This study investigated the changes before and after unilateral combined bypass surgery in pediatric MMD patients. We found that combined surgical revascularization effectively increased the rCBF and decreased the moyamoya vessel grade of the OP side. Furthermore, within short-term follow-up, the rCBF on the non-OP side changed minimally, but the Suzuki stage or moyamoya vessel grade deteriorated in 40.7% of the patients. The radiological progression preceded the rCBF decreasing.
The radiological progression pace is relatively slow in MMD patients over the course of their natural history. Ge et al.[23] retrospectively investigated 110 MMD patients and reported that only five (4.5%) cases progressed in Suzuki stage or PCA collaterals during a median follow-up of six months. Among the five cases, only one was pediatric and had progressed after 29 months of follow-up. Based on the results of Lee et al. [24], contralateral disease progression, as assessed by newly developed stenosis at the terminal ICA, the proximal MCA, or anterior cerebral artery, could be evident in 43 MMD patients (29.5%) with unilateral stenosis after a mean follow-up of 4.3 ± 2.4 years. They also found pediatric patients were more likely to develop contralateral progression. On the relationship between surgical treatment and MMD progression, Park et al. conducted a retrospective study focusing on pediatric MMD patients treated by indirect revascularization and found that 20 of 34 patients (58.8%) had contralateral progression following surgery, whereas the mean follow-up duration of their cohort was long with 35.3 months (IQR, 18.1–100 months) [25]. Our previous studies have demonstrated that unilateral combined bypass surgery was associated with rapid radiological progression of contralateral vessels at short-term follow-up, resulting in rapid aggravation of main trunk stenosis and decreased cerebral blood flow on the non-OP side [11, 13]. In the current study, we identified contralateral radiological progression in 11 pediatric patients (40.7%) within 3 to 6 months following unilateral combined bypass. As compared to previous literature, the pace of progress was rapid. Considering the more rapid progression in our short-term compared to long-term follow-up, there is a strong possibility that combined cerebral revascularization plays a significant role in MMD progression. On the non-OP side, combined revascularization might have different effects than indirect revascularization.
The factors affecting MMD progression have received widespread attention [25–27]. Younger age was reported to be associated with faster progression [11, 24]. Our study found that the earlier Suzuki stage on the non-OP side was associated with contralateral rapid progression. Based on those findings, we speculate that two mechanisms may contribute to such progression. Firstly, the initial stage of the Suzuki stage should be viewed as a starting point of disease with greater potential for progression. According to Kim et al.[28], cortical microvascularization (CM) was observed even at the very early stage of MMD before the main trunk occlusion, showing that active neovascularization is occurring at this stage. In our cohort, all 11 patients with non-OP side progression showed an increase in moyamoya vessel grade. Only five of these patients progressed in the Suzuki stage. CM and moyamoya vessels represent angiogenesis, which refers to the remodeling of an existing artery to increase its luminal diameter in response to maintaining cerebral blood flow. This capacity for vascular change and remodeling might be powerful at the early stage of the disease. Another mechanism involves more molecular signals. Nitric oxide (NO) relaxes smooth muscle cells and reduces the muscular tone of arterial walls [29]. Suzuki et al. reported successful combined bypass surgery suppressed NO release from endothelium [30]. In addition, Noda et al. found that the concentrations of NO metabolites were significantly reduced after the second combined bypass surgery compared to the first operation [31]. Therefore, combined revascularization on one side could increase the tension of the arterial wall on the contralateral side, deteriorating the arterial stenosis by NO-mediated vasodilation and control of cerebral circulation. Other cytokines, such as RNF213 and CRABP-I, may also participate in this process, but their roles in disease progression require future studies to explore [32, 33].
Our study has some limitations. Firstly, it was a retrospective study conducted at a single center. There are inherent biases associated with a retrospective study, as well as selection bias. Given the small sample size, multivariate analysis was not possible, which warrants to further study. Secondly, more detailed serial DSA studies could not be performed in pediatric patients. To demonstrate the changes in the main trunk and moyamoya vessels, superselective serial DSA may be more proper. Thirdly, we used published data that included both adult and pediatric patients and selected the data of pediatric ones for comparison, as the natural history of MMD progression in pediatric patients was less clear.