Angiographically, the CW is defined as a thin intraluminal filling defect located at the posterior wall of the internal carotid arterial bulb [19, 20]. In our study, the majority of CWs (62.2%) were found in the posterior wall, while some were present in the anterior and side walls. The overall prevalence of CW was 21.0% (299/1422), and out of these CW patients, 27.8% (83/299) experienced symptoms, which is higher than what previous studies have reported [5, 13]. The elevated prevalence of CW can be attributed to several factors. Firstly, our institution is a renowned national neurology research center in China, attracting patients from all over the country who have suspected neurological symptoms and seek medical attention. In addition, our study included individuals who had undergone both carotid CEUS and SWI over an 8-year period, resulting in a narrower inclusion criteria and consequently an increased detection rate.

Consistent with previous studies [14, 18, 21, 22], our results indicated that gender and age differences in the two groups were statistically significant. In the CW group, 57.4% of the participants were women with an average age of 50.61 (± 12.49) years. On the other hand, in the CW with plaque group, only 10.4% were women, with an average age of 63.87 (± 7.65) years. Abnormal hormone levels, potentially caused by endogenous or exogenous estrogen, may contribute to the higher prevalence of CW in women. This hypothesis is supported by a systematic review which found that a majority of female patients had a history of oral contraceptive use [22]. Additionally, plaque formation is a chronic disease that is related to smoking, alcohol, hypertension, and diabetes mellitus; therefore, CW with plaque is more prone to occur in the elderly. Turbulence in the area beneath CW causes decreased blood flow velocity, leading to the formation of high wall shear stress (WSS) at the proximal end of the stenosis. Conversely, blood flow stagnation and low WSS occur at the distal part [23]. The presence of low WSS contributes to the transformation of endothelium cells and affects the inflammatory process [24, 25], ultimately leading to the initiation and progression of atherosclerosis [26]. This intricate process of CW-plaque formation also provides insights into why the disease tends to occur later in life compared to CW alone.

Multi-modular ultrasound assists to differentiate CW and CW with plaque formation. On conventional ultrasound, CW appears as a hypo- or isoechoic shelf-like structure without motion, protruding into the lumen of the carotid artery. In contrast, CW with plaque formation has two distinct ultrasound manifestations. Firstly, the web can grow in a cliff-like structure along the short axis of the plaque, protruding from its surface into the lumen. The web angle in this type can be either acute or obtuse. Secondly, webs can develop parallel to the plaque’s long axis, appearing as a membrane-like structure with a smooth, flat cavity. This contrasts with plaque ulceration, where the cavity lacks a complete membrane-like structure on the surface and usually has an uneven bottom [9, 10]. The formation of the cavity-like structure between the web and plaque is a result of webs that emerge from the vessel wall or plaque surface at various angles [27]. In this case, the CW angle exhibited a reduced magnitude, approaching 0°. CDFI can visualize changes in blood flow patterns, such as swirling blood flow, and estimate the severity of stenosis using hemodynamic parameters. The CEUS manifestations of CW and CW with plaque are quite different. The webs were non-enhancing with filling defects, whereas 87 plaques were classified as grade 1 and 91 plaques were classified as grade 2. The CEUS presentation of CW is associated with its pathological features, unlike plaques, where the main pathology of CW is intimal hyperplasia and fibroplasia [28, 29], while vulnerable plaques can be accompanied by neovascularization [17]. On SMI, thin triangular endoluminal flaws were observed as a specific feature in 97.1% of CW and in 72.7% of CW with plaque. However, in the second type of CW with plaque, a transversal linear defect was presented on the cross-section without the presence of a triangular flaw along the longitudinal plane.

Blood flow stagnation in the CW is believed to contribute to the development of thrombosis and recurrent strokes. The impact of circulatory disturbances on thrombosis has long been debated. High WSS and sudden changes in blood flow encourage platelet aggregation and vasoconstriction. Conversely, stagnation of blood flow and a reduction in WSS become more noticeable after stenosis occurs. Theoretically, a large CW angle generates more turbulence due to the streamlined shape of the artery being better suited to a small CW angle. However, both the CW angle and degree of stenosis affect the increased turbulence intensity (TI) on the downstream side of CW [16]. When the CW angle remains constant, the TI rises with an increase in the stenosis degree. Conversely, when the stenosis rate remains the same, the TI decreases as the CW angle increases [16]. Elevated TI can lead to blood stagnation, thereby raising the risk of thrombosis and causing an ischemic stroke. Our results showed that the web length was a risk factor for luminal stenosis in CW patients, but the correlation between luminal stenosis and symptoms, CW angle and symptoms, and angle and stenosis remains unclear. In fact, unlike the CW with plaque group, most symptomatic CW patients (80%, 12/15) had stenosis of less than 50%. These findings align with a meta-analysis conducted by Zhang [22]. Nevertheless, despite both CW and carotid plaque being stenotic lesions, their blood flow characteristics differ because of variations in the geometry of stenotic lesions [16]. Our study showed that the CW angle in the CW group was smaller than that in the CW with plaque group, and the rate of stenosis was lower; both of these differences were statistically significant, but the symptom difference between the two groups was not. In addition to the geometric differences, plaque eccentricity and ulceration can increase downstream turbulence [24]. Moreover, web and plaque thickness, as well as plaque enhancement, was correlated with stenosis in the CW with plaque group, whereas luminal stenosis and plaque length were risk factors for symptoms. These findings indirectly suggest that there are different underlying mechanisms of stroke in CW patients and CW with plaque patients. Therefore, in future research, the construction of animal CW models and CW with plaque models, as well as the exploration of the similarities and differences between the two based on the stereo-geometric spatial position relationship and hemodynamic changes [19, 30], may help further explain the mechanisms of stroke occurrence caused by CW.

Furthermore, it is claimed that carotid revascularization may be more effective than medical management alone in preventing stroke recurrence in patients with CW [14, 22]. Among these two groups, patients with CW were more likely to choose conservative therapy than patients with CW and plaque. In our follow-up study of 177 patients who received medical management alone, 4.0% (7/177) experienced cerebrovascular events. When considering only the CW group, a stroke recurrence rate of 18.1% (2/11) was observed in symptomatic CW patients, which is consistent with previous studies [6, 14]. It is worth mentioning that standard medical management alone may not provide sufficient protection for CW patients who have concomitant atrial fibrillation [14]. Therefore, both CEA and CAS may be considered as potentially better secondary stroke prevention strategies for CW patients [6], although further clinical trials are needed to validate the efficacy of these invasive approaches.

Several limitations need to be addressed. Firstly, the study only included patients with CW and CW with plaque who underwent CEUS and SMI examinations. This may introduce patient selection bias and result in an elevated prevalence of CW. Secondly, this study focused on the clinical and multimodal sonographic characteristics of CW and CW with plaques. Unfortunately, no cohorts of subjects with only atherosclerosis plaque were included in this study, making it impossible to compare the findings against plaque without CW subjects. However, this is an exploratory direction for our future research, and external validation is warranted. Furthermore, although 24.1% of participants had CAE, not all specimens could be obtained due to disciplinary collaboration interests and economic costs to the patients. As a result, there is a lack of histological evidence for suspected CW and CW with plaque. Lastly, the short follow-up interval for some participants may underestimate the stroke recurrence rate.

In conclusion, the multimodal ultrasonic and clinical manifestations of CW and CW with plaque are substantially different. CWs typically exhibit iso- or hypoechoic shelf-like structures projecting to the lumen with swirling blood flow on CUS, accompanied by a thin triangular endoluminal defect on the longitudinal plane on SMI, and no enhancement on CEUS. On the other hand, CW with plaque is characterized by membrane-like structures protruding from the plaque surface into the lumen or growing along the long axis of the plaque. The latter is always accompanied by internal cavity. For CW patients, the web length is an independent risk factor for luminal stenosis. However, there is no obvious correlation between CW angle, length, and symptom development. For CW with plaque patients, luminal stenosis and plaque length are risk factors for symptoms.