Relationship between aneurysm wall enhancement and conventional risk factors in patients with unruptured intracranial aneurysms: A black-blood MRI study

Abstract

Background and purpose

Aneurysmal wall enhancement (AWE) has emerged as a new possible biomarker for depicting inflammation of the intracranial aneurysm (IA). However, the relationships of AWE with other risk factors are still unclear for unruptured IA. The purpose of this study was to investigate the association between AWE and other risk metrics.

Methods

Forty-eight patients with unruptured saccular IAs diagnosed by digital subtraction angiography were recruited to undergo magnetic resonance (MR) black-blood imaging. AWE was evaluated using the pre- and post-contrast black-blood MR images. Univariate and multivariate logistic regression analysis was performed to investigate the association of AWE with other risk factors, including size, maximal neck width, parent vessel diameter, location, multiplicity, daughter sacs and other clinical factors. The prevalence of AWE in each ISUIA grade was reported and compared by Wilcoxon rank sum test.

Results

In total, 61 aneurysms were detected in 48 patients. Aneurysm size was found to be an independent risk factor associated with AWE (OR 2.46 per mm increase, 95% CI 1.34–4.51; p = 0.004). Patient age was independently and inversely associated with AWE (OR 0.898 per year increase, 95% CI 0.812–0.994; p = 0.037). Higher prevalence of AWE was observed in larger aneurysms (12%, 71.4%, 100%, and 100% of ISUIA grade 1–4 IAs have AWE, respectively). Notably, 12% of small IAs (size <7 mm) exhibited AWE. The IAs with AWE had significant higher ISUIA grade than the IAs without (p < 0.001, Wilcoxon rank sum test).

Conclusions

The wall enhancement in contrast-enhanced black-blood MR images was independently associated with aneurysm size in unruptured IAs. However, some small unruptured aneurysms did exhibit wall enhancement, suggesting that AWE may provide additional aneurysm instability information to improve current size-based rupture risk evaluation metrics.

Introduction

Intracranial aneurysm (IA) is an important vascular abnormality, which has substantial mortality and morbidity caused by subarachnoid hemorrhage with aneurysm rupture.^1–6 In clinical practice, preventive treatments including microsurgical clipping and endovascular treatment are used to prevent the rupture of IA. However, all those treatments have a non-negligible risk of procedural morbidity.^5,7,8 Thus, assessment of the rupture risk for unruptured IAs is important for treatment decisions.

Currently, the most widely used IA rupture risk evaluation method in clinical practice is the aneurysm size measured by digital subtraction angiography (DSA), established by the International Study of Unruptured Intracranial Aneurysms (ISUIA).⁸ Other characteristics, such as the IA location, smoking, hypertension, age and gender are also considered to be associated with IA rupture.^8,9 Recently, post-contrast aneurysmal wall enhancement (AWE) in Gadolinium contrast-enhanced black-blood vessel wall magnetic resonance (MR) imaging has been used for IA.^10–12 The results of these studies suggested that AWE, which was considered to reflect aneurysm wall inflammation, may be a new imaging biomarker for IA risk evaluation. However, for unruptured IAs, the relationships of AWE with other risk factors are still unclear. Thus, in this study, we aimed to investigate the association between AWE and other risk metrics.

Method

Study population

This study was approved by the institutional ethics committee, and written informed consents were obtained from all participants before experiments. Forty-eight patients with untreated unruptured saccular IAs diagnosed by DSA were recruited to undergo MR imaging between November 2013 and July 2015. All the patients had no contraindications to MR imaging and contrast usage, including pregnancy or breast feeding, contrast allergy, claustrophobia, renal insufficiency, and presence of MRI-incompatible implants. Patient demographics (age, gender, etc.) and clinical presentations were collected using the electronic healthcare database.

Imaging protocol

DSA

DSA was performed on the biplane flat-panel digital subtraction unit (GE, USA; or Siemens, Germany). Under local anesthesia via unilateral femoral access route, a diagnostic catheter was used to obtain standard 2D posterior, anterior, lateral and oblique projections. Then, 3D rotational angiography was performed with 5 s run with contrast injection at a rate of 4 ml/s.

MRI

The MR imaging was performed on a 3.0T MR scanner (Achieva TX, Philips, Best, The Netherlands) with a 32-channel head coil. First, a 3D time-of-flight sequence was used to generate MR angiography for the localization of subsequent scans. Then, the IA walls were imaged by a 3D black-blood T1W-VISTA sequence which has inherent blood flow suppression before and after contrast agent administration.¹³ During the 3D T1W-VISTA imaging, a 54 mm-thick transverse slab was acquired to cover all the IAs in each patient. Other imaging parameters included: FOV = 160 × 160 mm²; voxel size = 0.6 × 0.6 × 0.6 mm³; TR/TE = 700/30 ms; turbo factor = 49, including 4 startup echoes; parallel imaging sense factor = 2. Post-contrast T1W-VISTA was performed about 6 min after an intravenous injection of Gd-DTPA (Magnevist; Bayer Schering Pharma, Berlin, Germany) at a dose of 0.1 mmol/kg. All imaging parameters were kept the same for the pre- and post-contrast T1W-VISTA imaging.

Image analysis

For DSA, the 3D rotational angiographic data were transferred to a workstation (Leonardo, Siemens) and reconstructed into a 3D model for each IA. The 3D IA models were reviewed by an experienced neuroradiologist (XL, 10 years of experience in neuroradiology) to find a best view angle to measure IA morphological indices, including aneurysm size, maximal neck width and parent vessel diameter, as well as location classification (anterior vs. posterior), presence of multiplicity and daughter sacs. Aneurysm size was defined by the maximum measurement of aneurysm width or aneurysm neck-to-dome length.¹⁴

For MR image analysis, two experienced reviewers (PL, 10 years of experience in neuroradiology; HQ, 3 years of experience in vascular imaging), blinded to DSA results and patients’ clinical manifestations, evaluated the wall enhancement of each aneurysm on the post-contrast T1W-VISTA image using the pre-contrast image as reference in consensus reading. Representative MR images with and without post-contrast AWE are shown in Figure 1.

Figure 1.

Representative pre- and post-contrast T1W-VISTA images of aneurysms with wall enhancement (a, b) and without (c, d). (a) a post-contrast-enhanced aneurysm located in anterior communicating artery with maximal aneurysm size of 9 mm. (b) a post-contrast-enhanced aneurysm located in basilar artery with maximal aneurysm size of 17.1 mm. (c) a post-contrast non-enhanced aneurysm located in posterior cerebral artery with maximal aneurysm size of 6 mm. (d) a post-contrast non-enhanced aneurysm located in basilar artery with maximal aneurysm size of 10.5 mm. The pre- and post-contrast images of the same aneurysm are shown in the same window/level.

Statistical analysis

Variables are presented as means ± standard deviation (SD) or n (%) as appropriate. Characteristics of AWE IAs and no AWE IAs were compared using the Student t-test or chi-square test as appropriate. Univariate and multivariate logistic regression analyses were performed for AWE. The variables that were statistically significant in univariate analysis were selected for multivariate logistic regression analysis. The odds ratio (OR), 95% confidence interval (CI), and p-value were reported. Then each IA was scored by the established four-grade aneurysm risk score (ISUIA: grade 1 (lowest risk): aneurysm size less than 7 mm; grade 2: aneurysm size 7–12 mm; grade 3: aneurysm size 13–24 mm; grade 4 (highest risk): aneurysm size ≥25 mm).⁸ The prevalence of AWE in each risk grade was reported and compared by Wilcoxon rank sum test. All statistics were done using SPSS (Version 19.0, SPSS Inc.); p < 0.05 was considered statistically significant.

Results

General characteristics of study population

Of 48 patients (36 females; age, 53.6 ± 12.1 years (mean ± standard deviation); age range, 16–74 years), 16 (33.3%) had hypertension, two (4.2%) had diabetes, one (2.1%) had hyperlipidemia, 10 (20.8%) were current smokers. In total, 61 saccular IAs were found from 48 patients. Ten (20.8%) patients had multi aneurysms and seven (11.5%) aneurysms had daughter blebs. Of 61 aneurysms, 46 (75.4%) aneurysms were located in the anterior circulation, including internal carotid artery (ICA)-ophthalmic artery (n = 24), ICA-posterior communicating artery (n = 4), ICA-cavernous sinus segment (n = 3), ICA-carotid terminus (n = 1), anterior communicating artery (n = 4), cerebral middle artery (n = 9), and cerebral anterior artery (n = 1); 15 (24.6%) aneurysms were located in the posterior circulation, including basilar artery (n = 13), posterior cerebral artery (n = 1), and posterior inferior cerebellar artery (n = 1).

Aneurysmal wall enhancement

In this population, AWE was detected in 33/61 (54.1%) unruptured aneurysms. Detailed characteristics of AWE and no AWE IAs are summarized and compared in Table 1. Aneurysm size was significantly different between aneurysms with and without AWE, in addition to patient age, gender, and presence of multiplicity.

Table 1.

The characteristics of aneurysms with AWE and without AWE.

Characteristics	IAs with AWEa	IAs without AWEa	p-valueb
Number of IAs	33 (54.1%)	28 (45.9%)
Age (years)	51.3 ± 12.4	58.0 ± 11.7	0.036*
Gender (female)	29 (47.5%)	17 (27.9%)	0.014*
Hypertension	11 (18.0%)	12 (19.7)	0.444
Diabetes	1 (1.6%)	2 (3.3%)	0.463
Hyperlipidemia	1 (1.6%)	1 (1.6%)	0.906
Smoking	3 (4.9%)	7 (11.5%)	0.776
Aneurysm size (mm)	15.1 ± 8.4	5.2 ± 2.2	<0.001*
Maximal neck width (mm)	4.9 ± 1.7	4.3 ± 0.8	0.070
Parent vessel diameter (mm)	4.2 ± 0.3	4.1 ± 0.3	0.599
Located in anterior circulation	25 (41.0%)	22 (36.1%)	0.068
Multiplicity	7 (11.5%)	15 (24.6%)	0.009*
Daughter sacs	3 (4.9%)	4 (6.6%)	0.526

^aThe values represent the number of patients and percentages (%) or mean ± SD (standard deviation). ^bp-values were from Student t-test or chi-square test as appropriate. *p < 0.05

In univariate analysis (Table 2), aneurysm size, patient age, gender, and presence of multiplicity were found to be significantly associated with AWE (p = 0.041, 0.019, 0.011, and <0.001, respectively). Multivariate logistic regression analysis (Table 2) revealed that maximal aneurysm size was independently associated with the presence of AWE (OR 2.46 per mm increase, 95% CI 1.34–4.51; p = 0.004), as well as patient age (OR 0.898 per year increase, 95% CI 0.812–0.994; p = 0.037).

Table 2.

Univariate and multivariate analysis for aneurysmal wall enhancement.

Characteristics	Univariate analysis		Multivariate analysis
	OR (95% CI)	p-value	OR (95% CI)	p-value
Age, year↑	0.954 (0.912–0.998)	0.041*	0.898 (0.812–0.994)	0.037*
Gender	4.69 (1.29–17.1)	0.019*	14.8 (0.973–224)	0.052
Hypertension	1.50 (0.530–4.25)	0.445
Diabetes	2.46 (0.211–28.7)	0.472
Smoking	3.33 (0.772–14.4)	0.107
Hyperlipidemia	1.19 (0.071–19.9)	0.906
Aneurysm size, mm↑	1.99 (1.37–2.90)	<0.001*	2.46 (1.34–4.51)	0.004*
Maximal neck width, mm↑	1.46 (0.960–2.24)	0.079
Parent vessel diameter, mm↑	1.55 (0.308–7.82)	0.593
Located in anterior circulation	1.17 (0.352–3.91)	0.795
Multiplicity	4.29 (1.40–13.1)	0.011*	2.46 (0.350–17.3)	0.366
Daughter sacs	1.67 (0.340–8.18)	0.529

^*p < 0.05.

As shown in Table 3, of 25 ISUIA grade 1 IAs, 12% have AWE, while 71.4% ISUIA grade 2 aneurysms (n = 21) have AWE; for aneurysms with higher ISUIA grade 3 (n = 10) and 4 (n = 5), 100% have AWE. In the Wilcoxon rank sum test, the IAs with AWE have significant higher ISUIA grade compared with the IAs without AWE (p < 0.001).

Table 3.

The prevalence of aneurysms with AWE in four ISUIA grades (ISUIA: grade 1 (lowest risk): aneurysm size less than 7 mm; grade 2: aneurysm size 7–12 mm; grade 3: aneurysm size 13–24 mm; grade 4 (highest risk): aneurysm size ≥25 mm).

ISUIA grade	1	2	3	4
AWE	3 (12%)	15 (71.4%)	10 (100%)	5 (100%)
No AWE	22 (88%)	6 (28.6%)	0	0
Total	25	21	10	5

Discussion

In this study, we found that the aneurysm size was independently associated with AWE in unruptured aneurysms, which was in contrast to that reported by Edjlali et al.¹¹ In their study, the aneurysm size ranged from 4 to 8 mm. However, in the 61 aneurysms in our study, aneurysm size ranged from 2.9 mm to 30.5 mm, hence we deem that the different study population selection may have resulted in this dissimilar result.

Although still needing further investigation, the AWE of unruptured aneurysms observed in MRI was considered to be caused by aneurysm wall inflammation and the vasa vasorum.^{10–12,15–17} Thus, the AWE may reflect physiologically unstable properties of the aneurysm wall other than the morphological features of IA. The results of this study suggest that greater inflammation and the vasa vasorum of the IA wall tended to exist in larger aneurysms. Pathological studies support the theory that inflammation and the vasa vasorum play important roles in the aneurysm enlargement. The inflammation of the aneurysm wall may be caused by the intramural bleeding from fragile vasa vasorum or atherosclerosis.^15,16 Many growth factors are released with inflammation, stimulating the proliferation of the vessel wall and further leading to aneurysm progression, which may explain the association between AWE and aneurysm size found in this study.¹⁶ Also, many kinds of proteases are secreted in inflammation, which destroy the extracellular matrix proteins and weaken the vessel wall.¹⁸ Thus, this finding is compatible with the trend observed in the ISUIA study that the rupture risk of IAs increases with the enlargement of aneurysm size.

One major drawback of the aneurysm size-based ISUIA standard is that some small aneurysms may still rupture. Previous investigation showed that up to 37% of patients with subarachnoid hemorrhage had aneurysms smaller than 5 mm in maximal diameter.¹⁹ Korja et al.²⁰ investigated the natural history of 118 unruptured IAs, and found 19% small aneurysms (<7 mm in size, ISUIA grade 1) ruptured during the lifelong follow-up period. In this study, although larger aneurysms were observed to have high prevalence of AWE, we found that as many as 12% small unruptured aneurysms (ISUIA grade 1, aneurysm size <7 mm) manifested AWE. This result suggests that AWE may provide additional information about aneurysm instability other than size. Thus, AWE may be a potential metric to improve the current IA risk evaluation standard.

In this study, we also found patient age was inversely associated with AWE, suggesting that age may confer a protective effect against aneurysm wall inflammation and vasa vasorum, thus the rupture risk. Although patient age has been regarded as a risk factor for rupture in most studies, our finding is similar to the study carried out by Juvela et al.,²¹ which reported that patient age inversely predicted subsequent aneurysm rupture in a long-term natural history study of unruptured IAs involving 142 patients. However, the reason that age may be a protective factor remains unclear. In the future, larger sample sizes and more detailed studies are needed to determine the potential role of age in predicting the presence of AWE.

One limitation of this study is patient recruitment bias, because it was carried out in a single hospital and patients with larger aneurysms were more willing to participate, leading to a high prevalence of larger aneurysms (36 out of 61 aneurysms were larger than 7 mm in size). This may explain the high prevalence of AWE (33/61) observed in this study, with our finding that larger aneurysms tend to have higher prevalence of AWE. The other limitation is that reading of the MRI images was not completely blinded to the risk factors, as many of the risk factors (for example size, morphology, multiplicity) would be evident when looking at the vessel wall images.

Conclusions

Wall enhancement in contrast-enhanced black-blood MR image was independently associated with aneurysm size in unruptured IAs. However, some (12%) small unruptured aneurysms (size <7 mm) did exhibit wall enhancement, suggesting that AWE may provide additional information about aneurysm instability to improve current size-based rupture risk evaluation metrics.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Commission of Beijing Municipal Science and Technology, municipal clinical special application study, the special fund project (No. Z14110000211441); National Natural Science Foundation (81371540, 81571667, 81171078 and 81471166); Beijing Talents Training Project (Category D) and Beijing Hygiene System High-level Hygienic Technical Personnel Training Program and the Talents Program of Beijing Tiantan Hospital (Hospital Backbone Program).