Circumferential wall enhancement with contrast ratio measurement in unruptured intracranial aneurysm for aneurysm instability

Abstract Background Aneurysm wall enhancement on high‐resolution vessel wall imaging (HR‐VWI) may represent vessel wall inflammation for unruptured intracranial aneurysms (UIAs). Further evidence for the role of circumferential aneurysm wall enhancement (CAWE) in evaluating the instability of UIAs is required, especially in small aneurysms (<7 mm). Methods We analyzed patients with saccular UIAs who prospectively underwent HR‐VWI on a 3.0 T MRI scanner in our center from September 2017 to August 2021. The presence of AWE was identified and quantitatively measured using the aneurysm‐to‐pituitary stalk contrast ratio (CRstalk) with maximal signal intensity value. The PHASES and ELAPSS scores were used to assess the risk of aneurysm rupture and growth. We evaluated the association of CAWE and CRstalk value with intracranial aneurysm instability. Results One hundred patients with 109 saccular UIAs were included in this study. Eighty‐three UIAs (76.1%) had a size smaller than 7 mm. PHASES and ELAPSS scores were significantly higher in UIAs with CAWE than in UIAs without CAWE (p < .01). The association of CAWE with PHASES and ELAPSS scores remained in small UIAs (<7 mm). The optimal cutoff value of CRstalk for CAWE was 0.5. PHASES and ELAPSS scores were significantly higher in UIAs with CRstalk ≥0.5 than in UIAs with CRstalk <0.5 (p < .01). Conclusions CAWE on HR‐VWI is a valuable imaging marker for aneurysm instability in UIAs. CRstalk value ≥0.5 may be associated with a higher risk of intracranial aneurysm rupture and growth.


INTRODUCTION
Unruptured intracranial aneurysms (UIAs) are pathological dilatations of the intracranial arteries with a population prevalence of approximately 3.2%, mainly in the circle of Willis and intracranial arterial bifurcations (Thompson et al., 2015). With the development of neuroimaging technology, UIAs have been discovered with increasing frequency.
The rupture risk of UIAs is low, with an annual rupture rate of approximately 1%. UIAs are the leading cause of spontaneous subarachnoid hemorrhage and can result in severe consequences once ruptured (Thompson et al., 2015). Therefore, early and effective identification of UIAs with a high risk of rupture is crucial. The need for the early treatment of UIA is currently determined in clinical practice mainly based on aneurysm size, morphology, and location. Surgical clipping or endovascular treatment has been recommended for aneurysms larger than 7 mm and those in the posterior circulation site (Wiebers, 2003).
However, management options for UIAs smaller than 7 mm are unclear.
Vessel inflammation has been shown to play an important role in the occurrence, development, and rupture of UIAs (Labeyrie et al., 2017;Tulamo et al., 2018). With the development of neuroimaging techniques, high-resolution vessel wall imaging (HR-VWI) on magnetic resonance can reveal aneurysm wall enhancement (AWE), reflecting the inflammatory status of UIAs (Edjlali et al., 2014;Hudson et al., 2019;Matouk et al., 2013). The assessment of AWE in UIAs mainly adopted a qualitative method, which had the advantages of simplicity and easy operation but could not avoid the subjectivity of the readers. Quantitative assessment of AWE has been recently proposed to analyze the degree of wall enhancement in UIAs, reducing the personal misjudgment of readers (Omodaka et al., 2016(Omodaka et al., , 2019Roa, Zanaty, Osorno-Cruz, et al., 2020). Although AWE on HR-VWI may represent vessel wall inflammation for UIAs, further evidence for the role of AWE in evaluating the risk of rupture and growth of UIAs is required, especially in small aneurysms (<7 mm). The purpose of this study was to investigate the association of aneurysm wall enhancement with the risk of rupture and growth in UIAs.

Study population
One hundred fifty-two consecutive patients with 162 UIAs were identified from a prospectively maintained database between September 2017 and August 2021 at our institution. The local institutional review board approved this study at our institution. The inclusion criteria were as follows: (1) age more than 18 years; (2) no clear history of subarachnoid hemorrhage; (3) untreated saccular UIAs confirmed by digital subtraction angiography; (4) aneurysm identified on MR angiography and images of HR-VWI without artifacts. We exclude the data of UIAs in the extracranial or cavernous sinus of the internal carotid artery (ICA).
We acquired data, including demographic characteristics, vascular risk factors, and the number, location, size, and morphology of UIAs.
The PHASES and ELAPSS scores were used to assess the rupture and growth risk of UIA, which represented the intracranial aneurysm instability (Backes et al., 2017;Greving et al., 2014).

Aneurysm wall enhancement on HR-VWI
MR was performed on a 3.0T MRI scanner (Achieva TX, Philips Healthcare, Best, the Netherlands) with a 32-channel head coil. The HR-VWI protocol included a two-dimensional (2D) T1-weighted blackblood vessel wall sequence and a 3D T1-weighted volume isotropic turbo-spin-echo acquisition (VISTA) sequence before and after intra-

Statistical analysis
Two readers who were blinded to the clinical data independently reviewed the HR-VWI T1-weighted images to identify the presence and pattern of AWE. A third reader resolved disagreements. Cohen κ statistics were used to assess the interreader agreement. κ Values > 0.80 were regarded as excellent for the identification of AWE (Landis & Koch, 1977). The cutoff values for CRstalk with the best F I G U R E 1 Circumferential aneurysm wall enhancement on high-resolution vessel wall imaging (HR-VWI) is shown in a middle cerebral artery aneurysm (a, three-dimensional (3D) digital subtraction angiography; b, precontrast 3D HR-VWI; c, postcontrast 3D HR-VWI). Focal aneurysm wall enhancement on HR-VWI is shown in an internal carotid artery aneurysm (d, 3D digital subtraction angiography; e, precontrast 3D HR-VWI; f, postcontrast 3D HR-VWI)

Clinical characteristics
One hundred patients with 109 saccular UIAs were included in this study. Fifty-two patients were excluded due to fusiform aneurysm (n = 28), extracranial or cavernous sinus of the ICA aneurysm (n = 7), without digital subtraction angiography examination (n = 5), aneurysm not been identified on MR angiography or with unfavorable HR-VWI images (n = 12). The mean age was 56.7 ± 11.2 years, and 60 (60%) were women. The mean size of aneurysms was 5.9 ± 4.6 mm (1.

CAWE and aneurysm instability
Twenty-one patients with twenty-three UIAs received a 2D HR-VWI sequence, and 79 patients with 86 UIAs were scanned by a 3D TA B L E 2 Characteristics of unruptured intracranial aneurysms smaller than 7 mm with and without circumferential aneurysm wall enhancement

CRstalk and aneurysm instability
Seventy-nine patients with 86 UIAs were scanned by a 3D HR-VWI sequence to quantify the CRstalk values in this study. On ROC curve analysis, the optimal cutoff value of CRstalk to differentiate CAWE from non-CAWE was 0.5, and the area under the curve was 0.953 ( Figure 2). Using a cutoff value of 0.5 for CRstalk, the sensitivity and specificity were 0.818 and 0.960, respectively.
CRstalk values increased significantly with the increasing aneurysm size, PHASES score, and ELAPSS score. The aneurysm size was significantly larger in the group with CRstalk ≥0.5 than those with CRstalk <0.5 (9.2 mm vs. 4.9 mm, p = .032). PHASES and ELAPSS scores were significantly higher in the CRstalk ≥0.5 group than in the CRstalk <0.5 group (4.4 vs. 2.2 points, p = .006; 16.5 vs. 10.2 points, p = .002, respectively). The proportion of CRstalk ≥ 0.5 increased with the increasing PHASES and ELAPSS scores (Table 3).

DISCUSSION
This study showed a significant correlation of CAWE with the risk of aneurysm rupture and growth. The aneurysm wall enhancement has TA B L E 3 Characteristics of unruptured intracranial aneurysms with CRstalk ≥0.5 and CRstalk <0.5 Abbreviations: ACA, anterior cerebral artery; CRstalk, aneurysm-to-pituitary stalk contrast ratio; ICA, internal carotid artery; MCA, middle cerebral artery; PC, posterior circulation; PComA, posterior communicating artery.
been used as an imaging marker of instability in UIA, which may correlate with inflammation revealed from histological findings (Gariel et al., 2020;Larsen et al., 2018;Quan et al., 2019;Shimonaga et al., 2018;Vergouwen et al., 2019). A larger wall enhancement area was independently associated with symptomatic UIAs . The specificity of CAWE for differentiating stable aneurysms from unstable aneurysms was higher than focal AWE (X. Wang, Zhu, et al., 2019).
A greater area of AWE may suggest a greater degree of inflammation, and CAWE was a more reliable imaging marker of aneurysm instability than AWE.
The ISUIA study showed that the risk of rupture in UIAs smaller than 7 mm was low, and the role of HR-VWI in evaluating aneurysms smaller than 7 mm remained unclear. In our study, 25.3% (21/83) aneurysms showed wall enhancement, and 9.6% (8/83) showed CAWE, which was similar to previous studies investigating small UIAs (Zhu et al., 2018;Zwarzany et al., 2021). Zhu et al. (2018) found that AWE was an independent predictor of ruptured aneurysms, and CAWE was significantly associated with ruptured aneurysms instead of AWE in aneurysms smaller than 7 mm. Zwarzany et al. (2021) showed that the PHASES score was an independent risk factor for AWE in UIAs smaller than 10 mm. We found a significant correlation between CAWE and PHASES and ELAPSS scores in small UIAs (<7 mm), although two scores of our study belong to the lower risk categories for aneurysm rupture and growth. Nearly half of patients with ruptured aneurysms would have been assigned into the low rupture risk class (five-year rupture risk <1%) if they had been discovered before the rupture in a retrospective application of PHASES score to the multicenter cohort of subarachnoid hemorrhage (Sturiale et al., 2021).
The ISUIA study showed that the rupture risk of aneurysms at anterior cerebral artery/posterior communicating artery/posterior circulation was higher than those at the middle cerebral artery and ICA (Wiebers, 2003). In a cohort of 79 patients with predominantly small UIAs, the strongest determinant of AWE was aneurysm size, followed by posterior communicating artery or middle cerebral artery aneurysm location (Backes et al., 2018). In our study of UIA with smaller than 7 mm, the percentage of CAWE in the middle cerebral artery was higher than in the anterior cerebral artery/posterior communicating artery/posterior circulation, and ICA.
There are several different modalities for quantitative measurement of aneurysmal wall enhancement to avoid the subjectivity of the readers (Omodaka et al., 2016;G.-X. Wang, Gong, et al., 2019). Roa et al. compared the sensitivity and specificity of three different quantitative modalities of AWE on HR-VWI among scanners from different manufacturers. They found that CRstalk using maximal SI was the best predictor of aneurysm instability (Roa, Zanaty, Osorno-Cruz, et al., 2020). In our study, the optimal cutoff value of CRstalk for CAWE was 0.5, with a sensitivity of 81.8% and a specificity of 96%. Roa et al. showed that the cutoff value of CRstalk for AWE was 0.60, with a sensitivity of 81.5% and a specificity of 61%. The value of CRstalk in small UIAs was lower than large UIAs . In our study, the cutoff value of CRstalk for CAWE was lower than that of previous studies, which may be that most of the aneurysms were smaller than 7 mm.  showed that daily intake of Aspirin was significantly protective for UIAs, reducing the odds of CRstalk ≥0.6 by an average of 78%, which indicated that CRstalk was a marker of inflammatory changes of the aneurysm wall.
We found that CRstalk values increased significantly with increasing aneurysm size, PHASES score, and ELAPSS score, indicating that CRstalk for CAWE may be a useful imaging marker to predict instability of UIAs.
This study has some limitations. First, this study was a single-center design. The subjects included were patients with UIA hospitalized in our hospital with selection bias. Second, the number of patients in this study was relatively small, and the percentage of CAWE was relatively low in small aneurysms, resulting in a bias for statistics analysis.
Third, the correlation between qualitative AWE patterns and quantitative CRstalk assessment was not performed in our study. The quantitative assessment of AWE using the wall enhancement index may improve assessing UIA instability (Fu et al., 2021). The thrombosis of the large aneurysms in this study was not assessed. Giant thrombosed aneurysms more often have a thick aneurysm wall with vasa vasorum and show aneurysm wall enhancement on HR-VWI. Finally, no followup study was performed to confirm that CAWE was an imaging marker of aneurysm instability.
Our findings show that CAWE on HR-VWI is a valuable imaging marker for intracranial aneurysm instability in small UIAs. CRstalk (using maximal signal intensity value) ≥0.5 may be associated with a higher risk of intracranial aneurysm rupture and growth.

CONFLICT OF INTEREST
All authors have no conflict of interest to declare.

AUTHOR CONTRIBUTIONS
Zhong-Song Shi participated in the design of the study. All authors participated in the interpretation and collection of the data. Xiao-Bing Wu wrote the initial manuscript. Zhong-Song Shi revised the manuscript.
All authors critically reviewed and edited the manuscript and approved the final version.

DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.