Influence of morphology and hemodynamic factors on rupture of multiple intracranial aneurysms: matched-pairs of ruptured-unruptured aneurysms located unilaterally on the anterior circulation

Approximately 15%-35% of aneurysm patients have multiple aneurysms [1]-[4]. Neurosurgeons face a special problem to treat them because when patient’s general clinical condition can’t undergo a full treatment or aneurysms are presented in locations that cannot be operated through a single treatment, the high-risk or duty aneurysm should be identified and operated first [5],[6]. For patients with subarachnoid hemorrhage (SAH), combing clinical, CT and angiographic findings, most bleeding sites can be identified but there are still some difficult cases. The misjudgment is dangerous because the untreated but true ruptured aneurysm may bleed again very soon. As for patients without SAH, considering the high rates of morbidity and mortality in the event of rupture, discriminating the aneurysms in danger of rupture before operation is valuable for preventive treatment too.

Previous studies displayed a number of characteristics that may be related to ruptured aneurysms, such as size, location, irregular shape (i.e. blebs, nipples or multiple lobes), etc. [7]-[9]. And recently, computational fluid dynamics (CFD) has become a popular tool for studying intracranial aneurysm hemodynamics and discriminating rupture status [10].

In this study, we investigated the rupture-related characteristics on 20 matched-pairs of ruptured-unruptured saccular aneurysms located unilaterally on the anterior circulation in the same patient. For they provide an ideal internal control for such patient-specific variables as genetic, age, sex, blood pressure, individual habits (including smoking, alcoholism), comorbidities present and so forth, and only focus on aneurysms characteristics. We compared their sites, morphology and hemodynamic factors and hope to get some illuminating results on aneurismal rupture. To our knowledge, the matched rupture risk data in one patient including morphological and hemodynamic factors is rarely reported.

Multiple aneurysms locating unilaterally on the anterior circulation are common and propose special challenge for neurosurgery. K. Mizoi et al. [17] mentioned that 19.4% (72/372) multiple aneurysms located unilaterally in the anterior circulation (not including the ACoA aneurysm) and 42.2% (157/372) multiple aneurysms included at least one on the ACoA (whether they located unilaterally or bilaterally was not concerned). For surgical outcomes, 17 of them got partial treatments only and of which 1 patient died due to postoperative bleeding from the untreated aneurysms [17]. Y. Orz. et al. [18] reported that 66.5% (147/221) multiple aneurysms located unilaterally in the anterior circulation, the total mortality rate after surgery is 15.2% and 15 of them got partial/two-stage treatments [18]. For Rinne et al. [19], the incidence percentage was 16.2% (49/302) and their results suggested that multiple aneurysms signicifantly increase the risk for poor outcome. For Imhof et al. [20], 44.6% (54/121) ruptured aneurysms had the coexisting unruptured aneurysms ipsilateral to the ruptured one. Of all the 124 patients with SAH and multiple aneurysm, 3 passed away immediately after admission and 64 got partial/two-stage treatments [20]. Partial/two-stage treatments are not rare for multiple aneurysms and it put forward a need to identify risky ones among all the coexisting aneurysms. Ruptured-unruptured aneurysm pair on the same patient’s ipsilateral anterior circulation is very interesting. It may be a good disease model not only to investigate characteristics linked to bled aneurysms but also to understand multiple aneurysms better.

As regards to the clinical data, we demonstrate that most cases are female (consistent with previous reports for association between the presence of multiple aneurysms and female sex [1],[3],[4]) and 65% have hypertension. Other coexisting additional disorders, such as DVT, HPL, AS, etc., can also exist. However, the precise role of these clinical factors in assessing rupture risk needs further study with larger sample size and comparative control group. There is no difference for which relative location (proximal/distal) would bleed first, so Liang-Der Jou et al.’s [21] previous speculation that the proximal aneurysm in serial aneurysms may be subject to a greater rupture risk whose research based on only hemodynamic analysis on 4 multiple aneurysms pairs but without clinical data analysis was not true situation for patients.

The ruptured aneurysms are more common to have irregular shape. Some clinical experience and human studies have reported the same found [7],[13],[22]-[24]. The focal bulges on the surface of aneurysm often indicates a weak and thinner wall which indicates a higher risk of aneurysmal rupture [13],[24].

The natural history studies on unruptured aneurysms (including single aneurysms and multiple aneurysms together) proposed aneurysms size to be key predictor for rupture, and diameters > 7 mm/10 mm represented much higher bleeding risk [7],[25]-[27]. In our study, the ruptured aneurysms have higher maximum height too. But studies on only multiple aneurysms seem to have different results. In our study the mean maximum height for all these 40 aneurysms is 3.94 ± 1.977 mm, which means that most aneurysms are small aneurysms with diameter <7 mm in size. Similarly, Jagadeesan et al. [28] reported that very small(≤3 mm) and small aneurysm (>3 mm but ≤7 mm) constituted the majority of ruptured aneurysms (24.6% and 50.7%) for multiple aneurysms. Lu et al.’s [2] retrospective study of 294 multiple aneurysms reported that 88.1% of the aneurysms were 5 mm or less. Size may be a good assessment factor for multiple aneurismal rupture, and what is interesting, multiple aneurysms maybe have a smaller size. However, further multicenter studies on larger multiple aneurysms databases are needed to verify the true situation.

The ruptured aneurysms have higher aspect ratio. Consistent with our observation, Sadatomo et al. [29] found that in cases with aspect ratio more than or equal to 1.8, 87% were ruptured aneurysms, whereas in cases with aspect ratio less than 1.8, 92% were unruptured aneurysms. Backes et al. [8] performed conditional univariable logistic regression analysis on 124 patients with 302 multiple aneurysms and found that aspect ratio ≥1.3 was associated with multiple aneurysm rupture independent of aneurysm size and location, and independent of patient characteristics. Ujiie et al. [30] performed an in vivo study and found that aspect ratio determined the intra-aneurysmal flow, a higher aspect ratio (>1.6) indicated a much slower circulation near the dome and flow stagnation was detected in the dome of irregular-shaped aneurysms (dumbbell-shaped and bleb) [30]. The dome often has flow stagnation [31],[32], which is related to intra-aneurysmal thrombosis and subsequent inflammatory changes in the aneurysm wall [30]. Higher aspect ratio may suggest a remodeling artery wall and risk for aneurismal rupture.

For hemodynamic factors analysis, we find that the ruptured aneurysms have lower WSSmin and more LSA. These data are consistent with our previous results showing that low WSS might be involved in increasing the risk of rupture [13]. The ruptured aneurysms more often have WSSmin on the dome. Previous studies found that unruptured aneurysms’ thin-walled dome regions co-localized with low WSS and the ruptured aneurysms’ bleeding points were often located at the dome with a low WSS [33]. So we suspect that WSSmin may be associated with flow stagnation at the dome as well as the localized pathologic aneurysm wall degeneration and thinning on the dome. These hemodynamic factors may help us to verify ruptured aneurysms and offer some insight into rupture mechanisms.

The present study had some limitations that need to be addressed. Rigid wall, laminar flow and Newtonian blood were used in our present aneurysm models. The flow conditions were not patient-specific. It is reported that using normal-resolution meshes (1 to 5 million tetrahedral) may underestimate the aneurysm WSS and WSSmax when compared with using high-resolution meshes (300,000 to 1 million elements) [10], while using generalized (typical flow rates in a healthy adult) and patient-specific inflow boundary conditions may results in different WSS magnitudes and hemodynamic characteristics [34]. However, matched pairs design in our study may help control for individual differences affecting the results. Sharing the same inflow boundary conditions on one side of ICA especially help avoid inflow boundary condition confounding. The other limitations were the effects of small sample size and a single center selection bias.

Intracranial aneurysms pairs with different rupture status in one patient’s ipsilateral anterior circulation may be a good disease model to investigate possible features linked to bled aneurysms independent of patient characteristics. The ruptured aneurysms manifested irregular shape, larger size, higher aspect ratio, lower WSSmin and more LSA compared with their unruptured mates. It may promote a better understanding of multiple aneurysms and help neurosurgeons to identify risky sites before operation.