Abstract
Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes. Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative review, we summarize the evidence supporting the potential causal relationship between ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing the causal link between non-stenotic plaques and ESUS and describe biomarkers of potential interest for future research. In support of the causal relationship between ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk features are five times more prevalent in the ipsilateral vs. the contralateral carotid and there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without high-risk features often coexist with other potential etiologies of stroke, notably atrial fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5–9%), and atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to confirm the causal link between non-stenotic plaques and ESUS. There are several ongoing studies exploring whether select protein and RNA biomarkers of plaque progression or vulnerability could facilitate the reclassification of some ESUS as large vessel strokes or help to optimize secondary prevention strategies.
Highlights
Ischemic stroke is considered cryptogenic when no definite cause is identified during the baseline etiological workup [1]
In the subgroup of cryptogenic strokes with complete workup, embolic stroke of unknown source (ESUS) is a clinical construct referring to non-lacunar ischemic strokes of presumable embolic origin despite the absence of any obvious sources of cardiac or arterial embolism (Figure 1) [2]
Because patent foramen ovale (PFO) closure or anticoagulation are not expected to prevent strokes due to large vessel atherosclerosis, trials of PFO closure or anticoagulation in elderly patients with a large PFO should carefully plan subgroup analyses according to the presence of alternative candidate causes of the recurrent stroke, notably an atrial cardiopathy or an ipsilateral non-stenotic carotid plaque that may coexist with PFO [43, 44, 121]
Summary
Ischemic stroke is considered cryptogenic when no definite cause is identified during the baseline etiological workup [1]. Studies of high-risk features have provided evidence of an association between non-stenotic carotid plaques and brain infarction in patients with ESUS, establishing causality remains challenging in most cases.
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