What is Embolic Stroke of Undetermined Source (ESUS), its diagnosis, and treatment in older adults with risk factors such as hypertension, diabetes, or hyperlipidemia?

Embolic Stroke of Undetermined Source (ESUS): Definition, Diagnosis, and Treatment

Definition

ESUS is a nonlacunar cryptogenic ischemic stroke detected by CT or MRI that remains unexplained after a standardized diagnostic workup has excluded all identifiable causes. 1

The diagnostic criteria require all of the following after adequate investigation 1:

• Non-lacunar stroke (not subcortical and <15 mm diameter) 1
• Absence of ≥50% stenosis in extracranial or intracranial arteries supplying the ischemic area 1
• No major cardioembolic source including:
  • Permanent or paroxysmal atrial fibrillation 1
  • Sustained atrial flutter 1
  • Intracardiac thrombus 1
  • Prosthetic cardiac valve 1
  • Atrial myxoma or other cardiac tumors 1
  • Mitral stenosis 1
  • Recent (<4 weeks) myocardial infarction 1
  • Left ventricular ejection fraction <30% 1
  • Valvular vegetations or infective endocarditis 1
• No other specific cause such as arteritis, dissection, migraine/vasospasm, or drug misuse 1

ESUS accounts for approximately 17% of all ischemic strokes (about 1 in 6 strokes), representing a subcategory of cryptogenic strokes. 1, 2

Diagnostic Workup

Required Initial Investigations

Prolonged cardiac monitoring is the cornerstone of ESUS diagnosis and is recommended as Class I evidence to inform treatment decisions. 1

The mandatory diagnostic pathway includes 1:

• Brain imaging: CT or MRI (MRI with DWI preferred for superior sensitivity) 1, 3
• Cardiac rhythm monitoring: Minimum 24 hours initially 1
• Echocardiography: To exclude structural cardiac sources 1
• Vascular imaging: CTA, MRA, or duplex ultrasound of intracranial and extracranial arteries supplying the affected brain area 1
• 12-lead ECG: To assess for atrial fibrillation/flutter and structural heart disease 1
• Laboratory tests: Complete blood count, electrolytes, coagulation studies, renal function, glucose, troponin, lipid profile, and HbA1c or glucose tolerance test 1

Extended Cardiac Monitoring Strategy

For patients ≥55 years with suspected cardioembolic mechanism but no atrial fibrillation on initial monitoring, prolonged ECG monitoring for at least 2 weeks is recommended. 1

The evidence strongly supports extended monitoring 1:

• 30-day external loop recorder detects atrial fibrillation in 16.1% vs 3.2% with 24-hour Holter (absolute difference 12.9%) 1
• Implantable loop recorders detect atrial fibrillation in 8.9% vs 1.4% with conventional follow-up (HR 6.4) 1
• Multi-phase sequential monitoring can detect atrial fibrillation in up to 23.7% of ESUS patients 1
• Detection increases with monitoring duration: 2% at 1 week to >20% by 3 years 1

Risk factors predicting higher atrial fibrillation detection include: increasing age, left atrial enlargement, cortical stroke location, and elevated CHA₂DS₂-VASc scores. 1

Treatment in Older Adults with Vascular Risk Factors

Antiplatelet Therapy (Current Standard)

Antiplatelet therapy is the recommended treatment for ESUS patients unless atrial fibrillation is detected, at which point anticoagulation becomes indicated. 1

For patients with ESUS and risk factors (hypertension, diabetes, hyperlipidemia) 1:

• Standard long-term therapy: Aspirin 50-325 mg daily, clopidogrel 75 mg daily, or aspirin 25 mg plus extended-release dipyridamole 200 mg twice daily 1
• Early dual antiplatelet therapy (DAPT): For recent minor stroke (NIHSS ≤3) or high-risk TIA (ABCD² ≥4), aspirin plus clopidogrel initiated within 12-24 hours and continued for 21-90 days, followed by single antiplatelet therapy 1
• DAPT beyond 90 days is not recommended due to excess hemorrhage risk without recurrent stroke benefit 1

Anticoagulation: Evidence and Limitations

Anticoagulation with NOACs has NOT proven superior to antiplatelet therapy for ESUS. 4

Major trials (NAVIGATE ESUS, RE-SPECT ESUS) involving 12,600 patients found that neither rivaroxaban nor dabigatran reduced recurrent stroke risk compared to aspirin. 4, 5 The 2024 ESC guidelines explicitly state that initiation of oral anticoagulation in ESUS patients without documented atrial fibrillation is not recommended. 1

Risk Stratification and Prognosis

Patients with ESUS have a recurrent stroke rate of 4-5% per year despite antiplatelet therapy. 1, 2 The CHA₂DS₂-VASc score independently predicts recurrence risk, with scores ≥2 showing approximately threefold higher stroke recurrence risk. 1

Clinical Implications for Older Adults with Risk Factors

Management Algorithm

1. Complete the standardized ESUS diagnostic workup to exclude all identifiable causes 1
2. Initiate extended cardiac monitoring (minimum 2 weeks, consider implantable loop recorder if high suspicion) 1
3. Start antiplatelet therapy unless atrial fibrillation is detected 1
4. Aggressively manage vascular risk factors: hypertension, diabetes, and hyperlipidemia require optimization as these are associated with ESUS 1
5. Continue cardiac surveillance as atrial fibrillation detection increases with longer monitoring duration 1

Common Pitfalls

Do not rely solely on clinical features without comprehensive imaging, as this leads to misclassification. 3 Approximately 25% of ischemic strokes remain cryptogenic despite adequate investigation, and extended monitoring beyond 24 hours significantly increases occult atrial fibrillation detection. 3

Do not assume all ESUS patients will benefit from anticoagulation—the heterogeneity within ESUS means that underlying mechanisms vary, including supracardiac atherosclerosis, covert atrial cardiopathy, and other embolic sources beyond atrial fibrillation. 4, 6

Emerging Considerations

Supracardiac atherosclerosis (carotid, vertebrobasilar, intracranial, and aortic arch plaques) represents an underestimated embolic source in ESUS, potentially larger than initially conceived. 6 Advanced imaging to identify high-risk plaques may guide future therapeutic strategies, though current evidence supports antiplatelet therapy as standard treatment. 6