Focal enhancement, hemodynamic parameters, and morphology
In this study, focal enhancement was colocalized with low AWSS, low maxOSI, and high LSA in agreement with results recently published by Xiao et al. and Khan et al. [
13,
31], confirming the assumption that enhanced regions possibly indicate the presence and localization of low-flow conditions in an aneurysm.
This observation adds to the assumption that the extent of focal enhancement depends on the prevalence of low-flow conditions. Furthermore, it seems likely that there is a continuous spectrum of the extent of wall enhancement correlated to a hemodynamic environment promoting wall destabilization that has to be considered when assessing rupture risk, rather than an either-or presumption that is implied when dichotomizing unruptured aneurysms into either enhancing (and thus at higher rupture risk) or non-enhancing. There was no significant correlation of AWSS, maxOSI, and LSA with EA when computed for whole aneurysms. Still, there was a trend towards higher LSA in aneurysms with a larger extent of enhancement (
P = 0.08222). This could be explained by the fact that the percentage of the aneurysm surface that was covered by enhancement was relatively low in the aneurysms included in this study (median 27%; see Table
3). Future longitudinal studies focusing on quantification of aneurysm wall enhancement on MR vessel wall imaging and correlated clinical parameters are warranted.
Numerous studies have described morphologic characteristics associated with a ruptured state, such as larger aneurysm size and greater aspect ratio [
15,
17,
22,
32,
33]. Yet, a retrospective longitudinal analysis conducted by Leemans et al. yielded no significant differences in hemodynamic and morphological parameters at baseline imaging in aneurysms that had grown versus stable aneurysms [
23]. Morphological and hemodynamic analysis in cases where longitudinal data are not available might therefore not be able to sufficiently discriminate between stable and unstable aneurysms. In our patient cohort, aneurysm enhancement was positively correlated with hemodynamic, morphologic, and histologic markers that have been linked to an unstable state, which supports the assumption that wall enhancement might reflect the complex interactions and multifactorial pathologic processes in aneurysm evolution leading to wall destabilization, while a direct causal relation to either of these factors cannot readily be assumed.
Low-flow conditions, thrombi, and histologic findings
In a comprehensive study linking macroscopic wall appearances to specific hemodynamic conditions, Cebral et al. found low AWSS to be associated with macroscopically hyperplastic and atherosclerotic wall segments [
34]. Concordantly, we observed histologic markers of inflammatory and remodeling processes in aneurysms with a greater extent of focal wall enhancement, suggesting that these pathologic conditions are more abundant in conjunction with low-flow conditions.
Moreover, rupture sites of intracranial aneurysms have been associated with low wall shear stress [
14,
34‐
36] and focal enhancement [
11,
12]. Still, a direct association of low-flow areas and possible future rupture site cannot directly be deduced from the results of the present study, because local matching of histologic findings and enhancements areas was not conducted.
Recently, Sato et al. published their results from a 7T vessel wall MRI study describing the double-layer appearance in thrombosed aneurysms and linking them to histologic signs of inflammation, in accordance with our results [
37].
Matsushige et al. described focal enhancement as possibly attributable to the presence of thrombotic material at rupture sites [
11]. Another study attempted to categorize aneurysm wall types and found thrombosis as a feature of categories with a higher proportion of ruptured aneurysms [
38]. These observations add to the assumption that slow blood flow and thrombus formation might play a substantial role in wall destabilization and can be visualized with MR vessel wall imaging.
Still, the observation that focal enhancement, albeit to a lesser extent, is also encountered in aneurysms lacking histologic signs of wall inflammation, possibly reflects the proposed theory that there are different pathways of wall destabilization in intracranial aneurysms [
39]. Substantial wall enhancement might primarily reflect the inflammatory pathway of wall remodeling, while the sensitivity for the mural-cell-mediated pathway could be diminished.
Cornelissen et al. assumed that wall enhancement is not causally linked with inflammatory processes but rather attributable to method-inherent failure of blood signal suppression in low-flow conditions [
40,
41]. The results of our study suggest that inflammatory changes probably add to the extent of wall enhancement, and that even without convincing proof of a causal link, wall enhancement indicates the presence of a hemodynamic environment promoting inflammatory and degenerative processes and might therefore still serve as a surrogate marker for aneurysm wall instability.
The extent of enhancement seems to depend on the sequence employed in the vessel wall MR protocol, with the T1 TSE black blood sequence like the one used in our study possibly being more sensitive for the detection of slow blood flow compared with motion-sensitized driven equilibrium (MSDE)-prepared sequences [
42].
This study has several limitations. The retrospective study design might imply a selection bias towards patients who underwent DSA and were potentially pre-selected for therapy due to their risk profiles. Additionally, histologic analysis was exclusively performed in patients who underwent clipping, possibly inducing bias towards aneurysms with morphologies unfavorable for endovascular therapy. Histological data were only available in nine aneurysms. Microsurgical clipping provides only specimens of the aneurysm dome; neck segments under the clip cannot be retrieved. The small sample size precluded subgroup analysis of histologic features with adequate power. We chose to restrict our analysis to middle cerebral artery aneurysms in an effort to exclude a possible heterogeneity in aneurysm phenotype caused by different pathogenetic mechanisms potentially underlying the evolution and progression of aneurysms in different locations [
43]. Additionally, an overestimation of the neck size using 3D imaging techniques can occur compared with 2D images, but careful segmentation using advanced algorithms was applied [
44,
45]. Finally, no patient-specific inflow conditions were available for the blood flow simulations. However, a comparison between enhanced regions and the whole aneurysm remains feasible.