Objective Morphological risk factors for the rupture of intracranial vertebral artery dissecting aneurysms (IVADAs) have not been well characterized. In this study, we aim to identify morphological characteristics associated with IVADA rupture.
Methods We conducted a retrospective study of 249 consecutive patients with single IVADAs (31 ruptured and 218 unruptured) admitted to Beijing Tiantan Hospital between January 2016 and December 2020. Various morphological parameters were measured using three-dimensional digital subtraction angiography images. Univariate and multivariate logistic regression analyses were performed to identify morphological characteristics associated with IVADA rupture.
Results Univariate regression analysis revealed that the coexistence of significant proximal and distal stenosis and posterior inferior cerebellar artery (PICA) involvement were associated with IVADA rupture, while the origin from the dominant vertebral artery was inversely associated with the rupture. Multivariate regression analysis demonstrated that the coexistence of significant proximal and distal stenosis (OR 22.00, 95% CI 5.60 to 86.70, p<0.001) and PICA involvement (OR 4.55, 95% CI 1.36 to 15.20, p=0.014) were independently associated with IVADA rupture.
Conclusion The coexistence of significant proximal and distal stenosis and PICA involvement were independently associated with IVADA rupture. These morphological characteristics may facilitate the assessment of rupture risk in patients with IVADAs.
Data availability statement
Data are available upon reasonable request. The data supporting the findings of this study are available from the corresponding author upon reasonable request.
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What is already known on this topic
Several studies have reported proximal and/or distal stenosis in ruptured intracranial vertebral artery dissecting aneurysms (IVADAs). However, the association between stenosis and IVADA rupture has not been well evaluated.
What this study adds
The coexistence of significant (50–99%) proximal and distal stenosis is independently associated with IVADA rupture.
How this study might affect research, practice or policy
The findings of this study may facilitate the assessment of rupture risk in patients with IVADAs.
Intracranial vertebral artery (VA) dissections are the most common intracranial artery dissections.1 2 Their clinical manifestations include posterior circulation ischemia, subarachnoid hemorrhage (SAH), and posterior fossa mass effect,3–5 which pose a high risk of rupture or re-rupture and can lead to a worse prognosis.1 6–9 There are three main morphological variations of intracranial VA dissections: dilatation without stenosis, aneurysmal dilatation alternating with stenosis, and steno-occlusive without aneurysmal dilatation.10 Morphological characteristics are highly associated with clinical manifestations.3 5 7 10–13
Intracranial VA dissecting aneurysms (IVADAs) are intracranial VA dissections with fusiform or saccular aneurysmal dilatation, and are more likely to rupture than those without dilatation.3 10 11 The rupture or re-rupture risk is the most important consideration in treatment method selection for IVADAs.14–16 Morphological characteristics can also be risk factors for IVADA rupture17 18; however, morphological risk factors for the rupture of IVADAs have not been well characterized.
Previous studies have revealed morphological differences between ruptured and unruptured IVADAs.3 10 17 18 Proximal and/or distal stenosis adjacent to aneurysmal dilatation is common in ruptured IVADAs.3 10 11 However, the association between stenosis and IVADA rupture has not been well evaluated. Additionally, studies on detailed morphological characteristics of ruptured IVADAs using three-dimensional digital subtraction angiography (3D-DSA) images are limited. Here we investigated a series of IVADA morphological characteristics, including stenosis, using 3D-DSA images to identify the characteristics associated with IVADA rupture. To the best of our knowledge, this is the first study to classify IVADA stenosis in terms of its degree and position-based relationship to dilatation, and to determine its association with the rupture of IVADAs.
This retrospective study was conducted on patients with IVADAs admitted to Beijing Tiantan Hospital between January 2016 and December 2020. All diagnoses were confirmed either by 3D-DSA alone or 3D-DSA combined with computed tomography (CT) angiography, magnetic resonance (MR) angiography, and/or high-resolution MR. The diagnostic criterion was fusiform or saccular aneurysmal dilatation accompanied by any sign of dissection, including a double lumen, intimal flap, and intramural hematoma. Patients with IVADAs involving but not limited to the V4 segment of the VA were included in this study. The exclusion criteria were as follows: (1) fusiform dilatation without a sign of a double lumen, intimal flap, or intramural hematoma; (2) dissection without aneurysmal dilatation; (3) dissecting aneurysms entirely located outside the V4 segment of the VA; (4) saccular aneurysms; (5) history of surgical clipping or endovascular treatment for IVADAs; (6) unqualified radiographic images; and (7) bilateral IVADAs. Patients were divided into a ruptured or unruptured group according to the signs of SAH that were confirmed by CT. Clinical data included age, sex, current smoking (within 6 months), current antithrombotic agent use (within 2 weeks), comorbidities (hypertension, hyperlipidemia, diabetes mellitus, and coronary artery disease), and coexistence with non-V4 cervicocerebral aneurysms.
All morphological parameters were measured using 3D-DSA images from a Siemens Artis Zee System (Siemens Healthcare, Erlangen, Germany). Two experienced researchers blinded to the patients’ clinical information interpreted the images independently and achieved consensus decisions. When the circumference of the parent artery was entirely involved, the height was determined as the maximum distance of IVADAs perpendicular to the centerline of the parent artery. When the circumference of the parent artery was partially involved, the height was determined as the largest perpendicular distance from the neck to the dome of IVADAs. The length was defined as the maximum length of the involved segment of the parent artery. A VA was defined as dominant if (1) it had a larger diameter (a side-to-side diameter difference ≥0.3 mm) or (2) it connected to the basilar artery (BA) more straightforwardly when both VAs had comparable diameters.19 Additionally, if one side of the VA was invisible or terminated in the posterior inferior cerebellar artery (PICA), the other side of the VA was considered to be the dominant VA. The entire circumference of artery involvement was defined as an entirely involved circumference of the parent artery from any viewing angle. Significant stenosis was defined as 50–99% stenosis of the parent artery adjacent to the aneurysmal dilation. The degree of distal stenosis was calculated by dividing the residual diameter (N) by the vessel diameter at a point distal to the stenosis where normal vessel caliber had been restored (D); the following formula was applied for the calculation: (1–N/D)×100% = degree of stenosis.20 If the caliber of the VA distal to a dissecting aneurysm was entirely abnormal, the diameter of the VA proximal to the dissecting aneurysm with a normal caliber was measured instead. The degree of proximal stenosis was also calculated using the same formula, with D representing the diameter of the VA with a normal caliber proximal to the stenosis. We classified significant stenosis into four types: without stenosis, proximal-only stenosis, distal-only stenosis, and coexistence of proximal and distal stenosis. The relationship of IVADAs to PICA was classified into the following four types: PICA-proximal, PICA-distal, PICA-involved, and PICA-absent.16 21
Continuous variables are presented as means±SDs, and categorical variables are presented as percentages. The inter-observer agreement in qualitative characteristics was evaluated using Cohen’s κ coefficient, while the inter-observer agreement in quantitative measurements was assessed using the intra-class correlation coefficient. A Cohen’s κ coefficient and intra-class correlation coefficient >0.75 were considered excellent. The Shapiro-Wilk test was used to evaluate the normality of data distribution. A Wilcoxon rank-sum test was performed to compare continuous variables. Pearson’s χ2 test or Fisher’s exact test was performed to compare categorical variables. Multiple imputations were used to address missing values in the covariates. The pooled results of five imputed datasets were reported. Univariate and multivariate logistic regression models were applied to identify the association between morphological characteristics and the rupture of IVADAs. The multivariate model included significant (p<0.10) variables detected in univariate models. The odds ratio (OR) and 95% confidence interval (95% CI) are also reported. All analyses were conducted with R (version 4.1.0, R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set at a two-tailed p value <0.05.
A total of 249 patients with IVADAs were enrolled in this study, of whom 31 had SAH. There were 185 (74.3%) males and 64 (25.7%) females, with a mean age of 51.9±9.5 years (range 6–75) and 53.2±14.2 years (range 6–77), respectively. Baseline characteristics are shown in table 1. No significant differences were observed in the baseline characteristics (age, sex, smoking, antithrombotic agent use, hypertension, hyperlipidemia, diabetes mellitus, coronary artery disease, and coexistence with non-V4 cervicocerebral aneurysms) between the ruptured and unruptured groups.
Inter-observer agreement of the measurements of all morphological parameters was considered excellent. The Cohen κ coefficients for VA dominance, the entire circumference of artery involvement, BA involvement, significant stenosis, and relationship to PICA were 0.859, 0.820, 1, 0.928, and 0.938, respectively. The intra-class correlation coefficient for length, height, and maximum diameter were 0.968, 0.933, and 0.971, respectively.
Morphological characteristics are shown in table 2. IVADAs were less likely to originate from the dominant VA in the ruptured group than in the unruptured group (44.8% vs 66.7%, p=0.021). There were significant differences in the type of significant stenosis (p<0.001) and the relationship to PICA (p=0.001). No significant difference between the two groups was found in other morphological characteristics, including maximum diameter, height, length, height/length ratio, the entire circumference of artery involvement, and BA involvement (p>0.05).
Morphological characteristics associated with the rupture of IVADAs
The results of the univariate and multivariate analyses are shown in table 3. Univariate analysis results indicated that IVADAs were less likely to originate from the dominant VA in the ruptured group than in the unruptured group (44.8% vs 66.7%; OR 0.42, 95% CI 0.19 to 0.94, p=0.034). The coexistence of significant proximal and distal stenosis (31.0% vs 2.3%; OR 22.18, 95% CI 6.69 to 73.58, p<0.001) and PICA involvement (54.8% vs 19.7%; OR 4.74, 95% CI 1.62 to 13.92, p=0.005) were more prevalent in the ruptured group than in the unruptured group. The height (OR 0.87, 95% CI 0.75 to 1.02, p=0.078) was another significant variable detected in the univariate analysis. These four significant variables were then analyzed in a multivariate logistic regression analysis, and the results showed that the coexistence of significant proximal and distal stenosis (OR 22.00, 95% CI 5.60 to 86.70, p<0.001) and PICA involvement (OR 4.55, 95% CI 1.36 to 15.20, p=0.014) were independently associated with the rupture of IVADAs.
In this study, we investigated a series of morphological characteristics of IVADAs measured using 3D-DSA. We found that the type of significant stenosis adjacent to aneurysmal dilatation and the type of IVADA relationship to PICA differed between ruptured and unruptured IVADAs. The coexistence of significant proximal and distal stenosis and PICA involvement were more prevalent in ruptured IVADAs than in unruptured IVADAs.
Stenosis and the rupture of IVADAs
A stenosis adjacent to aneurysmal dilatation is common in IVADAs,7 10 11 13 22 and can be located at the proximal, distal, or both ends thereof. In this study, we defined 50–99% stenosis as significant stenosis. Significant stenosis located next to an aneurysmal dilatation was found in up to 22.7% (56/247) of IVADA patients in our study. In addition, we found that significant stenosis was more prevalent at the proximal end (19.0%, 47/247) than at the distal end (9.3%, 23/247) of the dilatation. These findings are consistent with previously reported results.3 12
Several studies have reported proximal and/or distal stenosis in ruptured IVADAs3 10 11; however, the association between stenosis and IVADA rupture had not been well evaluated. Here, we classified significant stenosis into four types according to the positional relationship with IVADAs, and then assessed the association of the different stenosis types with IVADA rupture. We found that only the coexistence of significant proximal and distal stenosis was independently associated with the rupture status of IVADAs, while the proximal-only and distal-only significant stenosis were not.
Dissections between the intima and media tend to cause stenosis and occlusion, while dissections between the media and adventitia are likely to form aneurysmal dilatation.2 The ruptured IVADAs are transmural, with the rip penetrating all arterial wall layers where intimal tears, medial defects and adventitial ruptures coexist.23–25 Ro et al 23 found that medial defects of the artery wall were longer than intimal tears and dilated lesions. However, the stenoses observed in the Ro et al study were mainly located at the distal parts. Our findings support the hypothesis of following mechanism of stenosis formation: before adventitial rupture, stenosis may be formed gradually after blood has entered the artery wall through intimal tears and generates an inward growing medial hematoma at the proximal and distal parts of the dilatation. We propose that the coexistence of significant proximal and distal stenosis is a sign of severe expansion of acute medial hematoma and indicates a high risk of IVADA rupture. Further studies are needed to determine the predictive role of this morphological characteristic for IVADA rupture.
Association between PICA involvement and the rupture of IVADAs
The PICA involvement in ruptured IVADAs has been well documented3 21 and may be associated with ruptured VA dissections.18 Our findings provide further evidence to support the role of PICA involvement in IVADAs rupture. Previous studies on the hemodynamics of saccular aneurysms have shown that, compared with sidewall aneurysms, bifurcation aneurysms were in a more unfavorable hemodynamic environment and were more vulnerable to rupture.26 27 We hypothesize that this mechanism may also explain IVADA rupture. As an essential branch, the PICA primarily originates from the V4 segment of the VA. The origin of the PICA forms a bifurcation, which may complicate the blood flow pattern of IVADAs involving the PICA. This adverse hemodynamic environment may lead to IVADA progression, including dilatation.28 The trend of dilatation is thought to be associated with a high risk of rupture.23 A histological study of the VA showed that the media and adventitia became significantly thinner after the origin of the PICA. Moreover, near the origin of the PICA, the incidence of internal elastic lamina defects was very high.29 Therefore, the wall of IVADAs involving the PICA may also be weaker and have a higher rupture risk.
Our study has several limitations that should be noted. First, potential bias could have been introduced as the study was carried out retrospectively at a single institution. Second, due to the small number of related patients, we did not include a group of potential confounding factors, such as a family history of SAH, connective tissue disease, infectious disease, migraine, or craniocervical trauma in the baseline characteristics. Third, as morphological characteristics of ruptured IVADAs were obtained in the acute stage, those of the non-acute stage were unclear. Fourth, as our institution receives referred patients primarily with unruptured IVADAs, the proportion of patients with ruptured IVADAs in our cohort could be lower than that in the general population.
In this study, we identified two morphological factors that were independently associated with the rupture of IVADAs: (1) the coexistence of significant proximal and distal stenosis; and (2) PICA involvement. Further studies in larger cohorts are needed to determine the predictive role of these factors for the rupture of IVADAs.
Data availability statement
Data are available upon reasonable request. The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Patient consent for publication
The authors appreciated the statistical consultation provided by Yuesong Pan, PhD, China National Clinical Research Center for Neurological Diseases, Beijing, China.
Contributors JH designed and conceptualized the study; collected, analyzed, and interpreted the data; and drafted the manuscript. JC and XT interpreted the data and revised the manuscript. MH, LL, FP and HN collected the data. AL acted as the guarantor, designed and conceptualized the study, and revised the manuscript. FL designed and conceptualized the study and revised the manuscript.
Funding This study was supported by the National Natural Science Foundation of China (81870944), the National Natural Science Foundation of China (81771233), Specific Research Projects for Capital Health Development (2018‐2‐2041), the Beijing Science and Technology Planning Project (Z181100009618035), the Beijing Municipal Administration of Hospitals’ Ascent Plan (DFL20190501), and the Research and Promotion Program of Appropriate Techniques for Intervention of Chinese High-risk Stroke People (GN-2020R0007).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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