Endovascular treatment for M3 occlusions

Abstract

Introduction

Endovascular treatment (ET) is a beneficial treatment for M1–2 occlusions of the middle cerebral artery. Mortality and disability rates are high if large vessel occlusions are not treated. While these rates are lower in M3 occlusions, important branch blockages can lead to disability. Endovascular treatment of small vessel occlusions is difficult, and there are no studies on the effectiveness of endovascular treatment for M3 occlusions. Accordingly, in this study, our aim was to assess the feasibility, safety, and preliminary efficacy of endovascular therapy for M3 occlusions.

Methods

This study involved a retrospective analysis of a prospectively collected from two centres for acute ischemic stroke of the anterior system between July 2015 and April 2020. Demographic, radiologic, procedural and outcome variables were collected for patients who underwent endovascular therapy for acute ischemic stroke of the anterior system.

Results

Complete or near complete reperfusion (mTICI 2b-3) of the M3 occlusion was achieved in 15 cases (38.5%). Complete (mTICI 3) reperfusion was achieved in 24 cases (61.5%). Twenty-six patients were treated for primary M3 occlusion, while 13 patients with M3 occlusion were treated as a rescue strategy after successful treatment of a proximal greater vascular occlusion. Complete or near complete reperfusion (mTICI 2b-3) of primary occlusion was achieved in eight cases (30.8%), and complete (mTICI 3) reperfusion was achieved in 18 cases (69.2%). In addition, complete or near complete reperfusion (mTICI 2b-3) of rescue M3 occlusion was achieved in seven cases (%53.8), while complete (mTICI 3) reperfusion was achieved in six cases (46.2%). Only one patient with primary M3 occlusion had ICH due to extravasation. The patient's neurological examination one month later was normal.

Conclusions

This retrospective study demonstrates that endovascular treatment of M3 occlusions is safe, effective and reliable.

Introduction

Endovascular treatment (ET) is a beneficial treatment for M1–2 occlusions of the middle cerebral artery.^1–3 Mortality and disability rates are high if large vessel occlusions are not treated. ⁴ While these rates are lower in M3 occlusions, important branch blockages can lead to disability. Endovascular treatment of small vessel occlusions is difficult, and there are no studies on the effectiveness of endovascular treatment for M3 occlusions.^5,6 Accordingly, in this study, our aim was to assess the feasibility, safety, and preliminary efficacy of endovascular therapy for M3 occlusions.

Methods

Study design

This study involved a retrospective analysis of a prospectively collected from two centres for acute ischemic stroke of the anterior system between July 2015 and April 2020. Demographic, radiologic, procedural and outcome variables were collected for patients who underwent endovascular therapy for acute ischemic stroke of the anterior system. The middle cerebral artery is divided into two segments (M1 and M2) in the terminologia anatomica. However, surgical and radiological approaches use four segments (M1, M2, M3, M4), which were described by Gibo et al. ⁷ The M3 (opercular) segment of the middle cerebral artery is located after the circular sulcus of the insula. The M3 segment of the middle cerebral artery is located between the top of the Sylvian fissure and the cerebral cortex. In our study, all arteries were segmented anatomically by two invasive neurologists.

We gave intravenous tPA to all eligible patients following standard guidelines before the endovascular procedure. However, we did not wait for IV tPA response. We performed endovascular treatment with a stent retriever and/or selective intraarterial tPA into the clot for patients with intracranial occlusions. Control tomography was performed on all patients 24 h later.

The study's primary aim was to evaluate reperfusion according to the modified Treatment in Cerebral Ischemia (mTICI) scale. The study's secondary aims were to evaluate both the severity of the neurological deficit (based on National Institutes of Health Stroke Scale [NIHSS] scores on days 0 and 90) and treatment safety (measured by the occurrence of symptomatic intracerebral haemorrhage [ICH], fatal or non-fatal stroke, death from any cause, or neurological deterioration, such as clinical worsening within the first week). Symptomatic ICH was determined according to the definition of the European Cooperative Acute Stroke Study (ECASS) as follows: any type of ICH on any posttreatment imaging after the start of thrombolysis and an increase of ≥4 NIHSS points from baseline. This study was approved by the local Institutional Review Board with a waiver of informed consent.

Patients

Consecutive patients with acute ischemic stroke based on computed tomography (CT) and diffusion weighted-magnetic resonance imaging (MRI) without a CT angiography (CTA) or MR angiography (MRA) from the two centres were included in this study. The patients were 18 years of age or older and experienced an acute ischemic stroke of the anterior system caused by an intracranial occlusion.

The treatment decision was made by neurologists specialising in neuroendovascular issues and stroke. The patients undergoing intervention were thought to benefit from neuroimaging and clinical treatment. All patients who did not respond to IV tPA treatment diagnosed with a large vessel occlusion were taken for conventional angiography as soon as possible. We did not apply general anaesthesia in any patient with primary M3 occlusion. Sedation was performed in 37 patients.

Technique and the device description

All of the endovascular interventions were performed with a 6–8 F sheath via femoral, brachial or direct carotid artery puncture. One or more treatment strategies were applied for the intracranial occlusions (stent retriever and/or intra-arterial tPA). An Aperio® 3.5–28 mm thrombectomy device was used for M3 occlusions. Flat-tip Rebar® (0.18 mm) was used as a microcatheter. No aspiration catheter was used in any of the patients. ACTILYSE® was used as the thrombolytic agent. Digital subtraction angiography was performed, while the conventional method was used for direct clot imaging. Angiographic images were obtained from anterior to posterior angles, and multiple images were taken.

Primary M3 occlusions

We detected M3 occlusions based on angulations from anterolateral and vertical axis views on angiography. It was also focused to improve image quality. The tip of a neurointerventional guide catheter was placed as close as possible to the occlusion. Then, the clot was reached with 0.18–0.27-inch microcatheters. Long-sheath, flowgate balloon-guide and intermediate catheters were not used in the endovascular interventions for patients with M3 occlusion. Intra-arterial tissue plasminogen activator (IA tPA) alone was given to 20 patients. Select images were taken intraarterially after each 2–4 mg of tPA was administered. If recanalisation was achieved, we finished the process. Mechanical thrombectomy with a stent retriever alone was performed in two patients. In addition, thrombectomy was performed in three patients who were not recanalised with IA tPA.

Statistical analysis

All statistical analyses were performed with IBM SPSS version 22.0 for Windows. The Shapiro–Wilk's test and Q-Q plots were used to check the normality of the data. Levene's test was used to examine the homogeneity of group variances. The numerical variables were expressed as mean ± standard deviation or median (interquartile range: 1st quartile—3rd quartile) as appropriate, based on the normality of the variables. Further, the categorical variables were described as counts (n) and percentages (%). An independent samples t-test and Mann–Whitney U test were used to compare numerical variables between the groups. The Chi-square test, Chi-square with Yates continuity correction and Fisher's exact test were used to investigate the associations between groups and categorical variables according to the expected counts in each cell for 2 × 2 crosstabs. When the expected counts were less than 20%, values were determined via the Monte-Carlo simulation method to include such sources in the analysis. A p-value less than.05 was considered to indicate statistical significance.

Results

A total of 224 patients who experienced anterior system ischemic stroke were included in this study. All of these patients underwent endovascular treatment. Seven had anterior cerebral artery occlusion (A1 occlusion: 1, A2 occlusion: 1, A1 rescue: 1, A2 rescue: 4), 78 had middle cerebral artery occlusion, 19 had M2 occlusion, 20 had M2 rescue and 61 had carotid artery occlusion. Of these patients, 39 were treated due to M3 occlusion. Demographic and outcome data are detailed in Table 1. The mean age of all patients was 67.4 ± 13.6, and 52.2% (n = 117) of the patients were female. The mean age of the patients with M3 occlusions was 70.3 ± 11.8, and 64.1% (n = 25) of these patients were female. A total of 33% of all patients and 23.1% of patients with M3 occlusion were given intravenous tPA. The median preprocedure NIHSS score for all the patients was 18.8 ± 3.7, and for patients with M3 occlusions it was 16.^8,9

Table 1.

Demographic comparison between primary M3 and other anterior circulation endovascular patients.

Variables	Overall (n = 224)	M3-Occlusions (n = 39)	The Other Anterior Circulation Occlusions (n = 185)	p-value
Age (years)	67.38 ± 13.57	70.31 ± 11.83	66.76 ± 13.86	.138 a
Male gender	107 (47.8)	14 (35.9)	93 (50.3)	.145 b
Hypertension	149 (66.5)	28 (71.8)	121 (65.4)	.561 b
Diabetes Mellitus	44 (19.6)	3 (7.7)	41 (22.2)	.065 b
Dyslipidemia	53 (23.7)	12 (30.8)	41 (22.2)	.346 b
Atrial Fibrillation	60 (26.8)	10 (25.6)	50 (27)	.999 b
Smoking	40 (17.9)	6 (15.4)	34 (18.4)	.831 b
Heart Valve Replacement	7 (3.1)	0 (0)	7 (3.8)	.608 c
A History of Stroke	41 (18.3)	8 (20.5)	33 (17.8)	.869 b
Intravenous tPA	74 (33)	9 (23.1)	65 (35.1)	.205 b
NIHSS	18.82 ± 3.74	16 (14–18)	19 (17–23)	<.001 d
Stent-retriever	183 (81.7)	8 (20.5)	175 (94.6)	<.001 b
Minutes from LKN to puncture	286.92 ± 142	300 (230–360)	260 (180–316)	.205 d
Intra-arterial tPA	112 (50)	34 (87.2)	78 (42.2)	<.001 b
Dose of intra-arterial tPA	6.41 ± 7.75	10 (6.5–10)	0 (0–10)	.002 d
Minutes from puncture to reperfusion	51.73 ± 34.79	34 (24.5–37.5)	45 (30–67)	<.001 d
Perfusion				<.001 e
None	13 (5.8)	0 (0)	13 (7)
mTICI 2b-3	137 (61.2)	15 (38.5)	122 (65.9)
mTICI 3	74 (33)	24 (61.5)	50 (27)
Hematoma	34 (15.2)	2 (5.1)	32 (17.3)	.093 b
Mortality	49 (21.9)	3 (7.7)	46 (24.9)	.032 b
NIHSS in the 3rd month	8.85 ± 6.42	8 (6–13.5)	10 (1–14)	.815 d
mRS in the 3rd month	2.83 ± 1.49	2 (1–2)	3 (2–5)	<.001 d

Data were expressed as mean ± standard deviation or median (iqr: 1^st quartile – 3^rd quartile), and described as counts (n) and percentages (%)

Bold values show that statistically significant (p < .05)

^aIndependent sample t-test

^bChi-square test with Yates continuity correction

^cFisher's exact test

^dMann-Whitney U test

^eExact test with Monte-Carlo simulation

Complete or near complete reperfusion (mTICI 2b-3) of the M3 occlusion was achieved in 15 cases (38.5%). Complete (mTICI 3) reperfusion was achieved in 24 cases (61.5%). Complete or near complete reperfusion (mTICI 2b-3) of other anterior circulation occlusions was achieved in 129 cases (65.9%), while complete (mTICI 3) reperfusion was achieved in 50 cases (27%). Twenty-six patients were treated for primary M3 occlusion, while 13 patients with M3 occlusion were treated as a rescue strategy after successful treatment of a proximal greater vascular occlusion. Complete or near complete reperfusion (mTICI 2b-3) of primary occlusion was achieved in eight cases (30.8%), and complete (mTICI 3) reperfusion was achieved in 18 cases (69.2%). In addition, complete or near complete reperfusion (mTICI 2b-3) of rescue M3 occlusion was achieved in seven cases (%53.8), while complete (mTICI 3) reperfusion was achieved in six cases (46.2%). Only one patient with primary M3 occlusion had ICH due to extravasation. The patient's neurological examination one month later was normal. All of the M3 occlusion cases are described in Table 2.

Table 2.

Detailed demographic and procedural information for M3 occlusions.

Variables	M3-Primary (n = 26)	M3-Rescue (n = 13)	p-value
Age (years)	71.65 ± 11.83	67.62 ± 12.71	.321 a
Male gender	10 (38.5)	4 (30.8)	.733 c
Hypertension	20 (76.9)	8 (61.5)	.453 c
Diabetes Mellitus	2 (7.7)	1 (7.7)	.999 c
Dyslipidemia	10 (38.5)	2 (15.4)	.269 c
Atrial Fibrillation	7 (26.9)	3 (23.1)	.999 c
Smoking	5 (19.2)	1 (7.7)	.643 c
A History of Stroke	6 (23.1)	2 (15.4)	.694 c
Intravenous tPA	4 (15.4)	5 (38.5)	.129 c
NIHSS	14 (12.25–16.75)	18 (17–23)	<.001 d
Stent-retriever	5 (19.2)	3 (23.1)	.999 c
Minutes from LKN to puncture	280 (190–318)	336 (268–384)	.050 d
Intra-arterial tPA	23 (88.5)	11 (84.6)	.999 c
Dose of intra-arterial tPA	10 (8–10)	8 (6–10)	.078 d
Minutes from puncture to reperfusion	34.5 (32.5–40)	21 (20–25)	.003 d
Perfusion			.295 b
mTICI 2b-3	8 (30.8)	7 (53.8)
mTICI 3	18 (69.2)	6 (46.2)
Hematoma	1 (3.8)	1 (7.7)	.999 c
Mortality in the 3rd month	0 (0)	3 (23.1)	.031 c
NIHSS in the 3rd month	8 (6–9.75)	14 (11–14)	.030 d
mRS in the 3rd month	2 (1–2)	2 (2–3)	.003 d

Data were expressed as mean ± standard deviation or median (iqr: 1^st quartile – 3^rd quartile), and described as counts (n) and percentages (%)

Bold values show that statistically significant (p < .05)

^aIndependent sample t-test

^bChi-square test with Yates continuity correction

^cFisher's exact test

^dMann-Whitney U test

Discussion

Severe functional disability is associated with proximal artery occlusion in the anterior circulation. A total of 585 patients with M1 and M2 occlusions who underwent consecutive mechanical thrombectomy were studied. The neurological deficits of patients with M2 occlusions were similar to those with M1 occlusions. Similar rates of successful reperfusion (TICI score ≥2b 88.5 vs. 90.5%, p = 0.612) were found, but the mean food outcome (modified Rankin Scale ≤2) was lower for patients with M1 occlusions (37.2 vs. 54.3%, p < 0.001). Therefore, although the M2 occlusions were more distal, they benefited more from treatment. ¹⁰ M3 occlusions may lead to significant deficits depending on the “eloquence” of the supplied territory. For example, in terms of functional independence, the MCA-M3 occlusion causing hemiparesis and aphasia (Figures 1 and 2) was devastating for two patients. Early intra-arterial treatment with stent-retrieving devices is safe and effective for patients who have experienced acute ischemic stroke due to proximal artery occlusion in the anterior circulation and can be treated within 24 h of the time they were last known to be healthy. Few studies have comprehensively assessed the endovascular treatment of distal arterial occlusions.^5,6 While the safety and efficacy of IV tPA for acute ischemic stroke patients with distal arterial occlusions is well known, its use is often limited by the short therapeutic time window, and it has multiple contraindications.

Figure 1.

Male (69 years old) presented with a right hemiparesis and aphasia. He was taken to the intervention at the 7th hour. Diffusion weighted imaging (DWI) demonstrated a scattered lesion in the MCA territory (A). Digital subtraction angiography (DSA) demonstrated M3 cutoff (arrow) (B). Patient was treated with 8 mg intra-arterial tPA and achieve recanalization on final angiogram (C).

Figure 2.

Male (67 years old) patient had right hemiplegia, motor aphasia and conjugate eye deviation. He was intervened with IV tPA at the third hour. Diffusion weighted imaging (DWI) demonstrated a acute ischemic lesion in the MCA territory (A). Digital subtraction angiography (DSA) demonstrated M3 cutoff (arrow)(B-1). Patient was treated with 6 mg intra-arterial tPA and achieve recanalization on final angiogram (B-2).

In practice, it is generally accepted that endovascular treatment of the distal arteries can be technically more challenging due to the distal thrombus location and the tortuosity of the procedure. Moreover, these small vessels are potentially very fragile. The interventionist must pay particular attention to the risks of vessel perforation and haemorrhagic complications. Nevertheless, the number of endovascular treatments for acute ischemic stroke is increasing. Due to technological advancements and increasing experience in endovascular therapy, interventionalists are more willing to treat distal vessel occlusions. However, the effectiveness and safety of endovascular treatment for distal occlusions have not been clearly demonstrated. Specifically, there is little information about the safety and efficacy of reperfusion therapies for distal occlusions. In addition, there are no data on the specific context of endovascular treatment for M3 occlusions. The IMS-III trial (Interventional Management of Stroke III) reported five cases receiving endovascular treatment for occlusions involving M3, M4, or ACA. ⁷ In addition, the MR CLEAN trial (Multicenter Randomised Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands) reported three cases in which ACA occlusions were treated. However, this study did not describe patients with M3 occlusions. ¹ Yue Wan et al. reported two cases of M2/3 artery occlusions, which were successfully managed with endovascular treatment. ¹¹ Most endovascular trials have included patients with proximal occlusions. Due to the current lack of data on the effectiveness of endovascular treatment, its safety has not been clearly demonstrated for M3 occlusions.

It is important to emphasise that the number of patients with clinically severe M3 occlusions (NIHSS) in this study was higher than expected for typical isolated M3 occlusions. Further, some patients with isolated M3 occlusions had more severe clinical situations than patients with proximal occlusions. For example, M3 occlusion can cause different combinations of symptoms, including hemiplegia, hemianopia, aphasia and neglect because of involvement of the strategically important motor area. Possible reasons for admitting patients with this M3 occlusion to the angio unit were that we diagnosed large vessel occlusion clinically and did not use CT/MR angiography for neuroimaging before the endovascular procedure. Many of these cases included primary M3 occlusions, while other cases involved rescue endovascular treatment for intraprocedural distal embolisation during the treatment of primary proximal occlusions. In this study, the functional outcomes of patients with primary M3 occlusions on the 90th day were considerably better than their initial NIHSS scores. In addition, the 90-day functional outcomes of patients with rescue M3 occlusions were worse than those with primary M3 occlusions. We believe that collateral status was associated with the favourable clinical outcomes before the administration of reperfusion therapies in the cases of primary M3 occlusion.

Although primary M3 occlusions are important, there is also a potentially significant role of rescue M3 occlusion thrombectomy as a result of MCA or ICA thrombectomy. Several clinical studies, such as DEFUSE-3 (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) and DAWN (DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes Undergoing Neurointervention With Trevo), have shown that there is a need to revascularise distal vascular emboli after proximal vessel thrombectomies.^12,13 Similarly, the functional outcomes in this study were considerably better for rescue M3 occlusions.

Our study shows that endovascular treatment is safe for patients with primary M3 occlusions. The rate of ICH was 3.8% (none = 1). The range of symptomatic haemorrhage was 2% to 8% in the landmark endovascular clinical trials. This ICH due to extravasation, which was present in only one patient, was asymptomatic, and the patient's neurological examination one month later was normal (Figure 3). In addition, none of our patients with primary occlusions died during the three-month follow-up. While our ICH rate was 7.7% for rescue M3 occlusions, the three-month mortality rate of these patients was 23.1%. It is important to note that both the ICH and death rates in our rescue M3 occlusion cases were significantly higher than in cases of primary M3 occlusions. The possible causes were initial proximal vessel occlusion (decreased collateral support), the time-dependency effect of endovascular treatment for primary M3 occlusions and the fact that the recanalisation of rescue M3 occlusions occurred one hour later on average. Additionally, there was no serious systemic haemorrhaging, such as gastrointestinal or urinary tract haemorrhaging, in the cases with M3 occlusions in this study.

Figure 3.

Diffusion weighted imaging (DWI) demonstrated a acute ischemic lesion in right perisylvian area of the MCA territory (A). Digital subtraction angiography (DSA) demonstrated M3 cutoff (arrow)(B-1). Patient was treated with stent-retriever placement. Also, the dissection and vasospasm was observed after thrombectomy (B-2). Contrast extravasation in the right hemisphere on control tomography (C).

Jonathan et al. demonstrated that endovascular treatment in distal and more tortuous arteries is safe. However, studies have not considered interventions for distal artery occlusions, specifically endovascular interventions of M3 occlusions.^6,8,14,15 Our recanalisation rate was 100% for primary M3 and rescue M3 occlusions. In other studies, this rate has been around 80%.^4,6,11 We think that the high rate of recanalisation in our study is due to the fact that the procedure was performed by same experienced endovascular interventionists. For example, entrapment of the thrombus and M3 thrombectomy were performed in the same session for a patient with mobile thrombus (embolic) material in the distal right CCA (Figure 4).

Figure 4.

Diffusion weighted imaging (DWI) demonstrated a scattered lesion in the MCA territory (A). Digital subtraction angiography (DSA) demonstrated M3 cutoff (B-1). Full reperfusion was achieved with thrombectomy (B-2). The patient also had movable thrombus (embolic) material was presented in the bifurcation in the distal of the right CCA (C-1). Clot trapped and recanalization was achieved by placing a self-expandable stent.

Patients undergoing thrombectomy and intraarterial alteplase were also studied in the CHOICE randomised clinical trial, and the combination yielded excellent results. ⁹ It is important to note that our M3 occlusion series demonstrated improved recanalisation and clinical outcomes using the IA-tPA as well as stent retrievers. In addition, long-sheath, flowgate balloon-guide and intermediate catheters were not used in these cases. Thus, our procedure was cost-effective and required less time.

A careful risk–benefit assessment should be performed prior to the treatment of M3 occlusions. Because the M3 segment of the middle cerebral artery is more distal than its proximal counterparts, the vessel wall is smaller and thinner and more tortuous. Moreover, the M3 segment of middle cerebral artery represents a small tissue territory. However, M3 occlusions of the middle cerebral artery, including the frontal and angular branches, may result in severe neurological deficits. Hence, we recommend endovascular therapy for selected patients with supply areas of functionally significant parenchyma. Notably, we recommend that local IA-tPA be given first, and then mechanical thrombectomy with a small-calibre stent retriever can be used if it does not recanalise for patients with M3 occlusions.

This study has several limitations, including the relatively small sample size, its retrospective design and the fact that only two centres were involved. Moreover, we did not have a control group of medically treated M3 occlusions. The results of our study highlight the need for larger series studies on endovascular treatment for M3 occlusions.

Conclusions

This retrospective study demonstrates that endovascular treatment of M3 occlusions is safe, effective and reliable.