Unilateral Aplasia versus Bilateral Aplasia of the Vertebral Artery: A Review of Associated Abnormalities

Morphological characteristics of 108 cases of uni- and bilateral aplasia of the vertebral artery (VA) in reports or images of retrospective studies, including one recent case, published between 1967 and 2016 are analyzed. Incidence, gender, persistence of carotid-vertebrobasilar anastomosis (CVBA), associated with other vascular variants, and vascular pathology in each group of uni- and bilateral VA aplasia are mutually compared. Most of the cases of VA aplasia in ages 31 to 80 were discovered in USA, Japan, and India. The bilateral VA aplasia is more common in the male gender than in the female one. The side of the VA aplasia had a significant effect on the side of CVBA persistence. Associated aplasia of other arteries was more common in cases of unilateral VA aplasia. The left VA was more commonly hypoplastic in cases of single right VA aplasia than the right VA in cases of single left VA aplasia. Aneurysms of definitive arteries were more frequent in cases of single right VA aplasia than in cases of single left VA aplasia. We claim that the aplasia of the VA probably depends on genetic factors in some races, while diseases are expressed usually in persons over 30 years of age.


Introduction
The development of paired vertebral arteries (VAs) of 7 mm to 12 mm of the human embryo provides longitudinal anastomoses of so-called primitive proatlantal intersegmental artery (PIA) and six cervical intersegmental arteries (CIAs) that arise from the dorsal aorta on both sides. Actually, the sixth CIA according to Padget [1], or the seventh CIA according to Effmann et al. [2], becomes the VA and contributes to the subclavian artery (SA) in this embryonic stage, while the primitive PIA also supplies a caudal part of precursors of the basilar artery (BA), that is, paired longitudinal neural arteries (LNAs) on the developing hindbrain. After this period, the VA from its origin courses through prevertebral (V1), cervical (V2), atlantic (V3), and intracranial (V4) topographical parts before its connection with opposite artery in the BA [3].
The development of the internal carotid artery (ICA) is independent of the VA. Namely, only one part of the primitive ICA derives from the third primitive aortic arch, while all other ICA segments represent cranial extensions of the dorsal aorta on both sides. Transitory vascular channels or primitive carotid-vertebrobasilar anastomoses (CVBAs) between the LNAs and ICAs exist at a time when embryonic length is 4-5 mm [4][5][6][7][8]. The primitive hypoglossal (PHA), primitive otic (POA), and primitive trigeminal (PTA) arteries are determined, as cited [5][6][7][8], by their relationship with hypoglossal nerve, otic vesicle, and trigeminal ganglion, respectively, while the PIA is named according to the course between the occipital and cervical somites [1,6]. With the formation of the posterior communicating artery (PCoA) cranially and vertebrobasilar system caudally, CVBAs regress and usually disappear by the 14 mm stage of human embryo.
Doppler sonography of health infants showed that 114/7991 (1.4%) infants had unilateral VA aplasia-left in 0.51% and right in 0.91% of cases [9]. The persistence of CVBA(s) in cases of uni-or bilateral aplasia of the VA 2 BioMed Research International or in cases of normal VA on both sides after this period is conditioned by different vascular factors and however insufficiently explained [5][6][7][8]10].
Recent finding of aplasia of the right VA followed by the persistence of the left PTA and so-called intermediate communicating artery on the right side inspired the authors to review literature cases with established uni-and bilateral VA aplasia and their relationships with persistence of primitive or definitive anastomoses and/or vascular variants.

Methods
Morphological characteristics of 108 cases of total uni-and bilateral aplasia of the VA in single reports or images of retrospective studies published between 1967 and 2016 are separately analyzed. We included one personal case, as well as literature cases in articles available on Google display network or in the library archive of our Faculty of Medicine. Five general parameters, incidence, gender, persistence of CVBA, other associated vascular variants, and associated vascular pathology, in each group of uni-and bilateral VA aplasia are mutually compared.
So-called intermediate communicating artery (ICoA) is defined according to its schematic presentation in the book of Microneurosurgery [11] and previous findings in the fetuses [12] and adult cadavers [13].

Statistical Analysis.
The incidences of all cases of uniand bilateral VA aplasia in appropriate tables were noted; statistical test, 2 nonparametric test, was used. Statistical significance was noted in a case of < 0.05. Statistical analysis was performed using statistical software of IBM Corp., released in 2011, and IBM SPSS Statistics for Windows, Version 20.0, IBM Corp., Armonk, NY.

Theoretical Background
3.1. Bilateral VA Aplasia. There are cases without data about gender and 11/31 female and 19/31 male cases of bilateral VA aplasia; age of these cases ranged from 14 days to 76 years.
Two cases of associated arterial anastomoses and bilateral VAs aplasia were exceptions. Namely, Tsai et al. [18] have described that the left occipital-vertebral anastomosis enabled posterior circulation in a 36-year-old male, while Pauliukas [44] presented the BA in continuation of the left occipital artery (OA) on an angiogram.
CVBAs were only vascular variants associated with bilateral VA aplasia in 18/31 cases.
Otherwise, associated aplasia of other vessels was related to the PCoA that was found bilaterally in 3/31 cases [20,33,41] and unilaterally in 1 out of 31 cases [23], as well as to the BA also in one case [43], and to some dural sinuses simultaneously with bilateral internal jugular veins in another case [30].
Other associated vascular variations in 13/31 cases were found, mostly in the form of unusual side branches or fetal origin of the posterior cerebral artery (PCA) or additional anastomoses. So, the BA as a continuation of the left OA [44], the OA as a branch of the PPIA [25], or the posterior inferior cerebellar artery (PICA) as BA branch [21,25] or PPHA branch [33] was described. Fetal origin of the PCA [23,43] and anastomoses with thyrocervical and/or OA branches [22,27] in two particular cases were found. Enlargement of some dural sinuses and Galen's vein malformation [30], hypoplasia of bilateral posterior communicating arteries [42], irregular caliber of ICA [14], or tortuous course of the PPHA [41] was found in single cases.

Single
Left VA Aplasia. There were 24/46 female cases and 20/46 male cases and no data for 2 cases of single left VA aplasia; age of these cases ranged from the stillborn to the 83-year-old ones.

Single Right VA Aplasia.
There were 14/31 female cases, 14/31 male cases, and 3/31 cases without data about gender of single right VA aplasia; age of these cases ranged from 4 days to 79 years.
Associated aplasia of other vessels was related to the ICA on the right side in one case [105] and on the left side in the second case [106], bilateral external carotid arteries (ECAs) in one case [92], right SA branches in one case [107], BA in one case [90], unilateral PCoA in 4 cases including recent case [75,93,96], and bilateral PCoAs in three cases [87,88,99] and the right ACA (associated with bilateral PCoA aplasia) in one case [88].
Other associated vascular variations in 23/31 cases are found, mostly in the form of arterial hypoplasia or unusual origin or course and/or branches and/or termination. Associated hypoplasia of the left VA in 13/31 cases was documented (Table 5). Variable origin of some arteries in 5/31 cases including recent one was found [88,92,95,105]. Associated unusual branches or termination of arteries in 9/31 cases including the recent one [75,83,86,88,90,92,94,107] was documented.

Single Left VA versus Bilateral VA Aplasia. Calculated incidences of selected morphological parameters in
(1) Incidence was as follows: single left VA aplasia was more common than bilateral VA aplasia.      (2) Gender was as follows: although female gender was frequent in cases of single left VA aplasia, male gender was more frequent in cases of bilateral VA aplasia; generally, there was no significant sex difference in cases of the left VA aplasia, either single or associated with the right VA aplasia.
(3) Persistence of CVBA was characteristic as follows: (A) there was significant incidence of unilateral persistence of CVBA in cases of both single left and bilateral VA aplasia, especially in cases of single left VA aplasia; (B) as bilateral CVBA persisted in one-third of cases of bilateral VA aplasia, one can say that this bilateral persistence was not the rule; ( Table 7 are presented. (1) Incidence was as follows: right VA aplasia was more common when associated with left VA aplasia than when it was a single abnormality.
(2) Gender was as follows: although female gender was frequent in cases of single right VA aplasia while male gender was more common in cases of bilateral VA aplasia, generally, male gender was more common in cases of both single right and bilateral VA aplasia.
(3) Persistence of CVBA was characteristic as follows: (A) there was significant incidence of unilateral persistence of CVBA in cases of both single right and bilateral VA aplasia, especially in cases of single right VA aplasia; (B) bilateral persistence of CVBA in cases of single right VA aplasia was not found; it was significant in cases of bilateral VA aplasia; (C) there was no persistence of two different CVBAs in cases of single right VA aplasia, while they persisted with low incidence in cases of bilateral VA aplasia; (D) there was significant persistence of PIA in cases of bilateral VA aplasia in regard to single right VA aplasia; (E) there was persistence of PHA in one-half of cases of single right VA in regard to one-third of cases of bilateral VA aplasia; (F) PTA persisted in both right and bilateral VA aplasia with almost the same (low) frequency; and (G) there was, also, low frequency of persistence of additional arterial anastomoses in cases of both single right and bilateral VA aplasia.  Table 8 are presented.
(1) Incidence was as follows: single left VA aplasia was more common than single right VA aplasia. (2) Gender was as follows: although female and male gender were more common in cases of left VA aplasia than in cases of right VA aplasia, there was no significant sex difference in cases of unilateral VA aplasia. (3) Persistence of CVBA was characteristic as follows: (A) incidence of persistence of CVBA was high and almost equal in both cases of unilateral VA aplasia, but not as an absolute rule; (B) CVBA always presented if one VA is aplastic and the other VA is hypoplastic;  aplasia of the same four arteries, CCA, ICA, ACA, and PCoA, for both cases was characterized; aplasia of the AICA and SA was specific for single left VA aplasia, while aplasia of BA and SA branches was specific for single right VA aplasia; (B) there were more than one-third of cases of hypoplastic VA associated with aplasia of opposite VA; (C) the left VA was more commonly hypoplastic in cases of single right VA aplasia than the right VA in cases of single left VA aplasia; (D) characteristic finding was associated aplasia of other arteries in 8/16 and 6/13 cases, respectively, of mutual aplasia of one VA and hypoplasia of the other VA; and (E) associated vascular variants (except those of a vessel's aplasia and presence of CVBA) in one-third of cases of single left or right VA aplasia were presented. (5) Associated vascular pathology was presented as follows: (A) aneurysms of definitive arteries were more frequent in cases of single right VA aplasia than in cases of single left VA aplasia; (B) aneurysms of CVBAs were rare findings in both cases of unilateral VA aplasia; (C) different cerebral pathology in cases of single left and right VA aplasia in more than onethird of cases was documented; and (D) low incidence of noncerebral pathology, especially in cases of single left VA aplasia, was noted.

Uni-and Bilateral VA Aplasia versus Persistence of CVBA.
Generally, a relationship of the VA aplasia and persistence of CVBA was as follows: (A) the side of the VA aplasia has significant influence on the side of CVBA persistence ( < 0.001); (B) CVBA is significantly more common on the left side ( = 0.046 ( < 0.05)) independently of the side of VA aplasia; and (C) CVBA of ICA origin is significantly more common ( < 0.001).

Conclusions
Summarizing previous data, we point out the following facts: (1) Almost 50% of cases of uni-and bilateral VA aplasia in three countries, USA, Japan, and India, were discovered.
(2) Two-thirds of VA aplasia cases belonged to patients of ages 31 to 80.
(3) Although there was no significant sex difference in appearance of VA aplasia, male gender was more common in cases of bilateral VA aplasia.
(4) The side of the VA aplasia has significant influence on the side of CVBA persistence, or vice versa.
(5) CVBA persistence is significantly more common on the left side in cases of uni-and bilateral VA aplasia.
(6) Associated aplasia of other arteries was more common in cases of unilateral VA aplasia.
(7) The left VA was more commonly hypoplastic in cases of single right VA aplasia than the right VA in cases of single left VA aplasia.
(8) There was high incidence of cerebral artery stenosis, occlusion, cerebral infarction, or stroke in cases of single left and bilateral VA aplasia.
(9) Aneurysms of definitive arteries were more frequent in cases of single right VA aplasia than in cases of single left VA aplasia.

Disclosure
This work was partially presented at the 8th International Symposium of Clinical and Applied Anatomy in Budapest, Hungary, September 1-3, 2016, and at the 5th Congress of Serbian Anatomical Society with international participation in Novi Sad, Serbia, September 8-10, 2016.

Conflicts of Interest
The authors report no conflicts of interest concerning the materials or methods used in this study or the findings specified in this paper.