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Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography
Original Article
Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography Guang-xian Wang1, Li Wen1, Liu Yang1, Qi-chuang Zhang1, Jin-bo Yin2, Chun-mei Duan3, Dong Zhang1
OBJECTIVE: To study the clinical and morphologic characteristics associated with risk factors for the rupture of intracranial aneurysms (IAs).
-
METHODS: A total of 1115 consecutive patients with 1282 IAs were reviewed from August 2011 to February 2016. The patients and IAs were divided into ruptured and unruptured groups. Based on the clinical and morphologic findings, the risk factors for IA rupture were assessed using statistical methods.
having a high AR (>1), and having a small MD (<3.70 mm), were better predictors of rupture.
-
RESULTS: Age, hypertension, diabetes mellitus, and cerebral atherosclerosis were associated with ruptured IAs. IAs located in the anterior cerebral artery, the anterior communicating artery, the posterior communicating artery, and the internal carotid artery were associated with ruptured IAs. Ruptures were also associated with arterial bifurcations, irregular aneurysm shapes, and all continuous data, except neck width. Binary logistic regression showed that IAs located at bifurcations (odds ratio [OR], 1.804), with irregular shapes (OR, 4.677), with high aspect ratios (ARs) (OR, 5.037) or with small mean diameters (MDs) (OR, 0.495) are more prone to rupture. Receiver operating characteristic analysis showed that the threshold values of the AR and MD were 1 and 3.70 mm, respectively.
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CONCLUSIONS: Morphologic characteristics, such as being located at bifurcations, being irregularly shaped,
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Key words Angiography - Computed tomography - Intracranial aneurysm - Risk factors - Rupture - Subarachnoid hemorrhage -
Abbreviations and Acronyms AR: Aspect ratio CI: Confidence interval CT: Computed tomography CTA: Computed tomography angiography IA: Intracranial aneurysm MD: Mean diameters of the parent and daughter arteries OR: Odds ratio
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INTRODUCTION
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nruptured intracranial aneurysms (UIAs) are found in approximately 2%e10% of the general population.1 Most UIAs are usually silent and do not rupture during patients’ lifetimes,2 but rupture is characterized by high mortality and morbidity.3 Treatment-incidental UIAs remain controversial, although prophylactic treatment (microsurgical clipping or endovascular coiling) is also associated with risks.3 Thus, identifying the risk factors for UIA rupture would be of enormous clinical value. The risk factors for intracranial aneurysm (IA) rupture have been retrospectively studied by several groups over the past 2 decades. Certain morphologic risk factors (e.g., aneurysm size, irregular shape, and aspect ratio [AR]) and clinical factors (e.g., gender, hypertension, and smoking) were found to be associated with IA rupture.1-3 Recently, some prospective studies have reported differing results regarding the risk factors for UIA rupture.4-7 In theory, it is best to prospectively investigate IA rupture. However, doing so is difficult for the following reasons: 1) Ethical issues. For example, if it is determined that an aneurysm has increased in size and has an irregular shape, it may rupture at any time. The patient may die as a result of rupture if left untreated, but if the aneurysm
RIA: Ruptured intracranial aneurysm SR: Size ratio UIA: Unruptured intracranial aneurysm From the Departments of 1Radiology, 2Neurosurgery, and 3Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China To whom correspondence should be addressed: Dong Zhang, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.174 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
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ORIGINAL ARTICLE GUANG-XIAN WANG ET AL.
RUPTURE RISK OF INTRACRANIAL ANEURYSMS
is treated, the case must be excluded from the analysis. 2) IAs cannot be monitored in real time. Aneurysms may increase in size quickly before rupture and shrink thereafter, becoming the same size as they were several months or weeks before. 3) Most aneurysms remain silent during the course of a patient’s lifetime. 4) Patients with aneurysms may have significant stress and anxiety because of the aneurysms and may want to remove the ticking time bomb. In addition, previous studies have reported that hemodynamics play an important role in predicting IA rupture. However, computational fluid dynamic results have been conflicting regarding wall shear stress.8-10 Recently, a study reported no independent additional value of aneurysmal hemodynamics in discriminating rupture status.11 IA hemodynamics depend strongly on the geometry of the IAs and the feeding vessel.12 In addition, hemodynamic measurements are difficult to perform and often unavailable because of the expenses and time required.10 Therefore, a retrospective study is a simple method for evaluating the risk factors for IA rupture, but large sample sizes are needed. For these reasons, the purpose of this study was to investigate the clinical and morphologic characteristics associated with risk factors for the rupture of IAs. METHODS Patients This retrospective study was approved by our institutional ethics committee. From August 2011 to February 2016, 22,848 consecutive patients underwent head computed tomography (CT) angiography (CTA) examinations. Before the examination, all patients or their family members signed written informed consent. For the 1246 patients with IAs (5.5%), the patient exclusion criteria were as follows: 1) mycotic, traumatic, or fusiform aneurysms; 2) cases associated with arteriovenous malformations and poor image quality; and 3) an IA size smaller than 1.8 mm. A total of 1115 patients (466 ruptured and 649 unruptured) with 1282 IAs (466 ruptured and 816 unruptured) were available for analysis. The following clinical characteristics were collected: gender and age; status for hypertension, heart disease, diabetes mellitus, and cerebral atherosclerosis; current alcohol use and smoking statuses; history of subarachnoid hemorrhage from the same or another aneurysm; and the presence of multiple aneurysms. All clinical data except gender and age were recorded as either present or absent. In cases with multiple IAs, the ruptured IA (RIA) was determined based on the CT, angiographic, or operative findings. Based on a power analysis, the sample size met the requirements for this study. CTA and Image Analysis All CTAs were performed using a 64-slice CT machine (GE LightSpeed VCT [GE Healthcare, Milwaukee, Wisconsin, USA]). The CTA images were evaluated on a GE Advantix workstation (Advantage Windows 4.5). Two observers independently obtained all measurements, and the average value was used for subsequent statistical analyses. Bifurcation IAs were defined as lesions originating from major bifurcations, whereas side-wall IAs were defined as those located in only 1 parent vessel or at a branch that was smaller than the
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parent vessel (
Figure 1. A side-wall posterior communicating artery aneurysm with a daughter sac and a high aspect ratio. The image shows the method for the following dimension measurements: neck width (the largest cross-sectional diameter of the aneurysm neck); depth (the longest diameter between the neck and dome); width (the maximum distance vertical to depth); maximum size (the largest measurement in terms of maximum dome diameter or width); flow angle (angle between aneurysm depth vector and the vector of the centerline of the parent artery); and the mean diameter ((LP1þLP2)/2).
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ORIGINAL ARTICLE GUANG-XIAN WANG ET AL.
RUPTURE RISK OF INTRACRANIAL ANEURYSMS
RESULTS The clinical characteristics of the 1115 patients are listed in Table 1. The mean age was 58.2 12.6 years (56.8 12.9 years for men and 59.1 12.3 years for women). The mean ages were 60.89 12.49 for the unruptured and 54.58 11.78 years for the ruptured groups. Sixty years of age was chosen to dichotomize the sample. Age, hypertension, diabetes mellitus, and cerebral atherosclerosis were associated with IA rupture. Table 2 shows the morphologic characteristics of the IAs. IA rupture was associated with aneurysms located at the anterior communicating artery, anterior cerebral artery, posterior communicating artery, internal carotid artery, and bifurcations. Rupture was also associated with irregularly shaped IAs and with all continuous data, except neck width. The 17 considered variables (P 0.05) were entered into a forward conditional binary logistic regression model. IAs that were located at a bifurcation (OR, 1.804) or were irregularly shaped (OR, 4.677), as well as those with a high AR (OR, 5.037) or small MD (OR, 0.495), were better predictors of likely rupture (Table 3). The areas under the receiver operating characteristic curve for the AR and MD were 0.790 and 0.735, respectively (Table 4). The cutoff points for the AR and MD were 1 and 3.70 mm, respectively (Figure 3).
Figure 2. An anterior communicating artery A1-dominant aneurysm located at bifurcations, with the mean diameter defined as (LAþLBþLP)/3.
DISCUSSION
(for abnormally distributed data), and categorical data were compared using c2 tests. Forward binary logistic regression was performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the likelihood of aneurysm rupture. The cutoff value, sensitivity, and specificity were calculated using receiver operating characteristic curve analysis.
Most patients with IAs are asymptomatic, and not all IAs will rupture. Furthermore, the treatment of UIAs is still a controversial
Table 2. The Morphologic Characteristics of Aneurysms Unruptured (n [ 816)
Ruptured (n [ 466)
P
Anterior communicating artery
88 (10.8)
140 (30.0)
<0.001
Anterior cerebral artery
32 (3.9)
32 (6.9)
0.02
Morphologic Parameters Location
Table 1. The Clinical Characteristics of Patients with Aneurysms
Clinical Data Male
Unruptured (n [ 649), n (%)
Ruptured (n [ 466), n (%)
248 (38.2)
175 (37.6)
P 0.823
Age (60 years)
351 (54.1)
155 (33.3)
<0.001
Hypertension
304 (46.8)
178 (38.2)
0.004
Heart disease
61 (9.4)
36 (7.7)
0.328
Diabetes mellitus Cerebral atherosclerosis
52 (8.0)
26 (5.6)
0.041
155 (23.9)
14 (3.0)
<0.001
Current alcohol
122 (18.8)
108 (23.2)
0.075
Current smoking
156 (24.3)
125 (26.8)
0.290
2 (0.3)
1 (0.2)
1.000
History of SAH from the same aneurysm History of SAH from another aneurysm Multiple aneurysms
20 (3.1) 82 (12.6)
15 (3.2) 69 (15.0)
SAH, subarachnoid hemorrhage.
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0.897 0.296
Middle cerebral artery
141 (17.3)
81 (17.4)
0.320
Posterior communicating artery
156 (19.1)
161 (34.5)
<0.001
Internal carotid artery
373 (45.7)
31 (6.7)
<0.001
26 (3.2)
21 (4.5)
0.226
317 (38.8)
332 (71.2)
Posterior cerebral circulation Bifurcation Irregular shape Depth (mm)
<0.001
178 (21.8)
311 (66.4)
<0.001
4.79 3.43
6.57 3.18
<0.001
Width (mm)
5.38 3.42
5.68 3.27
<0.001
Neck width (mm)
4.67 1.93
4.45 1.81
0.051
Maximum size (mm)
6.00 3.48
7.70 3.48
<0.001
Aspect ratio
1.00 0.44
1.53 0.64
<0.001
Mean diameters of the parent and daughter arteries (mm)
3.62 0.91
2.86 0.73
<0.001
Size ratio
1.39 1.02
2.44 1.41
<0.001
Flow angle ( )
107.00 29.32 121.62 3.91 <0.001
Values are number (%) except where indicated otherwise.
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Table 3. Binary Logistic Regression Analysis for all Aneurysms Rupture Variable
Odds Ratio
95% Confidence Interval
Age (years)
1.005
0.411
0.993e1.018
0.005
Hypertension
0.948
0.732
0.697e1.288
0.054
P
b*
Diabetes mellitus
0.765
0.348
0.421e1.356
0.280
Cerebral atherosclerosis
0.762
0.236
0.487e1.195
0.271
Anterior communicating artery
1.305
0.268
0.815e2.091
0.266
Anterior cerebral artery
0.986
0.943
0.674e1.444
0.014
Posterior communicating artery
1.020
0.726
0.915e1.137
0.019
Internal carotid artery
1.074
0.101
0.986e1.169
0.071
Bifurcation
1.804
0.001
1.262e2.579
0.590
Irregular shape
4.677
<0.001
3.374e6.482
1.543
Depth (mm)
0.870
0.291
0.672e1.127
0.139
Width (mm)
0.837
0.423
0.749e1.236
0.177
Maximum size (mm)
1.100
0.099
0.982e1.233
0.096
Aspect ratio
5.037
<0.001
3.579e7.090
1.314
Mean diameter (mm)
0.495
<0.001
0.397e0.618
0.703
Size ratio
1.321
0.221
0.846e2.064
0.278
Flow angle ( )
0.999
0.878
0.993e1.006
<0.001
*Partial regression coefficient.
topic in neurosurgery. A simple and reliable method for evaluating the risk factors that can aid in the treatment decision for UIAs is not available. In addition to prospective studies and computational fluid dynamics, retrospective studies with large sample sizes are needed. In the present study, we compared patients with UIAs and RIAs and found that IAs located at a bifurcation and those with an irregular shape, a high AR, or a small MD were predictive of rupture. Certain clinical characteristics can influence whether an aneurysm ruptures. For instance, previous reports have shown that clinical characteristics such as female sex, age, hypertension, smoking, and multiple aneurysms were associated with IA rupture,6,18-21 whereas other studies have reported that demographic variables are not risk factors for rupture.17,22-26 The present study showed that none of these factors was associated with IA rupture. IAs usually occur at arterial bifurcations, and many cases of subarachnoid hemorrhage arise from bifurcation aneurysms.15 In the present study, we found that IAs located at bifurcations have a
higher risk of rupture than do those located on the side wall. The wall is weak at the bifurcation arteries, and the hemodynamic stress changes in these regions; thus, bifurcations are known to be vulnerable sites and may explain our results.27,28 An aneurysm with daughter sacs or a lobular shape was defined as having an irregular shape.14-16 Previous retrospective studies have reported that aneurysms with irregular shapes were associated with a higher risk of rupture.11,15,23,29-31 Recently, a prospective study7 indicated that UIAs with daughter sacs were also more likely to rupture. The present results also showed that an irregular shape was associated with aneurysm rupture, which may be because daughter sac walls are thinner than other sites and the irregular shape leads to blood flow pattern instabilities. Previous studies on AR and SR produced conflicting results. Many researchers9,13,17,24,26,29 have reported that SR rather than AR is a risk factor for IA rupture. However, other groups1,14,15,25,31,32 have reported that the larger the AR increase, the greater the risk of IA rupture. In addition, there is no consensus on the common threshold value of AR. In the present study, we found that the AR was significantly and positively correlated with IA rupture and that the threshold value of AR was 1, a smaller value than has been reported previously.1,31-33 These conflicting results can be explained by the use of different measurement methodologies. For example, AR has been calculated as the perpendicular height divided by the neck width32,33 and/or analyzed as a dichotomous variable of greater or less than 1.6 given previous results suggesting this value to be clinically significant.1,32 Although perpendicular height is usually equal to or less than the depth, the threshold value of AR obtained from this study was 1, compared with 1.18 reported by Dhar et al.33 On the other hand, some studies have used two-dimensional digital subtraction angiography, two-dimensional CTA, or even magnetic resonance angiography data.1,31,32 This study used three-dimensional data reconstructed from CTA, and these differences in imaging modalities may explain the different reported AR values. Other potential reasons for these varying results are regional and ethnicity factors. IAs arising from smaller vessels have thinner walls and would experience greater wall tension than those with greater wall thicknesses.34,35 We found that MD was an independent predictor of IA rupture, indicating that a smaller artery is associated with a higher risk of rupture. However, the present data must be confirmed in further studies given that RIAs can be affected by vasospasm, which affects the MD. Limitations The study had several limitations. First, the shape or size of the RIAs may have changed as a result of the rupture.36 Moreover, the IAs were not monitored in real time, and the median time span between imaging before and immediately after rupture was
Table 4. Area Under the Curve for Aspect Ratio and Mean Diameter Characteristics
Area
Threshold Value
P
Sensitivity (%)
Specificity (%)
95% Confidence Interval
Aspect ratio
0.790
1
<0.001
85.0
62.3
0.764e0.816
Mean diameter (mm)
0.735
3.70
<0.001
85.4
48.5
0.708e0.763
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ORIGINAL ARTICLE GUANG-XIAN WANG ET AL.
RUPTURE RISK OF INTRACRANIAL ANEURYSMS
after rupture.37,38 Second, because UIAs can grow and develop gross morphologic differences over time (e.g., form daughter sacs or grow lobules) and may rupture, it is best to dynamically observe size and morphologic changes. Third, family history was not considered in this study because these data were not recorded for many patients, particularly elderly patients. In future studies, a larger multicenter retrospective study with a larger patient sample would improve the significance of the findings. Inflammation is a key component in the pathophysiology of the formation and rupture of IAs.39 Aneurysmal wall enhancement is believed to reflect wall inflammation and measuring enhancement with high-resolution magnetic resonance imaging may assist in the evaluation of rupture risk. In addition, the wall of RIAs has higher metalloproteinase-9 expression than do UIAs. We are synthesizing a magnetic resonance imaging probe targeting metalloproteinase-9, by which rupture risk may be evaluated based on the enhancement degree of the aneurysm wall. Figure 3. The areas under the receiver operating characteristic curves for the aspect ratio (AR) and mean diameters of the parent and daughter arteries (MD) are 0.790 (95% confidence interval, 0.764e0.816) and 0.735 (95% confidence interval, 0.708e0.763), respectively. The cutoff points for the aspect ratio and mean diameters of the parent and daughter arteries are 1 and 3.70 mm, the sensitivities are 85% and 85.4%, and the specificities are 62.3% and 48.5%, respectively.
12 months (range, 0.3e96 months). During this time and before rupture, IAs can increase in size and form daughter sacs. However, previous studies have reported that IAs do not shrink
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CONCLUSIONS Aneurysms that are located at bifurcations and have irregular shapes, a high AR, and a small MD are more likely to rupture. Aneurysms with these characteristics should be actively treated. ACKNOWLEDGMENTS The authors thank American Journal Experts for assisting in the preparation of this article. We thank Ru-fu Xu, Professor of Epidemiology of the Xinqiao Hospital, Third Military Medical University, for statistical treatment.
7. 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;366:2474-2482. 8. Cebral JR, Mut F, Weir J, Putman C. Quantitative characterization of the hemodynamic environment in ruptured and unruptured brain aneurysms. AJNR Am J Neuroradiol. 2011;32:145-151. 9. Xiang J, Natarajan SK, Tremmel M, Ma D, Mocco J, Hopkins LN, et al. Hemodynamicmorphologic discriminants for intracranial aneurysm rupture. Stroke. 2011;42:144-152. 10. Nixon AM, Gunel M, Sumpio BE. The critical role of hemodynamics in the development of cerebral vascular disease. J Neurosurg. 2010;112:1240-1253.
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14. Ryu CW, Kwon OK, Koh JS, Kim EJ. Analysis of aneurysm rupture in relation to the geometric indices: aspect ratio, volume, and volume-to-neck ratio. Neuroradiology. 2011;53:883-889. 15. Wang GX, Zhang D, Wang ZP, Yang LQ, Zhang L, Wen L. Risk factors for the rupture of bifurcation intracranial aneurysms using CT angiography. Yonsei Med J. 2016;57:1178-1184. 16. Wang GX, Yu JY, Wen L, Zhang L, Mou KJ, Zhang D. Risk factors for the rupture of middle cerebral artery bifurcation aneurysms using CT angiography. PLoS One. 2016;11:e0166654.
11. Schneiders JJ, Marquering HA, van Ooij P, van den Berg R, Nederveen AJ, Verbaan D, et al. Additional value of intra-aneurysmal hemodynamics in discriminating ruptured versus unruptured intracranial aneurysms. AJNR Am J Neuroradiol. 2015;36: 1920-1926.
17. Cai W, Shi D, Gong J, Chen G, Qiao F, Dou X, et al. Are morphologic parameters actually correlated with the rupture status of anterior communicating artery aneurysms? World Neurosurg. 2015; 84:1278-1283.
12. Hassan T, Timofeev EV, Saito T, Shimizu H, Ezura M, Matsumoto Y, et al. A proposed parent vessel geometry-based categorizations of saccular intracranial aneurysms: computational flow dynamics analysis of the risk factors for lesion rupture. J Neurosurg. 2005;103:662-680.
18. Sonobe M, Yamazaki T, Yonekura M, Kikuchi H. Small unruptured intracranial aneurysm verification study: SUAVe study, Japan. Stroke. 2010;41: 1969-1977.
13. Baharoglu MI, Lauric A, Gao BL, Malek AM. Identification of a dichotomy in morphological predictors of rupture status between sidewall- and
19. Lindekleiv H, Sandvei MS, Njølstad I, Løchen ML, Romundstad PR, Vatten L, et al. Sex differences in risk factors for aneurysmal subarachnoid hemorrhage: a cohort study. Neurology. 2011;76: 637-664.
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20. Wermer MJ, van der Schaaf IC, Algra A, Rinkel GJ. Risk of rupture of unruptured intracranial aneurysms in relation to patient and aneurysms characteristics: an updated meta-analysis. Stroke. 2007; 38:1404-1410. 21. Nahed BV, DiLuna ML, Morgan T, Ocal E, Hawkins AA, Ozduman K, et al. Hypertension, age, and location predict rupture of small intracranial aneurysms. Neurosurgery. 2005;57:676-683. 22. Matsukawa H, Uemura A, Fujii M, Kamo M, Takahashi O, Sumiyoshi S. Morphological and clinical risk factors for the rupture of anterior communicating artery aneurysms. J Neurosurg. 2013;118:978-983. 23. Mehan WA Jr, Romero JM, Hirsch JA, Sabbag DJ, Gonzalez RG, Heit JJ, et al. Unruptured intracranial aneurysms conservatively followed with serial CT angiography: could morphology and growth predict rupture? J Neurointerv Surg. 2014;6:761-766. 24. Lv N, Feng Z, Wang C, Cao W, Fang Y, Karmonik C, et al. Morphological risk factors for rupture of small (<7 mm) posterior communicating artery aneurysms. World Neurosurg. 2016;87: 311-315. 25. Lin N, Ho A, Gross BA, Pieper S, Frerichs KU, Day AL, et al. Differences in simple morphological variables in ruptured and unruptured middle cerebral artery aneurysms. J Neurosurg. 2012;117: 913-919. 26. Lin N, Ho A, Charoenvimolphan N, Frerichs KU, Day AL, Du R. Analysis of morphological parameters to differentiate rupture status in anterior communicating artery aneurysms. PLoS One. 2013; 8:e79635. 27. Kang HG, Kim BJ, Lee J, Kim MJ, Kang DW, Kim JS, et al. Risk factors associated with the
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presence of unruptured intracranial aneurysms. Stroke. 2015;46:3093-3098. 28. van der Kolk NM, Algra A, Rinkel GJ. Risk of aneurysm rupture at intracranial arterial bifurcations. Cerebrovasc Dis. 2010;30:29-35. 29. Kang H, Ji W, Qian Z, Li Y, Jiang C, Wu Z, et al. Aneurysm characteristics associated with the rupture risk of intracranial aneurysms: a selfcontrolled study. PLoS One. 2015;10:e0142330. 30. 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;73:825-837. 31. Huang ZQ, Meng ZH, Hou ZJ, Huang SQ, Chen JN, Yu H, et al. Geometric parameter analysis of ruptured and unruptured aneurysms in patients with symmetric bilateral intracranial aneurysms: a multicenter CT angiography study. AJNR Am J Neuroradiol. 2016;37:1413-1417. 32. Amenta PS, Yadla S, Campbell PG, Maltenfort MG, Dey S, Ghosh S, et al. Analysis of nonmodifiable risk factors for intracranial aneurysm rupture in a large, retrospective cohort. Neurosurgery. 2012;70: 693-701. 33. Dhar S, Tremmel M, Mocco J, Kim M, Yamamoto J, Siddiqui AH, et al. Morphology parameters for intracranial aneurysm rupture risk assessment. Neurosurgery. 2008;63:185-196. 34. Carter BS, Sheth S, Chang E, Sethl M, Ogilvy CS. Epidemiology of the size distribution of intracranial bifurcation aneurysms: smaller size of distal aneurysms and increasing size of unruptured aneurysms with age. Neurosurgery. 2006;58:217-223.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 20 July 2017; accepted 31 October 2017 Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.174 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.174
Risk Factors for the Rupture of Intracranial Aneurysms Using Computed Tomography Angiography Guang-xian Wang1, Li Wen1, Liu Yang1, Qi-chuang Zhang1, Jin-bo Yin2, Chun-mei Duan3, Dong Zhang1
OBJECTIVE: To study the clinical and morphologic characteristics associated with risk factors for the rupture of intracranial aneurysms (IAs).
-
METHODS: A total of 1115 consecutive patients with 1282 IAs were reviewed from August 2011 to February 2016. The patients and IAs were divided into ruptured and unruptured groups. Based on the clinical and morphologic findings, the risk factors for IA rupture were assessed using statistical methods.
having a high AR (>1), and having a small MD (<3.70 mm), were better predictors of rupture.
-
RESULTS: Age, hypertension, diabetes mellitus, and cerebral atherosclerosis were associated with ruptured IAs. IAs located in the anterior cerebral artery, the anterior communicating artery, the posterior communicating artery, and the internal carotid artery were associated with ruptured IAs. Ruptures were also associated with arterial bifurcations, irregular aneurysm shapes, and all continuous data, except neck width. Binary logistic regression showed that IAs located at bifurcations (odds ratio [OR], 1.804), with irregular shapes (OR, 4.677), with high aspect ratios (ARs) (OR, 5.037) or with small mean diameters (MDs) (OR, 0.495) are more prone to rupture. Receiver operating characteristic analysis showed that the threshold values of the AR and MD were 1 and 3.70 mm, respectively.
-
CONCLUSIONS: Morphologic characteristics, such as being located at bifurcations, being irregularly shaped,
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Key words Angiography - Computed tomography - Intracranial aneurysm - Risk factors - Rupture - Subarachnoid hemorrhage -
Abbreviations and Acronyms AR: Aspect ratio CI: Confidence interval CT: Computed tomography CTA: Computed tomography angiography IA: Intracranial aneurysm MD: Mean diameters of the parent and daughter arteries OR: Odds ratio
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INTRODUCTION
U
nruptured intracranial aneurysms (UIAs) are found in approximately 2%e10% of the general population.1 Most UIAs are usually silent and do not rupture during patients’ lifetimes,2 but rupture is characterized by high mortality and morbidity.3 Treatment-incidental UIAs remain controversial, although prophylactic treatment (microsurgical clipping or endovascular coiling) is also associated with risks.3 Thus, identifying the risk factors for UIA rupture would be of enormous clinical value. The risk factors for intracranial aneurysm (IA) rupture have been retrospectively studied by several groups over the past 2 decades. Certain morphologic risk factors (e.g., aneurysm size, irregular shape, and aspect ratio [AR]) and clinical factors (e.g., gender, hypertension, and smoking) were found to be associated with IA rupture.1-3 Recently, some prospective studies have reported differing results regarding the risk factors for UIA rupture.4-7 In theory, it is best to prospectively investigate IA rupture. However, doing so is difficult for the following reasons: 1) Ethical issues. For example, if it is determined that an aneurysm has increased in size and has an irregular shape, it may rupture at any time. The patient may die as a result of rupture if left untreated, but if the aneurysm
RIA: Ruptured intracranial aneurysm SR: Size ratio UIA: Unruptured intracranial aneurysm From the Departments of 1Radiology, 2Neurosurgery, and 3Neurology, Xinqiao Hospital, Third Military Medical University, Chongqing, China To whom correspondence should be addressed: Dong Zhang, M.D. [E-mail: [email protected]] Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.174 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
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RUPTURE RISK OF INTRACRANIAL ANEURYSMS
is treated, the case must be excluded from the analysis. 2) IAs cannot be monitored in real time. Aneurysms may increase in size quickly before rupture and shrink thereafter, becoming the same size as they were several months or weeks before. 3) Most aneurysms remain silent during the course of a patient’s lifetime. 4) Patients with aneurysms may have significant stress and anxiety because of the aneurysms and may want to remove the ticking time bomb. In addition, previous studies have reported that hemodynamics play an important role in predicting IA rupture. However, computational fluid dynamic results have been conflicting regarding wall shear stress.8-10 Recently, a study reported no independent additional value of aneurysmal hemodynamics in discriminating rupture status.11 IA hemodynamics depend strongly on the geometry of the IAs and the feeding vessel.12 In addition, hemodynamic measurements are difficult to perform and often unavailable because of the expenses and time required.10 Therefore, a retrospective study is a simple method for evaluating the risk factors for IA rupture, but large sample sizes are needed. For these reasons, the purpose of this study was to investigate the clinical and morphologic characteristics associated with risk factors for the rupture of IAs. METHODS Patients This retrospective study was approved by our institutional ethics committee. From August 2011 to February 2016, 22,848 consecutive patients underwent head computed tomography (CT) angiography (CTA) examinations. Before the examination, all patients or their family members signed written informed consent. For the 1246 patients with IAs (5.5%), the patient exclusion criteria were as follows: 1) mycotic, traumatic, or fusiform aneurysms; 2) cases associated with arteriovenous malformations and poor image quality; and 3) an IA size smaller than 1.8 mm. A total of 1115 patients (466 ruptured and 649 unruptured) with 1282 IAs (466 ruptured and 816 unruptured) were available for analysis. The following clinical characteristics were collected: gender and age; status for hypertension, heart disease, diabetes mellitus, and cerebral atherosclerosis; current alcohol use and smoking statuses; history of subarachnoid hemorrhage from the same or another aneurysm; and the presence of multiple aneurysms. All clinical data except gender and age were recorded as either present or absent. In cases with multiple IAs, the ruptured IA (RIA) was determined based on the CT, angiographic, or operative findings. Based on a power analysis, the sample size met the requirements for this study. CTA and Image Analysis All CTAs were performed using a 64-slice CT machine (GE LightSpeed VCT [GE Healthcare, Milwaukee, Wisconsin, USA]). The CTA images were evaluated on a GE Advantix workstation (Advantage Windows 4.5). Two observers independently obtained all measurements, and the average value was used for subsequent statistical analyses. Bifurcation IAs were defined as lesions originating from major bifurcations, whereas side-wall IAs were defined as those located in only 1 parent vessel or at a branch that was smaller than the
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parent vessel (
Figure 1. A side-wall posterior communicating artery aneurysm with a daughter sac and a high aspect ratio. The image shows the method for the following dimension measurements: neck width (the largest cross-sectional diameter of the aneurysm neck); depth (the longest diameter between the neck and dome); width (the maximum distance vertical to depth); maximum size (the largest measurement in terms of maximum dome diameter or width); flow angle (angle between aneurysm depth vector and the vector of the centerline of the parent artery); and the mean diameter ((LP1þLP2)/2).
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ORIGINAL ARTICLE GUANG-XIAN WANG ET AL.
RUPTURE RISK OF INTRACRANIAL ANEURYSMS
RESULTS The clinical characteristics of the 1115 patients are listed in Table 1. The mean age was 58.2 12.6 years (56.8 12.9 years for men and 59.1 12.3 years for women). The mean ages were 60.89 12.49 for the unruptured and 54.58 11.78 years for the ruptured groups. Sixty years of age was chosen to dichotomize the sample. Age, hypertension, diabetes mellitus, and cerebral atherosclerosis were associated with IA rupture. Table 2 shows the morphologic characteristics of the IAs. IA rupture was associated with aneurysms located at the anterior communicating artery, anterior cerebral artery, posterior communicating artery, internal carotid artery, and bifurcations. Rupture was also associated with irregularly shaped IAs and with all continuous data, except neck width. The 17 considered variables (P 0.05) were entered into a forward conditional binary logistic regression model. IAs that were located at a bifurcation (OR, 1.804) or were irregularly shaped (OR, 4.677), as well as those with a high AR (OR, 5.037) or small MD (OR, 0.495), were better predictors of likely rupture (Table 3). The areas under the receiver operating characteristic curve for the AR and MD were 0.790 and 0.735, respectively (Table 4). The cutoff points for the AR and MD were 1 and 3.70 mm, respectively (Figure 3).
Figure 2. An anterior communicating artery A1-dominant aneurysm located at bifurcations, with the mean diameter defined as (LAþLBþLP)/3.
DISCUSSION
(for abnormally distributed data), and categorical data were compared using c2 tests. Forward binary logistic regression was performed to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for the likelihood of aneurysm rupture. The cutoff value, sensitivity, and specificity were calculated using receiver operating characteristic curve analysis.
Most patients with IAs are asymptomatic, and not all IAs will rupture. Furthermore, the treatment of UIAs is still a controversial
Table 2. The Morphologic Characteristics of Aneurysms Unruptured (n [ 816)
Ruptured (n [ 466)
P
Anterior communicating artery
88 (10.8)
140 (30.0)
<0.001
Anterior cerebral artery
32 (3.9)
32 (6.9)
0.02
Morphologic Parameters Location
Table 1. The Clinical Characteristics of Patients with Aneurysms
Clinical Data Male
Unruptured (n [ 649), n (%)
Ruptured (n [ 466), n (%)
248 (38.2)
175 (37.6)
P 0.823
Age (60 years)
351 (54.1)
155 (33.3)
<0.001
Hypertension
304 (46.8)
178 (38.2)
0.004
Heart disease
61 (9.4)
36 (7.7)
0.328
Diabetes mellitus Cerebral atherosclerosis
52 (8.0)
26 (5.6)
0.041
155 (23.9)
14 (3.0)
<0.001
Current alcohol
122 (18.8)
108 (23.2)
0.075
Current smoking
156 (24.3)
125 (26.8)
0.290
2 (0.3)
1 (0.2)
1.000
History of SAH from the same aneurysm History of SAH from another aneurysm Multiple aneurysms
20 (3.1) 82 (12.6)
15 (3.2) 69 (15.0)
SAH, subarachnoid hemorrhage.
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0.897 0.296
Middle cerebral artery
141 (17.3)
81 (17.4)
0.320
Posterior communicating artery
156 (19.1)
161 (34.5)
<0.001
Internal carotid artery
373 (45.7)
31 (6.7)
<0.001
26 (3.2)
21 (4.5)
0.226
317 (38.8)
332 (71.2)
Posterior cerebral circulation Bifurcation Irregular shape Depth (mm)
<0.001
178 (21.8)
311 (66.4)
<0.001
4.79 3.43
6.57 3.18
<0.001
Width (mm)
5.38 3.42
5.68 3.27
<0.001
Neck width (mm)
4.67 1.93
4.45 1.81
0.051
Maximum size (mm)
6.00 3.48
7.70 3.48
<0.001
Aspect ratio
1.00 0.44
1.53 0.64
<0.001
Mean diameters of the parent and daughter arteries (mm)
3.62 0.91
2.86 0.73
<0.001
Size ratio
1.39 1.02
2.44 1.41
<0.001
Flow angle ( )
107.00 29.32 121.62 3.91 <0.001
Values are number (%) except where indicated otherwise.
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Table 3. Binary Logistic Regression Analysis for all Aneurysms Rupture Variable
Odds Ratio
95% Confidence Interval
Age (years)
1.005
0.411
0.993e1.018
0.005
Hypertension
0.948
0.732
0.697e1.288
0.054
P
b*
Diabetes mellitus
0.765
0.348
0.421e1.356
0.280
Cerebral atherosclerosis
0.762
0.236
0.487e1.195
0.271
Anterior communicating artery
1.305
0.268
0.815e2.091
0.266
Anterior cerebral artery
0.986
0.943
0.674e1.444
0.014
Posterior communicating artery
1.020
0.726
0.915e1.137
0.019
Internal carotid artery
1.074
0.101
0.986e1.169
0.071
Bifurcation
1.804
0.001
1.262e2.579
0.590
Irregular shape
4.677
<0.001
3.374e6.482
1.543
Depth (mm)
0.870
0.291
0.672e1.127
0.139
Width (mm)
0.837
0.423
0.749e1.236
0.177
Maximum size (mm)
1.100
0.099
0.982e1.233
0.096
Aspect ratio
5.037
<0.001
3.579e7.090
1.314
Mean diameter (mm)
0.495
<0.001
0.397e0.618
0.703
Size ratio
1.321
0.221
0.846e2.064
0.278
Flow angle ( )
0.999
0.878
0.993e1.006
<0.001
*Partial regression coefficient.
topic in neurosurgery. A simple and reliable method for evaluating the risk factors that can aid in the treatment decision for UIAs is not available. In addition to prospective studies and computational fluid dynamics, retrospective studies with large sample sizes are needed. In the present study, we compared patients with UIAs and RIAs and found that IAs located at a bifurcation and those with an irregular shape, a high AR, or a small MD were predictive of rupture. Certain clinical characteristics can influence whether an aneurysm ruptures. For instance, previous reports have shown that clinical characteristics such as female sex, age, hypertension, smoking, and multiple aneurysms were associated with IA rupture,6,18-21 whereas other studies have reported that demographic variables are not risk factors for rupture.17,22-26 The present study showed that none of these factors was associated with IA rupture. IAs usually occur at arterial bifurcations, and many cases of subarachnoid hemorrhage arise from bifurcation aneurysms.15 In the present study, we found that IAs located at bifurcations have a
higher risk of rupture than do those located on the side wall. The wall is weak at the bifurcation arteries, and the hemodynamic stress changes in these regions; thus, bifurcations are known to be vulnerable sites and may explain our results.27,28 An aneurysm with daughter sacs or a lobular shape was defined as having an irregular shape.14-16 Previous retrospective studies have reported that aneurysms with irregular shapes were associated with a higher risk of rupture.11,15,23,29-31 Recently, a prospective study7 indicated that UIAs with daughter sacs were also more likely to rupture. The present results also showed that an irregular shape was associated with aneurysm rupture, which may be because daughter sac walls are thinner than other sites and the irregular shape leads to blood flow pattern instabilities. Previous studies on AR and SR produced conflicting results. Many researchers9,13,17,24,26,29 have reported that SR rather than AR is a risk factor for IA rupture. However, other groups1,14,15,25,31,32 have reported that the larger the AR increase, the greater the risk of IA rupture. In addition, there is no consensus on the common threshold value of AR. In the present study, we found that the AR was significantly and positively correlated with IA rupture and that the threshold value of AR was 1, a smaller value than has been reported previously.1,31-33 These conflicting results can be explained by the use of different measurement methodologies. For example, AR has been calculated as the perpendicular height divided by the neck width32,33 and/or analyzed as a dichotomous variable of greater or less than 1.6 given previous results suggesting this value to be clinically significant.1,32 Although perpendicular height is usually equal to or less than the depth, the threshold value of AR obtained from this study was 1, compared with 1.18 reported by Dhar et al.33 On the other hand, some studies have used two-dimensional digital subtraction angiography, two-dimensional CTA, or even magnetic resonance angiography data.1,31,32 This study used three-dimensional data reconstructed from CTA, and these differences in imaging modalities may explain the different reported AR values. Other potential reasons for these varying results are regional and ethnicity factors. IAs arising from smaller vessels have thinner walls and would experience greater wall tension than those with greater wall thicknesses.34,35 We found that MD was an independent predictor of IA rupture, indicating that a smaller artery is associated with a higher risk of rupture. However, the present data must be confirmed in further studies given that RIAs can be affected by vasospasm, which affects the MD. Limitations The study had several limitations. First, the shape or size of the RIAs may have changed as a result of the rupture.36 Moreover, the IAs were not monitored in real time, and the median time span between imaging before and immediately after rupture was
Table 4. Area Under the Curve for Aspect Ratio and Mean Diameter Characteristics
Area
Threshold Value
P
Sensitivity (%)
Specificity (%)
95% Confidence Interval
Aspect ratio
0.790
1
<0.001
85.0
62.3
0.764e0.816
Mean diameter (mm)
0.735
3.70
<0.001
85.4
48.5
0.708e0.763
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ORIGINAL ARTICLE GUANG-XIAN WANG ET AL.
RUPTURE RISK OF INTRACRANIAL ANEURYSMS
after rupture.37,38 Second, because UIAs can grow and develop gross morphologic differences over time (e.g., form daughter sacs or grow lobules) and may rupture, it is best to dynamically observe size and morphologic changes. Third, family history was not considered in this study because these data were not recorded for many patients, particularly elderly patients. In future studies, a larger multicenter retrospective study with a larger patient sample would improve the significance of the findings. Inflammation is a key component in the pathophysiology of the formation and rupture of IAs.39 Aneurysmal wall enhancement is believed to reflect wall inflammation and measuring enhancement with high-resolution magnetic resonance imaging may assist in the evaluation of rupture risk. In addition, the wall of RIAs has higher metalloproteinase-9 expression than do UIAs. We are synthesizing a magnetic resonance imaging probe targeting metalloproteinase-9, by which rupture risk may be evaluated based on the enhancement degree of the aneurysm wall. Figure 3. The areas under the receiver operating characteristic curves for the aspect ratio (AR) and mean diameters of the parent and daughter arteries (MD) are 0.790 (95% confidence interval, 0.764e0.816) and 0.735 (95% confidence interval, 0.708e0.763), respectively. The cutoff points for the aspect ratio and mean diameters of the parent and daughter arteries are 1 and 3.70 mm, the sensitivities are 85% and 85.4%, and the specificities are 62.3% and 48.5%, respectively.
12 months (range, 0.3e96 months). During this time and before rupture, IAs can increase in size and form daughter sacs. However, previous studies have reported that IAs do not shrink
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CONCLUSIONS Aneurysms that are located at bifurcations and have irregular shapes, a high AR, and a small MD are more likely to rupture. Aneurysms with these characteristics should be actively treated. ACKNOWLEDGMENTS The authors thank American Journal Experts for assisting in the preparation of this article. We thank Ru-fu Xu, Professor of Epidemiology of the Xinqiao Hospital, Third Military Medical University, for statistical treatment.
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Conflict of interest statement: The authors declare that the article content was composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Received 20 July 2017; accepted 31 October 2017 Citation: World Neurosurg. (2017). https://doi.org/10.1016/j.wneu.2017.10.174 Journal homepage: www.WORLDNEUROSURGERY.org Available online: www.sciencedirect.com 1878-8750/$ - see front matter ª 2017 Elsevier Inc. All rights reserved.
WORLD NEUROSURGERY, https://doi.org/10.1016/j.wneu.2017.10.174