Introduction

Moyamoya disease (MMD), also known as spontaneous steno-occlusion of the circle of Willis, is a cerebrovascular disease characterized by slow progressive narrowing leading to occlusion of the bilateral terminus of the internal carotid arteries and/or the initial segments of the anterior and middle cerebral arteries, with the appearance of compensatory abnormal vascular networks at the base of the brain [1,2]. The annual incidence of moyamoya disease ranges from 0.5 to 1.5 per 100,000 individuals in East Asian nations, while it is as low as 0.1 per 100,000 in other regions [3]. Due to the unclear pathogenesis of MMD, there is a current absence of specific pharmacological treatments available for MMD. Antiplatelet therapy is one of the most promising treatment options but randomized controlled trials are still necessary to confirm its effectiveness [4]. Thus, surgical procedures for intracranial and extracranial blood flow reconstruction remain the mainstay of clinical intervention for MMD [5].

Despite several studies addressing the efficacy of bypass surgery in mitigating recurrent strokes among adult moyamoya patients, the benefits of these interventions remain controversial [6–8]. The notion that revascularization procedures effectively enhance cerebral blood flow, thereby reducing the incidence of ischemic strokes, has been widely accepted by most scholars. However, a recent review denoted that surgery is not superior to medical management in patients presenting with cerebral ischemia [9]. JAM trial is the only single randomized control study of MMD, that compared revascularization with conservative treatment in patients with hemorrhagic MMD, showing substantially fewer recurrent hemorrhages in surgical patients [10]. The trial was criticized for unmasked outcome evaluation, low enrollment, and no postoperative complication which was too good to be true [11]. Several meta-analyses have been performed to elucidate the beneficial effects of revascularization surgery [12–16]. The limitations of these meta-analyses were pointed out by Moussouttas et al. [9], such as no specific data regarding the outcome types of hemorrhagic or ischemic events, and no mortality information. Moreover, the follow-up period varied greatly for each included study of meta-analysis, making outcome assessments difficult to compare.

It was concluded that the natural history of hemorrhagic MMD remains dynamic with cumulative risk of rebleeding being 7.8% at 5 years, 22.6% at 10 years, and 35.9% at 15 years, requiring long-term follow-up to fully understand the risk of rebleeding [17]. Similarly, Morioka et al. [18] reported that there is a higher risk of rebleeding in the first 6 years after initial hemorrhage. In 2016, a meta-analysis attempted to determine the best surgical management for adults with MMD by comparing long-term outcomes but with just more than 30 days of follow-up after surgery among direct, indirect, and combined bypass types [19]. In 2018, a long-term good functional outcome rate of 82% was achieved after revascularization in a meta-analysis where the long-term follow-up time was defined as at least 6 months [16]. Most of the existing systematic reviews defined events after 30 days or 6 months as late outcomes, but long-term retrospective studies have demonstrated that the incidence of adverse events is gradually increasing until 36 months after surgery, and some studies have reported that different surgical methods appear late crossovers on the bleeding free survival curve at 36 months after surgery. The considerable heterogeneity and inconsistent definitions of long-term outcomes may result in a lack of overall credibility in these findings. In a 10-year follow-up study, investigators observed a higher frequency of rebleeding cases during the 5–10 years after indirect revascularization for adult hemorrhagic moyamoya disease compared with the first 5 years after the procedure [20]. The long-term follow-up results after combined revascularization surgery also indicated a decreasing trend in cerebral blood flow in the territory of the middle cerebral artery (MCA) in the operated hemispheres as the follow-up period progresses [21]. Overall, the current results strongly suggest that the evaluation of postoperative outcomes following revascularization surgery should be extended to 5 years or even longer to reflect the long-term benefits or risks for patients. However, there is still insufficient evidence regarding long-term follow-up.

We design to conduct a systematic review and meta-analysis to clarify the long-term angiographic and functional outcomes with at least 5 years of follow-up under the uniform outcome measurement tools. Direct, indirect, and combined bypasses will be compared regarding the specific hemorrhagic or ischemic events or mortality rate in adults with MMD. Accordingly, we aim to summarize existing knowledge regarding the effect of surgery on MMD outcomes and guide the selection of surgical approaches to achieve long-term comprehensive clinical outcomes for patients.

This systematic review aims to assess the postoperative long-term outcomes after revascularization surgery of MMD in adult patients (aged 18 or older, with no limitations on sex and race). We seek to answer the following questions:

What is the overall incidence of angiographic and functional outcomes among adult patients who underwent revascularization surgery of MMD in the postoperative long-term period?

Is there a trend in the incidence of adverse events after surgery over time or in different regions of the world?

What is the relevance between revascularization bypass types and postoperative long-term adverse events among adult patients with MMD, and how to determine the best surgical management for adults with MMD?

Materials and methods

Our systematic review and meta-analysis protocol follows the PRISMA-P guidelines (S1 Table) [22]. This protocol has been registered on the PROSPERO (registration number ID: CRD42024550222). Since this investigation will not involve disclosure of patient information, ethics approval is waived. The PRISMA flow diagram will be used to record every step of the review process (Fig 1).

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Fig 1. PRISMA flow diagram.

https://doi.org/10.1371/journal.pone.0318370.g001

Search strategies

We will search the following five electronic databases: PubMed, Cochrane Library, MEDLINE Ovid, Embase Ovid, and Web of Science. The literature search will include studies published from the inception of the database to the date of the commencement of the review. Table 1 shows the initial draft search strategy for PubMed. The search strategies for other databases are shown in S1 Appendix. In addition, we will use the Cited Reference Search within Web of Science to check the bibliographies of included studies and any relevant systemic reviews for further references to relevant trials and search Google Scholar (scholar.google.co.uk/) to forward-track relevant references. If trial reports are unclear, we will contact the original authors for clarification and further data.

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Table 1. Search strategy for PubMed.

https://doi.org/10.1371/journal.pone.0318370.t001

Inclusion criteria.

1. Patients with MMD older than 18 years (the diagnostic criteria of MMD must be consistent with that of the original literature RCPTSOCW 2012 [5]);
2. Patients who underwent revascularization surgery either by direct bypass, indirect bypass, or combined bypass;
3. Articles reporting prespecified perioperative long-term outcomes after surgery at least more than 5 years;
4. Data should involve estimates of odds ratio (OR), relative risk (RR), or hazard ratio (HR) with 95%confidence interval (CI);
5. Reported in English or Chinese

Exclusion criteria.

1. It was an editorial, a review, a case report, or a cross-sectional study;
2. Did not separate pediatric from adult patients;
3. Did not report our outcomes of interest;
4. Studies lacking specific data for adult group or presenting data is difficult to extract (e.g., presented by line charts);
5. The enrolled patients had other intracranial diseases;
6. MMD was managed conservatively.

The results of the literature search will be imported into an EndNote V.X9.3.3 database, and duplicates will be removed. We will next establish several independent groups for each selecting stage in the EndNote database. Two independent investigators will screen the literatures in two stages. At first, they will review the titles and abstracts retrieved from database searches to evaluate all studies that meet the inclusion criteria. Next, they will retrieve the full-text articles for the remaining references and review authors will independently screen the full-text articles, identify studies for inclusion, and identify and record reasons for exclusion of the ineligible studies. All discrepancies will be resolved by consultation with a third investigator. For studies that share the same data source, we will prioritize studies with larger sample size and longer study durations in the meta-analysis.

Discussion

MMD remains a disease of low incidence, especially in Western countries. There are huge heterogeneities regarding the age, population, clinical presentation, and possible prognosis between western and eastern regions [4]. In addition, surgical modality of revascularization varied across different medical centers with inconsistent efficacy reported. Therefore, it is quite urgent but difficult to perform prospective or even randomized control studies to illustrate the best treatment.

The long-term treatment efficacy of bypass surgery depends on the hemodynamic change and bypass geometry. Computational fluid dynamics (CFD) simulation is a simple, low-cost, noninvasive tool in evaluating the efficacy of STA-MCA bypass from hemodynamic perspectives [24]. It was reported that bypass vessel remodeling occurred, resulting in an increased driving pressure and greater blood flow through the bypass after surgery in most cases [25]. Occasionally, bypass geometry variations, such as tortuosity and stenosis in STA, could significantly increase flow resistance, reducing the distal branch flow rate [26]. However, postoperative stenosis of the STA-MCA bypass is not necessarily negative. The postoperative improvement of distal hemodynamic environment can lead to the generation of collaterals, which might take over bypass function in the long term [27]. The efficacy and outcome of revascularization have been investigated in previous meta-analyses. However, to the best of our knowledge, no systematic review was reported to focus on the long-term outcome beyond 5 years follow-up which is crucial in the precise and comprehensive prognostic evaluation as the chronic hemodynamic changes of MMD and the recurrence of hemorrhage or infarction remain versatile after surgery [28]. We believe our data will be of vital importance in future clinical practice and research.

This study has several limitations. First, the pooled analysis will include both prospective and retrospective studies, the resulting bias in the retrospective studies might impact our overall conclusions. In addition, patients’ conditions on admission are not matched among the different groups, which might have biased our results. Besides, indications for revascularization surgeries could not be standardized.

Supporting information

Acknowledgments

We greatly thank Dr. Chuanyuan Tao for his valuable advice on developing this protocol.