The present study focused on R-ANs that exhibited multiple recurrences requiring repeated retreatment sessions, and is the first to reveal their detailed clinical characteristics. We demonstrated that large size (> 10 mm), and circumferential aneurysmal wall enhancement in VWI were relevant predictive risk factors for the development of R-ANs. We further found that repeated EVTs for R-ANs is a safe and effective treatment strategy. Multiple retreatment sessions achieved aneurysm stabilization and favorable aneurysm obliteration in 85.0% and 65.0% of patients, respectively, with a low complication rate (2.6%).

During the observational period of our study from 2016 to 2022, a total of 1,045 aneurysms were initially treated with EVT. Among them, 124 cases (11.9%) exhibited recurrence or regrowth that requiring retreatment. Previous studies [19, 20] have demonstrated the recanalization rates after EVT ranging from 10% to 33.6%, with retreatment rates between 4.7% and 12.3%,which are in line with our presented result. As for the re-recurrence after retreatment, although reports specifically addressing this issue remain limited [21, 22], the re-recanalization rates appears to be higher than after the initial EVT. In one large retrospective cohort study [21] including aneurysms requiring multiple EVT sessions, the initial recanalization rate was 7.6%, which increased to 48.8% (major recanalization, 25.6%) after the second EVT session. Our results are also showing the same trend, with an initial retreatment rate of 11.9% (124/1,045 aneurysms), and a re-retreatment rate of 20.0% (23/115 aneurysms). This increasing recanalization and retreatment rate after each EVT session may be due to technical and morphological challenges in achieving complete occlusion in certain aneurysms [21, 22]. Additionally, specific clinical factors may impede aneurysm thrombosis and occlusion, necessitating multiple EVT sessions. Furthermore, an unknown biological cascade induced by intra-aneurysm coil packing may contribute to aneurysm regrowth. Nevertheless, the higher incidence of recanalization in aneurysms requiring retreatment highlights the need for rigorous follow-up in such patients.

Several clinical factors have been identified as risk factors for aneurysm recurrence following EVT, including age, size, neck width, location, packing density, and treatment method [8, 10, 17, 18, 23]. However, risk factors for repeat recurrence (i.e. R-AN development), remain poorly studied. Recently, Bae et al. [11] demonstrated that neck width, comorbid polycystic kidney disease, use of stents, and occlusion status after retreatment are independent risk factors for second recurrence. Similarly, another study [21] demonstrated aneurysm location (posterior circulation), size, and occlusion status after retreatment as independent risk factors for re-recurrence. In addition to these findings, we demonstrated that large size (> 10 mm), circumferential aneurysmal wall enhancement on VWI, are relevant and independent risk factors associated with R-AN development.

Among the clinical risk factors identified, this is the first to demonstrate that ‘circumferential wall enhancement on VWI’ are the strong predictor of the development of R-ANs. Recently, wall enhancement of aneurysms on VWI has gained attention as a novel diagnostic biomarker that can evaluate the nature of aneurysms non-invasively, prior to the treatment [8, 14, 16]. Several studies have reported that aneurysmal wall enhancement is associated with aneurysm instability, including higher risk of rupture, growth, and symptomatic presentation [8, 12,13,14,15]. Furthermore, recent study [8, 15] revealed that aneurysmal wall enhancement is also correlated with recurrence after EVT.

Although the precise biological mechanisms underlying aneurysmal wall enhancement remain to be fully elucidated, it is currently hypothesized to reflect inflammatory activity within the aneurysm wall and/or the presence of intraluminal microthrombi [13, 15, 16]. Supporting this notion, previous pathological studies using human specimens and animal models have demonstrated immune cell infiltration, endothelial disruption, and thrombus organization in unstable aneurysms [24, 25]. Moreover, a recent report [26] identified an association between aneurysmal wall enhancement and elevated levels of the systemic immune-inflammation index (SII) [27], suggesting that inflammation may be a key biological mechanism contributing to aneurysm instability, that is, the development of R-AN.

While the full biological cascade remains incompletely understood, our findings indicate that circumferential wall enhancement is a clinically significant biomarker associated with repeat recurrence following EVT. From this perspective, the presence of this finding prior to treatment may warrant consideration of more durable therapeutic strategies, such as adoption of flow diverters, to achieve long-term occlusion. And also, rigorous post-treatment follow-up is essential in these high-risk cases.

In addition to the above noted clinical risk factors, our analysis suggested that the degree of aneurysm occlusion at the initial EVT may influence the risk of developing refractory aneurysms (R-ANs). We observed a clear trend toward a lower incidence of R-ANs in cases that attained more favorable occlusion status, such as Raymond-Roy Class 1 or 2, at the initial procedure. These findings are consistent with previous literature [28, 29], which emphasizes the importance of achieving dense and stable aneurysm occlusion during the initial EVT to minimize the risk of long-term recurrence. Incomplete embolization status, such as residual neck or dome filling, may subject to ongoing hemodynamic stress, thereby promoting progressive regrowth and increasing the need for retreatment. Therefore, optimizing the embolization strategy at the initial EVT session, whether through the appropriate selection of coil type, the use of adjunctive devices such as stents or balloons, or implementation of novel techniques seems to be essential to ensure a durable outcome. Furthermore, the emergence of novel technologies, such as flow diverters (FD) and intrasaccular devices like the Woven EndoBridge (WEB), may further refine the relationship between initial occlusion status and long-term disabilities in future studies.

Regarding the treatment strategy for R-AN, consistent with the findings of previous cohort studies, we clarified that multiple EVT sessions are safe and effective. However, the optimal treatment approach for R-AN remains controversial. While some reports suggest that clipping offers better durability and lower recurrence rates [9, 30], additional EVTs are generally preferred in actual clinical practice because of their safety and efficacy [11, 21, 22, 31]. Slob et al. [32] reported coiling of 41 aneurysms without any periprocedural complications, and Henkes et al. [19] also found no additional risk with second or even serial EVTs compared to initial treatment. Procedural rupture rates were decreased with repeated attempts (first, 3%; second, 1.1%), with no ruptures in the third or further subsequent treatment sessions [19]. In our retrospective analysis, the incidence rate of major periprocedural complications was 2.6%, with no aneurysm ruptures occurring during the treatment period.

Importantly, none of the R-AN cases in our series underwent microsurgical clipping. While clipping remains a potential curative option, its applicability may be limited in R-ANs due to technical challenges such as previously placed coils and stents, which can complicate surgical exposure and manipulation. Given these considerations, repeat EVTs would be considered a first-line treatment strategy for R-ANs, not only for its minimally invasive nature but also for its demonstrated safety and efficacy in appropriately selected cases.