CTA Plaque-RADS Predicts Ipsilateral Recurrence in Embolic Stroke

Unmasking the Source in Embolic Stroke of Undetermined Source

Embolic stroke of undetermined source (ESUS) remains a diagnostic and therapeutic challenge, representing a subset of ischemic strokes where the source of embolism is not identified despite standard diagnostic protocols. Secondary prevention remains controversial, as a 2024 meta-analysis of 13,970 patients found that direct oral anticoagulants did not significantly reduce recurrent stroke risk compared to aspirin (RR 0.95; 95% CI 0.83, 1.08; p = 0.45) [1]. This lack of overall benefit likely reflects the etiological heterogeneity of the condition, which includes diverse sources such as occult atrial fibrillation and paradoxical embolism through a patent foramen ovale (a persistent opening between the atria that may facilitate the passage of venous thrombi into the systemic circulation) [2, 3]. Recent data indicate that nonstenotic carotid plaques (atherosclerotic lesions that do not meet traditional criteria for high-grade narrowing) with high-risk features are present in 31% of cases ipsilateral to the stroke (95% CI 27, 36%) and may be a primary driver of recurrence [4]. Furthermore, specific high-risk characteristics like ulcerated plaques have been associated with an eightfold increase in the risk of recurrent events (OR 8.2; 95% CI 1.02, 66.07; p = 0.048), highlighting the need for advanced imaging to identify these vulnerable lesions and tailor clinical management [5].

Standardizing the Assessment of Nonstenotic Lesions

To systematically evaluate the role of these lesions, researchers conducted a single-center cohort study to assess a modified Computed Tomography Angiography (CTA)-based Plaque-Reporting and Data System (Plaque-RADS) for characterizing nonstenotic (less than 50%) carotid plaques (NSCPs). The study, which enrolled patients between January 2016 and June 2025, included 512 consecutive patients with ESUS who presented with a unilateral anterior circulation stroke and had undergone a neck CTA. The study population had a median age of 70 years, and 245 of the participants (47.8%) were women. The investigation aimed to determine if this standardized classification could reliably identify high-risk plaques that may be the source of embolism. The modified Plaque-RADS system categorizes NSCPs into four grades based on CTA imaging features. Category 1 signifies a normal vessel wall, and Category 2 includes plaques with a maximum wall thickness (MWT) of less than 3 mm. Higher-risk features define the subsequent categories: Category 3 includes plaques with an MWT of 3 mm or greater (subtypes 3ab) or the presence of ulceration (subtype 3c), while Category 4 is reserved for plaques with evidence of intraplaque hemorrhage (subtype 4a) or an intraluminal thrombus (subtype 4c). For the analysis, patients were stratified based on the presence of ipsilateral high-risk plaques (Plaque-RADS categories 3-4) versus low-risk plaques (categories 1-2). Critically for clinical application, the scoring system proved highly reproducible; inter-rater agreement for the CTA-based Plaque-RADS was excellent, with a Cohen κ of 0.83 (p < 0.001), a statistical measure indicating that different clinicians reached the same classification with high consistency.

Clinical Associations and Competing Embolic Sources

Applying the Plaque-RADS classification to the 512-patient cohort, the researchers found that 109 individuals (21.3%) had high-risk plaques (categories 3-4) in the carotid artery ipsilateral to their stroke, while the remaining 403 (78.7%) had low-risk scores. The analysis revealed a strong spatial association between these high-risk lesions and the clinical event. High-risk Plaque-RADS scores were significantly more frequent on the side of the stroke than on the contralateral side (21.3% vs 11.9%). After adjusting for potential confounders, the odds of finding a high-risk plaque on the ipsilateral side were more than two and a half times greater (adjusted odds ratio [aOR] 2.65, 95% CI 1.73-4.06, p < 0.001). This finding suggests that these plaques are not merely incidental atherosclerotic markers but are anatomically linked to the index stroke. Further analysis reinforced the idea that high-risk nonstenotic plaques may represent a distinct causal pathway within the heterogeneous ESUS population. The presence of an ipsilateral high-risk plaque was inversely associated with several well-established cardioembolic sources. For instance, patients with high-risk plaques were less likely to have coexisting atrial cardiopathy (34.9% vs 39.2%; aOR 0.59, 95% CI 0.36-0.96, p = 0.036), which refers to structural or functional changes in the left atrium that predispose to thrombus formation. The association was even more pronounced for paradoxical embolism, as the prevalence of a high-risk patent foramen ovale was substantially lower in the high-risk plaque group compared to the low-risk group (2.7% vs 21.8%; aOR 0.14, 95% CI 0.03-0.60, p = 0.008). Similarly, the rate of atrial fibrillation detected during follow-up after the initial stroke was significantly lower among patients with ipsilateral high-risk plaques (8.4% vs 17.5%; adjusted subdistribution hazard ratio [aSHR] 0.46, 95% CI 0.23-0.95, p = 0.037). These inverse relationships suggest that when a high-risk nonstenotic plaque is identified, it is less likely that a competing cardioembolic source is the true culprit, helping to refine the differential diagnosis in ESUS.

Predicting Recurrence and Refining Secondary Prevention

Longitudinal analysis of the cohort revealed that overall stroke recurrence did not significantly differ between the high-risk and low-risk groups during the follow-up period. However, a more granular assessment of stroke laterality demonstrated that the Plaque-RADS score is a potent predictor of site-specific events. Ipsilateral high-risk Plaque-RADS scores were significantly associated with an increased risk of ipsilateral stroke recurrence, with events occurring in 11.2% of patients in the high-risk group compared to 3.0% in the low-risk group. This represents a more than threefold increase in risk, reflected by an adjusted subdistribution hazard ratio (aSHR) of 3.19 (95% CI 1.15-8.83, p = 0.026). The use of an aSHR, a statistical method that accounts for competing risks such as death during the follow-up period, strengthens the association between these specific plaque features and recurrent local embolic events. The clinical utility of the CTA-based Plaque-RADS lies in its ability to be reliably applied in routine practice to categorize nonstenotic carotid plaques. By identifying a subgroup where the stroke is anatomically linked to a high-risk plaque rather than a cardioembolic source, clinicians can better navigate the diagnostic uncertainty inherent in ESUS. These findings support the role of high-risk nonstenotic lesions as a distinct causal mechanism, suggesting that these patients may require different secondary prevention strategies than those with suspected occult arrhythmias. The researchers emphasize that the increased risk of ipsilateral recurrence in this population underscores the need for randomized controlled trials to determine if targeted interventions, such as intensified antithrombotic or lipid-lowering therapies, can improve outcomes for this high-risk subgroup.

References

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2. Joglar JA, Chung MK, Armbruster AL, et al. 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2023. doi:10.1161/cir.0000000000001193

3. Mas J, Arquizan C, Lamy C, et al. Recurrent Cerebrovascular Events Associated with Patent Foramen Ovale, Atrial Septal Aneurysm, or Both. New England Journal of Medicine. 2001. doi:10.1056/nejmoa011503

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5. Jayyusi F, AlBarakat MM, Al-Rousan HH, et al. The Efficacy of Medical Interventions for Free-Floating Thrombus in Cerebrovascular Events: A Systematic Review. Brain Sciences. 2024. doi:10.3390/brainsci14080801