In a recent issue of JASE , Huang et al. presented an interesting meta-analysis regarding the diagnostic accuracy of contrast-enhanced ultrasonography (CEUS) for the detection of carotid atherosclerotic intraplaque neovascularization (IPN). Beyond the meta-analysis, which was limited to studies that provided data regarding the sensitivity and specificity of CEUS in the recognition of IPN, the investigators also conducted an extensive review of the available literature, for which they should be congratulated.

Proliferation of vasa vasorum and IPN have been recognized as important factors associated with plaque progression and vulnerability as well as with clinical symptoms. Several methods have been proposed for in vivo imaging and quantification of IPN, but CEUS remains the most widely applied and examined technique. However, as Huang et al. noted, studies using CEUS suffer from both a lack of standardization regarding protocols used for CEUS-assisted identification of IPN and substantial variance in reporting of their findings. Moreover, regarding IPN quantification protocols, a number of limitations are comprehensively summarized by Huang et al. Still, we would like to underline a couple of further issues. First, the dynamic autoregulation of intraplaque microcirculation that might alter the IPN temporal “depiction” under different clinical settings and/or plaque characteristics should not be disregarded. Second, the exact topography of the evaluated plaques may well act as a confounding factor. In particular, when plaques located in the posterior arterial wall are evaluated, microbubbles may produce acoustic shadowing that alters grayscale intensity and therefore image interpretation, a phenomenon known as far-wall pseudoenhancement.

Finally, an issue pinpointed as a limitation by Huang et al. is the identification of the truly culprit plaques in the case of cerebrovascular events. The investigators assumed that in symptomatic patients, the evaluated plaque (under CEUS) should be the culprit one, but this may not be always the case. This is of importance in the presented meta-analysis, because “symptom” has been used as a surrogate for positivity for IPN histologic plaque findings.

Indeed, our group (Vavuranakis et al. ) recently evaluated 14 patients using carotid atherosclerotic plaque scheduled for endarterectomy, using CEUS to assess IPN with a semiautomated protocol. The excised plaques were analyzed histologically and immunochemically. Interestingly, although (1) imaging enhancement in plaque brightness was observed both in stable and unstable plaques and (2) IPN (as assessed by CD34) was denser in unstable plaques, brightness enhancement (under CEUS) correlated with IPN only for stable plaques. This potentially indicates the direction that alternative mechanisms beyond IPN may contribute in imaging plaque enhancement during CEUS (e.g., direct microbubble penetration through plaque fissures). Of note, in our patient population, among eight symptomatic patients, seven unstable and one stable carotid plaque were identified ( P = .005).

Finally, it is worth mentioning that neovascularization within plaque is often described using different terms from those used in the search algorithm of this study (“carotid,” “contrast-enhanced carotid ultrasound,” and “intraplaque neovascularization”). For instance, the terms “neoangiogenesis” and “plaque neovessels” may be found in the literature, whereas the term “vasa vasorum” is frequently used instead of “neovascularization” in many studies examining carotid arteries using CEUS, although vasa vasorum are pathophysiologically different from “neovessels.” It would be interesting to explore whether these search terms can provide additional eligible studies that might strengthen the power of this meta-analysis.

In view of the aforementioned points, we wish to emphasize the diversity of methods in the available literature, the small number of studies, and the lack of adequately sized studies evaluating combined imaging and pathological data. Therefore, until sound interpretation of such data is provided, accurate and precise identification and quantification of IPN by CEUS may just be another unsolved mystery.