Are Strokes Mostly Genetically Based or Acquired? Stenosis vs Hypoplasia of Vertebral Artery Anomalous as The Leading Cause of Stroke (Anatomical Study of VA Anomalies in Neck Three-Dimensional Computed Tomography Angiography)

A thorough understanding of the vertebral artery (VA) variations and course of the artery and its related branches could signicantly enhance the ecacy and safety of interventions involving the neck and spine. Here, we aimed to investigate the incidence of various VA variations in individuals presenting with signs and symptoms of stroke with our neurology team. In this cross-sectional study, all patients referred to our specialized medical imaging center and underwent neck CT-angiography (CTA) were enrolled in this study for two years from September 2019 onward. Patients' information forms were obtained to collect demographic data.


Background
The vertebral artery (VA) arises from the respective subclavian artery and connects the opposite site branch to form the basilar artery [1]. The VA is anatomically divided into four segments: V1, preforaminal; V2, foraminal; V3, atlantic; and V4 intracranial [2]. Anatomical variations mainly involve the distal segments of VA (V3 and V4). Several embryological explanations for these variations have been proposed in the literature [3].
With the growing use of vascular angiography, uncommon cases of hypoplasia, origin stenosis, and altered origin have thoroughly been diagnosed [4]. In Kauffman's study, it was reported that patients with VA stenotic origin are correlated with less risk of stroke through intraarterial angiography [5]. The VA origin and aortic arch branching patterns should be assessed in cases of cerebrovascular accidents and VA dissection [6].
In Kim's study, Vertebral Artery Hypoplasia (VAH) greatly contributes to a rising risk of Posterior cerebellar stroke (PCS) [7]. However, the rates of VAH reported in the literature vary markedly because there is currently no standard de nition for this disorder [8]. The VA variations are highly signi cant from various clinical points of view. First of all, these variations could predispose some people to disorders impairing the blood supply to the head and neck. These could accompany other life-threatening vascular anomalies. In addition, spine surgeons and interventional radiologists might encounter problems in the VA during the procedure. It is noted that the incidence rate of VA injury in spine surgery has been reported to range from 0.3-8.2% [9][10][11].
Having a comprehensive understanding of the VA variations and course of the artery and its related branches preoperatively could signi cantly enhance the e cacy and safety of interventions involving the neck and spine, and subsequently enable surgeons to avoid injury [12]. In this study, we sought to investigate the incidence of various VA variations which would be helpful in head and neck surgery.
Meanwhile, understanding the incidence of VA anomalies and variations and identifying which anomalies are more common in each gender in patients who present with signs and symptoms of stroke increases the early diagnosis and prevents life-threatening complications. We are assessing individuals who presented with signs and symptoms of stroke to our neurology team and referred to our imaging centre to investigate the possibility of stroke.

Ethics approval
Ethical approval for this Study and use of patients three-dimensional computed tomography angiography (CTA) images for collection and study was obtained originally from the local ethics committee in Shahid Beheshti university of medical sciences, Tehran, Iran. The Iran National Committee for Ethics in Biomedical Research approved continuing this study.
We conducted this study using data and CTA images from Tooska Medical Imaging center. All study participants provided written informed consent for studying their images. Patients explained regarding how their clinical data would be used in the study process. The patients' information remained con dential and identities were anonymous. All materials and methods were performed in accordance with the relevant guidelines and regulations and written informed consent for publication was obtained from patients.

Study design and participants
The present study was a single-center retrospective observational investigation. Inclusion criterion for this study was: individuals who visited our neurology team with signs and symptoms of stroke or headache and dizziness in suspicious of posterior cerebellar stroke (PCS) were therefore referred to our specialized medical imaging centre (Tooska Medical Imaging Centre, Tehran, Iran). Exclusion criteria were patients in whom VA was not clear or patients without proper contrast injection. These patients underwent computed tomography (CT) angiography in September 2019, using the "census" sampling method. Eventually, 125 cases were applicable to this study after excluding subjects with undetectable VAs on their CTA. Patients' information forms were obtained to collect demographic details. Written consent forms were also obtained from each patient regarding how their clinical data would be used in the study process. The patients' information remained con dential and identities were anonymous.

Image acquisition and interpretation
A Lightspeed QXI four-slice CT scanner (GE, Milwaukee, WI, USA) was used in all examinations with a collimation of 1.25 mm, pitch of 0.75, and a table speed of 3.75 cm. Visipaque 320 (iodixanol, GE Healthcare) was injected as the contrast agent with an infusion speed of 1-3 ml per second. An experienced board-certi ed radiologist evaluated all obtained CTA images, recording VA characteristics regarding dominance and any possible anomalies, including anomalous origin, anomalous route, anomalous branching, stenosis, hypoplasia, atresia, thrombosis, and dissection.

Statistical analysis
All raw data were analysed using SPSS version 24 (IBM Corporation; formerly SPSS Inc.), and nominal data were reported in terms of frequency and percentage with 95% con dence interval (CI). Numeric data were reported as mean ± standard deviation (SD).

Results
In this section, we assess the prevalence of VA anomalies according to data from CT Angiography of patients who referred to the neurology team with signs and symptoms of PICA stroke. Initially, we studied the frequency of each variation followed by assessing the correlations between each anomaly. In the nal analysis, 125 patients (53.6% females, n = 67) were included after applying the inclusion and exclusion criteria with a mean age of 60.71 (range 25-87 years). Patients were categorized into ve groups based on age: under 30, 31-40, 41-60, 61-80, and over 80 years.

3.1-Dominance
In patients who presented the most frequent scenario was co-dominant with 83 cases followed by right dominant with 20 cases, the remaining ones being left dominant amounting to 16 cases. Hence, dominance was not identi ed in 6 patients ( Table 1).   (Table 2).

Anomalous route
In this study, only one case was reported as both VA entering the transverse foramina at C3-C4 level.

Anomalous branching
This anomaly was found in 5 cases, with 4 cases originating from V3 rather than V4 PICA, while only 1 case was reported as bilateral and in 1 case Right AICA originating from V4 rather than basilar.

Duplication
Duplication was reported in only 1 male patient with 2 branches originating from the aortic arch and left Subclavian common Artery (SCA). Left VA was duplicated and conjoined at V2.

Signi cant Stenosis
In the present study, signi cant stenosis was reported in 23 cases (18.4%). Origin of left VA was reported in 12 cases and origin of Rt VA was reported in 9 cases. In 2 cases, stenosis appeared at the distal of Lt VA, V4 segment of both Right and left VA before PICA (Table 3).

V4 Atresia, Thrombosis, Dissection
In this study, 3 cases were reported as V4 Atresia in which all of them are on the right. Thrombosis was reported in 4 cases and dissection appeared in 4 cases of which 1 was reported to be bilateral.

Hypoplasia
In this study, hypoplasia was detected in 22 patients (17.6%). hypoplasia found in 3 cases of V1-V3, 9 cases hypoplasia of V1-V4, 9 cases hypoplasia of V4 after PICA and 1 case hypoplasia of V4 (Table 4).   (Table 1). Among patients, 4.0% (n = 5) had an anomalous origin, of which 4 with left VA originated from the aortic arch, and in one patient, right VA originated from the right common carotid artery. Overall, males had more VA anomalies than females, 24.8% and 17.6%, respectively (in general, 42.4% of all participants) (p = 0.020). Referring to the anomalous route, in only one male patient did both VA enter the transverse foramina at the C3-C4 level. Besides, anomalous branching was reported in 5 patients (4.0%), of whom four with posterior inferior cerebellar artery (PICA) originated from the V3 segment rather than the V4 segment. One patient with right anterior inferior cerebellar artery (AICA) derived from the V4 segment rather than the basilar artery. Duplication was seen in one male patient whose left VA was duplicated with two branches originating from the aortic arch and left subclavian artery, conjoint at the V2 segment.
The most common anomaly in the study population was signi cant stenosis, which was observed in 23 patients (18.4%) at the origin of the left VA (12 patients), the origin of right VA (9 patients), distal left VA (1 patient), and V4 segments of both right and left VA before PICA. V4 atresia was also evident in three patients, all of whom were on the right side. VA hypoplasia was recorded in 22 patients (17.6%) as follows: V1-distal V2, 3 cases; V1-distal V3, 9 cases; and V4. Dissection was found in four patients of which three were in the 41-60 years age group.

Discussion
Our ndings revealed that approximately 42% of patients had at least one VA variation with a male preponderance. Co-dominance was the most commonly observed dominance. Among the variations, hypoplasia and signi cant stenosis were the most prevalent anomalies.
With advances in interventional radiology and surgical methods in the neck, a thorough knowledge of VA's anatomical variations regarding its origin, course, and branches is crucial to minimize procedurerelated complications [13]. Although colour Doppler ultrasonography has been traditionally considered the primary diagnostic modality in VA variations, CTA and MR angiography more accurately depict these variations and anomalies [14]. Coexisting intracerebral abnormalities in patients with VA variations should be investigated and vice versa, particularly in patients who experience cerebrovascular accidents [14].
Regarding dominance, the right outnumbered the left in our study. Our ndings echoed those documented in previous studies, in which right and left dominance were observed in 45% and 30%, respectively [1]. Some studies hypothesize that the VA's origin and diameter differences may result in cerebral disorders because of the altered cerebral haemodynamic [15]. Originating from the left aortic arch was observed in 3.2% of participants in this study. A left VA of aortic origin is correlated with a predilection for dissection, presumably due to the vessel's longer course in the neck [16]. This could also be attributed to congenital defects in the structural arterial wall and cerebral haemodynamic changes [14]. Our ndings are consistent with previous studies that also reported a greater incidence of VA variation in males [16].
Signi cant origin stenosis was detected in approximately 18% of our patients. A stenotic VA origin is principally associated with arterial thromboembolism and hypoperfusion. These patients generally have coexisting atherosclerotic stenosis in both carotid and renal arteries [17]. A stenotic VA origin with the vessel's tortuousness of origin raises the probability of stent fracture during the placement procedure [18].
Posterior circulation stroke in about 5% of patients was linked to VA origin stenosis [19].
Regarding VA branching variations, PICA originated from V3 rather than V4 in 3.2% of our patients. After the VA enters the suboccipital region, meningeal branches emerge, and its terminal and largest branchthe PICA -is given off [2]. Extradural origins of VA, similar to our ndings, were reported in about 4% of patients through previous studies [20]. PICA termination is widespread in cases of left VA origin from the aortic arch, and the extradural branches of VA should be taken into consideration [13].
The present study reveals that the VA variations, especially signi cant stenosis (23 cases) and hypoplasia (22 cases), are the two most common variations with signi cant stenosis occurring more than hypoplasia. It is important to differentiate between acquired narrowing and hypoplasia of the VA because each of these has a different atherosclerotic burden [7].

Conclusion
In conclusion, our study shows that stenosis is more frequent than hypoplasia, so the former could be the most acquired and preventable factor of stroke. Besides, anatomical variations, including origin and branching, should be seriously considered in surgical or interventional radiology procedures to minimize the complications. Ethical approval for this Study and use of patients three-dimensional computed tomography angiography (CTA) images for collection and study was obtained originally from the local ethics committee in Shahid Beheshti university of medical sciences, Tehran, Iran. The Iran National Committee for Ethics in Biomedical Research approved continuing this study.
We conducted this study using data and CTA images from Tooska Medical Imaging center. All study participants provided written informed consent for studying their images. Patients explained regarding how their clinical data would be used in the study process. The patients' information remained con dential and identities were anonymous.

Consent for publication
All images were performed in accordance with the relevant guidelines and regulations and written informed consent for studying and publication was obtained from all patients.

Availability of data and material
The computed tomography angiography (CTA) raw data generated and analyzed during the current study are available in the Dr So a Saburi repository, Radiologist and main director of Tooska imaging center, Email: dr.sabouri@hotmail.com.