ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS

CRYPTOGENIC STROKE

Created 17/12/2021, last revision 30/05/2023

Definition of cryptogenic stroke

cryptogenic stroke (CS) = stroke of unknown etiology (a diagnosis of exclusion)
- TOAST 5 (no strict diagnostic algorithm defined)
- ASCOD (Atherosclerosis, Small Vessel Disease, Cardiac Causes, Other, and Dissection)
- CCS (Causative Classification System)
- CISS
CS accounts for 15-40% of strokes (Yaghi, 2017)
- some report that CS is more common in younger patients (juvenile strokes) – accounting 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 the diagnostic criteria 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 only be made after a thorough diagnostic evaluation → see here
- detection of an occult paroxysmal AFib is a priority in older patients (EMBRACE, CRYSTAL AF)
- PFO detection 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 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 perforators 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 cardioembolic stroke [Ntaios, 2015]
suspicion of thromboembolism is supported by the following:
- MR SWI findings [Gratz, 2014]
- histologic examination of material from mechanical recanalization, where thrombus composition is similar in cardioembolic and ESUS patients [Tobias Boeckh-Behrens, 2019]
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 people < 50 years of age
- paroxysmal AFib and atherosclerotic plaques predominate in those > 50 years of age

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 with ESUS have a cryptogenic stroke, but the reverse is not always true

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 cryptogenic stroke (including ESUS) 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, search rigorously and repeatedly for cardioembolic etiology (especially paroxysmal AFib) that 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 + lifestyle modifications

randomized trials in ESUS patients have been negative so far ⇒ anticoagulation is not better than ASA
negative results of NAVIGATE ESUS trial with rivaroxaban 15 mg vs. ASA 100mg [Hart, 2018]
- although the 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 (higher ECG voltages, left atrial enlargement, NT-proBNP>250 pg/L)
- 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, PFO)