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Abstract
Background Evidence about the safety and the efficacy of flow diversion for distal anterior cerebral artery (DACA) aneurysms is scant. To provide further insight into flow diversion for aneurysms located at, or distal to, the A2 segment.
Methods Consecutive patients receiving flow diversion for DACA aneurysms were retrieved from our prospective database (2014–2020). A PRISMA guidelines-based systematic review of the literature was performed. Aneurysm occlusion (O’Kelly–Marotta=OKM) and clinical outcomes were evaluated.
Results Twenty-three patients and 25 unruptured saccular DACA aneurysms treated with flow diversion were included. Aneurysm size ranged from 2 mm to 9 mm (mean size 4.5 mm, SD ±1.6). Mean parent artery diameter was 1.8 mm (range, 1.2–3 mm, SD ±0.39). Successful stent deployment was achieved in all cases. Angiographic adequate occlusion (OKM C–D) at follow-up (14 months) was 79% (19/24 available aneurysms). No cases of aneurysm rupture or retreatment were reported. Univariate analysis showed a significant difference in diameter among aneurysms with adequate (4 mm) vs incomplete occlusion (7 mm) (P=0.006).
There was one transient perioperative in-stent thrombosis, and three major events causing neurological morbidity: two stent thromboses (one attributable to the non-adherence of the patient to the antiplatelet therapy); and one acute occlusion of a covered calloso-marginal artery.
Results from systematic review (12 studies and 107 A2–A3 aneurysms) showed 78.6% (95% CI=70–86) adequate occlusion, 7.5% (95% CI=3.6–14) complications, and 2.8%, (3/107, 95% CI=0.6–8.2) morbidity.
Conclusions Flow diversion among DACA aneurysms is effective, especially among small lesions. However, potential morbidity related to in-stent thrombosis and covered side branches should be considered when planning this strategy.
- aneurysm
- flow diverter
- stent
- subarachnoid
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Introduction
In the past decade, flow diversion has gained wide acceptance for the treatment of intracranial aneurysms. This strategy has been used for distal or bifurcation aneurysms, posterior circulation, ruptured lesions, or small or previously treated aneurysms.1–5 However, most of these indications should be considered off-label: results about these topics are controversial in the literature, and the safety of the flow diversion strategy should be proved.6–10 Aneurysms arising from the anterior cerebral artery (ACA) at, or distal to, the A2 segment are, in general, poorly represented in the series of flow diverters.11 The small parent artery diameter, the frequency of a wide neck, and the presence of a branching vessel often originating from the aneurysm, make these lesions challenging for the endovascular strategies. For these reasons, studies exploring flow diversion for distal ACA (DACA) aneurysms are required. A previous series of 15 patients harboring DACA aneurysms treated with flow diverters until 2017 was reported by our center.12 In this previous series, we underlined the efficacy of this strategy, but also some limitations related to the risk of ischemic complications due to the use of flow diversion in vessels with a dimeter close to 2 mm. Lately, given the increased operators' experience and the expansion of the indications for flow diversion, the attitude to using this strategy for distal intracranial locations substantially increased in our center. Accordingly, in the current study we aimed to present an additional 2 years of flow diversion treatment in distal locations, describing a larger experience of 25 consecutive A2–A3 aneurysms treated until 2020, reporting a longer clinical and radiological follow-up. In addition, through a PRISMA guidelines-based systematic review,13 we were able to compare our results to that reported in the literature, analyzing an additional 107 cases from 12 published studies.
Our aim was to give the most comprehensive analysis of the treatment-related outcomes of flow diversions for DACA aneurysms, combining our experience with the published available angiographic and clinical results.
Materials and methods
Patient selection
Our institutional prospectively maintained database of Endovascular Treatment of Intracranial Aneurysms was reviewed by two, and in case of inconsistency, by three investigators. All cases of DACA (A2–A3) aneurysms treated with flow-diverter stents between January 2014 and January 2020 were analyzed. Demographic data, aneurysm features and size, diameter of the parent artery, technical details of the endovascular treatment, clinical presentation, and follow-up were collected. A multidisciplinary consensus was made to decide the most appropriate treatment strategy.
Reasons for flow diversion strategy
The main reason for flow diversion treatment of aneurysms located at the A2–A3 segments of the ACA was the presence of a branching vessel rising from the aneurysm with a high risk of coil protrusion into the origin of the branch. In addition, large-neck lesions difficult to be treated with simple coiling, or recanalized aneurysms with a wide neck were evaluated for flow diversion strategy. In 19 cases, flow diversion was preplanned based on the characteristics of the lesion. In four cases coiling or balloon-assisted coiling were aborted, and flow diversion was performed, due to the unstable position of the microcatheter inside the aneurysm, or due to the coil protrusion outside the aneurysm neck.
Antiplatelet therapy
Antiplatelet therapy included daily dual antiplatelet medication with Lysine acetylsalicylate (L-ASA) 75 mg, and Clopidogrel 75 mg, starting 5 days before treatment, and maintained for 6 months until the first clinical and radiological follow-up. After 6 months, Clopidogrel was usually stopped, and L-ASA 75 mg was continued for a further 6 months. L-ASA was continued for life for the following reasons: presence of patient vascular risk factors; if persistent in-stent intimal hyperplasia >50% was seen at the 12 month angiography; and in case of ischemic events related to the stent. VerifyNow (Accumetrics, San Diego, California) was used to test the platelet inhibition (PRU=platelet reactivity unit). In case of platelet inhibition <30%, patients were treated with an additional dose of Clopidogrel 150 mg or were switched to Prasugrel 10–20 mg.
Technical description
All patients were treated under general anaesthesia via a transfemoral approach. Treatment was performed under intravenous heparinization (activated clotting time maintained above 250 s).
Through a 6F long femoral sheath introducer, a triaxial access was adopted in all patients. The size of the implanted flow diverter was chosen via a biplane 3D rotational angiography of the parent artery and target aneurysm. Preimplantation virtual device simulation was routinely performed with the Sim&Size software (Sim&Cure; Grabels, France), and the size of the flow diverter was chosen based on the simulation. The PED device was unsheathed under roadmap guidance through a 0.027-inch microcatheter navigated beyond the aneurysm neck. The SILK and the FRED junior were delivered through a 0.021-inch microcatheter. The correct deployment and vessel wall apposition were visualized with a VasoCT (Philips Healthcare, Best, The Netherlands) with diluted iodinated contrast medium.
Clinical and radiological assessment
Clinical evaluation was performed before, in the peri-procedural period (24–48 hours), and during long-term follow-up (6, 12, and 24 months after treatment). Adverse events were classified as transient (no impact on the neurological status), or permanent (associated with an irreversible worsening of the neurological condition). The modified Rankin Scale (mRS) was used for outcome assessment.
Aneurysm occlusion was, usually, evaluated with magnetic resonance angiography at 6 months, and digital subtraction angiography at 12 and 24 months. Angiographic occlusion was assessed according to the O’Kelly–Marotta14 (OKM) grading scale (occlusion grade: A=total filling, B=subtotal filling, C=entry remnant, D=no filling; degree of aneurysmal stasis: during the 1=arterial, 2=capillary, 3=venous phase). The angiographic outcome of the covered branches was evaluated immediately after stent deployment and during follow-up as: unchanged; narrowing and/or slow flow; and occlusion.
Systematic review
A comprehensive literature search of PubMed, Ovid EMBASE, and SCOPUS was conducted for studies published from 2005 to January 2020. PRISMA guidelines13 were followed. The search strategy is reported in online supplementary table 1. The selected studies are reported in online supplementary table 2. We included series reporting aneurysms arising from the DACA (pericallosal, A2–A3 segments) treated with flow diverter stents. Exclusion criteria were the following: case reports; review articles; non-English language studies; and in vitro/animal studies. The primary objective of this systematic review was to define the safety (treatment-related complication, morbidity rates), and the efficacy (technical success rate, long-term occlusion) of flow diversion for DACA aneurysms. Subgroups analysis of the angiographic and clinical outcomes were performed.
Supplemental material
Statistical analysis
The overall frequency (percentage) and 95% CI were calculated for all results. The Wald method was used to calculate CI for event rates. Statistical analysis was performed with GraphPad QuickCalcs software. A two-tailed t-test was used for continuous data and the chi-square test for categorical variables. Statistical significance was set at P<0.05.
Results
Baseline population characteristics
Twenty-three consecutive patients (12 women, 11 men; mean age, 61.5±10.5 years; range, 40–77 years) with 25 DACA aneurysms were treated with flow diversion at our center (table 1). All patients presented an excellent neurological condition (mRS0-1) before treatment, except five subjects with a slight pretreatment disability (mRS-2). Seventeen patients (74%) were hypertensive or smokers, whereas six patients (26%) did not present vascular risk factors. Four patients had multiple aneurysms (details in table 1).
Summary of patients and aneurysm characteristics
Aneurysm and treatment characteristics
All 25 aneurysms were saccular and unruptured lesions, localized in the A2 or A3 segments, and originating from a branching vessel. The mean size was 4.5 mm (SD ±1.6; range, 2–8 mm). Seven aneurysms originated from the frontopolar (FP) division (28%), 14 from the calloso-marginal (CM) division (56%), two from the anterior internal frontal artery (AIFA) division (8%), one from the middle internal frontal artery (MIFA) (4%), and one from the superior parietal artery (SPA) (4%). Eight aneurysms (32%) were previously coiled and treated with flow diversion because of the recanalization. Among these, six (24%) were previously ruptured.
The Pipeline Embolization Device (PED; Covidien, Irvine, California) was the most used stent (18 aneurysms), followed by the SILK (Balt Extrusion, Montmorency, France) (five aneurysms), and Flow-Redirection Endoluminal Device (FRED; MicroVention, Tustin, California) (two aneurysms). One aneurysm was treated with the first-generation PED, 15 were treated with the second-generation PED (Pipeline Flex), and two aneurysms with the third-generation PED (Pipeline Shield) (table 1). One patient was treated with two telescopic PEDs because of two aneurysms along the pericallosal artery (table 1, patient number 5).
Angiographic outcome
Successful flow diverter deployment was obtained in all cases.
Twenty-four aneurysms were available during a mean angiographic follow-up of 14 months (range 8–30 months). One patient performed an MRI follow-up (patient 11) because of the total occlusion of the stent. Complete occlusion (OKM D) was achieved among 17 (71%) aneurysms, whereas near-complete occlusion (OKM C) was detected among two cases (8%), with an overall rate of adequate occlusion (OKM C–D) of 79% (19/24 aneurysms). Incomplete occlusion (OKM B) was found among five lesions (21%). These incompletely occluded aneurysms were not retreated, and they were stable at the last angiographic follow-up. No cases of aneurysm rupture were reported. Asymptomatic mild stent stenosis (less than 50%) were observed among four cases (16.6%).
Univariate analysis (analyzing aneurysm and neck diameters, parent artery diameter, previous coiling, type of stent, presence of vascular risk factors) showed a significant difference in diameter among aneurysms with adequate occlusion (4 mm) compared with those having incomplete occlusion (7 mm) (P=0.006) (online supplementary table 3).
Clinical outcome and procedure-related complications
Overall, four patients showed ischemic complications in the perioperative period. No long-term adverse events were reported. There was one transient ischemic event, and three permanent ischemic complications. Three cases of complications (patients 5, 11, and 13) were already reported in a previous publication.12 Patient 5 (table 1) was treated with two telescopic PEDs. Immediately after treatment the patient developed a punctiform basal ganglia lesion associated with a transient completely reversible hemiparesis 24 hours after treatment. This was likely related to an embolic complication from the guiding catheter due to a longer procedural time because of the telescopic strategy. Patient 11 discontinued the dual antiplatelet therapy after 10 days from treatment, developing a complete SILK stent occlusion, causing an infarct on the ACA territory diagnosed after 24 hours from symptoms onset. Patient 13 partially recovered from a moderate right hemiparesis due to a FRED stent thrombosis 12 hours after treatment, completely recanalized after intravenous Abciximab injection.
Finally, patient 22 (figure 1) developed an acute occlusion of the calloso-marginal and frontopolar arteries covered with a PED. The stent had landed with lower porosity proximally compared with distally. This was mainly based on the following reasons. First, the larger proximal diameter of the parent artery (2.1–1.8 mm) contributed to the lower porosity of the proximal segment of the stent. In addition, during stent deployment, due to the tortuous arterial anatomy, we filled a higher loading force on the microcatheter, causing a moderately higher degree of compaction of the proximal device (figure 1D). Thus, the lower porosity at the origin of the branching vessels was responsible for the acute slow flow of the covered arteries (figure 1E). Mean arterial blood pressure was increased up to 100 mmHg, however, the patient developed an ischemic lesion on the ACA territory with a permanent deficit of the left foot dorsiflexion (figure 1G,H,I).
(A) (Patient 22). Right internal carotid artery angiogram (antero-posterior view) showing a previously coiled and recanalized A2 aneurysm. (B) The frontopolar artery (black arrowhead) and the calloso-marginal artery (red arrowhead) originated from the aneurysm. (C) A PED 2.5×12 mm (red arrow) was deployed from the A2 to the pericallosal artery, covering the aneurysm neck and the frontopolar and calloso-marginal arteries. (D) Due to the difficult anatomy, the PED was deployed with a slightly higher loading force on the microcatheter, resulting in a compression of the proximal segment of the stent (red arrow): in addition, the larger proximal diameter of the parent artery (2.1–1.8 mm) contributed to the lower porosity of the proximal segment of the stent. (E) Immediately after flow diverter deployment, the covered frontopolar and calloso-marginal branches were occluded, with a parenchymal defect on the anterior cerebral artery (ACA) territory. (F) Mean arterial blood pressure (MAP) was increased intraoperatively (MAP=100 mmHg). (G) Magnetic resonance perfusion imaging showed a significant hypoperfusion (T max delay) on the ACA territory. Patient had left leg weakness and was monitored in the intensive care unit with the aim of maintaining the MAP between 90 and 100 mmHg. intravenous infusion of tirofiban was performed. The branches were patents, but the patient had some ischemic lesions on the DWI (H) and FLAIR sequences (I), leading to a weakness of the left foot dorsiflexion.
Overall, the mean clinical follow-up was 18 months (range, 3–30). Two patients (8.6%) (patients 11 and 22) presented a poor neurological outcome (mRS >2) at follow-up.
Angiographic outcome of covered branches
We reported one symptomatic case of severe slow flow of a covered calloso-marginal artery (patient 22). During the 18-month angiographic follow-up, asymptomatic branch narrowing was observed in four patients (18%), while asymptomatic branch occlusion was reported in one patient (4.5%) (figure 2).
(A) (Patient 16). Right internal carotid artery angiogram (lateral view) depicting a medium-sized saccular unruptured aneurysm at the origin of the calloso-marginal artery. (B) A PED 2.5×12 mm was successfully deployed covering the aneurysm neck and the calloso-marginal branch. (C and D) A 12-month angiographic follow-up showing the complete aneurysm occlusion, as well as the occlusion of the calloso-marginal artery, without ischemic clinical and radiological complications.
Results from the systematic review
Twelve studies were collected from the literature search, with 107 cases of DACA aneurysms treated with flow diversion (table 2). Successful stent deployment was achieved in 95.3% of patients (102/107, 95% CI=89–98). Long-term complete/near-complete occlusion rate was 78.6% (70/89, 95% CI=70–86). Occlusion among the PED group vs other devices were 85.5% (53/62, 95%CI=74–92) and 63% (17/27, 95%CI=44–78), respectively.
Results from systematic review: outcomes after flow diversion treatment of distal anterior cerebral artery aneurysms
The overall treatment-related complication rate was 7.5% (8/107, 95% CI=3.6–14). Most of them were periprocedural/early events (within 30 days) (7/107=6.5%, 95% CI=2.9–13). Transient complications were 4.6% (5/107, 95% CI=1.7–10), while morbidity was 2.8% (3/107, 95% CI=0.6–8.2). In-stent stenosis during follow-up was reported among 2% of patients (1/103, 95% CI=0.1–7).
Treatment with PED was associated with 7% (5/71, 95% CI=2.6–16) of complications, whereas treatment with other stents (SILK and FRED) was associated with 8.3% rate (3/36, 95% CI=2.1–22) of adverse events.
Occlusion of covered side branches was 16.3% (9/55, 95% CI=8.6–28.5), with 3.6% rate (1/51, 95% CI=3–13) of associated symptoms.
Discussion
Angiographic outcome
Our angiographic results are in line to what is reported in the literature, with approximately 78% of adequate occlusion (OKM C–D) after flow diversion treatment.15 ,16 ,17 ,8 9 12 Similarly, the 71% rate of complete occlusion (OKM D) in our experience was quite comparable to the published results (66%). This is the largest study focusing on the flow diversion treatment for DACA aneurysms. Interestingly, we found that the only factor influencing the rate of A2–A3 aneurysm occlusion was the aneurysm size: in our series, smaller lesions with a mean diameter of 4 mm had a higher rate of adequate occlusion compared with larger aneurysms (7 mm). It is important to point out that, in our series, flow diverters were used in vessels with a diameter lower than their nominal size. Accordingly, all the stents were slightly or moderately oversized (diameter between 2 mm and 2.75 mm) resulting in a reduction of the metal stent coverage at the level of the aneurysm neck, potentially influencing the occlusion rate when compared with other locations of the circulation.18
Aneurysm size has been reported as an independent factor of aneurysm occlusion. Bender et al,19 in a series of 445 intracranial aneurysms treated with flow diverters, underlined that an increased aneurysm size was directly correlated with poor occlusion at follow-up (OR=3.58, P=0.03).
In general, the presence of a branch vessel coming from the aneurysm has been reported as another important factor negatively influencing the aneurysm occlusion rate. Kan et al20 published a series of PED placed across the ostium of 701 aneurysms. Fifteen of them incorporated an end vessel without distal collateral, and none of the aneurysms were occluded. Accordingly, in the absence of collateral circulation, the persistent runoff into branches originating from the aneurysms negatively influenced the aneurysm occlusion, likely for an incomplete neointimal response at the level of the stent.21 22 Surprisingly, in our series, incorporation of a branch vessel was not associated with an increased aneurysm incomplete occlusion (online supplementary table 3). This was probably related to the presence of collaterals of the frontal and orbito-frontal region that lead the asymptomatic occlusion or flow remodeling of the covered branches. Accordingly, the rate of narrowing and occlusion of the covered A2–A3 branching vessels was considerably higher (23% in our series and 16% in the literature) compared with the reported occlusion rate of the supraclinoid ICA vessels, such as the ophthalmic (6%) and the anterior choroidal artery (1%).21
Finally, both in our series (68.4% vs 31.6%) and in the literature (85.4% vs 63%), although not statistically significant, the use of the PED was associated with a slightly better angiographic result compared with other devices. Similar results have been underlined in a recent meta-analysis of flow diversion treatment of distally located anterior circulation aneurysms, in which PED was associated with an increased occlusion rate, compared with other stents.11 In the present review, almost 70% of the A2–A3 aneurysms were treated with PED: accordingly, the higher rate of occlusion after PED can be partially influenced by the higher number of PED cases.
Treatment-related complications
A recent meta-analysis of approximately 500 distal anterior circulation aneurysms reported a 12.5% rate of complications after flow diversion.11 The present review of the literature, focusing on the A2–A3 aneurysms, underlined an overall rate of adverse events of 7.5%, with a 2.8% rate of morbidity. In our series, morbidity was slightly higher compared with what was reported in the literature, with three patients out of 23 experiencing permanent complications. Interestingly, most of the adverse events were ischemic complications related to perioperative/early in-stent thrombosis. The average preoperative A2–A3 diameter in our series was 1.8 mm, which is smaller than the mean arterial diameter reported in most of the series of flow diversion among small vessels.19 This can partially explain the higher rate of ischemic events found in our series. In addition, it is important to underline that one patient (patient 11) experienced a stent occlusion due to the non-adherence to the dual antiplatelet therapy. Bender et al,6 in a recent study of flow diversion among 53 patients with vessels<2 mm, reported 17% rate of complications, with 4.5% major strokes related to acute stent occlusion.
It is likely that new antiplatelet agents, having a stronger platelet inhibition with a lower platelet resistance (eg, Prasugrel), can be systematically used for patients receiving flow diversion treatment for aneurysms located in small vessels, such as the A2–A3 segments. A recent meta-analysis reporting endovascular treatments for intracranial aneurysms among 682 and 672 patients receiving Prasugrel and Clopidogrel, respectively, showed a significant lower rate of ischemic complications among the Prasugrel group (2% vs 6%, P=0.03).23
Another important concern of the use of flow diverters in distal locations, is the risk of symptomatic occlusion of covered vessels.24 In our study, while the rate of asymptomatic flow remodeling and occlusion was quite high, only one patient developed a symptomatic acute occlusion of a calloso-marginal artery covered with a PED (patient 22). Investigating the literature, symptoms related to covered side branches among A2–A3 aneurysms treated with flow diverters are close to 4%.9 25 26 A recent multicenter experience of aneurysms treated with the Silk Vista Baby, reported one case of acute side branch occlusion among four patients with pericallosal artery aneurysms.25 Mohlenbruch et al9 in a multicenter series of 13 A2–A3 aneurysms treated with FRED, reported one case of acute slow flow of a covered side branch causing multiple but asymptomatic ischemic lesions. Despite safety concerns about flow diversion in small distal anterior cerebral arteries, it is important to point out that A2–A3 aneurysms are also challenging lesions for other strategies. Complication rate after surgical treatment is close to 15%,27 and outcomes after endovascular embolization are quite heterogeneous (complications rates between 2% and 18%).28–30
In our experience, 70% of patients were treated with PED which is deliverable through a 0.027-inch microcatheter. It is important to underline that attempts to catheterize small-sized distal intracranial vessels with these relatively rigid microcatheters might increase the procedural complication risk. Indeed, other flow diverters with a lower profile are nowadays available, and they could be deployed through 0.021-inch9 or 0.017-inch microcatheters.31 Based on our experience, we are, in general, more confident about the sizing, deployment, and mechanical behavior of the PED. However, because of the not negligible rate of ischemic events in small vessels treated with high-mesh density stents, we are progressively increasing the use of low-profile braided stents for distally located small unruptured aneurysms. These stents have a higher porosity and can be deployed through a 0.021-inch or 0.017-inch microcatheter. Based on the recent literature, the rate of complications is close to 5% for lesions treated with LEO Baby32 33 and p48 stents,34 and they may represent an alternative strategy for small aneurysms arising from small vessels (as the pericallosal artery).
Limitations of the study
Our study has limitations related to the single-center, retrospective design, and a relatively small number of patients. Statistical analysis of factors influencing aneurysm occlusion is probably not adequately powered to show statistical significance. Finally, only small and retrospective series were available for the systematic review.
Conclusions
Our experience, in accordance with the results of the literature, underlines the efficacy of the flow diversion treatment for DACA aneurysms. Larger aneurysm diameter can limit the effectiveness of the treatment, with small lesions presenting better results compared with medium-sized aneurysms. However, potential morbidity related to in-stent thrombosis and covered side branches should be considered when planning this strategy. These results may provide further insight into the safety of the flow diversion in this specific location.
References
Footnotes
Contributors Substantial contributions to the conception or design of the work; or the acquisition, analysis, or interpretation of data for the work: FC, AF, ID, CD, PH, GG, CR, AB, VC – Drafting the work or revising it critically for important intellectual content: FC, AF, ID, VC – Final approval of the version to be published: FC, AF, ID, CD, PH, GG, CR, AB, VC – Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: FC, AF, ID, CD, PH, GG, CR, AB, VC.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial, or not-for-profit sectors.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval Ethics approval was not required because all data derived from our approved retrospective hospital database. Due to the retrospective nature of this study, the requirement for informed patient consent was waived.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement Data are available upon reasonable request. Deidentified participant data used in this manuscript will be available upon resonable request.