Older age, carotid artery stenosis, and female sex as factors correlated with twisted carotid bifurcation based on 457 angiographic studies

Background: Twisted carotid bifurcation (TCB) is a well-known anatomical variation of the carotid bifurcation in patients undergoing carotid endarterectomy. However, few investigations of TCB have focused on patients without internal carotid artery (ICA) stenosis. This study was performed to analyze the characteristics of TCB in patients with ICA stenosis and other diverse pathologies. Methods: All conventional cerebral angiographies performed in our institute for any reason from January 2012 to December 2018 were reviewed. The patients were divided into two groups, the TCB group and the anatomically normal non-TCB group, and the basic characteristics of the groups were analyzed. Results: Both sides of the carotid bifurcation were clearly visualized in 457 patients. TCB was found in 89 of 457 patients (19.5%); among these 89 patients, 74 (83.1%) had TCB only on the right side, 8 (9.0%) only on the left side, and 7 (7.9%) bilaterally. TCB was found more frequently on the right than left [81 (17.7%) and 15 (3.3%), respectively, on each of the 457 sides ( p < 0.0001)]. TCB was significantly more frequent in older patients ( p = 0.02), female patients ( p < 0.001), and patients with ICA stenosis or occlusion at the bifurcation ( p = 0.005). The prevalence of TCB was 19.5%, and 84.4% of cases were on the right side in patients with diverse pathologies. Conclusions: Older patients, female patients, and patients with ICA stenosis or occlusion are more prone to have TCB.


Introduction
The internal carotid artery (ICA) usually runs dorsolateral to the external carotid artery (ECA) at the carotid bifurcation in the neck.However, the ICA is sometimes positioned dorsal, dorsomedial, or even medial to the ECA, resulting in a so-called twisted carotid bifurcation (TCB) [8] as shown in Fig. 1.TCB has also been named twisted ICA, [5] retropharyngeal ICA, [14,15,18] lateral ECA, [2] lateral position of the ECA, [19,22,4,6] dorsomedial origin of the ICA, [17] or side-by-side positioning.[9] Even though TCB has been reported from as early as 1841, reported by Hyrtl, [5] little has been investigated to date.Only vascular surgeons or neurosurgeons who perform carotid endarterectomy (CEA) have paid attention to TCB.Indeed, most previous reports of TCB were based on case series of CEA for ICA stenosis and mainly focused on surgical results.[12,20,23,[5][6][7][8] However, anatomical as well as clinical characteristics of carotid bifurcation should be further investigated, and the knowledge should be made widely available to the physicians who potentially deal with carotid bifurcation, such as endovascular surgeons, otolaryngologists, radiologists, or anatomists.
From previous literature, the only common characteristic of TCB is overwhelming right-side dominance, i.e., one-third to 100%.The aim of this study is to investigate not only the side dominance but also the prevalence and other characteristics of TCB in patients with ICA stenosis and other diverse pathologies.

Materials and methods
This retrospective observational clinical study was approved by the institutional ethics committee, and patient consent was not required.The data were appropriately deidentified.The study was performed in line with the principles of the Declaration of Helsinki.We reviewed all conventional cerebral angiography examinations performed at our institute for any reason from January 2012 to December 2018.The anteroposterior view of the carotid bifurcation, if available, was evaluated by two certified neurosurgeons at our institute.TCB was defined as the center of the ICA located medially to the center of the ECA in the anteroposterior view, as adopted in previous reports.[8,20] If the relationship between the ICA and ECA was unclear, other modalities such as three-dimensional computed tomography angiography or magnetic resonance angiography, if available, were also utilized.The patient's status was reviewed on each individual medical chart.We estimated a multivariate logistic regression model using the presence or absence of TCB as the dependent variable.The predictor variables were age, sex, hypertension, diabetes mellitus, dyslipidemia, and pathology requiring angiography.All statistical analyses were performed using SPSS Statistics Version 27 (IBM, Armonk, NY, USA).

Results
We reviewed 1335 consecutive conventional cerebral angiography examinations but excluded 878 studies because the bilateral carotid bifurcations were not available for various reasons (e.g., carotid bifurcation not visualized, unilateral study, or poor image quality).Only the latest study was included if repeated in a single patient.Finally, 457 studies including 914 sides were evaluated.In the patient-based analysis, TCB was found in 89 (19.5%) of 457 patients; among these 89 patients, 74 (83.1%) had TCB only on the right side, 8 (9.0%)only on the left side, and 7 (7.9%)bilaterally.In the side-based analysis, TCB was found more frequently on the right than left [81 (17.7%) and 15 (3.3%), respectively, on each of the 457 sides] (Pearson's chi-square = 50.7,p < 0.0001).The patients were divided into two groups, namely those with TCB (TCB group) and those with a normal anatomical carotid bifurcation (non-TCB group), and the demographic differences were compared between the two groups using logistic regression (Table 1).The analysis demonstrated that the patients in the TCB group were significantly older [TCB group 71 (4− 85), non-TCB group 67 (3− 93), p = 0.026], more frequently had ICA stenosis at the bifurcation (p = 0.005), and were more often female (p < 0.001).In addition, age difference between male and female patients in each group were compared using Mann-Whitney U test.In TCB group, the median age of male and female patients were 71.0 (53− 83) and 72.5 (4− 85), respectively, and in non-TCB group, those were 67.0 (3− 93) and 67.0 (9− 92),

Discussion
The etiology of TCB is unknown.Some previous studies have suggested that TCB is congenital [6] or that it is associated with hypertension and diabetes, [8] whereas another study showed no correlation with risk factors for arteriosclerosis.[17] However, no study to date has clarified the etiology.The present study involving a wider spectrum of patients newly revealed that higher age, presence of ICA stenosis, and female sex are predisposing factors for TCB.The higher age and higher rate of ICA stenosis in the TCB group suggest that TCB is related to arteriosclerosis, which may have implications for the etiology of TCB.A previous investigation of carotid angiography examinations of 587 sides (336 right, 251 left) for various reasons such as head trauma, subarachnoid hemorrhage, or intracranial neoplasm concluded that TCB was more frequent in the higher age group.[19] Our study also demonstrated higher occurrence of TCB in older patients.We also observed that rotation of the ICA progressed over time in some patients (Fig. 2).This finding may support the association of TCB with aging and/or arteriosclerosis.However, hypertension, diabetes mellitus, and dyslipidemia, all of which are risk factors for arteriosclerotic change, were not significantly associated with TCB in our study.This dissociation tells us that the etiology may not be merely arteriosclerosis.In fact, only one previous study of TCB showed a significant correlation with hypertension and diabetes mellitus; the remaining studies performed to date did not prove any correlation with these risk factors [12,20,23,[5][6][7][8] (Table 2).In addition, the statistical significance in women was extremely strong (p < 0.001).Only one case series of CEA produced results in agreement with these.[8] Men are more prone to undergo CEA than women with a ratio of 2.3:1.0-8.5:1.0.[12,20,23,[5][6][7][8] This might explain the absence of female dominance in most of the CEA case series.The strong female dominance in the present study may be related to some factors of sex differences, such as genetic or hormonal factors associated with the etiology of TCB.
The prevalence and the right-side dominance in our study show tendencies similar to those in previous studies.The prevalence of TCB in past CEA series ranged from 3.6% to 15.1%, [12,20,23,[5][6][7][8] whereas that in the present study was 19.7%.Our prevalence was somewhat higher because the ratio of women was much higher in our study.The prevalence of TCB was also reported in a limited number of studies examining nonspecific objectives as follows: four cadaveric series [1,10,13,2] showing a prevalence of 7.5-16.0%,and two angiographic series [19,21] showing a prevalence of 12.3% and 13.0%, respectively.The right-side dominance in the previous CEA series [12,20,23,[5][6][7][8] as well as the cadaveric [1,13] and angiographic [21] series ranged from 66.6% to 100%, whereas ours was 83.1%.In addition, most sporadic cases of TCB reportedly occur on the right.[11,16,22,24,3,4] Our study also showed overwhelming right-side dominance despite the wider spectrum of pathologies.The reason for this dominance remains unclear even though the architectural difference in aorta has been suggested.[6,8].
This study had two main limitations.First, an observational retrospective clinical study such as this cannot reflect the natural incidence of a phenomenon.Despite our wider range of patients, the cohort cannot be considered a normal population.Patients who undergo cerebral angiography must have an underlying abnormality, which may have introduced bias into the results.Second, only a limited number of younger patients were included.Younger patients rarely undergo angiography because of the low potential for vascular abnormalities.Moreover, angiography carries some risks in pediatric patients, such as the requirement for sedation or anesthesia as well as harm to the small and fragile vessels.
In conclusion, this is the first study to investigate the prevalence and characteristics of TCB in a wide spectrum of patients.TCB was found in almost 20% of the patients, and more than 80% of TCB was on the right side; these findings are consistent with previous CEA case series.Higher age, female sex, and incorporation with ICA stenosis were significant risk factors for TCB.As for the future perspectives, the etiology, and the reason for the right-side dominance of TCB should be investigated.

Ethics approval
This retrospective observational clinical study was approved by the institutional ethics committee.

Fig. 1 .
Fig. 1.Digital subtraction angiography showing a representative case of twisted carotid bifurcation in the (a) anteroposterior view and (b) lateral view from the right.Black arrows indicate the internal carotid artery.Note that the internal carotid artery runs medial to the external carotid artery at the bifurcation on the anteroposterior view, and these arteries overlap on the lateral view.A, anterior; R, right.

Fig. 2 .
Fig. 2. Magnetic resonance images at the level of the carotid bifurcation in the same 68-yearold man in (a) 2013 and (b) 2018.The patient had a twisted carotid bifurcation on both sides.The solid white lines indicate the vertical plane from the center of the external carotid arteries, and the dashed lines connect the centers of the external carotid artery and internal carotid artery.The angle between the solid and dashed lines is the angle of the twisted carotid bifurcation.The angles are larger on both sides in (b) than in (a), suggesting that the rotation of the twist progressed over time.R, right.

Table 1
Analysis of clinical characteristics.
a ICA stenosis of >50% at the carotid bifurcation b Includes intracranial artery stenosis, cerebralinfarction, transient ischemic attack, or acute mechanical thrombectomy respectively, which were not significant (p = 0.804 and p = 0.137, respectively).

Table 2
Summary of previous carotid endarterectomy case series.TCB twisted carotid bifurcation, N/A not applicable."◌" indicates a positive correlation with TCB, and "× " indicates no correlation