Introduction

Acute ischemic stroke (AIS) as a result of isolated primary occlusion of the anterior cerebral artery (ACA) accounts for only 0.5–3% of all strokes [1] but may lead to significant handicap. Patients typically present with contralateral weakness of the leg and may suffer cognitive deficits and behavioral changes due to ischemia in limbic and frontal areas of the brain [2]. Occasionally, contralateral weakness of the face and arm is present when the medial lenticulostriate arteries are involved[3]. Since the publication of five large trials in 2015, [4,5,6,7,8] endovascular treatment (EVT) has become standard care for AIS due to proximal anterior circulation occlusions[9]. However, the majority of patients in the EVT trials had an internal carotid artery (ICA) or proximal middle cerebral artery (MCA) occlusion. Of all 5 trials, only the Multicenter Randomized Clinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands (MR CLEAN) allowed inclusion of patients with ACA occlusions, and only three such patients were included[4]. As such, the benefit of EVT for ACA occlusions remains uncertain and data on treatment outcomes in clinical practice are scarce. Observational data suggest that EVT for these patients is safe and feasible, but the reported number of patients is limited [10,11,12,13]. Current guidelines do not provide clear recommendations for ACA occlusions and treatment for these patients varies between countries, centers, and interventionalists[14]. The aim of this study was to describe the results and outcome of EVT in patients with primary ACA occlusions using a large Dutch national EVT registry [15].

Methods

Study design

The MR CLEAN Registry is a multicenter, nationwide, prospective, consecutive database of patients treated with EVT for AIS in the Netherlands. Patients were included if they underwent arterial puncture with the intention to perform EVT for AIS. The choice of EVT technique and device was left to the treating interventionalist. Radiological baseline and follow-up imaging were centrally adjudicated by an independent core laboratory of trained physicians blinded to all clinical and treatment data except for symptom side. The MR CLEAN Registry study protocol was evaluated by the ethics committee of the Erasmus MC, University Medical Centre, Rotterdam, the Netherlands (MEC-2014-235). Permission to carry out the study as a registry was granted.

We used data of patients treated between March 16, 2014, from the first patient treated after the MR CLEAN trial [4], and January 1, 2019. We compared patients with ACA occlusions on computed tomography angiography (CTA), aged 18 years or older, who were treated in a MR CLEAN trial center, with patients with occlusion of the ICA or proximal MCA (M1 and M2 parts). Patients with secondary (periprocedural) occlusion of the ACA or additional occlusions in different vascular territories were excluded.

Outcome measures

Our primary outcome was functional outcome measured on the modified Rankin Scale (mRS, ranging from 0, no symptoms, to 6, death) at 90 days after stroke onset. Secondary clinical and radiological outcomes were 90-day functional independence (mRS 0–2), National Institutes of Health Stroke Scale (NIHSS) score at 24–48 h, delta-NIHSS (baseline NIHSS minus NIHSS score at 24–48 h), NIHSS improvement (\(\ge\) 4 NIHSS points improvement between baseline and 24–48 h), and successful reperfusion (expanded thrombolysis in cerebral infarction (eTICI) score 2b–3). Safety outcomes were 90-day mortality, symptomatic intracranial hemorrhage (sICH), peri-operative complications (vessel perforation, dissection), and neurological deterioration (\(\ge\) 4 NIHSS points worsening between baseline and 24–48 h).

Statistical analysis

All analyses were descriptive because of the low number of patients with ACA occlusions. Summary statistics are presented as mean with standard deviation for normally distributed data, and median with interquartile range (IQR) for non-normally distributed data. We compared outcomes of patients with ACA occlusions with those of MR CLEAN Registry patients with ICA or proximal MCA occlusions. For binary categorical outcomes, Fisher’s exact test was used in case of expected counts of zero and Chi-Square test if there were no expected counts of zero. For ordinal outcomes, the Chi-Square test for trend was used. For the semi-continuous outcome measure of delta-NIHSS, which was non-normally distributed, the Kruskal–Wallis test was used. Missing data were not imputed. The level of significance was set at p < 0.05. All statistical analyses were performed with IBM SPSS Statistics version 23.0.0.0 (New York, NY, United States 2017).

Data availability

In compliance with the General Data Protection Regulation, source data will not be made available for other researchers. Analytic methods, study materials, scripts of the statistical analyses, and their output are available from the corresponding author on reasonable request.

Results

In total, 5193 patients were included in the MR CLEAN Registry between March 16, 2014 and January 1, 2019. Data on the site of occlusion on baseline CTA were missing for 210/5193 (4.0%) patients. Only 11 patients (0.2%) had a primary ACA occlusion on CTA at admission. Four out of 11 patients had a occlusion in the A1 segment (36%) and seven patients in the A2 segment (64%) (Fig. 1). In patients with ACA occlusions, median age was 69 (IQR 65–74 years) versus 72 (IQR 62–81) in patients with ICA or MCA occlusions. Three (27%) patients with ACA occlusions were female versus 2396 (48%) in the ICA/MCA group. Median NIHSS score on admission was lower in patients with ACA occlusions (11, IQR 9–14) compared to patients with ICA or MCA occlusions (15, IQR 11–19; Table 1).

Fig. 1
figure 1

Patient inclusion flow chart A1, first segment of anterior cerebral artery; A2, second segment of anterior cerebral artery; ACA, anterior cerebral artery; CTA, computed tomography angiography; MCA, middle cerebral artery; M1, first segment of middle cerebral artery; M2, second segment of middle cerebral artery; MR CLEAN, Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands

Full size image
Table 1 Demographic variables
Full size table

Functional outcomes

Functional outcome at 90 days after AIS did not differ between patients with ACA occlusions and those with ICA or MCA occlusions (Fig. 2). Four of 11 patients (36%) with ACA occlusions were functionally independent at 3 months, versus 1949/4815 (41%) patients with.

Fig. 2
figure 2

Ordinal mRS outcomes in patients with ACA occlusions versus ICA or MCA (M1/2) occlusions in the MR CLEAN Registry ACA anterior cerebral artery, mRS modified Rankin Scale score

Full size image

ICA or MCA occlusions (Table 2). In patients with ACA occlusions, median NIHSS score at 24–48 h after AIS onset was 11 (IQR 2–13) with a median delta-NIHSS of -1 (IQR -7 to 2). In patients with ICA or proximal MCA occlusions, median NIHSS score at 24–48 h after AIS onset was 9 (IQR 3–17) with a median delta-NIHSS of -4 (IQR -9 to 0). Three of 9 patients (33%; 2 missing data) in the ACA group showed improvement of ≥ 4 points on the NIHSS versus 2427/4518 patients (54%) in the ICA or MCA group.

Table 2 Results IPO-ACA versus all other occlusions
Full size table

Radiological outcomes

Successful recanalization was achieved in 4/9 (44%) of patients with ACA occlusions (Table 2). Of these patients, 2/4 (50%) were functionally independent at 3 months versus 2/5 (40%) of patients with partial or no recanalization. Successful recanalization was achieved in 3083/4787 (64%) of patients with ICA or proximal MCA occlusions. Of these patients, 1451/2977 (49%) achieved functional independence at 3 months versus 418/1656 (25%) of patients with partial or no recanalization. Procedural characteristics are shown in Table 3.

Table 3 Procedure characteristics in treated ACA strokes
Full size table

Safety outcomes

Mortality at 90 days was 27% (3/11) in the ACA group versus 26% (1263/4815) in patients with ICA or MCA occlusions (Table 2). One of 11 patients (9%) in the ACA group had sICH, and one patient (9%) deteriorated ≥ 4 points on the NIHSS. No periprocedural dissection or perforation occurred in this group. In patients with ICA or proximal MCA occlusions, 294/4972 (6%) had sICH, periprocedural dissection occurred in 77/4330 (2%), and 65/4318 (2%) suffered peri-procedural perforation.

Discussion

In this Dutch national cohort of EVT-treated patients, ACA occlusions were uncommon, occurring in only 0.2% of 4983 patients. Complication rates and functional outcomes of patients with ACA occlusions were similar to those of patients with ICA or proximal MCA occlusions. However, analyses were limited by the small ACA sample size. Successful reperfusion was achieved in less than half of patients with ACA occlusions.

Even though ACA occlusions were an inclusion criterion in the MR CLEAN trial, less than 1% of patients in the subsequent MR CLEAN Registry were treated for ACA occlusions. As ACA occlusions may account for up to 3% of all stroke cases, [1] this suggests under-treatment and possibly under-recognition of ACA occlusions. The uncertainty of the available evidence and lack of consensus on the benefit of EVT for ACA occlusions in stroke may have negatively impacted the number of patients with ACA occlusions treated with EVT in our study. ACA occlusions in stroke may be more likely to be missed on baseline CTA, as the acute diagnostic workup for stroke patients typically focusses on the MCA branches [16]. In addition, due to variations in ACA anatomy and collateral blood flow, ACA strokes are often accompanied by non-specific symptoms and ACA occlusions may initially lead to little or no recognized sequelae [2, 3]. Careful evaluation of the ACA on imaging is warranted in all patients with stroke-like symptoms, specifically those presenting with disproportionate lower extremity weakness. Useful sequences for evaluating the ACA are maximum intensity projections—specifically the sagittal reconstructions—as well as multiphase CTA and/or CT Perfusion imaging (CTP) [3]. In recent years the increasing use of CTP has improved detection of large and medium vessel occlusions (LVO, MeVO) [10]. This may have led to increased detection and EVT of ACA occlusions in more recent years.

Data on outcomes of EVT in patients with ACA occlusion are scarce. Most studies are retrospective and include a small number of patients, even when large patient databases are used [11,12,13]. Despite high reported percentages of successful recanalization, several studies report functional independence rates after treating ACA occlusions of less than 40% [11,12,13, 17]. As ACA occlusions tend to be classified as MeVO [18], some studies on outcomes in EVT-treated stroke patients with MeVO also included ACA occlusions [19, 20]. Several trials on EVT in MeVO are currently ongoing, most notably EndovaSCular TreAtment to imProve outcomEs for Medium Vessel Occlusions (ESCAPE-MeVO, NCT05151172), Distal Ischemic Stroke Treatment With Adjustable Low-profile Stentriever (DISTALS, NCT05152524), EnDovascular Therapy Plus Best Medical Treatment (BMT) Versus BMT Alone for MedIum VeSsel Occlusion sTroke (DISTAL, NCT05029414), and Evaluation of Mechanical Thrombectomy in Acute Ischemic Stroke Related to a Distal Arterial Occlusion (DISCOUNT, NCT05030142). However, the inclusion of other types of MeVO such as MCA- M2-4 occlusions, ACP-P1-2, and PICA and AICA occlusions may affect the evidence on benefit of EVT for ACA occlusions. Most observational studies do not differentiate between primary ACA and secondary ACA occlusions (e.g., iatrogenic after intravenous thrombolysis or EVT) [3, 20]. In our study, the rate of successful reperfusion after EVT for primary ACA occlusions was only 44%, which is lower compared to other reported series (73–100%), though our rate of functional independence was in line with previous studies [11,12,13, 17, 21].

Technically, endovascular procedures in the ACA are more challenging compared to the MCA territory. Technical difficulty increases with more distal occlusions (i.e., A2/A3 compared to A1). Catheterizing the ACA from the distal ICA is more difficult due to its curved anatomy and interventionalists need to avoid crossing the anterior communicating artery. The lower recanalization percentage in this study may be explained by the high number of patients with A2 occlusions (64%) in our cohort. The high number of patients with A2 occlusions may also explain the significantly lower NIHSS scores in patients with ACA occlusions at baseline.

Our study has limitations. First, the number of included patients with ACA occlusions was small, limiting the power and reliability of the comparisons made. The small group size also made further statistical modeling with covariate adjustment unfeasible. Second, the MR CLEAN Registry only included EVT-treated patients, so true treatment benefit of EVT compared to best medical care only could not be determined. ACA occlusions may occur more often, but may not be not treated with EVT in the absence of proven treatment benefit and clear guidelines, after which they would not be included in our current data set. Evaluation of consecutive EVT-treated and non-EVT-treated patients with ACA occlusions would be of great value. Third, the eTICI score used in the MR CLEAN Registry may be suboptimal in measuring the benefit of EVT in patients with ACA occlusions. The eTICI score is mostly used for assessing the MCA territory. As such, interpretation and scoring of the ACA territory may be subject to higher interobserver variability. Lastly, the data in our cohort span a period of several years, starting at the beginning of the widespread use of EVT in treating AIS. In recent years, EVT techniques have improved by using smaller or adjustable stent retrievers, increasingly more experienced interventionalists, and ongoing research [22]. Consequently, current interventions may actually lead to better recanalization and functional outcomes in patients with ACA occlusions [22]. The recent introduction of new generation small caliber catheters and low-profile stent retrievers has allowed access to more distal sites of ACA. The effect on outcome of EVT for distal (ACA) occlusions is currently being investigated in several clinical trials, such as DISTALS and DISCOUNT [23]. More data and analyses of existing data are needed to determine the benefit and safety of EVT in patients with ACA occlusions. Ideally, these data should be prospective in order to gather high-quality evidence on this topic.

Conclusion

In this Dutch national cohort of EVT-treated patients, patients with ACA occlusions were uncommon, occurring in only 0.2% of 4983 patients. Complication rates and functional outcomes were similar to those of EVT-treated patients with ICA and proximal MCA occlusions, though analyses were limited by the small ACA occlusion group sample size. Successful reperfusion was achieved in less than half of patients with ACA occlusions. These data may suggest that EVT is safe in ACA stroke, though more technically challenging. Prospective research is needed to confirm data on feasibility, safety, and outcomes of EVT for ACA strokes.

Disclosures

CBLMM received grants from CVON/Dutch Heart Foundation, Stryker, European Commission, TWIN, and Dutch Health Evaluation Program) and is a shareholder of Nico.Lab. DWJD received grants from Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker, Penumbra Inc., Medtronic, Thrombolytic Science LLC, and Ceronovus. JMC received grants from Boehringer Ingelheim, Bayer, and Medtronic. PJvD received support from Stryker. WHvZ received personal support from Cerenovus, Stryker, Nicolab, and Philips. CPS received support from Neurophyxia BV. HBvdW received funding for consultancy from Bayer and TargED, and was paid to his institution. Others disclose nothing. MU received grants from Dutch Heart Foundation.