Rupture risk of small intracranial aneurysm: comparison between small ruptured intracranial aneurysm and large unruptured intracranial aneurysm

doi:10.21203/rs.3.rs-3229882/v1

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Rupture risk of small intracranial aneurysm: comparison between small ruptured intracranial aneurysm and large unruptured intracranial aneurysm

https://doi.org/10.21203/rs.3.rs-3229882/v1

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Background

Size is one of the risk factors of intracranial aneurysms (IAs) rupture, but not a reliable marker of rupture risk. Two groups of IAs, ruptured IAs (RIAs) smaller than 5 mm and unruptured IAs (UIAs) larger than 10 mm, were compared to investigate the clinical and morphological characteristics associated with the risk factors for the rupture of small IAs.

Methods

The clinical data of 189 consecutive patients with 193 IAs were reviewed. The patients and IAs were divided into ruptured (smaller than 5 mm) and unruptured groups (larger than 10 mm). The characteristics of the patients and the IAs were compared between the two groups, and the rupture risk factors for small IAs were assessed using multiple logistic regression.

Results

Patient age (odds ratio [OR], 0.955), IA located at the internal carotid artery (OR, 0.202), irregular shape (OR, 0.083) and parent vessel diameter (OR, 0.426) were negatively correlated with a risk of small IA rupture. IAs located at bifurcations (OR, 6.766) were positively correlated with a risk of small IA rupture.

Conclusions

In addition to IA size, other factors, such as patient age, IA location, shape and parent vessel diameter, can influence the risk of small IA rupture.

Intracranial aneurysm

Computed tomography angiography

Morphology

Rupture

Risk factor

Intracranial aneurysms (IAs) are common, and most of them are usually asymptomatic during the patient’s lifetimes [1]. However, once an IA rupture is often associated with high mortality and high morbidity [2]. Hence, the accurate evaluation of rupture risk is crucial to inform the management of patients with unruptured IAs (UIAs). Traditionally, a large size IA was considered an important risk factor for rupture [3]. A recent report also suggested that small UIAs have low growth and low rupture rates and that very small UIAs have little or no risk for rupture [4]. Nevertheless, in clinical practice, the proportion of small (≤ 5 mm) ruptured IAs (RIAs) among total RIAs was 45–50% [5]; unexpectedly, many large (≥ 10 mm) UIAs remained stable for a long time. This means that size alone is not a reliable marker of rupture risk. Here, we compared the differences in the clinical and morphological features between these two groups to investigate the risk factors for rupture of small IAs.

Patients

The retrospective study was approved by each participating center’s institutional ethics committee and the requirement for informed consent from patients was waived. Patients with small RIAs (≤ 5 mm) and large UIAs (≥ 10 mm) were included. The exclusion criteria were as follows: 1) patients with mycotic, traumatic, or fusiform IAs; 2) patients with arteriovenous malformations or poor quality images; and 3) patients with an UIAs size smaller than 10 mm or a RIAs size larger than 5 mm. Patients with UIAs were followed for at least 2 years via outpatient department visits or telephone survey. For patients with multiple IAs, the RIA was determined based on the CT, angiographic, or operative findings. Ultimately, a total of 189 consecutive patients (110 ruptured and 79 unruptured) with 193 IAs (110 ruptured and 83 ruptured) at two participating centers (x and x) were retrospectively enrolled.

Patient clinical information, such as sex, age, and clinical history (e.g., smoking, status for hypertension), was collected from electronic medical records and summarized for analysis by two assessors.

Imaging analysis

All patients underwent head CT examinations on 64-slice CT machines (Revolution HD; GE Healthcare, Wisconsin, USA; or LightSpeed VCT; GE Healthcare, Chicago, Illinois, USA). The CTA images were transferred to a GE Advantix workstation (Advantage Windows 4.5) to generate 3-dimensional volume renderings (VRs) and then evaluated. One observer obtained all measurements to avoid interobserver variability.

Morphological parameters included IA location, type (sidewall or bifurcation type), shape (simple or irregular), size (maximum size, neck width, depth, and width), parent vessel diameter, aspect ratio (AR; depth/neck width), depth/width ratio (DW), size ratio (SR; depth/parent vessel diameter), and bottleneck factor (BF, width/neck width ratio). These parameters were identified and described in previous studies [6, 7].

Statistical analysis

Statistical analyses were performed with SPSS 25.0 (SPSS Inc., Chicago, Illinois, USA). Categorical data are presented as n (%) and were compared using Fisher’s exact tests. Continuous data are presented as mean ± standard deviation (SD) and were compared using Mann‒Whitney U tests. Multiple logistic regression analysis was used to assess independent predictors for rupture. A P value < 0.05 was regarded as statistically significant.

The clinical data of the 189 patients are listed in Table 1. The mean age of the patients was 57.0 ± 13.0 years (54.3 ± 14.2 years for men and 58.4 ± 12.3 years for women). No significant differences were found between the two patient groups, except for significantly younger age in the rupture group.

Table 1

The clinical data of patients with aneurysms.
Clinical data	Ruptured (n = 110)	Unruptured (n = 79)	P
Male	39 (35.5%)	23 (29.1%)	0.433
Age (years)	53.94 ± 11.36	61.33 ± 14.05	< 0.001
Hypertension	41 (37.3%)	27 (34.2%)	0.759
Heart disease	5 (4.5%)	5 (6.3%)	0.744
Diabetes mellitus	11 (10.0%)	7 (8.9%)	1.000
Cerebral atherosclerosis	1 (0.9%)	5 (6.3%)	0.084
Current alcohol	27 (24.5%)	14 (17.7%)	0.288
Current smoking	25 (22.7%)	19 (24.1%)	0.863
Multiple aneurysms	11 (10.0%)	14 (17.7%)	0.133

Table 2 summarizes the morphological characteristics of the IAs. IAs located at the anterior communicating artery, internal carotid artery or bifurcation location; those with an irregular shape; and those with continuous data were associated with ruptured IAs. Notably, almost all of morphological characteristics except for HW and parent vessel diameter in the ruptured group were smaller than those in the unruptured group.

Table 2

Morphologic characteristics of the aneurysms.
Morphologic characteristics	Ruptured (n = 110)	Unruptured (n = 83)	P
Location
Internal carotid artery	7 (6.4%)	38 (45.8%)	< 0.001
Middle cerebral artery	18 (16.4%)	8 (9.6%)	0.205
Anterior cerebral artery	8 (7.3%)	2 (2.4%)	0.192
Anterior communicating artery	42 (38.2%)	9 (10.8%)	< 0.001
Posterior communicating artery	27 (24.5%)	19 (22.9%)	0.865
Posterior cerebral circulation	8 (7.3%)	7 (8.4%)	0.791
Bifurcation	88 (80.0%)	22 (26.5%)	< 0.001
Irregular shape	31 (28.2%)	61 (73.5%)	< 0.001
Maximum size (mm)	4.29 ± 0.66	17.17 ± 5.69	< 0.001
Neck width (mm)	3.17 ± 0.71	8.64 ± 3.11	< 0.001
Depth (mm)	3.54 ± 0.75	14.78 ± 5.21	< 0.001
Width (mm)	3.17 ± 0.73	14.39 ± 5.71	< 0.001
Parent vessel diameter	3.16 ± 0.77	4.03 ± 0.88	< 0.001
AR	1.18 ± 0.41	1.84 ± 0.70	< 0.001
DW	1.16 ± 0.29	1.09 ± 0.32	< 0.001
SR	1.37 ± 0.49	4.03 ± 1.56	< 0.001
BF	1.03 ± 0.28	1.78 ± 0.74	< 0.001
AR, aspect ratio; DW, depth/width ratio; SR, size ratio; BF, bottleneck factor

Considering that the size of an UIA is significantly larger than that of a RIA, the parameters that are larger than that of a RIA were excluded. The factors that were significantly associated with the incidence of small IA rupture were patient age, location at the internal carotid artery and anterior communicating artery, a bifurcation location, irregular shape, parent vessel diameter, and DW. Then, the 7 variables were entered into the forward stepwise multiple logistic regression model. Table 3 revealed that location at a bifurcation [odds ratio, (OR) 6.766] strongly affected the risk of small IA rupture, while patient age (OR 0.955), location at the internal carotid artery (OR 0.202), irregularity (OR 0.083) and parent vessel diameter (OR 0.426) were associated with a decreased risk of small IA rupture.

Table 3

Multiple logistic regression model for prediction of small aneurysm rupture.
	OR	95% CI	B	P
Age	0.955	0.919–0.992	-0.046	0.018
Internal carotid artery	0.202	0.052–0.786	-1.601	0.021
Bifurcation	6.766	2.386–19.191	1.912	< 0.001
Parent vessel diameter	0.426	0.238–0.761	-0.853	0.004
Irregular shape	0.083	0.031–0.219	-2.491	< 0.001
Anterior communicating artery	0.617	0.180–2.112	-0.482	0.442
DW	1.759	0.431–7.172	0.564	0.431
OR, odds ratio; CI, confidence interval; B, partial logistic coefficient; DW, depth/width ratio

In this study, in the comparison between small RIAs and large UIAs, we found that patient age, location at the internal carotid artery, location in bifurcations, irregular shape and parent vessel diameter were associated with a risk of small IA rupture.

For many years, IA size has been considered the main factor associated with rupture risk and treatment, and small IAs are often left untreated and monitored by imaging. Many studies have suggested that small UIAs have low growth and low rupture rates [3, 4, 6–8]. However, according to recent reports, the actual number of ruptures was not low, the proportion of small RIAs among total RIAs was up to 50% [5] and 41% [9], respectively. This means that we cannot rely solely on the size of the IA to determine the rupture risk, while other clinical and morphologic characteristics should be noted.

The role of age in the risk of IA rupture is unclear. Some studies have reported that patient age is not associated with IA rupture [4,6,8,10,11]. Additionally, several studies have reported a positive correlation between age and IA rupture [12, 13]. However, recent studies have indicated that patient age is inversely related to IA rupture [5, 7, 14, 15], which is consistent with this report. The inverse relationship between age and IA rupture may be associated with hemodynamics. With increasing age, cerebral atherosclerotic or calcified walls slow the flow of blood entering the IA and reduce wall shear stress [16].

IAs usually occur at the circle of Willis, especially at the anterior communicating artery, posterior communicating artery and internal carotid artery. Location is considered an important factor for IA treatment decisions [3]. Moreover, an IA located at anterior communicating artery and posterior communicating artery was believed to have a high risk of rupture [15, 17]. In this study, although the anterior communicating artery was found to be highly associated with IA rupture in univariate analyses, it did not achieve significance in multivariate regression analysis. One of the reasons may be that the small sample size limited the morphological analysis. Another reason is that the IA is located at an anterior communicating artery and at the bifurcation. The rupture risk is different between sidewall- and bifurcation-type IAs. Bifurcations are known to be vulnerable sites because the wall is weak and because hemodynamic stress changes in these regions [7, 18]. Moreover, IAs located at the internal carotid artery are less likely to rupture because they are usually the sidewall type.

In general, an IA with an irregular shape is more likely to become unstable or rupture because its irregular shape leads to unstable blood flow patterns [19]. However, our present results show that an IA with an irregular shape has a lower risk of rupture. One of the reasons is that a large IA is more likely to lobulate, and a large diameter may counteract the instability of the blood flow pattern. Another reason is that small IAs are not yet lobulated or that shallow lobulation has been missed. Hence, the negative correlation between irregular shape and IA rupture is debatable.

We found that a small parent vessel diameter is associated with a higher risk of IA rupture. The reason may be that IAs arising from smaller vessels have thinner walls and may experience greater wall tension [20]. This also confirms that IAs located at the internal carotid artery are less likely to rupture because the internal carotid artery is often larger in diameter than other arteries.

Limitations

This study had several limitations. First, we compared two groups of IAs. Patients with RIAs larger than 5 mm or UIAs smaller than 10 mm were excluded, which may have biased the selection of patients and may have led to statistical bias, and the results may not be applicable to other sizes of IAs. Second, the RIAs and UIAs had different statuses. Although no evidence confirmed that IAs shrink after rupture, the size and shape may be changed after IA rupture and may lead to statistical bias. Third, patient intake of aspirin or a statin was not investigated, and these drugs may reduce the incidence of IA rupture [21]. Fourth, this is a retrospective study with a small sample size, so there is a risk of bias. Fifth, our follow-up time needs to be extended, and some UIAs may rupture in the future. Further prospective studies with a larger patient sample would improve the significance of the findings.

By comparing smaller RIAs and larger UIAs, we found that younger age, location at a bifurcation, and a small parent vessel diameter were independently associated with the rupture of small IAs. Small IAs located at the internal carotid artery and with an irregular shape were less likely to rupture. These risk factors should be validated in future studies.

Ethical Approval

All aspects of this study were approved by the ethics committee of the Banan Hospital, Chongqing Medical University, Chongqing, China (No.:2021015). The requirement for informed consent is waived by the ethics committee of the Banan in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Authors' contributions

GW: conceptualization. LZ, LL and LW: data curation. LZ and XL: investigation. GW: methodology. LZ: writing-original draft. All authors read and approved the final manuscript.

Funding

This study was supported by the Joint Project of Science and Health of Chongqing City, China (2023MSXM022) and Banan District Science and Technology Bureau of Chongqing City, China (KY202208135759002).

Consent for publication

Not applicable.

Availability of data and materials

Data will be made available on request.

Ujiie H, Sato K, Onda H, Oikawa A, Kagawa M, Takakura K, et al. Clinical analysis of incidentally discovered unruptured aneurysms. Stroke. 1993;24: 1850-6.
van Gijn J, Kerr RS, Rinkel GJ. Subarachnoid haemorrhage. Lancet. 2007;369:306-18.
Wiebers DO, Whisnant JP, Huston J 3rd, Meissner I, Brown RD Jr, Piepgras DG, et al. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362:103-10.
Lee KS, Zhang JJY, Alalade AF, Vine R, Lanzino G, Park N, et al. Radiological surveillance of small unruptured intracranial aneurysms: a systematic review, meta-analysis, and meta-regression of 8428 aneurysms. Neurosurg Rev. 2021;44(4):2013-23.
Ikawa F, Morita A, Tominari S, Nakayama T, Shiokawa Y, Date I, et al. Rupture risk of small unruptured cerebral aneurysms. J Neurosurg. 2019:1-10.
Guang-Xian Wang, Lan-Lan Liu, Yan Yang, Li Wen, Chun-Mei Duan, Jin-Bo Yin, et al. Risk factors for the progression of unruptured intracranial aneurysms in patients followed by CT/MR angiography. Quant Imaging Med Surg. 2021;11(9):4115-24.
Suzuki T, Takao H, Rapaka S, Fujimura S, Ioan Nita C, Uchiyama Y, et al. Rupture Risk of Small Unruptured Intracranial Aneurysms in Japanese Adults. Stroke. 2020;51(2):641-3.
Malhotra A, Wu X, Forman HP, Grossetta Nardini HK, Matouk CC, Gandhi D, et al. Growth and Rupture Risk of Small Unruptured Intracranial Aneurysms: A Systematic Review. Ann Intern Med. 2017;167(1):26-33.
Bender MT, Wendt H, Monarch T, Beaty N, Lin LM, Huang J, et al. Small Aneurysms Account for the Majority and Increasing Percentage of Aneurysmal Subarachnoid Hemorrhage: A 25-Year, Single Institution Study. Neurosurgery. 2018;83(4):692-9.
Villablanca JP, Duckwiler GR, Jahan R, Tateshima S, Martin NA, Frazee J, et al. Natural history of asymptomatic unruptured cerebral aneurysms evaluated at CT angiography: growth and
rupture incidence and correlation with epidemiologic risk factors. Radiology. 2013;269:258-65.
UCAS Japan Investigators, Morita A, Kirino T, Hashi K, Aoki N, Fukuhara S, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med. 2012;366:2474-82.
Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysm characteristics: an updated meta-analysis. Stroke. 2007;38(4):1404-10.
Greving JP, Wermer MJ, Brown RD Jr, Morita A, Juvela S, Yonekura M, et al. Development of the phases score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol. 2014;13:59-66.
Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke. 2010;41:1969-77.
Juvela S, Poussa K, Lehto H, Porras M. Natural history of unruptured intracranial aneurysms: along-term follow-up study. Stroke. 2013;44:2414-21
Castro MA, Putman CM, Sheridan MJ, Cebral JR. Hemodynamic patterns of anterior communicating artery aneurysms: a possible association with rupture. Am J Neuroradiol. 2009; 30:297-302.
Zhang Y, Jing L, Liu J, Li C, Fan J, Wang S, et al. Clinical, morphological, and hemodynamic independent characteristic factors for rupture of posterior communicating artery aneurysms. J Neurointerv Surg. 2016;8(8):808-12.
Kang HG, Kim BJ, Lee J, Kim MJ, Kang DW, Kim JS, et al. Risk factors associated with the presence of unruptured intracranial aneurysms. Stroke. 2015;46:3093-8.
Elsharkawy A, Lehecka M, Niemelä M, Kivelev J, Billon-Grand R, Lehto H, et al. Anatomic risk factors for middle cerebral artery aneurysm rupture: computed tomography angiography study of 1009 consecutive patients. Neurosurgery. 2013;73:825-37.
Yu J, Wu Q, Ma FQ, Xu J, Zhang JM. Assessment of the risk of rupture of intracranial aneurysms using three-dimensional cerebral digital subtraction angiography. J Int Med Res. 2010;38:1785-94.
Can A, Rudy RF, Castro VM, Yu S, Dligach D, Finan S, et al. Association between aspirin dose and subarachnoid hemorrhage from saccular aneurysms: A case-control study. Neurology. 2018;91(12):e1175-e1181.

No competing interests reported.

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Rupture risk of small intracranial aneurysm: comparison between small ruptured intracranial aneurysm and large unruptured intracranial aneurysm

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Abstract

Background

Methods

Results

Conclusions

Introduction

Materials and methods

Patients

Imaging analysis

Statistical analysis

Results

Discussion

Limitations

Conclusions

Declarations

References

Additional Declarations

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