Multiple intracranial aneurysm (MIA) refers to aneurysms with two or more intracranial vessels, accounting for 15–45% of all intracranial aneurysm patients (1). Aneurysmal rupture is the cause of non-traumatic subarachnoid hemorrhage (SAH) in 85% of cases, with an incidence of 9 per 1,00,000 patients/year (2, 3). SAH patients who are not treated at presentation have a 1-year mortality rate as high as 65% (4). With appropriate treatment, this rate decreases to 18% (5). Both morbidity and mortality rates have been decreasing in conjunction with advances in SAH diagnosis and treatment over time. In 2019, 400,000 people died of SAH worldwide; the highest death rate was in Asia (6).

Treatment decision-making requires a thorough evaluation of the patient's condition and comorbidities, the location of the ruptured aneurysm, and the characteristics of other aneurysms. To date, no standardized protocol for the treatment of SAH patients with multiple intracranial aneurysms has been established. The primary decision with such patients is whether to initially treat only the ruptured aneurysm and then the remaining ones at a later stage or to treat all the aneurysms in a single stage. This study aimed to compare the safety and efficacy of single- and multiple-stage endovascular treatment of patients with multiple intracranial aneurysms who present with aneurysmal rupture.

Patients' characteristics and aneurysm characteristics are summarized in Table 1. In total, the 61 study patients harbored 136 aneurysms. The number of patients with 2, 3, and 4 aneurysms was 50, 8, and 3, respectively. In total, 63 aneurysms were embolized using coils alone (39 were ruptured aneurysms). The stent utilization rate for the responsible aneurysm was higher in the one-staged treatment group (48.4%) than in the staged treatment group (23.3%). In this study, the size of ruptured aneurysms ranged from 2.1 to 14.2 mm (5.0 ± 2.4) and the size of unruptured aneurysms ranged from 1.6 to 10.2 mm (3.7 ± 1.6), with a p-value of < 0.05. The Raymond–Roy classification immediately after treatment was as follows: complete embolization, 97 aneurysms; neck remnant, 32 aneurysms; and sac remnant, seven aneurysms. A total of 30 patients had hypertension. Hunt-Hess grading I to III at admission was as follows: 26 cases (83.9%) in the one-staged treatment group and 24 cases (80%) in the staged treatment group. Specific information on all patients is shown in Table 1.

The prevalence of intracranial aneurysms in adults is ~3.2% (7). There are ~15–22% of patients with unruptured intracranial aneurysms and 20–33% of patients with aneurysmal subarachnoid hemorrhage who harbor multiple IA (3). The study by Mocco et al. (8) reported that aneurysm size and location are significant predictors of rupture. Feng et al. (9) believed that multiple aneurysms do not increase the risk of rupture of individual aneurysms, but the potential cumulative effect may improve the risk of SAH in patients with multiple intracranial aneurysms. In addition, the morbidity and mortality rates of patients with aneurysmal SAH are higher in patients with multiple aneurysms than in those with single intracranial aneurysm (SIA). In patients with multiple intracranial aneurysmal subarachnoid hemorrhages, ~2–5% of ruptured aneurysms cannot be identified, and the prognosis for these patients is usually poor.

Nehls et al. (10) noted that in patients with multiple intracranial aneurysms, the most common location of the aneurysm was the posterior communicating artery, while the anterior communicating artery aneurysm was most likely to rupture. In our study, the most common locations of aneurysms were the internal carotid artery (33.1%), followed by the posterior communicating artery (23.5%) and anterior communicating artery (12.5%), while the most common locations of ruptured aneurysms were posterior communicating artery (29.5%), followed by internal carotid artery (21.3%) and anterior communicating artery (19.7%), similar to the results reported in the literature. Backes et al. (11) reported that ruptured aneurysms were not the largest aneurysms in 29% of patients with multiple intracranial aneurysms. In our study, the size of ruptured aneurysms ranged from 2.1 to 14.2 mm (5.0 ± 2.4), and the size of unruptured aneurysms ranged from 1.6 to 10.2 mm (3.7 ± 1.6), with a p-value of < 0.05. There were 15 patients whose ruptured aneurysm was not their largest aneurysm (24.6%). Therefore, it seems that aneurysm size or aneurysm location alone is not an adequate predictor of aneurysm rupture. In SAH patients with multiple aneurysms, the location of the ruptured aneurysm is generally determined based on the degree and location of hemorrhage on computed tomography and the site of cerebral vasospasm on digital subtraction angiography. A clear pattern of bleeding, such as a clear lateralization, is highly accurate in providing a correct diagnosis of a ruptured intracranial aneurysm (10). However, it can be difficult to identify a ruptured intracranial aneurysm if SAH is diffusely present or if the MIA is located in the same area. Orning et al. (12) claimed that 4.3% of aneurysms were incorrectly identified in patients with multiple intracranial aneurysmal subarachnoid hemorrhage in their institution. Matouk et al. (13) suggested that high-resolution magnetic resonance angiography can be used to determine the location of the ruptured aneurysm in patients with multiple aneurysms and emphasized that the aneurysmal wall in ruptured aneurysms becomes significantly enhanced. The misidentification of ruptured aneurysms may have a significant impact on patient prognosis as patients may experience rebleeding and severe brain injury secondary to rebleeding, which are known predictors of poor outcomes (14, 15). Currently, aneurysm morphology and hemodynamic parameters are also widely used in the identification of ruptured aneurysms. Backes et al. (11) demonstrated that irregular shape and aspect ratio ≥1.3 were significantly associated with aneurysm rupture. Nehls et al. (10) found that irregularities in aneurysm morphology were more indicative of aneurysm rupture than size. Neyazi et al. (16) showed that the aspect ratio (AR) and the maximum relative resistance time (Aneurysm_RRT_max) were significantly associated with the rupture of aneurysms. Hadjiathanasiou et al. (17) found that irregularly shaped aneurysms were more likely to rupture than regularly shaped aneurysms. Tang et al. (18) developed a predictive model by studying intracranial mirror aneurysms and concluded that neck width, bleb formation, and size ratio were independent risk factors for aneurysm rupture, which yielded good results in a validation cohort. Walther et al. (19) demonstrated that the machine learning approach is better than the PHASES score for rupture prediction of UIAs, particularly for patients in geographically constrained areas.

In SAH patients with multiple aneurysms, the ruptured aneurysm should be treated aggressively and early to prevent further rupture. However, the treatment of unruptured aneurysms is controversial. It has been suggested in the literature that in patients with multiple intracranial aneurysmal subarachnoid hemorrhage, there may be an increased risk of surgical complications when treating unruptured aneurysms in the acute phase (17). In our study, 30 patients opted for staged treatment, and only one hemorrhagic stroke occurred. Li et al. (20) reported that one-stage treatment was safe regardless of whether the multiple aneurysms were in the acute phase of bleeding. In our study, compared to the staged treatment group, stroke complications were higher in the one-stage treatment group, but there was no statistical difference between the two groups (p > 0.05). Since the annual rupture rate of unruptured intracranial aneurysms is ~1.9% (21), some experts suggested that treating all intracranial aneurysms in one stage would not only reduce the risk of aneurysm rupture but also save patients the cost of treatment. Cheong et al. (22) analyzed over 300 cases of multiple aneurysms and found that the rate of rupture of previously unruptured aneurysms in patients with a history of SAH ranged from 0.28 to 1.63%. In addition, Hino et al. treated 76 cases of multiple aneurysms, and four of the six patients with incorrectly identified ruptured aneurysms had postoperative rebleeding (14). These results support the use of one-stage embolization for multiple aneurysms to prevent problems caused by untreated aneurysm rupture and misidentification of ruptured aneurysms. In our study, one patient was not treated promptly for an unruptured aneurysm and had a rebleeding event at follow-up. In addition, 31 patients in our center were not actively treated for the remaining aneurysms after treating only the ruptured aneurysm in phase I. They chose to follow up on unruptured aneurysms, which are still at a potential risk of rupture.

In the cases of multiple intracranial aneurysmal subarachnoid hemorrhage, both one-stage treatment and staged treatment have their advantages. For the one-stage treatment group, first, the rupture of untreated unruptured aneurysms is avoided. Second, it reduces the financial burden on the patient. One-stage procedures can provide considerable cost savings. One-stage endovascular treatment of multiple intracranial aneurysms avoids repeated general anesthesia and groin punctures compared to staged treatment. Third, it eliminates patient concern and anxiety regarding the rupture of untreated aneurysms. In our study, 10 complications occurred in the one-stage treatment group, including one SAH related to the recurrence of an embolized aneurysm using coils alone. One patient experienced thromboembolism in a central retinal artery branch. This was probably because the procedure was long and saline was not continuously infused through the introducer catheter. One patient developed a cerebral infarction 7 months after all aneurysms were treated. Multiple-stage treatment can also have advantages. First, the use of dual antiplatelet therapy in the acute post-SAH period is avoided. For the staged treatment group, we prefer to embolize the ruptured aneurysm using coiling alone in a first-stage procedure in order to avoid the use of stents (except for special types of aneurysms such as blood blister aneurysms, dissecting aneurysms, or wide neck aneurysms). Incidence rates of bleeding and ischemic complications are high in aneurysmal SAH patients who undergo stent-assisted coil embolization (23–25). Nagahama et al. (26) concluded that dual antiplatelet therapy in aneurysmal SAH patients reduces the incidence of cerebral vasospasm and delayed cerebral ischemia without increasing the risk of hemorrhagic complications. In our study, the utilization rate of stents was higher in the one-stage treatment group than in the staged treatment group for ruptured aneurysms (P < 0.05); however, for unruptured aneurysms, the utilization rate of stents was higher in the staged treatment group (P < 0.05) than in the one-stage treatment group due to our preference for stent-assisted coil embolization of aneurysms in the second stage of treatment to prevent coil dislodgement into the parent artery and to reduce the recurrence of the aneurysm. In addition, there are other treatment strategies for patients with aneurysmal SAH. Waldau et al. (27) prevented acute rebleeding by embolizing only the apex of the ruptured aneurysm in a first-stage procedure; complete embolization was performed in a second procedure. They concluded that this protocol yielded good clinical outcomes. For wide-necked aneurysms, this strategy can be considered when stent placement is contraindicated or undesirable. Second, the procedure time when treating only the ruptured aneurysm is decreased. Longer procedure time is associated with a higher incidence of ischemic and/or hemorrhagic complications. Moreover, critically ill patients often have difficulty tolerating a long procedure. In our study, five complications occurred in the multiple-stage group. One was SAH caused by the rupture of an untreated aneurysm.

Jeon et al. (28) reported on a clinical study of 167 patients (418 aneurysms in total) treated in one session. Post-operative DSA showed complete occlusion of 186 (51.8%) aneurysms. Li et al. (20) reported their experience of one-stage treatment in 33 patients (72 aneurysms). The Raymond–Roy classification immediately after treatment was as follows: complete embolization, 39 aneurysms; neck remnant, 27 aneurysms; and sac remnant, six aneurysms. In our study, the Raymond–Roy classification immediately after treatment was as follows: complete embolization, 97 aneurysms; neck remnant, 32 aneurysms; and sac remnant, seven aneurysms. In addition, given the rapid development of interventional techniques and materials, specific techniques have emerged for the treatment of specific MIAs. For adjacent ruptured multiple aneurysms, Peng et al. (29) reported that single LVIS bridging was effective and feasible in a one-stage procedure. For multiple wide carotid aneurysms located at the same site in the ipsilateral internal carotid artery, simultaneous embolization of both aneurysms with only one stent is technically feasible and economical (30).

In aneurysmal SAH patients with multiple aneurysms, patient condition, aneurysm location, size, neck width, and parent artery condition should be fully evaluated before selecting a treatment strategy. When treating only the ruptured aneurysm in a patient in whom multiple-stage treatment is planned, the rupture risk of the untreated aneurysm(s) should be fully assessed. Morphological and hemodynamic parameters can be used as indicators to assess the risk of rupture, such as maximum aneurysm diameter, aspect ratio, size ratio, wall shear stress (WSS), and oscillatory shear index (OSI), which have all been shown to have a correlation with aneurysm rupture (31–33).

There are many shortcomings in this study. (1) The sample was small and further validation with a larger sample is still needed. (2) The treatment span is long and the treatment concept may have changed due to the rapid development of endovascular intervention and material science. (3) Treatment selection bias existed. When the responsible aneurysm cannot be identified or both aneurysms are at high risk of rupture, we can only choose to treat all aneurysms in one stage.

Aneurysmal SAH in patients with multiple aneurysms is a difficult clinical problem. The ruptured aneurysm should be determined and aggressively treated. Bleeding risk should be assessed in the unruptured aneurysms before proceeding with individualized treatment. Both single- and multiple-stage endovascular treatment is safe and effective in aneurysmal subarachnoid hemorrhage patients who harbor multiple aneurysms. The staged treatment group had fewer complications than the one-stage treatment group but their aneurysm recurrence rate was significantly higher. To balance the risks of stent thrombosis and antiplatelet agent-induced hemorrhage, we typically embolize the ruptured aneurysm using coiling alone in a first-stage procedure followed by treatment of any remaining aneurysms in a later stage when the patient's condition allows. However, it is necessary to enroll a larger population to define the treatment efficacy of the two groups.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

HL: research design. GZ, WZ, HC, and YS: performed research. CM and LM: data analysis and interpretation. GZ and ZL: manuscript preparation. All authors contributed to the article and approved the submitted version.