The contralateral progression in a cohort of Chinese adult patients with unilateral moyamoya disease after revascularization: a single-center long-term retrospective study

Moyamoya disease (MMD) is a chronic cerebrovascular occlusive disease that is characterized by developing stenosis or occlusion at the distal internal carotid artery (ICA) and/or the initial anterior cerebral artery (ACA) and middle cerebral artery (MCA), complemented with the formation of intensive moyamoya-like vessels [23]. The typical MMD was defined as moyamoya-specific angiographic changes in bilateral hemispheres [6]. However, MMD can be considered “unilateral” if typical MMD angiographic changes are observed on one side, while normal angiography on the contralateral side [15, 17]. The annual incidence of bilateral MMD and unilateral MMD is respectively 1.13/100,000 and 0.23/100,000 in Japan [7]. The age distribution of MMD is significantly bimodal, with a moderate peak in the first decade of life and a major peak at 35–45 years of age [3]. This brings about essential questions: Is adult MMD a continuum of pediatric MMD? Does unilateral MMD, which is more common in adults, progress to bilateral MMD [15]? Previous studies had mainly focused on the contralateral progression changes in pediatric MMD patients [20, 21], while large series concerning the progression from adult unilateral MMD to bilateral lesions, especially in those with Chinese ethnic background, were rare [14, 16]. Up to now, there were only 14 clinical studies regarding the unilateral MMD processed to bilateral lesions [8, 9, 11‐16, 18‐21, 24, 26] (6 from South Korea, 6 from Japan, 1 from the USA, 1 from China). The sample size of unilateral MMD patients in all studies was relatively small (< 70), except the latest two (> 100) [18, 26].

The present study described the clinical features in a cohort of Chinese adult patients with unilateral MMD after revascularization from our hospital and tried to clarify the characteristics of contralateral progression in these patients.

Unilateral MMD had been considered “probable” MMD to distinguish it from the “defined” bilateral MMD. To avoid possible misunderstandings, the term “unilateral MMD” had been proposed in the guideline for MMD in 2011 [17]. Same genetic defects such as the RNF213 mutation might result in different phenotypes of unilateral or bilateral MMD [2]. However, up to now, it is still not clear whether there is a certain degree of difference in etiology and natural history between the unilateral and the usual bilateral MMD. Even so, the unilateral MMD might be a suitable model to examine the pathogenetic process of MMD, because the bilateral MMD exhibits complex and ambiguous pathological findings that do not allow identification of cause versus effect [18]. In order to accurately analyze the progression of the unilateral MMD, MMS was excluded in our study because the MMS-associated diseases such as sickle cell disease, Graves’ disease (GD), and Down syndrome [1, 5] might have positive or negative effects on the angiographic and symptomatic progression. For example, Chen et al. [5] observed that the disease progression was more frequent in MMS patients with GD than that in patients without GD during the follow-up period, especially in unilateral disease.

Unilateral MMD was reported more common in females [7]. In our study, the female–male ratio was approximately 1.5:1, which was consistent with previous studies. Unilateral MMD was frequently reported to develop into bilateral lesions in pediatric patients [9]. The similar phenomenon was rarely reported in adult patients [8], and the progress rate of unilateral MMD to bilateral MMD was varied in previous studies. According to our literature review, 2 studies [15, 16] only focused on adult patients (progress rates were 17.8% and 36.4%, respectively), while 6 studies [9, 11, 20, 21, 24, 26] only focused on pediatric patients. The median progress rate in previous studies was 29.01% (ranges from 0 to 100%). In our study, all included samples were adult unilateral MMD patients. The progress rate was 9.0%, which was lower than previous reports. The reason might be due to the relatively short follow-up duration in our study. In previous studies, the contralateral progression could take 7 to 8 years after initial diagnosis [16]. Therefore, the period between primary diagnosis and disease progression was notably extended in some cases, and long-term follow-up would be crucial for the detection of the complete progression of unilateral MMD. The different definitions of “unilateral MMD” in various studies might also have an impact on the progression rate. For example, some researchers not only considered patients with normal angiographic findings of the contralateral hemisphere as “unilateral,” but also those with mild abnormalities in the contralateral ICA, MCA, or ACA [14, 22], while some others only included patients with a normal angiographic appearance in the contralateral side [24]. In the present study, patients who originally showed contralateral cerebrovascular stenosis on DSA, even very slight, were judged as bilateral MMD and excluded in the patient selection stage. Therefore, during the limited follow-up period, we might observe fewer progressive patients. In addition, the Chinese ethnic background might also contribute to the lower progress rate, since almost all previous reaches were conducted within the Japanese or South Korean population who seem to have more excessive prevalence and incidence of MMD [25]. Indeed, the progress rate in a cohort of Chinese adults and pediatric MMD patients reported by Zhang et al. [26] in 2016 was also relatively lower (16.5%) than most studies.

Several studies have reported various risk factors regarding the contralateral progression, such as the age at diagnosis [24], the contralateral equivocal/mild angiographic stenosis change [14], and the familial history [20]. In our study, although we compared several parameters between the progression group and the non-progression group, no significant risk factor had been found. The lack of significance might be due to the small numbers analyzed, because statistical analysis for risk factors on progression in only 8 patients with progression lacks reference significance; however, other possible explanations are also suggested. On the one hand, there existed contradictory results regarding those reported risk factors among the previous studies. For example, Kelly et al. [14] observed that the initial contralateral ACA angiographic defect represented an indicator of contralateral progression, while Yeon et al. [24] reported no association between the visibility of the contralateral A1 segment and the contralateral progression. On the other hand, the mechanisms of unilateral progression to bilateral MMD might involve genetic and structural complexity such as the dysregulation of endothelial remodeling and vascular cells [4], which need more professional detection methods to explore. Recently, Lee et al. [18] used the time-of-flight (TOF) sequence from brain magnetic resonance imaging (MRI) to measure the endothelial shear stress around the normally appearing terminal ICA and found that the endothelial shear stress was an independent indicator to predict the contralateral progression of unilateral MMD. Another factor, the degree of involvement of the posterior circulation, may also represent a possible “biomarker” for aggression of disease progression [10]. However, there was no posterior circulation involvement in our 8 patients with contralateral progression.

The exploration of how unilateral MMD develops to bilateral MMD could provide indirect but indispensable evidence to understand the MMD as an entirety and progressive diseases. Clinically, the identification of unilateral patients liable to develop bilateral disease also would be of considerable clinical benefit [24]. Understanding the expected process of progression, accompanied with the understanding of specialized risk factors related to the development of the contralateral lesions, would give neurosurgeons a more precise clue to design personalized follow-up strategies [26]. For the unaffected side, instead of prophylactic contralateral revascularization, careful and long-term follow-up was more necessary for the early detection of contralateral progression, so as to timely determine surgical revascularization. Early detection and prevention of ischemic or hemorrhagic stroke were crucial for improving the prognosis of patients.

We found a 9.0% progression rate of unilateral MMD after revascularization develops to bilateral MMD in a cohort of Chinese adult MMD patients. Our results indicated that some of the unilateral MMD were early forms of bilateral MMD rather than a separate condition; therefore, neurosurgeons ought to notice this potential change during the postoperative follow-up period.