INTRODUCTION
Intracranial aneurysms (IAs) affect approximately 2-5% of the general population and are the leading cause of spontaneous subarachnoid hemorrhage (SAH), a condition associated with high mortality and long-term neurological disability. SAH accounts for nearly 5% of all strokes but contributes disproportionately to stroke-related years of life lost. Several epidemiological studies have highlighted the burden of aneurysmal SAH and its significant socioeconomic impact [3,6,9].
Hemodynamic forces and aneurysm geometry play crucial roles in aneurysm formation, progression, and rupture. Previous studies have identified aneurysm size, aspect ratio, size ratio, and geometric configuration as important predictors of rupture risk [1,11]. Advances in operative microscopy have improved visualization of aneurysm anatomy, enabling more precise intraoperative assessment and surgical planning [4]. These technological improvements have enhanced the ability to evaluate aneurysm morphology and its relationship with rupture risk.
Apart from size, several morphoanatomical parameters, including aspect ratio, size ratio, height-width ratio, aneurysm shape, aneurysm angles, and aneurysm location, have been shown to influence the risk of rupture [11]. Detailed analysis of these geometric and angular parameters may provide valuable insights into aneurysm stability and intraoperative behavior.
Recent evidence suggests that intracranial aneurysms develop within a chronic inflammatory microenvironment. Elevated serum homocysteine contributes to endothelial dysfunction and vascular remodeling, while high-sensitivity C-reactive protein (hs-CRP) serves as a marker of systemic inflammation and vascular injury [5,8]. These biomarkers have been implicated in aneurysm formation and progression; however, their relationship with aneurysm morphology and intraoperative rupture remains incompletely understood.
Among circulating inflammatory markers, hs-CRP and homocysteine were selected as exploratory biomarkers due to their reported associations with vascular inflammation and endothelial dysfunction. However, these markers are not aneurysm-specific and were included primarily to assess their potential adjunctive value alongside morphometric parameters. hs-CRP is a well-validated systemic inflammatory marker implicated in vascular wall remodeling, while homocysteine has been associated with endothelial dysfunction, smooth muscle proliferation, and vascular remodeling.
The combined assessment of morphometric parameters and inflammatory biomarkers may improve preoperative risk stratification and surgical decision-making. However, limited prospective data are available regarding their role in predicting intraoperative rupture during microsurgical clipping.
Given the absence of robust prospective data examining angular morphometry in relation to intraoperative rupture, this study sought to clarify whether specific geometric configurations may predispose to surgical instability independent of conventional size parameters.
In this study, a clear distinction is maintained between preoperative aneurysm rupture (defined as spontaneous rupture leading to subarachnoid hemorrhage prior to surgical intervention) and intraoperative rupture (defined as iatrogenic rupture occurring during microsurgical dissection or clip application). These entities differ fundamentally in their pathophysiology, clinical implications, and prognostic significance. Preoperative rupture reflects the natural history of aneurysm instability, whereas intraoperative rupture represents a procedural complication influenced by both aneurysm characteristics and surgical factors. Accordingly, the present analysis focuses exclusively on intraoperative rupture as the primary outcome variable, while preoperative rupture status is treated as a baseline clinical characteristic rather than a grouping variable.
MATERIALS AND METHODS
Study design and population
This prospective observational study was conducted at a tertiary care neurosurgical center between January 2023 and December 2025 after approval from the Institutional Ethics Committee. Written informed consent was obtained from all participants.
Inclusion criteria
Patients aged >18 years with single-lobed anterior communicating artery aneurysms ≥2 mm who underwent microsurgical clipping, including patients presenting with aneurysmal subarachnoid hemorrhage as well as those treated in the early elective setting.
Exclusion criteria
Patients with multiple aneurysms, pseudoaneurysms, dissecting aneurysms, renal impairment, malignancy, hypothyroidism, pregnancy, recent surgery, vitamin or folate supplementation, antiepileptic drug use, hormone therapy, or refusal to consent were excluded.
Patients with clinical or laboratory evidence of acute infection, chronic inflammatory disease, periodontal disease, or elevated baseline leukocyte counts were excluded to minimize confounding of hs-CRP levels.
Clinical assessment
All patients were evaluated using the Modified Fisher Grade, Hunt and Hess Scale, and World Federation of Neurosurgical Societies (WFNS) grading. All included patients presented with aneurysmal subarachnoid hemorrhage (Fisher Grade ≥1). Preoperative rupture status (ruptured vs. unruptured at presentation) was recorded for all patients and included as a baseline clinical variable.
Radiological assessment
All patients underwent CT Angiography (CTA) using 128-slice scanners. Morphometric parameters measured included:
1. Aneurysm size ‒ The maximum distance from the aneurysm dome to the plane of the aneurysm neck.
2. Height ‒ The maximum perpendicular distance from the aneurysm dome to the neck plane.
3. Width ‒ The maximum diameter of the aneurysm measured parallel to the neck plane.
4. Neck diameter ‒ The maximum width of the aneurysm neck at its junction with the parent vessel.
5. Aspect ratio ‒ The ratio of aneurysm height to neck diameter, calculated as maximum aneurysm height divided by neck width.
6. Size ratio ‒ The ratio of aneurysm height to the mean diameter of the parent vessel.
7. Height-width ratio ‒ The ratio of maximum aneurysm height to maximum aneurysm width.
8. Vessel angle ‒ The angle between the centerline of the inflow vessel and the plane of the aneurysm neck.
9. Flow angle ‒ The angle between the center line of the inflow (parent) vessel and the maximum height axis of the aneurysm.
10. Parent vessel angle ‒ The angle formed between the proximal segments of the parent arteries at the aneurysm origin.
11. Inclination angle ‒ The angle between the main axis of the aneurysm dome and the plane of the aneurysm neck.
Measurements were performed by two independent observers, and average values were used (Fig. 1).
Biochemical analysis
Preoperative venous blood samples were collected. hs-CRP was measured using immunoturbidimetry. Serum homocysteine was measured using enzymatic recycling methods. Blood samples were obtained preoperatively prior to craniotomy. In patients presenting with SAH, samples were collected within 24 hours of admission.
Surgical procedure
All procedures were performed under general anesthesia using an operating microscope for aneurysm clipping. Craniotomy and approach were individualized. Intraoperative rupture and inflammatory changes were documented. Patients were categorized based solely on the occurrence of intraoperative rupture (IOR) during surgery, irrespective of their preoperative rupture status (i.e., presence or absence of subarachnoid hemorrhage at presentation). Preoperative rupture was not used as a grouping variable in order to avoid conflating spontaneous aneurysm rupture with procedure-related intraoperative events. IOR was defined as active arterial bleeding from the aneurysm dome or neck occurring during surgical dissection or clip application that required hemostatic intervention, including temporary clipping, suction control, or additional clip placement. Minor oozing without the need for active hemostatic measures was not classified as IOR. The timing of rupture (during dissection versus during clip application) was recorded intraoperatively. Aneurysm inflammation was defined based on predefined intraoperative macroscopic criteria, including wall thickening, yellowish discoloration, adhesions to surrounding structures, and wall friability. These findings were prospectively documented using a standardized checklist. However, no formal grading scale or histopathological confirmation was available.
Operating surgeon profile
A total of two consultant neurosurgeons performed the procedures. Each surgeon had more than 10 years of independent vascular neurosurgical experience and had performed over 150 aneurysm clippings prior to study initiation. Case distribution among surgeons was comparable. Surgical technique, temporary clipping strategy, and dissection approach were standardized across operators to minimize inter-surgeon variability.
Outcome measures
Primary outcome: Intraoperative aneurysm rupture. Presenting rupture status was recorded but not used as a grouping variable for analysis.
Secondary outcome: Association of morphological and biochemical parameters with aneurysm inflammation.
Statistical analysis
Data were analyzed using SPSS version 26.0. Continuous variables were expressed as mean±standard deviation. Independent t-tests were used for group comparisons. Pearson correlation was used for association analysis. Inter-observer reliability for morphometric measurements was assessed using the intraclass correlation coefficient (ICC). An ICC >0.80 was considered indicative of excellent agreement. The ICC for angular measurements ranged from 0.82 to 0.91, indicating excellent agreement. A p-value ≤0.05 was considered statistically significant.
The study was conducted and reported in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. A patient enrollment flow diagram is provided (Fig. 2).
RESULTS
Of 52 patients screened, 37 met the inclusion criteria and were analyzed, of whom 13 experienced intraoperative rupture. There was no statistically significant difference in mean age between the groups (55.85±12.33 vs. 53.96±12.21 years; p=0.659). Similarly, gender distribution was comparable between the two groups (Table 1). There was no statistically significant difference in baseline clinical severity as assessed by Hunt & Hess, WFNS, or Modified Fisher Grades (Table 1).
The mean duration from ictus to surgery was slightly longer in the unruptured group compared with the ruptured group (4.46 vs. 4.08 days); however, this difference was not statistically significant (p=0.78) (Table 2).
Morphometric analysis demonstrated that aneurysm size (4.26 vs. 3.85 mm), height (4.04 vs. 3.55 mm), width (4.65 vs. 4.61 mm), height-width ratio (0.88 vs. 0.78), aspect ratio (1.02 vs. 0.81), and size ratio (1.49 vs. 1.44) were higher in the ruptured group compared with the unruptured group. In contrast, neck diameter (4.50 vs. 4.08 mm) and parent vessel diameter (2.93 vs. 2.77 mm) were higher in the unruptured group. However, none of these parameters showed statistically significant differences between the groups (Table 3).
The mean aneurysm inclination angle was higher in ruptured aneurysms than in unruptured aneurysms (87.68° vs. 82.01°), although this difference did not reach statistical significance (p=0.25). In contrast, vessel angle (74.76° vs. 56.80°, p=0.03) and flow angle (153.24° vs. 137.58°, p=0.035) were significantly higher in the ruptured group. The parent vessel angle was significantly greater in the unruptured group (121.88° vs. 98.85°, p=0.02) (Table 4).
Biochemical analysis revealed that serum homocysteine levels (12.47±5.25 vs. 9.38±3.48 μmol/L, p=0.041) and hs-CRP levels (68.86±57.36 vs. 30.86±49.85 mg/L, p=0.032) were significantly higher in aneurysms with intraoperative inflammatory changes compared with non-inflamed aneurysms. However, inflammatory changes were observed in 61.54% of ruptured aneurysms (8/13) and 62.5% of unruptured aneurysms (15/24), with no statistically significant association between inflammation and intraoperative rupture (p=0.12).
DISCUSSION
IOR remains a well-recognized complication of aneurysm clipping and was historically associated with poor clinical outcomes in the pre-microsurgical era [7]. Identification of reliable predictors of intraoperative rupture is therefore essential for improving perioperative planning and surgical safety. Although irregular aneurysm morphology is a known risk factor for aneurysmal subarachnoid hemorrhage, its association with intraoperative rupture remains controversial [4]. Importantly, the primary focus of the present study was on morphometric predictors of intraoperative rupture, with inflammatory biomarkers evaluated as secondary, exploratory variables.
It is essential to distinguish intraoperative rupture from spontaneous (preoperative) aneurysm rupture. While numerous studies have evaluated morphological predictors of aneurysm rupture in the natural history context, intraoperative rupture represents a fundamentally different phenomenon [1,11]. It is influenced not only by intrinsic aneurysm wall stability but also by surgical manipulation, exposure, and hemodynamic fluctuations [1,7]. Therefore, morphometric parameters identified in this study should be interpreted as predictors of intraoperative instability rather than true rupture risk in the natural history sense.
As all patients in this cohort presented with aneurysmal subarachnoid hemorrhage, the findings specifically reflect predictors of intraoperative rupture in already ruptured aneurysms. The observed intraoperative rupture rate of 35.1% appears higher than commonly reported rates in the literature (approximately 3-19%) [2]. This may be attributable to the exclusive inclusion of anterior communicating artery aneurysms, which are technically challenging due to complex vascular anatomy and deep operative corridors [4]. Additionally, a proportion of patients presented in the acute phase following SAH, potentially contributing to friable aneurysm walls. The prospective documentation of even minor bleeding episodes requiring temporary clipping may also have increased the reported IOR rate.
Several studies have demonstrated the importance of morphological parameters in predicting aneurysm rupture. Dhar et al. [1] reported that size ratio and undulation index were independently associated with rupture risk and suggested that these parameters may serve as useful predictors. Similarly, Zheng et al. [11] identified size ratio, height-width ratio, inclination angle, aneurysm shape, and location as significant independent predictors of rupture. In contrast, in the present study, aneurysm size, height, neck width, vessel diameter, height-width ratio, aspect ratio, and size ratio were higher in the ruptured group but did not reach statistical significance. These differences may be attributable to the relatively small sample size and the inclusion of a homogeneous aneurysm population.
Intraoperative rupture is influenced not only by aneurysm morphology but also by surgical manipulation, temporary clipping strategy, blood pressure fluctuations, and intraoperative hemodynamic factors [1,11]. Although surgical techniques were standardized, these factors may have contributed to rupture occurrence.
Larger vessel and flow angles may reflect altered inflow jet dynamics and increased focal wall stress at the aneurysm dome [1]. Such geometric configurations could predispose to intraoperative fragility during surgical manipulation.
Notably, our study demonstrated that vessel angle and flow angle were significantly higher in ruptured aneurysms, whereas parent vessel angle was significantly greater in unruptured aneurysms. These findings suggest that angular parameters reflecting local hemodynamic stress may play a more critical role in determining intraoperative instability than conventional size-based measurements.
From a surgical standpoint, aneurysms demonstrating larger vessel and flow angles may warrant early proximal control, meticulous arachnoid dissection before dome manipulation, and liberal use of temporary clipping. Preoperative recognition of unfavorable angular geometry on CTA may allow the surgeon to anticipate intraoperative instability and plan an operative strategy accordingly.
With regard to inflammatory biomarkers, Telles et al. [5] reported that fusiform morphology was associated with elevated CRP levels in unruptured aneurysms but not in ruptured lesions. In our study, serum hs-CRP and homocysteine levels were significantly higher in aneurysms exhibiting inflammatory changes, indicating an association with aneurysm wall inflammation. However, these biomarkers were not independently associated with intraoperative rupture.
Similarly, Wei et al. [10] reported an association between serum homocysteine levels and aneurysm rupture; however, this study primarily evaluated systemic and lifestyle-related factors and does not establish causality. In contrast, our findings did not reveal a significant relationship between homocysteine levels and intraoperative rupture. This discrepancy may reflect differences in study design, patient population, and outcome definitions.
The relatively elevated hs-CRP levels observed in this cohort may partly reflect systemic inflammatory response in patients presenting with acute subarachnoid hemorrhage. Acute-phase reactant elevation following hemorrhage cannot be completely distinguished from localized aneurysm wall inflammation. Therefore, hs-CRP values in this study should be interpreted as markers of systemic inflammatory burden rather than direct histopathological evidence of aneurysm wall inflammation.
Postoperative complications in our cohort were limited. Vasospasm occurred in a small number of patients in both groups without statistical significance. One patient developed a postoperative epidural hematoma requiring surgical evacuation. Four patients died during the study period, two due to pneumonia and two due to intraventricular hemorrhage, reflecting the multifactorial nature of morbidity and mortality in aneurysm surgery.
Overall, these findings suggest that while biochemical markers such as hs-CRP and homocysteine may reflect systemic or aneurysm-associated inflammation, they appear to have limited utility in predicting intraoperative rupture when compared with morphometric parameters. Geometric and angular parameters appear to have greater relevance in predicting the risk of intraoperative rupture. Future studies should include multivariate models adjusting for age, size, and rupture status.
Limitations
This study has several limitations. First, the relatively small sample size limits statistical power and may have reduced the ability to detect significant differences in certain morphometric variables. The limited number of intraoperative rupture events also precluded multivariate regression modeling, as events per variable were insufficient (<10 per predictor) to permit reliable logistic analysis. Consequently, independent predictors of rupture could not be established.
Second, this was a single-center study restricted to anterior communicating artery aneurysms. Although this homogeneity reduces anatomical variability, it may limit the generalizability of the findings to aneurysms at other intracranial locations or different patient populations. A formal a priori sample size calculation was not feasible due to limited prior data on angular morphometric predictors of intraoperative rupture; therefore, all eligible patients during the study period were included.
Third, intraoperative rupture is influenced not only by aneurysm morphology but also by surgical handling and operative nuances. Despite procedures being performed by experienced vascular neurosurgeons using standardized techniques, subtle variations in intraoperative strategy could not be completely controlled and may have affected rupture rates.
Fourth, morphometric measurements were derived from computed tomography angiography and intraoperative visualization. Although standardized protocols and interobserver agreement measures were employed, imaging-based reconstruction and intraoperative assessment remain susceptible to measurement bias.
Fifth, aneurysm wall inflammation was evaluated based on intraoperative appearance and circulating biomarkers without histopathological confirmation or a validated grading scale. This subjective assessment introduces potential interobserver variability and may not fully reflect the underlying inflammatory burden of the aneurysm wall. In addition, subclinical inflammatory conditions could not be entirely excluded and may have influenced serum biomarker levels.
Finally, only two systemic inflammatory markers (hs-CRP and homocysteine) were assessed. Other inflammatory mediators implicated in aneurysm pathobiology, such as interleukins, matrix metalloproteinases, and tumor necrosis factor-α, were not evaluated, limiting comprehensive characterization of the inflammatory milieu.
Future multicenter studies with larger cohorts, histopathological validation, standardized morphometric protocols, and multivariate statistical modeling are warranted to confirm these findings and further elucidate the relationship between aneurysm geometry, inflammation, and intraoperative rupture risk.
CONCLUSIONS
Angular morphometric parameters appear to be important predictors of intraoperative rupture (surgical instability) rather than spontaneous aneurysm rupture. In particular, vessel angle, flow angle, and parent vessel angle were found to be significant markers of surgical instability during microsurgical clipping of intracranial aneurysms, whereas conventional size-based parameters show limited predictive value.
Although elevated serum hs-CRP and homocysteine levels are associated with aneurysmal inflammation, they do not independently correlate with intraoperative rupture. These findings highlight the greater relevance of geometric and hemodynamic factors over systemic inflammatory markers in predicting intraoperative aneurysm instability. Preoperative CTA-based assessment of angular parameters may aid surgical risk stratification.
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