Cerebral aneurysms associated with moyamoya disease (MMD) remain a potential hemorrhagic factor, with a reported incidence of 3%-18% [1-3]. Based on the anatomic location, these aneurysms can be broadly classified as major trunk aneurysms located on the circle of Willis and peripheral cerebral aneurysms (PPCAs) originating from the choroidal, lenticulostriate, meningeal, or moyamoya arteries. MMD-associated aneurysms are more prone to bleeding because of their fragile aneurysmal wall and increased hemodynamic stress, which predisposes them to a poor prognosis [4-8].

Considering these risks, prompt and appropriate interventions are required to treat such aneurysms. Direct surgical or endovascular treatment is widely accepted for hemorrhagic aneurysms of the major trunk of the intracranial arteries. However, optimal treatment for ruptured PPCAs remains controversial. Some authors recommend direct treatment, including endovascular embolization or open surgery, whereas others advocate conservative observation or cerebral revascularization because of the tendency for spontaneous regression [2,5-51].

Notably, studies on ruptured PPCA associated with MMD are relatively few, and all of them are small, single-center, retrospective studies and case reports. To the best of our knowledge, there has been no comprehensive literature review on these studies. Consequently, we conducted a systematic review of MMD-related ruptured PPCAs published over the past 40 years to synthesize evidence on the clinical characteristics, treatment strategies, and prognostic factors, with the aim of improving the current understanding of this rare but important clinical entity.

A total of 48 studies with 121 eligible patients were included in this systematic review (Figure 1). The characteristics of these publications are described in Supplementary Table 1. Regarding the bias concern in this systematic review of case reports, a JBI critical appraisal checklist for case reports (Joanna Briggs Institute, Adelaide, Australia; https://synthesismanual.jbi.global) is provided for the included articles (Supplementary Table 2).

MMD-associated PPCA has been rarely reported. Only 121 ruptured PPCAs have been described in patients with MMD in the past 40 years. We hypothesized that these aneurysms may be underestimated in patients with MMD based on the following findings: this lesion often remains undiagnosed unless it ruptures; it tends to be missed by routine brain imaging, especially when the size is small. Therefore, catheter-based cerebral angiography is recommended for the detection of aneurysms, when possible.

The exact mechanisms contributing to the formation, growth, and rupture of such aneurysms have not been clearly elucidated. Several factors may be involved, including pathological vascular architecture, long-term hemodynamic stress, and aneurysm location [5-7,41]. Unilateral MMD is susceptible to the formation of anterior circulation aneurysms on the unaffected side, whereas bilateral MMD is prone to the formation of posterior circulation aneurysms [1]. Under normal circumstances, high Suzuki stages are often associated with uncoordinated distribution of the cerebral circulation and development of collateral compensation in the posterior circulation, thereby predisposing to the PPCA formation owing to the long-term hemodynamic burden on the fragile collateral vessels [1,52,53]. Recent clinical studies suggested the impact of choroidal anastomosis (so-called choroidal channel) as dangerous collaterals with a high bleeding risk among the variety of “periventricular anastomosis” in adult patients with hemorrhagic MMD [52-54]. Based on this observation, PPCAs at choroidal channel are considered to be at a high risk of rupture, which requires prompt management.

In terms of ethnicity, the largest number of participants were from Asia, particularly China, followed by Korea and Japan. Our study revealed that the mean age at diagnosis was 40.8±15.1 years, and there was a higher prevalence in females than in males, which is consistent with the findings of previous studies [55,56]. Compared with SAH in main trunk aneurysms, the most common hemorrhagic type in PPCAs was IVH with or without ICH. Such aneurysms occurred more frequently in the PChA and AChA. Therefore, PPCA should be considered as a potential cause of hemorrhagic MMD, particularly when manifested as IVH with or without ICH, and catheter-based angiography is essential to identify this underestimated but important lesion.

Theoretically, the presence of MMD-associated PPCA represents a potential hemorrhagic risk if not obliterated. Some studies show that hemorrhagic MMD has higher rates of rebleeding (28%-35%) and mortality (7%-10%) [4,5,41,57,58]. The rate of good outcome after the first rupture was 60%, whereas it decreased to 40% after further bleeding [4,57]. Rhim et al. [41] reported that the rate of rebleeding in aneurysm-related hemorrhagic MMD (8/19, 42.1%) was significantly higher than that of aneurysm-unrelated hemorrhagic MMD (13/58, 22.4%); all aneurysmal rebleeding events occurred at least 6 months after the initial hemorrhage. Iwama et al. [59] reported 7 participants with rebleeding at the same site, 4 with MMD-associated aneurysms, and most rebleeding episodes (6/7, 85.7%) were observed within 2 months after the first onset. In the present study, aneurysmal rebleeding occurred in 9.1% of the cases, and the rate of poor outcome was 63.6% among them; in terms of timing, 70% of aneurysmal rebleeding occurred within the first 35 days. Therefore, elimination of such aneurysms to prevent recurrent rupture is plausible but remains controversial. Several authors have preferred to treat this lesion with direct endovascular or surgical intervention, whereas others have opted for revascularization surgery or conservative management, because of its tendency to regress spontaneously [2,5-51,60].

Endovascular embolization is recommended as a safe, feasible, and effective treatment option for most PPCAs in patients with MMD [2,5,7,21,22,24,25,27,28,30,33,37-39,41,43,45,46,51]. Kim et al. [5] reported on a cohort of 8 ruptured PPCAs in MMD cases treated with endovascular therapy, 7 of which were uneventful. Endovascular treatment was attempted in 42 patients and was successful in 35. In contrast to the treatment of main trunk aneurysms, liquid adhesive embolization, rather than coiling with or without a stent-assisted technique, is the preferred option for aneurysms of the collateral vessels. In the cases we identified, 25 (71.4%) of the 35 patients who underwent successful endovascular treatment were treated with n-butyl cyanoacrylate, ethylene-vinyl alcohol copolymer (Onyx), or cyanoacrylate (Glubran). Typically, aneurysms and their adjacent parent arteries are occluded together. Some authors have explained the use of liquid embolic agents for aneurysm obliteration because the lesion and the collateral vessel tend to be small and fragile, and the delivery of the detachable coil or stent might predispose them to rupture or dangerous tearing [5,15]. In addition, accessible selective catheterization is critical to the technical success of embolization because the parent artery is usually thin and tortuous. Our current study showed that 7 (16.7%) of 42 PPCAs could not be embolized because of approach inaccessibility [5,9,26,28,36,39,47].

Direct surgery, such as neck clipping or aneurysm resection, has been considered too risky for the treatment of MMD-associated ruptured PPCAs for the following reasons: these aneurysms are generally small and deep-seated, making them difficult to localize and identify; surgical clipping is difficult to perform in some cases due to the lack of a defined aneurysm neck; these aneurysms are prone to re-rupture with significant morbidity and mortality during intraoperative dissection and retraction, given their fragile characteristics; there is a potential risk of injury to the abnormal, fragile collateral vessels during surgical exposure; patients with MMD might be more susceptible to cerebral ischemia because of the poor reserve capacity of hemodynamics [2,39,40,42]. Under such circumstances, direct surgical repair might be a significant challenge and is not recommended for these aneurysms. Nevertheless, this therapeutic strategy has unique advantages over the other three, including surgical hematoma evacuation and aneurysm acquisition for further histopathological examination. The pathological features of MMD-associated PPCAs remain unclear owing to limited histopathological data and because they are typically considered as pseudoaneurysms based on their anatomic location and tendency for early morphologic change [2,25,48,49,51]. However, in this review, of the 10 PPCAs with available histopathological diagnosis, 6 (60%) were saccular aneurysms and the other 4 (40%) were pseudoaneurysms [1,6,10-12,14,17,18,29].

Cerebral revascularization has been reported as an alternative treatment to eliminate MMD-associated PPCAs [2,15,16,19,31,39,48,49]. Ni et al. [2] treated 13 MMD-related PPCAs with pure revascularization (superficial temporal artery-middle cerebral artery bypass combined with encephalo-duro-myo-synangiosis) because of microcatheter inaccessibility, of which 12 were obliterated and 1 remained stable during the follow-up period. Liu et al. [39] performed bilateral encephalo-duro-arterio-synangiosis to treat 5 pediatric PPCAs, 3 of which regressed spontaneously and the other 2 were stable at follow-up. Here, we observed 27 ruptured PPCAs treated with revascularization, of which 22 disappeared, 4 were stable, and 1 decreased in size. The exact mechanism underlying the spontaneous resolution of this lesion after bypass surgery is currently unknown. However, the reduction of the hemodynamic burden on the aneurysm and its parent artery by bypass surgery explains this phenomenon to some extent [48,49]. In particular, Lee et al. [49] found dynamic changes in diameter associated with altered hemodynamics in the parent artery (from 2.42 mm initially to 5.33 mm and finally to 1.51 mm), which poses a risk of aneurysm rupture. Moreover, there is a potential risk of PPCA formation and rupture if hemodynamic stress is not effectively reduced, even after surgical revascularization, as shown in two reported cases [26,40]. The authors suggested that impaired collateral circulation after bypass could result in aneurysm formation, and diminished collateral circulation during the follow-up period might be a sign of aggravated hemodynamic stress leading to aneurysm formation. Notably, de novo aneurysm formation around the anastomosis site or within the collateral vascular network after revascularization surgery cannot be ignored [61-67]. This postoperative complication has been rarely reported but may be clinically underestimated because it is often asymptomatic and undiagnosed [62]. Regarding the mechanism of aneurysm formation after intracranial anastomotic surgery, the following hypotheses have been proposed: disruption of the internal elastic layer and tunica media of the arterial anastomosis during the revascularization procedure might lead to traumatic aneurysm formation at the suture line; the jet blood flow from the donor arteries could directly impact the artificial T-bifurcation, causing wall stress shear and leading to spindle-like dilatation around the site of anastomosis, predisposing to the aneurysm formation under the influence of increased hemodynamic stress; a patient with MMD with the genetic variant RNF213 c.14576G>A might carry a higher risk of repeated de novo aneurysm formation. The time from bypass surgery to aneurysm diagnosis in the reported cases ranged from 6 months to 20 years, suggesting that aneurysm formation is probably time-dependent [61-67]. Therefore, long-term surveillance after cerebral revascularization seems to be essential.

Conservative therapy was selected as a viable alternative for MMD-related hemorrhagic PPCA in the following situations: high-risk surgical procedures; inaccessible endovascular approach; and the potential tendency of the aneurysm to resolve spontaneously [5,7-9,11-13,17,28,34-36,41,43]. Our review of the literature showed that 33 ruptured PPCAs were treated with conservative observation, of which 22 (66.7%) spontaneously regressed and 2 (6.1%) remained stable. The mean time to aneurysm disappearance was 6.1 months, ranging from 3 weeks to 1 year. Some authors have speculated that cerebral vasospasm and secondary thrombosis might explain the phenomenon of spontaneous aneurysm regression in the setting of conservative treatment [8,36]. Considering that such aneurysms usually originate from small-caliber collateral branches, vasospasm after aneurysmal hemorrhage might lead to the retention of blood flowing into the aneurysm sac, thereby resulting in thrombosis obliteration. In addition, some authors have suggested spontaneous regression as the natural history of pseudoaneurysms [68,69]. Notably, conservatively managed MMD-associated ruptured PPCAs are at a high risk of recurrent hemorrhage, which correlates with high morbidity and mortality. In the present review, we identified 11 cases of aneurysm re-rupture; all rebleeding occurred during the observation period [10,12,14,16,26,32,35,40,47,50]. Most rebleeding events (70%) occurred within the first 35 days after ictus. The rates of rebleeding and the associated poor prognosis in these patients were as high as 26.8% and 63.6%, respectively, suggesting that aggressive intervention should be undertaken to prevent future rupture.

The overall outcomes of these patients were favorable (86.8%). Good outcomes were achieved in 97.1%, 65.4%, 96.3%, and 84.8% of the cases treated with endovascular embolization, direct surgery, cerebral revascularization, and conservative observation, respectively. These results indicate that the therapeutic effect of embolization may be comparable to that of revascularization, all of which are superior to conservative observations. The treatment outcomes of direct open surgery were the worst. However, it should be emphasized that most participants in the open surgery group were treated 15 years ago, when knowledge about this lesion was relatively inadequate and the surgical procedures were potentially more invasive. Studies have reported that the advancement and application of stereotaxy, neuronavigation, and neuroendoscopic techniques have made open surgery safer, more effective, and less invasive [10,23,29,42]. However, the prognostic factors for patients with MMD-associated PPCAs remain unclear. Our review identified the independent risk factors for poor outcomes in these patients, including impaired consciousness and aneurysm rebleeding. Patients with impaired consciousness or aneurysm rebleeding showed an 8.6- and 16.5-fold increased risk of adverse prognosis, respectively, compared with those without symptoms.

This systematic review has several limitations. First, some eligible records may have been excluded because only PubMed was searched. Second, we only included articles published in English; thus, articles from high-incidence regions in other languages, such as Chinese, Japanese, and Korean, were excluded. Third, there is the potential for study heterogeneity, and a statistical bias exists. Fourth, our results were based on retrospective case series and single-case reports, which are considered lower-quality evidence. Fifth, the reliability of our study is weakened by the small sample size. Nevertheless, this review provides preliminary evidence for the selection of appropriate treatment options for such aneurysms.

MMD-associated ruptured PPCAs are more prevalent in females, with a peak age of onset at 41-50 years. These aneurysms most commonly arise from the choroidal arteries and frequently present with IVH with or without ICH. When hemorrhagic MMD is encountered, PPCA should be considered, and catheter-based angiography is essential to identify such lesions. Endovascular intervention or bypass surgery may be a first-line therapeutic option. In certain cases, particularly when urgent hematoma evacuation is required, direct open surgery may be an alternative. However, detailed preoperative planning and intraoperative technical assistance are required to reduce procedure-related complications. Conservative observation should be chosen with caution because of the high risk of aneurysm rebleeding and the associated worse outcomes, unless individuals are deemed unsuitable for surgical or endovascular treatment. The overall outcome seemed to be favorable, and impaired consciousness and aneurysm rebleeding may be independent risk factors for an unfavorable prognosis. We emphasize the importance of personalized treatment plans to balance the benefits and risks. Further studies with larger sample sizes or randomized controlled trials are warranted to facilitate a better understanding of this rare but clinically important condition.