David Goldemund M.D.
Updated on 11/04/2024, published on 17/12/2021

Definition of cryptogenic stroke

ESUS (Embolic Stroke of Undetermined Source)

ESUS criteria  (must meet all)
Non-lacunar infarction detected on the brain CT/MRI

  • cortical/subcortical ischemia
    • ≥ 15 mm in at least one direction on CT
    • ≥ 20 mm on MR-DWI
  • brainstem lesions located laterodorsally in the territory of circumflex arteries < 1.5 cm (not considered lacunar infarcts, unlike lesions in the perforator territory)
Absence of extra- or intracranial atherosclerosis leading to ≥ 50% stenosis in the artery supplying the infarcted area (CTA/MRA/ultrasound)
Absence of a significant cardioembolic source (e.g., AFib, intracardiac thrombus, myxoma, etc.)
Absence of other specific causes of stroke (dissection, vasculitis, etc.)
Vascular imaging supporting embolic etiology
  • evidence of abrupt absence of contrast agent, consistent with a blood clot within otherwise angiographically normal appearing intracranial arteries
  • evidence of complete recanalization of the previously occluded artery
  • presence of multiple acute infarcts occurring in close temporal relation without detectable abnormalities in the relevant vessels
  • ESUS is associated with a higher recurrence risk, similar to that of cardioembolic stroke  Risk of stroke recurrence (Ntaios, 2015) [Ntaios, 2015]
  • suspicion of thromboembolism is supported by:
  • ESUS may be caused by unrecognized cardioembolic etiology (i.e., TOAST 2) or by embolization from non-stenotic plaques in the aorta and carotid artery (TOAST 1)
    • paradoxical embolization (PFO) or other non-atherosclerotic causes are more common in individuals < 50 years of age
    • paroxysmal AFib and atherosclerotic plaques predominate in those > 50 years of age
Cryptogenic stroke
  • a diagnosis of ESUS implies that the stroke is embolic in origin (given the non-lacunar characteristics of the ischemia)
  • the source of the embolus is unknown after a thorough evaluation
  • although cryptogenic stroke implies that the cause is unknown, the stroke is not necessarily embolic
  • individuals diagnosed with ESUS have a cryptogenic stroke, but the reverse is not always the case

Cryptogenic stroke recurrence

  • short-term risk of recurrent cryptogenic stroke is 1.6% at 7 days, 3-4.2% at 1 month, and 5.6% at 3 months (Lovett, 2004)
  • patients with ESUS have a relatively high recurrence rate compared to other stroke subtypes (nearly 20% at 2 years)  (Ntaios, 2015)


  • the mainstay of prevention of cryptogenic stroke (including ESUS) is antiplatelet therapy
    • ASA or clopidogrel or short-term DAPT (ASA+CLP)
    • ticagrelor is not recommended in this indication (negative posthoc analysis of ESUS patients in the SOCRATES trial)  (AHA/ASA 2021 3/B-NR)
  • DOACs are not recommended  (AHA/ASA 2021 3/B-R)
  • in younger patients with significant PFO and no other plausible cause of stroke, consider PFO occlusion
  • in older patients, rigorously and repeatedly search for cardioembolic etiology (particularly paroxysmal AFib), as this would be an indication for anticoagulant therapy
    • in a study that followed ESUS patients for up to 3 years, the rate of paroxysmal AFib was as high as 41.4%[Kitsiou, 2021]
    • use a long-term loop recorder or implantable device
  • vascular risk factor management + lifestyle modifications are also essential

ESUS and anticoagulation

  • randomized trials involving ESUS patients have yielded negative results so far ⇒ anticoagulation is not superior to ASA
  • negative results of NAVIGATE ESUS trial with rivaroxaban 15 mg vs. ASA 100mg [Hart, 2018]
    • however, a positive effect of rivaroxaban was found in the subgroup with moderate and severe left atrial enlargement – patients with left atrial diameter > 4.6 cm had 1.7% vs. 6.5%/year stroke risk (rivaroxaban vs. aspirin) [Healey, 2019]
  • neutral results of the RESPECT-ESUS trial (ASA vs. dabigatran 110/150 mg) [Diener, 2019]
  • negative results with apixaban in selected patients
    • ARCADIA apixaban vs. ASA in patients with atriopathy (characterized by higher ECG voltages, left atrial enlargement, and NT-proBNP>250 pg/L) – apixaban did not significantly reduce recurrent stroke risk compared with aspirin
    • ATTICUS apixaban vs. ASA in patients with additional risk factors (left atrial size > 45 mm, spontaneous echo contrast in the LAA, LAA flow velocity ≤ 0.2 m/s, CHA2DS2-VASc score ≥ 4, or PFO)

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Cryptogenic stroke