The Clinical Characteristics and Treatment Considerations for Intracranial Aneurysms Associated With Middle Cerebral Artery Anomalies: A Systematic Review

Background: As a result of their low incidence, most of the studies on intracranial aneurysms associated with middle cerebral artery (MCA) anomalies were presented as case reports or small case series. No systematic review on this specific entity has been conducted. Methods: A PubMed search of the published studies was performed on April 6th, 2019 for patients who had intracranial aneurysms associated with MCA anomalies. The languages included in this study were English, Chinese, and Japanese. Results: Finally, 58 articles reporting of 67 patients including 1 case in our center were included. The identified patients (37 females, 55.2%) aged from 4 to 81 (49.85 ± 15.22) years old. 50 (50/67, 74.6%) patients presented with hemorrhagic stroke either from the MCA anomalies associated aneurysms or other sources. 63 aneurysms (63/67, 94.0%) were saccular, 3 (4.5%) were dissecting or fusiform, and 1 (1.5%) was pseudoaneurysm. 32 (32/65, 49.2%) patients had other concurrent cerebrovascular anomalies. 56 (83.6%) patients underwent open surgeries, 8 (11.9%) patients underwent endovascular treatment, and 3 (4.5%) patients were conservatively managed. 56 (56/61, 91.8%) patients achieved a good recovery. Conclusions: The pathophysiological genesis of intracranial aneurysms associated with MCA anomalies is still obscure. The inflicted patients tend to have other concurrent cerebrovascular anomalies, which denotes that congenital defect in cerebrovascular development might play a role in this process. Most of the affected patients could experience a good recovery after treatment.


INTRODUCTION
Middle cerebral artery (MCA) is the largest and most important branch of the internal carotid artery. Compared to its counterparts of the posterior circulation, MCA has a lower incidence of vascular anomalies (1). In general, MCA anomalies include accessory MCA (ac-MCA), duplicate MCA (d-MCA), d-MCA origin, MCA fenestration, and twig-like MCA (Figure 1). FIGURE 1 | The accessory MCA (brown branch) can originate from the A1 segment (A, Type 1), A1-A2 junction (B, Type 2), and A2 segment (C, Type 3) of the anterior cerebral artery. The aneurysms (black dots) associated with accessory MCA can locate at the beginning or the trunk of the accessory MCA. The duplicate MCA (brown branch) can originate from the ICA bifurcation or between the AchA and MCA (D). The aneurysms (black dots) associated with duplicate MCA can locate at the beginning or the trunk of the duplicate MCA. A fenestration can occur on the M1 segment of an MCA (E). The aneurysms (black dots) associated with MCA fenestration can be proximal to, in, or distal to the fenestration. When duplicate MCAs fuse into one single trunk, it is called duplicate MCA origin (F). The aneurysms (black dots) associated with duplicate MCA origin can locate at the beginning of each branch or the fused trunk. AchA, anterior choroidal artery; ICA, internal carotid artery; MCA, middle cerebral artery.
The ac-MCA is generally defined as a vessel arising from the anterior cerebral artery (ACA) and then passing into the Sylvian fissure along with the MCA. While the branch arising from the ICA and coursing along the MCA is called d-MCA. If two isolated branches course in parallel along the Sylvian fissure and then fuse into one MCA, this variation is called d-MCA origin. When the MCA bifurcates early after arising from the ICA and then fuse into one trunk again, it is called MCA fenestration. When the MCA trunk never develops during the embryological stage and is replaced by a plexiform arterial network, this variation is called twig-like MCA.
In rare circumstances, the MCA anomalies can be associated with intracranial aneurysms (2)(3)(4). As a result of their low incidence, most of the studies on intracranial aneurysms associated with MCA anomalies were presented as case reports or small case series. So, large-scale investigation of these rare entities in a single center is difficult. A systematic review of the reported cases is more feasible. To our knowledge, no systematic study on these rare entities has been performed. Issues regarding the demographic, clinical, therapeutic, and prognostic characteristics of intracranial aneurysms associated with MCA anomalies are to be further explored. In this study, we would conduct a systematic review on this specific entity to expanding our understanding of these rare entities. Only articles of which the full text or enough information could be obtained were included in this study. Reference lists of the identified articles were also manually searched for additional studies. Glasgow Outcome Scale was used for the outcome assessment. A Glasgow Outcome Scale score ≥4 was defined as good recovery. An aneurysm <10 mm was defined as small aneurysm.

Definition of Intracranial Aneurysm Associated With MCA Anomalies
Intracranial aneurysms located at the beginning or on the trunk of the abnormal MCAs were considered as in association with MCA anomalies. Aneurysms having no direct anatomical neighborhood with the MCA anomalies were excluded in the final analysis.

Location of Ac-MCA and the Associated Aneurysm
Based on their sites of origin along the ACA, the ac-MCA were divided into 3 types: 1) originating from the A1 segment of the ACA, 2) originating from the anterior communicating artery (AComA) or the A1-A2 junction, 3) originating from the A2 segment. The locations of aneurysms were at the beginning or the trunk of the ac-MCA (Figures 1A-C).

Location of d-MCA Associated Aneurysm
The locations of aneurysms were at the beginning or on the trunk of the d-MCA (Figure 1D).

Location of MCA Fenestration Associated Aneurysm
The locations of aneurysms were proximal to the fenestration, in the fenestration, or distal to the fenestration ( Figure 1E).

d-MCA Origin Aneurysm
The locations of aneurysms were at the beginning of any branch of the duplicate origins or on the fused common trunk ( Figure 1F).

General Information
The PubMed search identified 113 records. 59 records were excluded based on titles and abstracts screening. After assessing the full text of the remaining 54 articles, 5 were further excluded. A manual searching of the reference lists of the remaining 49 articles was performed, which yielded 9 additional articles. Finally, 58 articles reporting of 67 patients including 1 case in our center were included for the analysis. Searching strategy is presented in Figure 2.
Duplicate MCA Origin Aneurysm d-MCA origin aneurysm was only identified in a 49-year man incidentally, who was admitted for vertigo (59). No other cerebrovascular anomaly was reported. The saccular unruptured d-MCA origin aneurysm was microsurgically clipped. The postoperative course was uneventful and no neurological deficit was reported.

Illustrative Case
A 59-year old man was admitted for sudden onset of headache 2 days before. He was a smoker and denied history of any chronic diseases. He was alert on admission. Physical examination was unremarkable except for neck rigidity. Head computed tomography (CT) revealed subarachnoid hemorrhage of modified Fisher grade 2 (Figures 3A,B). Further CT angiography showed the A1 segments of the bilateral ACAs gave rise to their respective ac-MCAs ( Figure 3C). A saccular aneurysm was noted at the origin of the left ac-MCA (Figures 3C,D). No other cerebrovascular anomaly was noted. After discussion between the neurosurgical and neurointerventional members and sufficient negotiation with the patient's legal relatives, endovascular coiling of the aneurysm was planned.
Preprocedural digital subtraction angiography also confirmed the findings on CT angiography (Figures 4A,B). An Echelon-10 (Medtronic, Irvine, CA) microcatheter was advanced into the left ACA directed by a 0.010-in guidewire. The tip of the microcatheter was introduced into the aneurysm. The aneurysm was satisfactorily coiled using 3 detachable coils with preservation of the distal ACA and ac-MCA (Figures 4C,D). He experienced an uneventful postprocedural recovery and was discharged the next day without neurological deficit. Followup CT angiography 1 year later revealed no recurrence of the aneurysm.

DISCUSSION
According to Padget's description, at 34-36 days of the embryonal stage (12-14 mm), multiple plexiform arterial twigs develop just distally to the anterior choroidal artery (60). The plexiform arterial twigs would evolve into the MCA and lateral striate arteries through subsequent fusion and regression. Hypothetically, failure of this process can lead to diverse variations of the MCA (e.g., ac-MCA, d-MCA, MCA fenestration, d-MCA origin, and twig-like MCA) (1). In general, the incidence of any MCA anomalies is very low (1,(61)(62)(63). However, in even rarer circumstances, the MCA anomalies could be associated with intracranial aneurysms (2)(3)(4). As a result of the low incidence of MCA anomalies, the reported cases of MCA anomaly-associated intracranial aneurysms were all presented as case reports or small case series. Hence, the true incidence of intracranial aneurysms in patients with MCA anomalies or in the general population is still unknown. According to Teal et al., anomalous arteries originating from the ACAs and coursing in parallel to or in close relationship with the MCA were defined as ac-MCAs. And those arising from the ICA were considered d-MCAs (64). The ac-MCA could be subdivided into three types based on their sites of origin (Figures 1A-C). Type I originates from the A1 segment of the ACA, type II originates from the A1-A2 junction (including the AComA), and type III originates from the A2 segment. According to Kai et al., the d-MCA was further divided into two types (type A and type B) ( Figure 1D) (34). The d-MCA arising from the The mechanism of the development of MCA anomalyassociated aneurysms is an interesting issue and has not been deliberately investigated. Though some authors have suggested that hemodynamic stress at the origin of the abnormal vessel might contribute to the formation of the aneurysm, we don't think this hemodynamic alteration is specific for this type of aneurysm (17,19). First, hemodynamic stress is the common cause for the formation of intracranial aneurysms. Second, no definite study shows that the incidence of intracranial aneurysms in patients with MCA anomalies is higher than that in the general population. Third, no investigation comparing the hemodynamic stress between the MCA anomalies and normal intracranial vessels has been published. In this study, we noticed that 49.2% of the patients had other concurrent cerebrovascular anomalies, which implied that this specific subset of patients might have congenital defect in cerebrovascular development and be prone to cerebrovascular anomalies.
According to this study, the morphology and location of the MCA anomaly-associated aneurysms were similar to those of other intracranial aneurysms. Most (63/67, 94.0%) of the intracranial aneurysms associated with MCA anomalies were saccular. And 63 (63/67, 94.0%) of the aneurysms were smaller than 10 mm. For the aneurysms associated with ac-MCA, d-MCA, and duplicate MCA origin, 46 (46/55, 83.7%) were located at the origin of MCA anomalies.
In contrast to the tendency to endovascular treatment for other intracranial aneurysms, 83.6% of the reported patients with MCA anomaly-associated aneurysms underwent open surgeries, and only 11.9% of the patients underwent endovascular treatment. This phenomenon is still obscure. In our opinion, the reasons are multi-factorial. First, as a result of the technical constraint, earlier cases were prone to undergo open surgeries. And then, due to the unconventional locations and low incidence, medical practitioners are prone to adopt the seemingly safer open surgical approach. Lastly, due to the specific local angioarchitecture, endovascular treatment might be more difficult. However, according to our study, the outcome of the patients undergoing endovascular treatment was not inferior to that of the patients undergoing open surgeries. And most of the cases undergoing endovascular treatment were reported recently (22,39,46,47,56). We believe that with the advancement in endovascular technology, more and more patients with MCA anomaly-associated aneurysms would undergo endovascular treatment.

Limitations
The studied patients in this review was extracted from retrospective case reports or small case series. So, our study has some limitations. The occurrence of MCA anomaly-associated aneurysms might be underestimated due to the reporting bias. As a result of the rarity of the studied disease, it's hard to expect that the responsible surgeon or institution could have sufficient experience in dealing with it, which would certainly have a great impact on the decision-making and treatment outcome. The treatment option, instrument, and concept had progressed greatly in the past decades for intracranial aneurysms, which would also affect the treatment selection and outcome. Some important anatomical, clinical, therapeutic, and prognostic details might be missed due to the different reporting customs. Statistical analysis is inappropriate for this kind of study. No comparative study between endovascular treatment and open surgery could be performed at present. Hence, the conclusions drawn from this review might be affected by the inherent bias of the evaluated case reports.

CONCLUSIONS
MCA anomalies are a subset of rare intracranial vessel anomalies. Their associated intracranial aneurysms are even rarer that only sporadic cases have been reported. The pathophysiological genesis of this subset of entities is still obscure. The patients with MCA anomaly-associated aneurysms tend to have other concurrent cerebrovascular anomalies, which denotes that congenital defect in cerebrovascular development might play a role in this process. Most of the affected patients could experience a good recovery after treatment.

DATA AVAILABILITY STATEMENT
All datasets generated for this study are included in the article/ supplementary material.

ETHICS STATEMENT
Written informed consent was obtained from the patient for publication of this manuscript and any accompanying images. Copy of the written consent is available for review by the Editor of this journal.