Created 17/12/2021, last revision 11/01/2023

Definition of cryptogenic stroke

  • cryptogenic stroke (CS) = stroke of unknown etiology (a diagnosis of exclusion)
  • CS accounts for 15-40% of strokes  (Yaghi, 2017)
    • some report CS to be more common in younger patients (juvenile strokes) – it accounts for up to 40% of patients < 55y of age  [Bang, 2014] [Meier, 2003], [Putaala, 2009] 
    • in contrast, other studies found lower rates of CS in younger versus older patients
    • results depend on which diagnostic criteria are used (TOAST overestimates the number of patients with stroke of undetermined etiology (TOAST 5), mainly because patients with two or more potential etiologies fall into this group
  • diagnosis of cryptogenic stroke can be made only after a thorough diagnostic evaluation → see here
    • detection of an occult paroxysmal AFib is a priority in older patients (EMBRACE, CRYSTAL AF)
    • detection of PFO is a priority in younger patients
    • search for aortic arch atherosclerosis, atrial cardiopathy, and sub-stenotic atherosclerosis (unstable non-stenotic plaques)
  • the well-defined subtype of CS is Embolic Stroke of Undetermined Source (ESUS)

ESUS (Embolic Stroke of Undetermined Source)

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  • ESUS has a higher risk of recurrence, similar to cardioembolic strokes  Risk of stroke recurrence (Ntaios, 2015) [Ntaios, 2015]
  • suspicion of thromboembolism is supported by the following:
  • ESUS may be caused by unrecognized cardioembolic etiology (i.e., TOAST 2) or 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 those aged < 50 years
    • paroxysmal AFib and atherosclerotic plaques predominate at ages > 50 years
Cryptogenic stroke
  • a diagnosis of ESUS implies that the stroke is embolic in origin (given the non-lacunar attributes of the ischemia)
  • the source of the embolus is unknown despite a minimal standard evaluation
  • although cryptogenic stroke implies that the cause of the origin is unknown, the stroke is not necessarily embolic
  • individuals with ESUS have a cryptogenic stroke, but the converse 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)
  • there is a relatively high recurrence rate in patients with ESUS compared to other stroke subtypes (nearly 20% at 2 years)  (Ntaios, 2015)


  • the mainstay of prevention is antiplatelet therapy
    • ASA/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 (especially paroxysmal AFib), which would be an indication for anticoagulant therapy
    • in a study monitoring ESUS patients for up to 3 years, the detection of paroxysmal AFib was as high as 41.4%[Kitsiou, 2021]
  • vascular risk factor management and lifestyle modifications

ESUS and anticoagulation

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Cryptogenic stroke