Prevalence and Clinical Implications of the Primitive Trigeminal Artery and its Variants: A Meta-Analysis

Journal Pre-proof Prevalence and clinical implications of the primitive trigeminal artery and its variants: a meta-analysis Karolina Brzegowy, Przemysław A. Pękala, MD, PhD, Michał P. Zarzecki, Jakub R. Pękala, Joyeeta Roy, MD, Hasina M. Aziz, R. Shane Tubbs, PhD, MS, PA-C, Jerzy A. Walocha, MD, PhD, Krzysztof A. Tomaszewski, MSPC, MBA, MSc (Edin), MD, PhD, Marcin Mikos, MD, PhD PII:

S1878-8750(19)32472-6

DOI:

https://doi.org/10.1016/j.wneu.2019.09.042

Reference:

WNEU 13341

To appear in:

World Neurosurgery

Received Date: 23 May 2019 Revised Date:

5 September 2019

Accepted Date: 6 September 2019

Please cite this article as: Brzegowy K, Pękala PA, Zarzecki MP, Pękala JR, Roy J, Aziz HM, Tubbs RS, Walocha JA, Tomaszewski KA, Mikos M, Prevalence and clinical implications of the primitive trigeminal artery and its variants: a meta-analysis, World Neurosurgery (2019), doi: https://doi.org/10.1016/ j.wneu.2019.09.042. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.

Title: Prevalence and clinical implications of the primitive trigeminal artery and its variants: a meta-analysis Authors: Karolina Brzegowy1,2, Przemysław A. Pękala, MD, PhD1,2, Michał P. Zarzecki1,2, Jakub R. Pękala1,2, Joyeeta Roy, MD2,3, Hasina M. Aziz1,2, R. Shane Tubbs, PhD, MS, PA-C3, Jerzy A. Walocha, MD, PhD1,2, Krzysztof A. Tomaszewski, MSPC, MBA, MSc (Edin), MD, PhD1,2, Marcin Mikos, MD, PhD2,5 Affiliations: 1 Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland 2 International Evidence-Based Anatomy Working Group, Krakow, Poland 3 Department of Anatomy, University of Otago, Duedin, New Zeland 4 Seattle Science Foundation, Seattle, Washington, USA 5 Faculty of Medicine and Health Sciences, Andrzej Frycz Modrzewski Krakow University, Krakow, Poland Corresponding Author’s name and current institution: Krzysztof A. Tomaszewski Department of Anatomy, Jagiellonian University Medical College, Krakow, Poland 12 Kopernika St, 31–034 Krakow, Poland Telephone number 48124229511 Fax number 48124229511 Corresponding Author’s Email: [email protected]

Key Words: carotid-basilar anastomosis; internal carotid artery; fetal intracranial artery; primitive trigeminal artery; vascular anatomy

Running Title: Primitive trigeminal artery and its variants

Declarations of interest: none

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Introduction

The primitive trigeminal artery (PTA), the most common and the largest persistent carotidbasilar anastomosis, derives its name from its usual course in proximity to the trigeminal ganglion.1,2 The PTA was first described by Quain (1844) and Sutton (1950) in cadaveric and angiographic studies, respectively. Currently it is reported mostly as an incidental finding during routine diagnostic imaging procedures.3 Owing to the recent development of diagnostic imaging and the popularization of endoscopic approaches to the skull base, the artery and its variants have become more frequently reported.4 The PTA gross anatomy is known well; however, its clinically important features and prevalence with respect to ethnic and sex subgroups have not yet been investigated fully in a meta-analysis.

The PTA usually originates from the cavernous/C4 internal carotid artery (ICA).5,6 It typically terminates at the basilar artery (BA), between the origins of the superior cerebellar artery (SCA) and anterior inferior cerebellar artery (AICA) (Fig. 1).5,7,8 PTA variants (PTAVs) are arteries that arise from the ICA and continue as the cerebellar arteries (SCA/AICA/PICA).

Recognition of the PTA/PTAV laterality is important in neurosurgical procedures in the paraand intra-sellar regions (Fig. 2).9,10 A lateral-type PTA courses in proximity to the III, IV, V and VIth cranial nerves and can compress them, contributing to trigeminal neuralgia as well as oculomotor, trochlear and abducent nerve palsies.6,11,12 Similarly, PTAVs have been associated with trigeminal neuralgia.13 Failure to recognize a lateral-type PTA can result in hemorrhagic complications during the percutaneous gasserian ganglion procedure.13,14 The medial-type PTA

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is particularly clinically important as it courses through the sella, running close to the pituitary gland10. The presence of an intrasellar-type PTA warrants extreme caution during transsphenoidal approaches to the skull base, such as the endoscopic endonasal surgery for pituitary adenoma.4,9,15

Numerous classification systems have been developed to describe the PTA and PTAVs. Saltzman [1959] distinguished two main types of PTAs according to their contribution to the blood supply to the posterior part of the Circle of Willis (CoW). In type I, the PTA supplies the entire vertebrobasilar system above the anastomosis - distal BA, both posterior cerebral arteries (PCAs), and both SCAs, which results in the posterior communicating arteries (PComs) becoming redundant and regressing. In type II, the PTA supplies the SCAs bilaterally, but the PCAs receive blood through the PComs. Saltzman also described a variation that seems to combine both types, the PTA supplying the SCAs bilaterally and the PCA contralaterally.16 Later authors made this artery eponymous as Satzman type III. However, the literature reveals that all arteries matching neither the Saltzman I nor the Saltzman II category, such as PTAVs, are erroneously assigned to type III.9,17

While Saltzman described only PTAs, Weon (2011) extended his classification to PTAVs. Weon’s types 1 and 2 were the same as Saltzman I and II, respectively. Weon’s type 3 was the third-type vessel originally described by Saltzman. Type 4 differed from type 3 only in the PCA supply, which was ipsilateral. Weon further subclassified PTAVs connected to the SCA, AICA and PICA as types 5a, 5b, and 5c respectively.18 In contrast, Ouchi (2010) subclassified PTAVs as types A (not uniting with BA or SCA) and B (PTAV uniting with ipsilateral SCA), and this

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concept has been adopted in more recent studies.15,19 These different approaches to PTA and PTAV classifications make it hard to compare studies and estimate the true prevalences of particular PTA and PTAV patterns.

Detailed anatomical knowledge is required for therapeutic embolization procedures in patients with a carotid-basilar anastomosis. A PTA that predominantly supplies the distal vertebrobasilar system requires careful attention during surgical dissections and cannot undergo occlusion. Moreover, a PTA can serve not only as a collateral circulation channel but also as a pathway for emboli. In the presence of a PTA or a PTAV, endovascular procedures for aneurysms or malformations should be modified in order to avoid brainstem and cerebellar ischemia.18

Preoperative detection of a PTA and its variants and detailed anatomical knowledge of their course is necessary for developing optimal treatment plans and reducing the hemorrhagic and ischemic hazard posed by these vessels in neurosurgery. Taking this into account, the aim of the present study was to perform a systematic review of the literature and to meta-analyze the extracted data to determine the prevalences of PTA and PTAV and their clinically important features.

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Material and methods

Search Strategy

A broad search of major electronic databases (PubMed, ScienceDirect, EMBASE, Web of Science) was conducted to identify all studies eligible for inclusion in the meta-analysis. No date limits or language restrictions were applied. The following search terms were used: primitive trigeminal artery, persistent primitive trigeminal artery, persistent trigeminal artery variant, PPTA, PTAV, carotid-basilar anastomoses, carotid-vertebrobasilar anastomoses, persisting embryonic vessels. The references of the included studies were searched to identify any further potentially relevant articles. PRISMA guidelines were strictly followed throughout the search process and the meta-analysis.

Eligibility assessment

Eligibility for inclusion in the meta-analysis was assessed by three independent reviewers. All cadaveric or radiological studies reporting relevant and extractable data on the prevalence and anatomical characteristics of PTA and PTAVs were included.

The exclusion criteria included: (1) case reports, conference abstracts and reviews; (2) studies containing incomplete or irrelevant data; (3) studies performed on fetuses; (4) studies performed on patients with trigeminal neuralgia. All studies with the potential for inclusion in the metaanalysis published in languages not spoken fluently by the authors were translated by medical

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professionals fluent in both English and the language of the original article. Any disagreements arising during eligibility assessment were settled by a consensus among all the authors. When necessary and possible, authors of the original articles were contacted via email for further details.

Data extraction Data from the included studies were independently extracted by two reviewers and included prevalence, sex, origin, side, laterality (intrasellar/parasellar), course (according to the classification system used by the author) and associated basilar artery hypoplasia. The authors adopted a simple division of possible artery variants into two categories to assess the true prevalence of each: (1) PTA, an artery originating from the ICA and anastomosing only with the BA; (2) PTAV, an artery originating from the ICA and anastomosing with at least one cerebellar artery (AICA/PICA/SCA). As anatomical definitions of PTA and PTAVs differ among studies, the authors examined the definitions provided in each paper to assign the reported vessels to the main categories (PTA/PTAV) and further into subcategories within the Saltzman and Weon classifications.16,18 In the event of any discrepancies in study data, authors of the original articles were contacted via email for clarification. Statistical analysis The statistical analysis was conducted by KP using MetaXL 5.3 by EpiGear International Pty Ltd (Wilston, Queensland, Australia). The pooled prevalence estimates were calculated using the random effects model. The Chi2 test or the I2 statistic was used to assess heterogeneity among the included studies. For the Chi2 test, significant heterogeneity among studies was indicated by a p-

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value of <0.10. The I2 statistic was interpreted as follows: 0% to 40% might not be important; 30% to 60% could represent moderate heterogeneity; 50% to 90% could represent substantial heterogeneity; and 75% to 100% could represent considerable heterogeneity.20 In addition, subgroup analyses were performed to probe for sources of heterogeneity. These were based on the type of study (cadaveric or radiological), modality (conventional angiography [CA], computed tomography angiography [CTA], magnetic resonance angiography [MRA]), sex, side (left or right) or geographical location (continent). Confidence intervals were used to compare the subgroups. The differences between two or more groups were considered statistically insignificant whenever the confidence intervals between them overlapped.20 Quality assessment The AQUA tool was used to estimate the quality and reliability of the included studies. Five domains were evaluated in the analysis: Objective(s) and Subject Characteristics, Study Design, Methodology Characterization, Descriptive Anatomy, and Reporting of Results. Each domain was assessed as of either “Low,” “High” or “Unclear” risk of bias.21

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Results

Study Identification The study identification process is summarized in Figure 3. A total of 1811 articles potentially meeting the inclusion criteria were initially identified through database searching. A further 74 studies were found during the reference searching. A total of 144 studies were assessed for eligibility by full text, 39 of them eventually being included in this meta-analysis. 5,8,9,15,19,22-55,

Characteristics of included studies The characteristics of included studies are presented in Table 1. A total of 39 studies (110,866 subjects) were evaluated in the meta-analysis. Four of these studies (involving 4421 subjects) were cadaveric and 36 (involving 106,445 subjects) were radiological. The radiological group comprised studies based on CA (27 studies involving 50,740 subjects), CTA (two studies involving 3236 subjects) and MRA (12 studies involving 53,421 subjects). Two radiological studies were conducted using all three modalities. The included studies were published between 1948 and 2016 and demonstrated a broad geographical distribution, most of them originating from Asia.

Quality assessment The AQUA tool evaluation is summarized in Table 1. Most of the studies revealed the “Objective(s) and subject characteristics” and “Methodology characterization” to be at “High” risk of bias, whereas almost all of them had a “Low” risk of bias in the “Study design” and “Reporting of results” domains.

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Combined prevalence of PTA and its variants The analysis of the combined prevalence of the PTA is given in Table 2. A total of 39 studies (involving 110,866 subjects) reported data on the prevalence of PTA and its variants. The overall pooled prevalence estimate of the PTA and its variants was 0.4% (95%CI 0.3%-0.5%). A total of seven studies (involving 17,971 males and 18,807 females) provided data on gender distribution. The PTA and PTAVs were found to be more prevalent among females (0.7% [95%CI 0.5%0.8%]) than males (0.4% [95% CI 0.3%-0.6%]). The arteries were more often present on the left side (55.6% [95% CI 50.1-60.7]) than the right (44.4% [95% CI 39.1-49.6]). In modality analysis, the pooled prevalence rate was slightly higher in MRA (0.5% [95%CI 0.3%-0.6%]) and cadaveric (0.4% [95% CI 0.0%-0.9%]) studies than in studies based on CA (0.3% [95%CI 0.3%0.5%]) ot CTA (0.3% [95%CI 0.2%-0.6%]). Geographical analysis showed that Asia had the highest prevalence of the PTA and its variants (0.5% [95% CI 0.3%-0.6%]), followed by Europe (0.4% [95% CI 0.2%-0.5%]), whereas South America had the lowest prevalence (0.2% [95% CI 0.1%-0.3%]).

Individual prevalences of the PTA and the PTAV The analyses of PTA and PTAV prevalences are presented in Tables 3 and 4, respectively. A total of 33 studies (involving 96,986 subjects) reported data on the prevalence of the PTA only, contributing to a pooled prevalence of 0.3% (95% CI 0.2%-0.4%). Seventeen studies (involving 67,386 subjects) provided data on the prevalence of PTAVs individually, giving a pooled prevalence estimate of 0.2% (95% CI 0.1%-0.3%). A total of seven studies (involving 19,076 males and 18,807 females) assessed the sex predilection for the PTA and showed it to be twice as

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common in females than males, with prevalence rates of 0.4% (95%CI 0.3%-0.5%) and 0.2% (95%CI 0.2%-0.3%), respectively. A total of six studies (involving 18,278 males and 18,505 females) found PTAVs to be just as common in males (0.2% [95%CI 0.1%-0.3%]) as females (0.2% [95%CI 0.1%-0.4%]). A total of 22 studies (205 PTAs) assessed PTA laterality and 11 studies (109 left and right sides) analyzed PTAV laterality. No side predilection was found, with each of the main variants appearing on each side with the rate of 0.1%. Additionally, 19 articles (282 PTAs) reported data on the prevalence of bilateral PTAs, which was found to be 1.3% (95%CI 0.2%-2.9%).

Origin and course of the primitive trigeminal artery and its variants A total of six studies (involving 78 subjects with PTA or PTAV) investigated the origin of the PTA and the PTAVs. The most common (97.6% [95%CI 93.7-100.0]) point of origin was the C4 part of ICA, according to the Bouthillier classification (1996).56 A C2 ICA origin was observed in 2.4% (95%CI 0.0-6.3) of the PTAs and its variants. A total of 10 studies (involving 187 subjects) reported data on the type of course of PTA and its variants. Analysis showed that 89.0% (95%CI 84.2%-93.1%) of the PTAs and PTAVs took a course lateral to the dorsum sellae, while the remaining 11.0% (95%CI 6.9%-15.8%) went through the sella turcica and coursed in proximity to the pituitary gland.

Basilar Artery hypoplasia in presence of the PTA and its variants Five studies (involving 96 subjects) reported data on basilar artery (BA) hypoplasia in patients with a PTA or a PTAV. Some degree of hypoplasia was noted in 42.5% (95%CI 23.0%-63.1%)

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of the subjects. Data regarding the level of hypoplasia were not extracted because they were presented as “high”/“moderate”/“low” so the assessments were subjective. Classifications of the PTA Two studies (involving 44 PTAs) classified the PTA according to Saltzman, and showed Type III to be the most prevalent with a pooled prevalence of 56.1% (95%CI 41.8%-71.0%). Type I was encountered in 27.4% (95%CI 15.4%-41.9%) of patients and type II was found in 16.5% (95%CI 6.9%-29.2%). Three studies (involving 47 PTAs) classified the PTA according to Weon.18 Weon type 1 was the most prevalent with a pooled prevalence of 45.2% (95%CI 27.3%64.2%). Type 3 was found in 33.0% (95%CI 16.8%-51.8%), followed by type 4 (11.6% [95%CI 1.9%-26.6%]) and type 2 (10.2% [1.3%-24.7%]).

Classifications of the PTAV A total of seven studies (involving 32 PTAVs) classified PTAVs according to their connection to a cerebellar artery: SCA/AICA/PICA. Most PTAVs (72.1% [95%CI 50.0%-95.7%) anastomosed with the AICA. The pooled prevalence of PTAV anastomosing with PICA was 17.7% (95%CI 1.9%-44.2%) and with SCA was 10.2% (95%CI 0.0%-30.2%). Two studies (involving 67 PTAVs) assigned PTAVs into “PTAV A” and “PTAV B” categories. The “PTAV A” category was the more frequently reported, with a pooled prevalence of 86.7% (95%CI 73.3%-96.2%).

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Discussion

The PTA and PTAVs are rare, but the presence of these arteries during neurosurgical procedures near the gasserian ganglion or cavernous sinus and in the para- and intra-sellar regions can lead to catastrophic hemorrhagic or ischemic complications if unnoticed. The aim of our metaanalysis was to pool all the available studies with data on the prevalences of the PTA and PTAVs and their clinically important features in order to gain novel insight into the most common anatomical configurations of these vessels. The PTA was more frequent than the PTAVs, the pooled prevalences being 0.3% and 0.2%, respectively. Subgroup analysis based on geographical location showed that the PTA and its variants were most prevalent in Asian patients, with a pooled prevalence of 0.5%. However, this could be because the vast majority of studies originated from Asia. Our analysis concluded that the PTA and its variants were least common in the South American population (0.2%), and were more commonly found in females. Such results may idicate possible genetic factor behind the presence of PTA.57 However, this issue requires further investigation.

Subgroup analysis based on the modalities deployed showed the lowest prevalence of the PTA and PTAVs in CA and CTA studies (0.3%). Although it provides the best spatial resolution, CA is presumed to be inherently biased because of its dependence on flow.19 Patients undergoing CA could also contribute to selection bias as it is an invasive procedure and usually not performed without indications.3,5 As the PTA and PTAVs course near the skull base, they might not always 11

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be recognized in CTA. For this reason, such studies are not popular and only two CTA papers were included in our meta-analysis. This problem could be overcome by using MRA, and our study showed that it had the highest rate of detection of the PTA and PTAVs (0.5%). Researchers consider MRA a superior method of investigating the anatomical characteristics of the PTA and PTAVs, and it should be performed preoperatively before the para- and intra-sellar regions are approached.19,54 The analysis showed that the PTA/PTAV most frequently (89%) takes a course lateral to the sella turcica. The lateral-type PTA and PTAVs, because they are closely related to the trigeminal nerve root entry zone, are associated with trigeminal neuralgia (TN).3,12,58,59 Previous studies have shown that the PTA has a higher prevalence in patients suffering from TN (2.2%) than in the general population (0.4%).11 Thus, patients suffering from TN should undergo MRA to exclude PTA as a potential cause. Trigeminal neuralgia does not occur in patients with a medialtype PTA.8 Moreover, TN should be treated cautiously by the percutaneous gasserian ganglion procedure in the presence of a PTA or PTAV.9,13,14 The medial-type PTA, although rare (11% of PTAs), carries an inherently high risk of hemorrhage during surgical dissection.3 Recognition of this type of PTA is crucial prior to endoscopic transsphenoidal surgery for pituitary adenomas.9,15 Some researchers question the significance of the Saltzman and Weon classifications, pointing out that PComs and SCAs are supratentorial while the rest of the vertebrobasilar system is infratentorial and therefore embryologically different.19,49 Moreover, PTAs that cannot be assigned to either of the classifications have been reported.9 Chen (2011) reported a PTA that terminated at the P1 segment of the PCA. Considering its contribution to the blood supply and concurrent BA dysplasia, the artery was classified as Weon type I.5 Nevertheless, both classifications can be used to illustrate the PTA’s contribution to the cerebral blood supply. We 12

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recommend adhering to the Weon classification of the PTA and PTAVs, as Saltzman type III is often misused and its frequencies reported in the literature vary. In Weon type 1 (45.2 %) the entire vertebrobasilar system above the anastomosis (distal BA, both SCAs, both PCAs) receives blood through the PTA from the ICA. This type of PTA must be preserved during surgery, since massive hemorrhage can result if it is injured. In the less common Weon type II (10.2%), the PTA is not a mandatory channel and the PComs and the BA remain the dominant supply to the PCA. This PTA type can be embolized to reduce intraoperative bleeding.4 Due to anatomic difficulties, the endovascular approach is the treatment of choice of the persistent primitive trigeminal artery-carotid cavernous fistulas. In such cases, it is essential to identify the Weon type of the PTA.60,61 Before surgery, it is essential both to identify the territories dependent on the PTA (Saltzman/Weon classifications) and to assess PTA laterality. An example of such preoperative planning is an algorithm for a skull base tumor concomitant with PTA developed by Shen (2016).4 A PTA causes anatomical disturbances in the CoW.12,62 Many studies have reported an association between BA hypoplasia and a PTA.8,9,15,18,47 Owing to the additional supply from the ICA, there are fewer flow-related stimuli for both the BA below the anastomosis and the vertebral arteries.3 The degree of hypoplasia could be related to the functional significance of a PTA.19 The BA above the anastomosis is of normal caliber.17 When a PTA is the dominant blood supply to the posterior part of the CoW, surgical or spontaneous occlusion of the ICA, and emboli passing from the ICA, can cause brainstem ischemia and infarction because perfusion in the hypoplastic vertebral and proximal BAs is low.6,58 Our analysis revealed some degree of BA

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hypoplasia in nearly half of the patients with PTA (42%). In view of this high prevalence, BA hypoplasia can be considered an ancillary sign of a PTA.8,17 If there is a PTA/PTAV, endovascular neurosurgical procedures require proper modification. Hypoplastic or compressed vertebral and basilar arteries may preclude catheter advancement. In such cases, PTA provides an alternative approach to the posterior circulation.63 Ikushima (2002) reported an aneurysm of the BA accessed via the PTA.64 Recent studies support the notion that most cerebrovascular diseases in the presence of a PTA are incidental findings.3,19,65 Some papers describe its association with different neurological conditions, although this can probably be attributed to selection bias from patients undergoing CA.8 Furthermore, Wenz et al. (2015) rejected the hypothesis that the PTA is associated with a higher incidence of moyamoya disease, as they did not find a higher prevalence of PTA among a cohort of patients with this disorder.33,66 There is a lack of consensus in the literature about the prevalence of aneurysms in patients with PTA. Nevertheless, the PTA itself is a potential site of aneurysms as it forms a bifurcation. A PTAV was first angiographically described by Teal (1972). A “classic” PTAV arises from the ICA and courses further as one of the cerebellar arteries, SCA/AICA/PICA, classified by Weon as types 5a, 5b and 5c, respectively.58 According to its original definition, it does not communicate with the BA.44,67 However, some studies report a PTAV with a persistent connection to the BA.19,44,49,68 Classification of such a vessel is still under debate. After an exhaustive literature search, the authors of the current paper want to point out that: (1) the segment of a PTA-cerebellar artery communicating with the BA is often hypoplastic and thus cannot contribute significantly to the

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blood supply to the vertebrobasilar system; (2) the clinical significance of a PTAV relates to its blood supply to the cerebellum.44,69 Taking both these issues into consideration, we assigned vessels with connections to both the cerebellar artery and the BA to the PTAV category. Furthermore, Rhee (2007) described a PTAV with double branching into both the SCA and AICA.40 Another study reported a PTAV that did not anastomose with any other artery.5 Although the anatomical variations described are very subtle, hemodynamic balance between a PTAV and the cerebellar arteries is important in planning treatment for associated vascular pathologies.3 Considering contribution to the blood supply to be the most important factor, a simple classification into three main categories can be adopted. The PTAV is therefore an artery that arises from the ICA and: (a) courses further as one cerebellar artery (a “classic” PTAV), which can be subdivided into SCA, AICA and PICA types; (b) branches into two cerebellar arteries; (c) courses further as a cerebellar artery with a persistent connection to the BA (Fig. 4). We believe that a simple approach will facilitate further research on PTA and PTAVs, but we also acknowledge that this classification has some limitations. Although it is consistent with hypotheses of PTA/PTAV development proposed by Gregg (2017), other researchers point out that the SCA is of different embryological origin from the AICA and PICA.19,70 We believe that a simple classification of PTAs and PTAVs will facilitate future development of surgical strategies and algorithms for endovascular management of PTA aneurysms and PTA-cavernous fistulas as well as other lesions localized in para- and intrasellar regions. Our meta-analysis provides most up-to–date evidence-based data about the PTA and PTAVs. Such information can be easily accessed by clinicians without the need to search through

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thousands individual of articles. We hope that novel insight gained from our meta-analysis will aid in preoperative planning and reduce the incidence of iatrogenic injuries. We believe that data from evidence based anatomy can be utilized by young neurosurgeons during their training as well as by more experienced physicians to systematize their knowledge.71

The main limitation of this meta-analysis is a relative paucity of studies that report the sex of the subjects. However, the relevant analysis could be performed on the basis of a few studies with a comprehensive set of characteristics of the PTA and PTAVs. Also, a few cadaveric studies, which are recognized as gold standard, could be considered a weak point of this analysis. Subgroup analysis of cadaveric studies was performed using the available material, but there is a strong need for further, large and accurate cadaveric studies. The authors are also aware of the fact that the population of Brazil is made up by a large number of Europeans as well as 1.2% people of Japanese origin. For the purpose of a uniform analysis, we assumed that the ethnicity of the study group was the same as the country of origin of the study. Unfortunately, most anatomical studies do not provide detailed information about the ethnicity of the analyzed population. Future studies should attempt to incorporate such data in order to facilitate further research.

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Conclusions Our main findings revealed that the PTA and its variants were present in 0.4% of the population. These arteries most often originated from the C4 ICA (97.6%) and coursed lateral to the dorsum sellae (89.0%). Although the PTA and PTAVs are rare, they are of great importance for neurosurgeons, as an injury or occlusion to these vessels can result in serious complications. On the basis of our anatomical findings, we recommend that efforts be made to identify a potential PTA or its variant via MRA before a surgical approach to para- and intra-sellar regions in order to preclude hemorrhage and ischemia.

Acknowledgements None

Funding statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Conflict of interest statement None

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22.

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FIGURE LEGENDS Figure 1. The primitive trigeminal artery Figure 2. Types of course of primitive trigeminal artery and its variants A – parasellar; B - intrasellar

Figure 3. Prisma flowchart showing identification, evaluation and inclusion of studies in the meta-analysis Figure 4 - Types of primitive trigeminal artery (PTA) and primitive trigeminal artery variants (PTAVs) Types 1-5 – PTA according to Weon; type 6 – PTAV with double branching; type 7 - PTAV with persistent connection to the basilar artery; type 8 - a PTA joining a P1 part of posterior cerebral artery (PCA)

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SUPPLEMENTARY MATERIALS Supplement 1 - PRISMA Checklist

24

Table 1. Characteristics of included studies and quality assessment by the Anatomical Quality Assessment (AQUA) tool Study ID

Country

Allen 200522

USA

Almeida 196523

Brazil

ArraezAybar 20168

France

Bai 201315

China

Buffard 196524

France

Busch 196625

Austria

Carcavilla 197526

Spain

Chen 20115

China

Dickmann Argentin 196827 a Gessini 195428

Italy

Harrison 195329

USA

Higano 198730

Japan

Kim 20159

France

Type of study

Number of patients

radiologi cal

481

radiologi cal

6000

radiologi cal

2410

radiologi cal

6063

radiologi cal

1200

cadaveric

1000

radiologi cal

1470

radiologi cal

4650

radiologi cal

2000

radiologi cal

160

radiologi cal

582

radiologi cal

827

radiologi cal

8900

% PTA & PTAV prevalen ce (# of Objectiv e(s) and PTAs study and PTAVs) character istics

Risk of bias - AQUA tool

Study design

Methodo Descripti Reportin logy ve g of character anatomy results ization

1 (5) Low

Low

High

Low

Low

High

Low

High

Low

Low

Low

Low

High

High

Low

Low

Low

High

High

Low

High

Low

High

Low

Low

Low

Low

High

Low

Low

High

Low

High

Low

Low

Low

Low

Low

Low

Low

High

Low

High

Low

Low

High

Low

High

Low

Low

High

Low

High

Low

Low

High

Low

High

Low

Low

Low

Low

Low

Low

Low

0.1 (6)

0.4 (9)

0.6 (38)

0,6 (7)

0.3 (3)

0.2 (3)

0.5 (25)

0.4 (7)

1.3 (2)

0.5 (3)

0.6 (5)

0.2 (18)

Kitami 198531

Japan

radiologi cal

704

Krayenbu Switzerla radiologi hl 195732 nd cal

141

Kwak 198333

Japan

Nakajima 197634

Japan

Oliveira 199135

Brazil

Ouchi 201019

Japan

Ouriel 198836

USA

Park 198837

Korea

Pecker 196738

France

Poblete 195439

Chile

Rhee 200740

Korea

Russel 196041

USA

Samra 196942

USA

Schiefer 195943 Siqueira 199344

radiologi cal

1009

radiologi cal

3841

radiologi cal

2000

radiologi cal

16415

radiologi cal

765

radiologi cal

3552

radiologi cal

1677

radiologi cal

874

radiologi cal

4054

cadaveric

3000

radiologi cal

1500

Germany radiologi cal

1657

Brazil

radiologi cal

5500

Sunderlan Australia cadaveric d 194845

210

Suto 199846

Japan

Uchino 199647

Japan

radiologi cal

1100

radiologi cal

503

0.9 (6) High

Low

High

Low

Low

High

Low

High

High

Low

High

Low

High

Low

Low

High

Low

High

High

Low

High

Low

High

Low

Low

Low

Low

Low

Low

Low

High

Low

High

High

Low

Low

Low

High

Low

Low

High

Low

High

Low

Low

High

Low

High

Low

Low

Low

Low

High

Low

Low

High

Low

High

Low

Low

High

Low

High

Low

High

Low

Low

High

Low

Low

High

Low

High

Low

Low

High

Low

High

Low

Low

Low

Low

Low

Low

Low

Low

Low

High

Low

Low

2.1 (3)

0.3 (3)

0.3 (12)

0.2 (3)

0.6 (103)

0.5 (4)

0.3 (10)

0.4 (7)

0.2 (2)

0.1 (5)

0.1 (3)

0.1 (8)

0.5 (16)

0.3 (3)

1.4 (5)

0.5 (7)

1.4 (5)

Uchino 200048

Japan

Uchino 201249

Japan

Weon 201150

Korea

Wiedema nn 195951

radiologi cal

523

radiologi cal

3491

radiologi cal

7329

Germany radiologi cal

7382

Wise 195752

USA

Wollschla eger 196453

USA

Yan 201354

China

Yilmaz 199555

Turkey

radiologi cal

397

radiologi cal & cadaveric

611

radiologi cal

2488

radiologi cal

4400

1 (18) Low

Low

High

Low

Low

Low

Low

Low

Low

Low

Low

Low

Low

Low

Low

High

Low

High

Low

Low

High

High

High

Low

High

High

High

High

Low

High

High

Low

High

Low

Low

Low

Low

High

Low

Low

0.5 (24)

0.3 (6)

0.1 (1)

0.3 (19)

0.3 (4)

0.8 (1)

0.1 (2)

PTA – primitive trigeminal artery; PTAV – primitive trigeminal artery variant

Table 2. Total pooled prevalence of Primitive Trigeminal Artery and its variants in population Category

# of studies (# of subjects)

Pooled Prevalence: % (95% CI)

I2: (95% CI)

Overall

39 (110866)

0.4 (0.3-0.5)

78.8 (71.5-84.2)

Males

7 (17971)

0.4 (0.3-0.6)

50.4 (0.0-79.0)

Females

7 (18807)

0.7 (0.5-0.8)

0.0 (0.0-70.2)

Left side

27 (326)

55.6 (50.1-60.7)

0.0 (0.0-30.28)

Right side

27 (326)

44.4 (39.1-49.6)

0.0 (0.0-30.28)

Unilateral

29 (345)

98.4 (96.9-99.5)

0.0 (0.0)

Bilateral

19 (282)

1.3 (0.2-2.9)

0.0 (0.0)

Cadaveric studies

4 (4421)

0.4 (0.0-0.9)

67.8 (6.3-88.9)

Radiological studies

36 (106445)

0.4 (0.3-0.5)

79.1 (71.5-84.6)

CA studies

27 (50740)

0.3 (0.3-0.5)

65.8 (48.7-77.1)

CTA studies

2 (3236)

0.3 (0.2-0.6)

0.0 (0.0)

MRA studies

12 (53421)

0.5 (0.3-0.6)

81.0 (67.8-88.8)

Asia

16 (60949)

0.5 (0.3-0.6)

80.0 (68.4-87.4)

Europe

10 (25997)

0.4 (0.2-0.5)

73.4 (50.0 (85.9)

North America

7 (7336)

0.3 (0.1-0.6)

62.4 (14.5-83.5)

South America

5 (16374)

0.2 (0.1-0.3)

50.0 (0.0-81.7)

Table 3. Pooled prevalence of Primitive Trigeminal Artery (PTA) Category

# of studies (# of subjects)

Pooled Prevalence: % (95 CI)

I2: (95 CI)

Overall

33 (96986)

0.3 (0.2-0.4)

63.4 (46.9-74.8)

Males

7 (19076)

0.2 (0.2-0.3)

0.0 (0.0-60.4)

Females

7 (18807)

0.4 (0.3-0.5)

0.0 (0.0-36.7)

Left side

22 (205)

53.2 (46.6-59.9)

0.0 (0.0-43.6)

Right side

22 (205)

46.8 (40.1-53.4)

0.0 (0.0-43.6)

Cadaveric studies

4 (4421)

0.4 (0.0-0.9)

67.8 (6.3-88.9)

Radiological studies

34 (101775)

0.3 (0.2-0.4)

62.9 (46.3-74.3)

CA studies

11 (20849)

0.2 (0.1-0.3)

76.1 (54.2-87.5)

CTA studies

2 (3236)

0.3 (0.2-0.6)

0.0 (0.0)

MRA studies

11 (50474)

0.3 (0.2-0.4)

37.6 (0.0-69.3)

Table 4. Pooled prevalence of Primitive Trigeminal Artery Variants (PTAV) Category

# of studies (# of subjects)

Pooled Prevalence: % (95 CI)

I2: (95 CI)

Overall

17 (67386)

0.2 (0.1-0.3)

82.3 (72.7-88.5)

Males

6 (18278)

0.2 (0.1-0.3)

71.5 (34.0-87.7)

Females

6 (18505)

0.2 (0.1-0.4)

79.9 (56.5-90.8)

Left side

11 (109)

59.9 (50.8-68.7)

46.7 (0.0-73.5)

Right side

11 (109)

40.1 (31.3-49.2)

60.9 (24.4-79.8)

CA studies

9 (20849)

0.2 (0.1-0.3)

76.1 (54.2-87.5)

MRA studies

10 (46819)

0.2 (0.1-0.3)

81.1 (66.3-89.4)

Abbreviation List: AICA – anterior inferior cerebellar artery; BA – basilar artery; CA – conventional angiography; CoW – circle of Willis; CTA – computed tomography angiography; ICA – internal carotid artery; PCom – posterior communicating artery; PICA – posterior inferior cerebellar artery; PLBA - primitive lateral basilovertebral anastomosis; PLNAs - paired longitudinal neural arteries; PTA – primitive trigeminal artery; PTAV – primitive trigeminal artery variant; SCA – superior cerebellar artery

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