In the treatment of cerebral aneurysms, flow diversion method has become frequently used by neurointerventionalists (1). This method has notably high efficacy and is a favorable option for treating complex wide-necked aneurysms (2). Its therapeutic window has been expanded to include smaller aneurysms with unfavorable morphology, which carry a high risk of coil embolization because of the potential for coil herniation into the parent vessel. Flow diversion is distinguished by high occlusion rates and the lack of a requirement for intrasaccular navigation, as is necessary with simple and adjunctive coiling techniques (3, 4). A drawback to the use of these intracranial stents is the need for continuous dual antiplatelet therapy (DAPT), to avoid implant thrombosis and associated ischemic complications (5). Another potential drawback is the potential for covered side-branch occlusion. Although the clinical significance of this occurrence remains debated, treating physicians should consider this aspect during decision-making and avoid it if possible (6).

The intra- and periprocedural complications of flow diversion can be divided into two main categories: ischemic and hemorrhagic (7). Hemorrhagic complications can occur both during embolization, owing to vessel injury and aneurysm rupture, and post-procedurally, as in delayed aneurysm ruptures, owing to aneurysm wall lysis after rapid thrombosis inside the sac (8, 9). Ischemic complications have been reported in approximately 7–10% of patients receiving flow diversion (10, 11). One potential late ischemic complication is the development of in-stent stenosis (ISS) after device implantation. Despite the effectiveness of prescribed antithrombotic medications, ISS is encountered in 10–50% of flow diversion cases (12, 13). ISS development, although frequently asymptomatic, can potentially lead to irremediable neurological damage.

Although several hypotheses regarding ISS and its formation have been proposed, the essence and exact pathophysiology of this condition largely remain unclear (14). Factors intrinsic to the implant and/or the treated vessel play crucial roles in ISS development. The consensus regarding ISS pathophysiology is that device implantation causes vascular injury, thereby initiating a biochemical inflammatory cascade (15). Platelet aggregation and subsequent leukocyte infiltration are the first events in response to this injury. Gradually, the secretion of various growth factors and cytokines leads to the activation and proliferation of the vessel endothelium, which begins to cover the struts of the stent (16). Vascular smooth muscle cells are also a vital part of the process because their activation due to induced stress from the stent can lead to vessel remodeling in later phases (17, 18). An additional pathological mechanism arising from endothelial cell damage is endothelial nitrous oxide synthase dysfunction, which plays crucial roles in multiple pathways associated with thrombosis and adhesion molecule expression (19). Other factors known to affect endothelial physiology and ISS development include age, sex, hypertension, and smoking (20–22).

Herein, this study sought to establish whether a correlation between stent oversizing and ISS development might exist in patients with supraclinoid internal carotid artery (ICA) aneurysms treated with flow diversion. Other previously described risk factors, such as age, sex, hypertension, and smoking status, were also examined to assess their effects on ISS development (23).

A retrospective study of patients with internal carotid aneurysms treated in our hospital between September 2022 and May 2023 was conducted.

The formation and clinical significance of ISS remain unclear. Studies on flow diversion have indicated markedly different rates of this complication, from 8% to more than 40% (13, 16, 25). ISS is frequently reported to have a benign clinical course and has been observed to regress in follow-up in some studies spontaneously (26). The presented clinical experience in this study indicated a much higher percentage than previously reported, because of the narrow threshold for defining any vessel reduction as ISS. Despite the definition used, only two of the patients in the study exhibited any notable chronic clinical symptoms during follow-up, which were attributed to the observed stenosis. Thus, ISS can be considered a mostly “quiet” complication that theoretically can spontaneously resolve. However, in severe cases of ISS, the prolonged time during which it forms also enables the dilation of collateral pathways supplying regions of the brain that develop vascular deficiency (25). To date, the management of ISS by treating physicians has mainly been conservative, with few to no options for acute management (27). DAPT is frequently prolonged until subsequent follow-up. In the described cases of symptomatic ISS, that strategy was also adopted and achieved satisfactory results. Some authors have indicated that angioplasty is an invasive technique that can resolve stenosis; however, its inherent risks, such as parent vessel damage and embolic complications, must be weighed against its potential benefits (16). Another potential option for dealing with this phenomenon has already been implemented in cardiology, with the prescription of Cilostazol for patients with coronary stent restenosis (28). This drug’s effect on intimal overgrowth can be linked with suppression of P-selectin expression on platelets and the following upregulation of leukocyte Mac-1 (29). Some authors have already published their evaluation of the efficacy and safety of Cilostazol in patients with ISS after flow diversion with promising results (30). Although ISS is rarely symptomatic, its complications can be dire and challenging to address; therefore, preventive strategies are the most logical course of action. To achieve prevention, identification, and avoidance of risk factors associated with ISS development would provide the most benefits for patients. Narrowing the therapeutic range of flow diverters to primarily elective cases might yield satisfactory results.

The study included only patients with supraclinoid aneurysms of the ICA for several reasons. First, these segments of the cerebral vasculature are relatively easy to assess on both DSA and MRI, and they could be reliably measured in different projections. Second, aneurysms at the ophthalmic and terminal segments are among the most common locations of this pathology; therefore, a substantial number of patients could be included to interpret their risk factors in the context of ISS. Finally, their use in treating smaller aneurysms markedly increased after the initial introduction of flow diverters for treating wide-neck bifurcation aneurysms. Flow diversion has become a mainstream treatment for aneurysms at this location, because of its high technical success rate and favorable safety profile (31). Therefore, a specific evaluation of the risk factors and clinical significance of ISS in the distal ICA might most reliably benefit patients undergoing endovascular treatment of cerebral aneurysms at that location. The findings could be implemented in the context of flow diversion in more distal vascular territories, such as the middle and anterior cerebral arteries (32).

Several factors might potentially be responsible for ISS development. One of the most crucial and bioactive components of the vessel wall is the endothelium, which is involved in the early response to hemodynamic changes to maintain vessel wall homeostasis. Endothelial cells have mechano-transductor properties, which are implemented through their intra- and extracellular matrix components, and stretch-activated ion channels (33, 34). Any changes in laminar flow or wall shear stress induce cell reactions in the cells to maintain normal blood flow’s physiological conditions. When a stent is delivered, several pathological processes occur, including endothelial damage, inflammatory reactions, and microflow disturbances near the struts of the stent (35). The implanted devices exert mechanical stress, because of their self-expanding nature. With oversizing, the stent maintains a constant radial force, aiming to reach the device’s nominal diameter. Consequently, the stent is comparable to a “loaded spring” that continually applies outward pressure on the vessel, which further increases with greater oversizing (36, 37). The mechanical damage to endothelial cells caused by device implantation also hinders their ability to produce vasoactive substances, such as nitrous oxide, which regulates thrombus formation and cell proliferation (19). All of these conditions are a prerequisite for endothelial dysfunction, pathological reparation, and aggressive neo-proliferation to occur. In this sample of patients, it was observed that the distal landing zone of the stents was more prone to ISS formation. Possibly, the pathological process in that segment might be exacerbated with greater oversizing. A mechanical threshold for the vessel wall might exist, beyond which a more pronounced reaction is induced. Oversizing considering not only the proximal landing zone but also the distal landing zone might remedy some ISS cases, according to the statistical analysis.

Cell senescence is another crucial protective factor against ISS. Studies have indicated that younger age is an independent risk factor for ISS formation (12, 38). Diminished cell proliferation ability in older patients has been suggested as the reason for the lower incidence and severity of ISS in this population. This series is consistent with this explanation, as lower rates of ISS in older patients were evaluated in the study.

The evaluation of the effects of sex on ISS did not reach statistical significance, possibly because the study included substantially more women than men, thus potentially resulting in bias. Nevertheless, other studies have demonstrated that women have an elevated risk of developing significant ISS (12, 38).

A perhaps more controversial result from the analysis pertained to the effects of smoking on ISS. Smokers in the study developed less significant stenosis than non-smokers at follow-up. Smoking increases the overall cardiovascular risk of every procedure, because of its effects on innate thrombocyte reactivity, vessel rigidity, and enhancing anatomical tortuosity. Its relative protective value can be attributed to its contribution to chronic vessel damage and endothelial dysfunction (39), through which it also raises the presumed threshold of iatrogenic damage necessary for ISS to become pronounced.

In summary, stent oversizing is a crucial condition for successfully treating cerebral aneurysms with flow diversion. According to the manufacturer’s recommendations, the devices were oversized with respect to the most significant part of the vessel to be stented. The use of a stent diameter greater than the vessel diameter is aimed at achieving several goals. First, the stent achieves adequate wall apposition because of the constant application of outward radial force, thereby decreasing the risk of acute thrombosis between the stent struts and the uncovered endothelial layer. Another benefit of oversizing is diminished risk of aneurysmal endoleak, which might compromise treatment outcomes (40). A key aspect of oversizing is the decreased risk of stent migration Finally, oversizing increases the implant porosity, which might aid in keeping the covered side branches patent and functional (41). A drawback of oversizing observed herein was that this increased porosity was a risk factor for aneurysm occlusion, because of the diminished flow disturbance inside the sac. Thus, oversizing is a core technical step in flow diversion therapy, but, to date, no attention has been paid to the other end of the spectrum. The results from this study emphasize the need for more precise recommendations regarding the correct choice of stent size, considering all arterial segments.

One main limitation of this study is that all patients were treated with a single device type. Additional studies assessing other flow diverter stents are needed to appreciate stent oversizing as a risk factor for ISS fully. Another potential limitation is that not all patients were followed up through DSA, thus potentially introducing bias in the target vessel measurement results.

ISS is observed in many patients treated with flow diversion. Most frequently, this phenomenon is completely asymptomatic, and symptomatic cases can often be managed through conservative means, such as DAPT continuation. This study observed a significant correlation between the degree of stent oversizing and ISS incidence and severity at mid-term follow-up. Based on these findings, it may be recommended to use device diameters accounting for both the proximal and distal landing zones of the target vessel. Older patients and smokers had less severe ISS than other patients in the cohort at follow-up.