RESEARCH—HUMAN—CLINICAL STUDIES RESEARCH—HUMAN—CLINICAL STUDIES

Morphological Parameters Associated With Middle Cerebral Artery Aneurysms Anil Can, MD*‡ Allen L. Ho, MD* Ruben Dammers, MD, PhD‡ Clemens M.F. Dirven, MD, PhD‡ Rose Du, MD, PhD* *Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts; ‡Department of Neurosurgery, Erasmus Medical Center, Rotterdam, The Netherlands Content of the manuscript will be presented as a poster at the AANS Annual Meeting in Washington, DC in May 2015. Correspondence: Rose Du, MD, PhD, Department of Neurosurgery, Brigham and Women’s Hospital, Harvard Medical School, 75 Francis St, Boston, MA 02115. E-mail: [email protected] Received, November 8, 2014. Accepted, January 22, 2015. Published Online, March 2, 2015. Copyright © 2015 by the Congress of Neurological Surgeons.

BACKGROUND: Morphological factors contribute to the hemodynamics of the middle cerebral artery (MCA). OBJECTIVE: To identify image-based morphological parameters that correlated with the presence of MCA aneurysms. METHODS: Image-based anatomic parameters obtained from 110 patients with and without MCA bifurcation aneurysms were evaluated with Slicer, an open-source image analysis software, to generate 3-dimensional models of the aneurysms and surrounding vascular architecture. We examined segment lengths, diameters, and vessel-to-vessel angles of the parent and daughter vessels at the MCA bifurcation. In order to reduce confounding by genetic and clinical risk factors, 2 control groups were selected: group A (the unaffected contralateral side of patients with unilateral MCA bifurcation aneurysms) and group B (patients without intracranial aneurysms or other vascular malformations). Univariate and multivariate analyses were performed to determine statistical significance. RESULTS: One hundred ten patients who were evaluated from 2007 to 2014 were analyzed (73 patients with MCA aneurysms and 37 control patients). Multivariate analysis revealed that a smaller parent artery diameter (group A: odds ratio [OR] 0.20, P , .01, group B: OR 0.23, P , .01) and a larger daughter-to-daughter branch angle (group A: OR 1.01, P = .04, group B: OR 1.02, P = .04) were most strongly associated with MCA aneurysm presence after adjusting for other morphological factors. CONCLUSION: Smaller parent artery diameter and larger daughter-to-daughter branch angles are associated with the presence of MCA bifurcation aneurysms. These easily measurable parameters may provide objective metrics to assess aneurysm formation and growth risk stratification in high-risk patients. KEY WORDS: Aneurysm, Fluid dynamics, Middle cerebral artery, Morphology Neurosurgery 76:721–727, 2015

DOI: 10.1227/NEU.0000000000000713

U

nruptured intracranial aneurysms (IAs), which occur in nearly 3% of the population, are being found more often owing to the availability of high-resolution magnetic resonance (MR) imaging and MR angiography.1 Although the underlying etiology of IAs is still not clearly understood, it is widely accepted that aneurysm formation is likely to be a multifactorial process involving genetic, anatomic, and

ABBREVIATIONS: CI, confidence interval; CTA, computed tomography angiography; ICA, internal carotid artery; IA, intracranial aneurysm; MCA, middle cerebral artery; PCoA, posterior communication artery; WSS, wall shear stress

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environmental (eg, smoking and hypertension) risk factors.2-4 Predisposition through familial occurrence, various syndromic diseases (eg, autosomal polycystic kidney disease, Ehler-Danlos syndrome) and several loci that have been linked to the presence of IAs, underline the role of genetics in aneurysm formation.5,6 In addition to genetic and environmental risk factors, hemodynamic stress is thought to be crucial in the natural history of IAs given that IAs particularly develop at specific locations where, for example, the wall shear stress (WSS) appears to be high.7,8 These forces may trigger focal degenerative mechanisms at the vessel wall and are affected by the geometry of the surrounding vascular tree. Therefore, an investigation focusing on the morphological

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CAN ET AL

association of the surrounding vasculature and IA presence will aid in the understanding of the pathogenesis of IAs and the prediction of aneurysm formation.9 Aneurysms of the middle cerebral artery (MCA) constitute approximately 20% of all cerebral aneurysms with the MCA bifurcation as the most common subtype.10 Previous studies have demonstrated that morphological factors of surrounding vasculature are correlated with aneurysm formation9,11-21 and rupture,20,22-35 but the contribution of vascular morphology to MCA aneurysm formation has not been described in a location-specific manner before. We present a large sample of MCA aneurysms that were assessed using a diverse array of morphological variables related to the surrounding vasculature to determine the parameters associated with aneurysm presence. In order to reduce confounding by genetic and environmental risk factors, we paired the aneurysmal side with the unaffected side within the same patients. In addition, we used a second control group without IAs or other (vascular) malformations.

METHODS Patient Selection The study population consisted of 73 patients with MCA aneurysms and 37 control patients without aneurysms evaluated at the Brigham and Women’s Hospital between 2007 and 2014. Exclusion criteria for the aneurysm group included aneurysms that were associated with arteriovenous malformations or those that lacked computed tomography angiography (CTA). Two control groups were selected for data analysis. Control group A consisted of the unaffected contralateral side of patients with unilateral MCA bifurcation aneurysms. Control group B consisted of patients without intracranial arteriovenous malformations, tumors, moyamoya disease, significant stroke, subarachnoid hemorrhage in basal cisterns, vasospasm, intracranial hemorrhage, subdural hematoma, or any arterial abnormality in the circle of Willis that had undergone cerebral angiography and CTA imaging as part of a diagnostic workup for different pathologies. Patient data on risk factors commonly associated with aneurysm development were collected, including smoking status, family history, and history of hypertension. The study was approved by the Brigham and Women’s Hospital Institutional Review Board.

Definition of Morphological Parameters We examined diameters and vessel-to-vessel angles of the main surrounding vessels around the MCA, including the M1 parent artery and daughter branches (Figure). The diameter of a particular vessel is determined by averaging the diameter of the vessel at the neck of the (potential) aneurysm (D1) with the diameter of the cross section at 1.5· D1 distance from the neck of the (potential) aneurysm. This average diameter was calculated for the M1 parent artery and the daughter arteries. From the individual daughter diameters, we calculated the average diameters. The daughter-to-daughter angle is defined as the angle formed between the 2 daughter arteries as measured from the direction of flow. Additionally, the distance from internal carotid artery (ICA) bifurcation to MCA bifurcation was measured.

Statistical Analysis Demographic and clinical characteristics were analyzed for differences by MCA-aneurysm presence by use of the x2 and 2-tailed t test for binary and continuous variables, respectively. A matched case-control design was used to compare the vasculature of MCA aneurysms with the unaffected contralateral side (control group A). Univariate and multivariate conditional logistic regression were performed to compare the value of each clinically relevant morphological parameter between the aneurysmal and nonaneurysmal side (control group A). For comparison with control group B, standard univariate and multivariate logistic regression was used. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to determine the strength of the association. All tests were 2-sided, and P , .05 was considered statistically significant.

Reconstruction of 3-Dimensional Models We utilized 3-D Slicer (referred to as “Slicer” in the following text), an open source, multiplatform visualization and image analysis software,36,37 as described previously.38 Composite 3-dimensional (3-D) models of MCA aneurysms and their surrounding vasculature were generated with preoperative CTA images. All CTAs were performed on a Siemens SOMATOM Definition scanner with slice thickness of 0.75 mm and increments of 0.5 mm. The vascular compartment was isolated using threshholding. Aneurysm borders and contours were then reconstructed by using a triangle reduction and smoothing algorithm. This 3-D surface model of the aneurysm and surrounding vessels could be manipulated freely in the Slicer environment. Diameters and angles were then manually measured with fiducial-based tractography.

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FIGURE. Three-dimensional model of MCA bifurcation aneurysm depicting morphological variables of the surrounding vasculature. The diameters of the parent and 2 daughter arteries were measured. The daughter-todaughter angle refers to the angle formed between the 2 daughter branches in the direction of flow. D, diameter.

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(62) (35) (65) (11)

.312 .157 .312 .429

1.02 (1.001-1.026) .037d 1.04 (0.940-1.164) .421 1.01 (1.000-1.024) .053 1.04 (0.944-1.147) .444 1.01 (1.000-1.024) .039d 0.94 (0.850-1.041) .235 82.71 (30.23) 16.72 (4.17) 94.83 (39.88) 16.44 (4.35)

80.31 (27.45) 1.01 (1.000-1.020) .043d 15.79 (3.88) 0.98 (0.897-1.070) .652

.200 2.16 (0.676-7.415) 0.85 (0.313-2.278) .743 1.65 (0.656-4.160) .287 .550 0.80 (0.382-1.673) 2.17 (0.38)

P Value OR (95% CI) P Value

0.32 (0.133-0.727) .009d

OR (95% CI) P Value

.001d 0.20 (0.074-0.53)

OR (95% CI) P Value OR (95% CI)

0.25 (0.101-0.598) .002d 3.17 (0.45)

Multivariate Analysisb Univariate Analysisb

Control B (n = 37) Mean (SD)

PA diameter, parent artery diameter; DA diameter, mean daughter artery diameter; D-D angle, daughter-to-daughter angle; ICA, internal carotid artery; MCA, middle cerebral artery; ICA-MCA, ICA bifurcation to MCA bifurcation distance; CI, confidence interval. MCA aneurysm group vs control group A—conditional logistic regression (paired). c MCA aneurysm group vs control group B—logistic regression (unpaired). d Significant.

MCA, middle cerebral artery; SD, standard deviation.

23 13 24 4

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b

(75) (49) (55) (16)

.413

2.18 (0.49)

53 6 12.3 (17-80) 51 6 16.6 (22-85)

P Value

2.14 (0.42)

Mean age 6 SD (range) Female, n (%) Hypertension, n (%) Smoking, n (%) Family history, n (%)

55 36 40 12

Control Group B

3.14 (0.44)

MCA Aneurysm

a

a

Characteristic

Control A (n = 73) Mean (SD)

TABLE 1. Demographic Information and Clinical Risk Factors of 73 Patients With Unilateral MCA Aneurysms and 37 Patients Without Intracranial Aneurysms (Control Group B)a

MCA Aneurysm (n = 73) Mean (SD)

MCA Aneurysms vs Control Group B MCA aneurysms were associated with greater daughter-todaughter angle, smaller mean daughter artery diameter, and larger

TABLE 2. Univariate and Multivariate Conditional Logistic Regression for Presence of MCA Aneurysmsa

MCA Aneurysms vs Control Group A In univariate analysis, MCA aneurysms were associated with smaller parent artery diameter (OR 0.25, 95% CI 0.101-0.598, P , .01) and larger daughter-to-daughter angle (OR 1.01, 95% CI 1.000-1.020, P = .04) and these relationships were preserved in a multivariate conditional logistic regression model that revealed that smaller parent artery diameter (OR 0.20, 95% CI 0.074-0.533, P , .01) and greater daughter-to-daughter angle (OR 1.01, 95% CI 1.000-1.024, P , .05) were significantly associated with MCA aneurysm presence after correcting for other variables. The mean diameter of daughter arteries and the mean distance from ICA to MCA bifurcation were smaller in the MCA aneurysm group, but these relationships were not statistically significant.

Univariate Analysisc

A total of 110 patients fulfilled the inclusion criteria (73 patients with MCA aneurysms and 37 control patients without IAs). Demographic and clinical data are provided in Table 1. The mean age of patients with MCA aneurysms was 53 6 12.3 years (range 17-80 years). There were no significant differences in demographic (age, sex) and clinical (hypertension, smoking, family history) risk factors between patients with MCA aneurysms and patients without IAs (control group B). Basic characteristics of the MCA and control groups are shown in Table 2, including mean parent and daughter diameters, ICA bifurcation to MCA bifurcation distance, and daughter-to-daughter angles. Table 2 also shows the results of univariate and multivariate analyses with regard to morphological parameters of the surrounding vasculature.

2.88 (0.53)

RESULTS

PA diameter, mm DA diameter, mm D-D angle ICA-MCA, mm

Multivariate Analysisc

All statistical analyses were performed using STATA Statistical Software: Release 13 (College Station, Texas: StataCorp LP) and Excel 2007 (Microsoft Corp., Redmond, Washington).

0.23 (0.080-0.604) .005d

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ICA to MCA bifurcation distance in a univariate logistic regression model in comparison with patients without IAs, but these relationships were not statistically significant. Additional multivariate analysis revealed that both smaller parent artery diameter (OR 0.23, P , .01) and larger daughter-to-daughter angle (OR 1.02, P = .04) were significantly associated with MCA presence after correction for other morphological parameters.

DISCUSSION The exact pathophysiologic mechanism of IA formation remains controversial. The development of IAs is believed to be attributed to a variety of factors classified as either congenital (structural), genetic, or acquired, owing to factors such as smoking and hypertension.1 Patients with a family history of IAs are believed to be at higher risk for aneurysm formation and are screened routinely on a systematic basis, but it is practically impossible to predict precisely the location of aneurysm formation and thereby study the initiation and early development of aneurysms.10 However, in addition to the above-mentioned genetic and acquired factors, hemodynamic stress is thought to play an important role in aneurysm formation, by triggering focal degenerative mechanisms at the vessel wall.26,39-41 Hemodynamic factors, such as WSS and circumferential wall stress, are affected by the geometry of the surrounding vascular tree. Thus, we examined the relationships among the surrounding vasculature of the MCA bifurcation between the aneurysmal and unaffected side (control group A), as well as between patients with MCA aneurysms and patients without IAs (control group B), in order to determine the anatomic parameters associated with MCA aneurysm presence, and to minimize confounding by genetic predisposition, hypertension, smoking status, and other clinical risk factors. In our study, the presence of MCA aneurysms was significantly associated with a smaller parent artery diameter and a larger daughter-to-daughter artery angle. Therefore, our findings underline the possibility that anatomic factors as related to their influence on hemodynamics may provide objective metrics to assess aneurysm formation and growth risk stratification in high-risk patients. Prior studies, mostly focusing on anterior communicating artery and posterior communication artery (PCoA) aneurysms, have examined the morphological factors of surrounding vasculature and supported the hypothesis that the geometry of the surrounding vasculature is integral to the formation of IAs.9,11-16,18-21,24 Studies examining the association of anterior communicating artery -aneurysm formation with surrounding geometry observed positive correlations between A1-A2 diameter ratio and aneurysm formation,20 and high incidence of A1 dominance to supply both A2s.21 Similarly, studies focusing on PCoA aneurysms found aneurysms to be associated with shorter length of the supraclinoid ICA,16 and a smaller angle between the internal carotid artery and the PCoA.17 In contrast to our study, most such studies compared their findings with controls without aneurysms. However, the likelihood of aneurysm formation is

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greater if the patient has certain risk factors (eg, female, smoking, age, and hypertension).1,39 To control for the confounding effects of these risk factors, we paired the aneurysmal side with the unaffected side within the same patient. Anatomically, MCA aneurysms are located at the bifurcation point of the parent vessel (M1) into the daughter branch vessels. The effects of parent artery diameter and branch vessel angles can therefore be conceptualized as the hemodynamics of a vascular bifurcation point. Theoretically, the angles of daughter branches and vessel radii follow principles of work minimization,15 a parametric optimization model for the growth and adaptation of the arterial tree,42,43 as described by Murray.44,45 Ingebrigtsen et al15 hypothesized that normal MCA bifurcations would follow the principles of minimum work and that the presence of an aneurysm would be associated with deviations from optimum bifurcation geometry. Although they showed that normal MCA bifurcations indeed closely approximated optimality principles, these optimality principle parameters (eg, junction exponents and differences between optimal and observed daughter angles) were not predictive for MCA aneurysm formation in multivariate analysis.15 However, they found that the observed branch angles were significantly larger in the aneurysmal group, in corroboration with our findings. The larger the bifurcation angle becomes, the more the forces exerted by the daughter arteries will offset each other and the less they will compensate for the forces exerted on the apex by the parent artery.14,40,46,47 The relation between high WSS and the earliest signs of IA formation has been demonstrated in various animal experiments, showing that hemodynamic stress could cause wall remodeling and potential degeneration by causing endothelial injury.48-56 In addition, several studies have also demonstrated that a larger bifurcation angle may lead to lower WSS, which has been linked with endothelial dysfunction and aneurysm progression due to endothelial proliferation and apoptosis.57-64 In addition, a smaller parent vessel diameter causes a higher jet flow at the apex of the bifurcation, resulting in a region of maximum hemodynamic stress.40 As blood flows from the parent to the daughter artery, a decrease in flow velocity occurs at the apex with subsequent decrease in kinetic energy leading to structural fatigue of the artery wall and formation of an aneurysm.40,65 These findings illustrate that abnormal (eg, both low and high) WSS can drive IA pathogenesis, causing vascular remodeling.8,53,66-68 Thus, simple morphological parameters, namely larger daughter-todaughter angles and smaller MCA diameters, with their associated hemodynamic changes may be useful in predicting aneurysm formation in high-risk patients. However, the pathophysiology of (MCA) aneurysm formation is multifactorial and further investigation is needed to predict initiation of IAs in patients with anatomic risk factors for aneurysm formation. Limitations The main limitations to this study are related to the retrospective design. We cannot conclude that a larger daughter-to-daughter

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angle causes aneurysm formation, as we cannot exclude the possibility that aneurysm formation affected surrounding vessel geometry given the lack of data on the geometry before and after aneurysm formation. Thus, all inferences made about the parameters examined can be associated with aneurysm presence only, and are not necessarily predictors of formation risk. Finally, measurements were performed manually rather than automated. Although this may introduce some slight variability in the results, it is a much more applicable technique in the clinical setting. Care was taken to avoid interobserver variation on diameter measurements, but resultant bias cannot be excluded.

CONCLUSION Our study of the morphological characteristics of the surrounding vasculature specific to MCA aneurysms showed that the presence of MCA aneurysms was significantly associated with smaller parent artery diameters and larger daughter angles. These findings are consistent with accumulating evidence that surrounding vascular anatomy characteristics may have a significant effect on aneurysm hemodynamics that could influence formation risk. Measurements of these simple morphological factors can be easily performed by clinicians when examining reconstructions of highrisk patients and may aid in the risk assessment of the patient. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

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COMMENTS

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he authors report their use of an open source image-based software package to generate 3-D models of unruptured middle cerebral artery (MCA) aneurysms and surrounding vasculature. Using this software, they examined segment lengths, diameters, and vessel-tovessel angles of the parent and daughter vessels at the MCA bifurcation to identify image-based morphological parameters that correlated with the presence of MCA aneurysms. In order to reduce confounding by genetic and clinical risk factors, they utilize the contralateral unaffected side as a control group in patients with MCA aneurysms, and the vasculature of patients without intracranial vascular abnormalities as an additional control group. Seventy-three patients with MCA aneurysms and 37 control patients were retrospectively evaluated, and the authors found that a smaller parent artery diameter and larger daughter-todaughter branch angles are associated with the presence of MCA bifurcation aneurysms. It is well known that bifurcation geometry plays an important role in aneurysm formation,1 and prior animal studies have demonstrated the relationship between high wall shear stress and aneurysm formation.2 The results of this study are consistent with evidence that surrounding vascular morphology and hemodynamic changes have an important effect on aneurysm formation. Although the multifactorial pathophysiology of intracranial aneurysms cannot be ignored, the authors were able to reduce confounding factors by using control groups. The main limitations of the study are related to the retrospective design and, therefore, to the lack of data on the geometry before and after aneurysm formation. Additionally, variability in measurements is likely to occur when they are performed manually; and, moreover, when one individual performs the measurements. However, this is an interesting and wellwritten article that provides parameters that could be useful for risk stratification of high-risk patients. The 3-D Slicer appears to be a reasonable tool that may become useful. Yoshua Esquenazi Dong Kim Houston, Texas

1. 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(1):145-151. 2. Nakatani H, Hashimoto N, Kang Y, et al. Cerebral blood flow patterns at major vessel bifurcations and aneurysms in rats. J Neurosurg. 1991;74(2):258-262.

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MIDDLE CEREBRAL ARTERY ANEURYSMS

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he authors present an interesting article on the morphological findings present in patients with MCA aneurysms. The exact pathophysiology of cerebral aneurysm formation remains elusive. However, its etiology can be broadly categorized into 2 main types, hemodynamic and structural factors. The former includes shear forces that can act at the MCA bifurcation to create aneurysms. The latter are genetic mutations or injury/inflammatory cascades that predispose the arterial wall toward weakening and dilatation. This article focuses on potential anatomic conformations that could either be associated with or contribute to aneurysm development. The authors discovered differences in daughter-to-daughter angles and parent vessel diameters on the aneurysmal side compared with the contralateral, unaffected MCA. Those

NEUROSURGERY

who espouse a hemodynamic etiology to aneurysms will find these observational data supportive of computational fluid dynamics (CFD) models that demonstrate altered wall shear stress and endothelial dysfunction as causative of aneurysms. However, the authors rightly point out that these morphological findings are associated with aneurysm formation not necessarily causative. Whether these anatomic variations caused the aneurysm or simply formed due to the aneurysm itself is unknown. Additional CFD or animal models might refine this observational data further. Louis J. Kim Seattle, Washington

VOLUME 76 | NUMBER 6 | JUNE 2015 | 727

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Morphological parameters associated with middle cerebral artery aneurysms.

Morphological factors contribute to the hemodynamics of the middle cerebral artery (MCA)...
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