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Embolic Stroke of Undetermined Source and Symptomatic Nonstenotic Carotid Disease.

The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria have been published in 1993 (Table 1), and they are the most commonly used criteria to classify stroke etiology. Embolic stroke of undetermined source (ESUS), often called cryptogenic stroke, is a diagnosis of exclusion that accounts for 9% to 25% of all ischemic strokes. The average recurrence rate of ESUS is 4.5% per year, despite prophylactic treatment with antithrombotic agents. With improved cardiac imaging and prolonged monitoring for arrhythmia, it has been recognized that a substantial number of ESUS cases might actually be better classified elsewhere such as within the cardioembolic strokes due to covert atrial fibrillation or as paradoxical emboli due to patent foramen ovale. Clot composition of thrombectomy specimens shows a high platelet content in many cryptogenic patients which suggests that unrecognized arteriogenic causes are also common. According to TOAST, the definition of large artery atherosclerosis strokes is based on the degree of stenosis—only patients with carotid or other extracranial/intracranial lesions >50% stenosis according to the NASCET (North American Symptomatic Carotid Endarterectomy Trial) criteria are included in this definition. However, numerous studies describe the association of certain plaque characteristics, such as intraplaque hemorrhage and plaque thickness with strokes in general and ESUS in particular, regardless of the degree of stenosis (Table 2). Rothwell et al showed that plaque surface irregularity on angiography is strongly associated with an increase in ipsilateral stroke risk irrespective of the stenosis degree. It has also been shown that nonstenotic carotid plaques are much more common ipsilateral to the side of stroke in patients with ESUS. These findings suggest that nonstenotic carotid disease might play a role in stroke etiology (symptomatic nonstenotic carotid disease [SyNC]) We recently conducted a survey among 198 stroke neurointerventionalists from 44 countries. Participants were presented a case-scenario with multiple diffusion-restricted lesions on diffusion-weighted magnetic resonance imaging in the left middle cerebral artery territory and left-sided nonstenotic carotid plaques of varying morphology. The patient’s stroke workup was otherwise negative. Participants were asked whether they think that the nonstenotic carotid plaque could be a possible source of the strokes (ie, whether these patients could be SyNC cases). The results for the different nonstenotic lesions are summarized in Figure 1. Although there is compelling evidence for a link between nonstenotic carotid plaques and stroke, it is currently hard to pinpoint a definition of SyNC: Which imaging features should be mentioned in such a definition? Does the degree of stenosis play a role at all? Should the definition of SYNC require ipsilateral strokes confirmed on imaging or are clinical symptoms consistent with acute stroke or transient ischemic attack sufficient? It is possible that such a definition of SYNC would vary based on the imaging modality used, and it might evolve over time as more data on the natural history of nonstenotic carotid plaques become available. However, we think that there is an urgent need for such a definition—otherwise, patients with SyNC will continue to be classified as ESUS, and this would preclude any targeted secondary stroke prevention strategies. Thus, we suggest the following provisional working definition of SyNC (Table 3). Based on imaging findings and the presence/absence of other stroke causes, this classification allows for stratification into definite, probable, and possible SyNC. Exemplary cases of probable and definite SyNC are shown in Figures 2 and 3. As more and more studies focus on SyNC as a potential source of stroke, the natural history of nonstenotic carotid plaques will be better understood. While it is important to define management strategies for SyNC, unsystematic treatment that is not backed up by sufficient evidence should be avoided. Confirming the link between nonstenotic carotid plaques and strokes, that is, confirming SyNC as a stroke etiology, would be a first step toward targeted treatment and prevention strategies in this patient subgroup, which is currently classified as stroke of undetermined source, and for whom no tailored treatment is available yet.