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J Neurosonol Neuroimag > Volume 16(2); 2024 > Article
Safouris, Palaiodimou, Magoufis, Kargiotis, Psychogios, Theodorou, Sidiropoulou, Frantzeskaki, Mantatzis, Spiliopoulos, Nardai, and Tsivgoulis: Safety and Efficacy of Endovascular Therapy in Distal Vessel Occlusions

Abstract

Endovascular therapy (EVT) is strongly indicated for acute ischemic stroke (AIS) caused by large vessel occlusion (LVO) in the anterior and posterior circulation according to international recommendations, but the benefit is unclear for AIS patients with distal vessel occlusions (DVO) since these patients were systematically excluded from the vast majority of randomized controlled clinical trials (RCTs) establishing the safety and efficacy of EVT. Observational data from multiple registries appear promising but also highlight numerous challenges: identification of DVO is not straightforward and may necessitate advanced imaging, potential clinical benefits from the intervention are more limited than in LVOs since DVO patients present with milder deficits, recanalization of smaller caliber arteries is technically challenging and associated with greater risk for complications namely symptomatic intracranial hemorrhage and vessel perforation. There are multiple ongoing RCTs evaluating the safety and efficacy of EVT in AIS patients with DVOs in Europe, North America and Australasia. In view of the former considerations the current narrative review aims to present the different approaches to define DVO, summarize the epidemiology and natural history of DVO under best medical treatment, outline the diagnostic utility of different imaging modalities and critically address the observational data on the benefits and risks of EVT for DVO, with a special focus in M2 middle cerebral artery occlusions. Finally, we will also discuss the design and methodology of ongoing RCTs that will provide definitive data on the safety and efficacy of EVT for AIS patients with DVO.

INTRODUCTION

Endovascular treatment (EVT) for acute ischemic stroke (AIS) has been established as a highly effective treatment for patients with large vessel occlusion (LVO) significantly improving outcomes and survival.1-4 Landmark randomized-controlled clinical trials (RCTs) have demonstrated the efficacy and safety of EVT in both the anterior and posterior cerebral circulation, in prolonged time windows and extended established brain infarctions. For every 100 LVO patients treated with EVT, 17 more patients will have a better functional outcome compared to best medical treatment, and 6 lives will be saved.5 This overwhelming treatment benefit has incited off-label treatment for more distal occlusions, facilitated by rapid advances in stent-retriever and thromboaspiration catheter technology permitting access to distal vessel occlusions (DVO) in smaller caliber arteries.
DVO refers to intracranial arterial occlusions amenable to endovascular treatment, excluding LVO such as the terminal internal carotid artery (ICA), M1 segment of the middle cerebral artery (MCA), basilar artery (BA), or vertebral artery (VA) occlusions that impair BA flow. While there is no universally accepted definition, DVO generally includes occlusions in smaller, more distal branches of the cerebral circulation, which play a critical role in perfusion and are increasingly recognized as therapeutic targets in stroke care.
However, the persistence of EVT benefits to distal and medium vessel occlusions remains uncertain due to a lack of RCTs specifically targeting this subgroup. The current AHA/ASA (American Heart Association/American Stroke Association) guidelines consider EVT reasonable for carefully selected patients with AIS within 6 hours of symptom onset and who have causative occlusion of the M2 or M3 segments of the MCA as well as of the anterior cerebral arteries (ACA), VA and posterior cerebral arteries (PCA) (level IIb).2 The ESO/ESMINT (European Stroke Organisation– European Society for Minimally Invasive Neurological Therapy) guidelines suggest that EVT is reasonable for M2 occlusions but fail to provide recommendation regarding occlusions involving the M3-M4 segments of the MCA, the ACA, or the PCA.1 Consequently, our current understanding of EVT’s safety and efficacy in this context is based predominantly on observational studies and subgroup analyses of RCTs that included a minority of patients harboring DVO.
In view of the former considerations the current narrative review aims to present the different approaches to define DVO, summarize the epidemiology and natural history of DVO under best medical treatment, outline the diagnostic utility of different imaging modalities and critically address the observational data on the benefits and risks of EVT for DVO. Finally, we will also discuss the design and methodology of ongoing RCTs that will provide definitive data on the safety and efficacy of EVT for AIS patients with DVO.

DEFINITION

It is widely accepted that LVOs comprise occlusion of the ICA (mean diameter 3.8 mm), M1 segment of the MCA (2.7 mm) and the BA (3.2 mm).6-8 These are the occlusion sites for which EVT has been proven safe and effective. Occlusions of the M3 MCA or more distal MCA branches, A2 anterior cerebral artery (ACA) or more distal ACA branches, P2 or more distal PCA branches and the cerebellar arteries (superior, anterior inferior and posterior inferior cerebellar arteries [SCA, AICA, PICA]) are considered distal.
The definition of M2 segments within the MCA is complex due to anatomical variability, as the MCA can bifurcate, trifurcate, or give rise to multiple branches resembling a candelabra.9 Among various proposed methods, the simplest definition identifies M2 as the segments originating at the bi- or trifurcation of the M1 trunk. However, this bi/trifurcation-based classification does not distinguish between proximal and distal M2 segments, a limitation relevant for clinical practice and research. Seminal clinical trials of EVT in the anterior circulation largely excluded or underrepresented M2 occlusions, defining them based on M1 branching patterns (Table 1). Notably, despite M2 occlusion being an exclusion criterion in many trials, some patients with M2 occlusions were inadvertently included and later confirmed through central adjudication. The HERMES meta-analysis, pooling data from individual patient-level studies, included these cases and demonstrated a consistent benefit of EVT in M2 occlusions. M2 occlusions were further subclassified into proximal (located up to the mid-sylvian point) and distal occlusions. Of the cases analyzed, 116 were proximal M2 occlusions, while only 14 were distal, highlighting the predominance of proximal occlusions in EVT trials.10 Despite significant benefits for proximal M2 occlusions for the primary outcome (mRS 0–2 at 3 months; Odds ratio 2.7, 95% CI 1.13–6.37, p=0.03), the extremely low number of distal M2 occlusions precluded any attempt of statistical analysis. It thus becomes clear that randomized data for M2 occlusions favor EVT but only for proximal M2 occlusions. In conclusion, randomized data support treating M2 occlusions up to the mid-sylvian point as LVO and occlusions distal to mid-sylvian point should be considered DVO.
To accommodate these anatomic variations, an international consensus statement has set apart proximal vessel occlusions (PVOs) or LVOs to DVOs or medium vessel occlusions (MVOs) by using distance-tortuosity and a vessel diameter cut-off of 2mm.11 For example, in Fig. 1, time of flight magnetic resonance angiography of a 61-year-old female patient presenting with TIA reveals a bifurcation 5 mm from MCA origin on the left (white arrow) and 30 mm on the right side (black arrow). The proximal bifurcation of the left MCA stem produces two M2 segments, medium in diameter but proximal; an occlusion of such an artery would lead to a proximal, medium vessel occlusion and management should be indistinguishable from LVO. Contralaterally, an M2 occlusion would lead to an M3-like, thus distal, medium vessel occlusion, and decision for EVT should be individualized. Despite its comprehensive approach, there are practical difficulties in measuring arterial diameters in an acutely occluded M2 branch during an emergent procedure. In addition, “proximal, medium vessel occlusion” is a novel category comprising mostly proximal M2 branches, complicating rather than clarifying treating decisions in the emergency setting.
An alternative approach by a single-center group proposed the term MeVO (medium vessel occlusion) for M2-M3, A2-A3 and P2-P3 occlusions with substantial clinical deficit, either (a) National Institutes of Health Stroke Scale (NIHSS) 5 or more or (b) NIHSS<5 with a disabling deficit.12 We find that this definition is less likely to be widely adopted for two reasons: first it introduces a clinical criterion (NIHSS scale) that complicates classification and, second, makes no distinction of proximal versus distal M2 occlusions.

PRIMARY VERSUS SECONDARY OCCLUSION

DVOs can be further categorized into primary or secondary. Secondary DVOs result from the dissolution of an LVO, which can occur spontaneously or as a complication of IVT or EVT. DVOs may either affect brain areas not previously compromised by ischemia typically due to clot fragmentation, or within the initial ischemic area leading to suboptimal reperfusion.11 A dreaded complication of EVT during the retraction of an M1 thrombus is its distal embolization to ACA, leading to increased mortality and disability.13 Although EVT may be technically feasible and effective in treating iatrogenic DVOs, the risks are not fully understood, and more passes during thrombectomy can increase the risk of blood-brain barrier disruption, symptomatic intracranial hemorrhage (sICH), and poor outcomes.14 The current review will only consider primary DVOs.

DVO EPIDEMIOLOGY

In the Screening Technology and Outcome Project in Stroke (STOP Stroke) study consecutive AIS and transient ischemic attack (TIA) patients underwent CT angiography (CTA).15 Vascular occlusion was found in 41% of strokes and TIAs combined. Of these, most (26%) harbored LVOs (ICA, M1 and BA), 20% had M2 MCA occlusions and 6% had DVO: A1 (0.3%), A2 (1.0%), vertebral artery (VA; 2.4%), P1 PCA (1.2%), P2 PCA (1.3%).
A more comprehensive study on DVO frequency is based on the French Dijon Registry; 29% of ischemic stroke cases presented with visible arterial occlusion mainly on CTA but also on MRA, transcranial doppler or DSA.16 Among these patients 58% presented with LVO: extracranial ICA, tandem occlusions, terminal ICA, M1, M1-M2 and BA. The rest 42% had DVO: M2 (18%), M3/M4 (6%), ACA (3%), PCA (7%), VA (7%), PICA (0.4%), SCA (0.4%)
In the German Registry 25% of AIS stroke patients presented with LVO: M1 (15%), ICA (9%) and BA (1.5%). 17% of patients presented with DVO; of note, all M2 occlusions were included in this group: M2 (9.6%), M3 (2.9%), VA (3%), P1 PCA (2.2%), P2 PCA (1%), A1 ACA (0.2%), A2 ACA (1.5%).17 Notably, the authors comment that some DVOs were probably missed by imaging since only 22% received CT perfusion (CTP). This is a critical point since DVO prevalence depends not only on patient group (confirmed AIS versus possible stroke, including or not TIAs) but also on imaging protocol.

DVO DETECTION

Using single-phase CTA in the acute setting may miss up to 20% of vascular occlusions in the anterior circulation, mostly M2 occlusions.18 In the prehospital triage of patients with suspected stroke (PRESTO) study, sensitivity for DVO detection was suboptimal: 36% of M2 MCA, 71% of A2 ACA, all A3 ACA and M3 MCA, 80% of intracranial VA and 20% of P2 PCA occlusions were missed in the acute setting.19 Experienced neuroradiologists and image manipulation using maximum intensity projection coronal, sagittal or axial volume-rendering may improve the diagnostic accuracy. Multiphase CTA completes the arterial phase with early and late venous phase acquisition, necessitates no post-processing of images nor additional iodinated contrast injection and has been proposed to assess collateral network and aid in patient selection especially in more prolonged time windows.20 Another advantage of the technique is that it shows increased sensitivity for DVO detection.21 Color-coded multiphase CTA maps using an automated image-analysis software package (FastStroke research prototype; GE Healthcare, Milwaukee, WI, USA) may increase sensitivity.22 Artificial intelligence models have been proposed to further improve DVO detection,23 but sensitivity remains moderate.24,25 Data derived from multiphase CTA may also be used to construct perfusion maps of the brain.26 Automated systems may still not outperform neuroradiologists for detecting DVO occlusion. However, the fact that they may confirm or refute initial diagnostic hypotheses and thus influence clinical decisions is important, especially since software is “blind” to the patient’s neurological deficit and thus, may perform a non-biased analysis.27
By producing maps of contrast delay, CTP points to the area of arterial occlusion and thus aids in the rapid detection of DVO. Adding CTP to CTA in the acute stroke setting increased the sensitivity for detecting distal occlusions from 52% to 77% and reduced the time needed by the examiners to reach the diagnosis since they may focus their attention on the arterial branch providing blood to the underperfused area.28

DVO NATURAL HISTORY

DVO cause milder symptoms and carry better prognosis than LVO. However, the outcomes of many patients with DVO remain dismal even after the delivery of intravenous thrombolysis (IVT). Data from 2 multicenter prospective cohort studies of IVT up to 12 h after symptom onset based on CTA, the INTERRSeCT (The Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography) and the PRoveIT (Precise and Rapid Assessment of Collaterals Using Multi-Phase CTA in the Triage of Patients With Acute Ischemic Stroke for IA Therapy) were pooled to study the effect of IVT in DVO patients (M2 MCA, M3 MCA, A2 ACA, A3 ACA, P2 PCA, or P3 PCA segment occlusion) not treated with EVT.29 One out of two patients had a modified Rankin Scale (mRS) of 2 or greater at 90 days with best medical therapy (BMT) and one out of three were functionally dependent (mRS-scores of 3-6) at three months.29 One out of 20 patients had a stroke recurrence and one out of eleven was dead at 3 months. Recanalization on follow-up imaging was strongly associated with favorable outcomes but was only confirmed in one out of two patients treated with IVT.29 In a multicenter study monitoring IVT with transcranial Doppler, distal occlusions had greater odds of early recanalization after IVT than proximal occlusions, but still, the majority of distal MCA occlusions did not recanalize (44% recanalization). 30 Notably, earlier onset-to-treatment times are associated with faster and more effective recanalization in AIS patients with LVO and DVO receiving IVT and undergoing continuous TCD-monitoring to detect recanalization in real-time.31

OBSERVATIONAL DATA FOR EVT SAFETY AND EFFICACY IN DVO

There have been many observational studies examining the safety and efficacy of EVT in AIS patients with DVO. A recent systematic review included 14 non-randomized and 2 randomized studies comparing EVT to BMT in DVO attributed acute ischemic stroke patients.32 After adjustment for potential confounders, EVT showed significantly better odds of functional independence than BMT, but without significant differences in excellent functional outcomes and mortality. Subgroup analysis showed higher sICH rates in low-NIHSS (<6) patients and a subsequent sensitivity analysis, excluding 3 studies encompassing patients with mild strokes, showed significantly higher odds of excellent functional outcomes with EVT but without significant differences in the outcomes of functional independence, sICH and mortality. However, most included patients presented with M2 MCA occlusions without distinction between proximal and distal occlusions, whereas the same limitation is reproduced in other systematic reviews.33 This is a crucial point since EVT for proximal M2 MCA occlusions is probably beneficial, as previously discussed, and M2 MCA occlusions should be considered as LVO and thus be excluded from RCTs for DVO. In a single observational study that excluded all M2 occlusions, there were no significant differences between EVT and BMT in terms of disability (mRS ordinal shift), rates of excellent outcomes, or mortality; multivariable logistic regression analyses also confirmed these findings.34 Data from the multicenter prospective French registry ETIS (Endovascular Treatment for Ischemic Stroke) showed successful reperfusion in 85% of treated patients with distal M2 MCA occlusions, low sICH rates of 5%, relatively low rates of favorable outcome in 46% of patients and mortality in 17%; the investigator also performed a meta-analysis of observational studies of distal M2 MCA occlusions but results were limited by extreme heterogeneity in the definitions of the distal M2 MCA segment.35
A recent meta-analysis for PCA AIS revealed that while EVT may be effective in alleviating disabling deficits, the odds for functional independence were not significantly different to BMT, while EVT was associated with higher odds of sICH. These findings were corroborated by a large propensity score matched analysis of real-world data from the National Inpatient Sample of the United States: EVT compared to BMT was associated with lower rates of good discharge outcomes, higher rates of in-hospital mortality, and higher rates of ICH and subarachnoid hemorrhage in AIS patients with PCA occlusion.36
In a propensity-matched case-control study of the Treatment for Primary Medium Vessel Occlusion Stroke (TOPMOST) that represents an international, retrospective, multicenter, observational registry for DVOs, the investigator documented similar efficacy and safety outcomes for primary isolated ACA occlusions of the A2–A4 segments in patients treated with EVT and BMT. However, improved reperfusion was associated with favorable functional outcome in the EVT cohort.37
One of the less well-studied non-LVO is isolated VA occlusions that do not impede flow to the BA; such occlusions are proximal to the basilar artery and as such, characterizing them as “distal” is a misnomer. The Best revascularisation approach for posterior circulation strokes with isolated vertebral artery occlusion (BRAVO) study, a retrospective, observational, international multicentre registry, revealed significantly worse outcomes for patients treated with EVT compared to BMT.38,39 These findings, largely attributable to higher rates of ischemic early neurological deterioration and sICH, are against EVT for isolated VA occlusions that do not impede BA flow.

TECHNICAL CONSIDERATIONS FOR EVT IN DVO

The mounting observational evidence indicates a less favorable risk-benefit balance of EVT in DVO as compared to LVO. There are several reasons that might explain this discrepancy. First, detecting a DVO may require advanced neuroimaging and consideration of multiple factors, delaying treatment times.40
Second, distal arteries of lower caliber may not accommodate distal access catheters (DAC) and insufficient catheter length limits advancing the triaxial system (balloon guiding catheter; BCG, DAC and stent retriever) that is considered optimal set up for LVOs.41 In the setting of DVOs, using a BGC resulted in lower successful recanalization rates and longer procedural times but was also associated with a lower risk of distal embolization.42 The risk of vasospasm, dissection and hemorrhagic complications may also increase.43-45 Vessel perforation with active extravasation during EVT is reportedly twice as frequent after DVO EVT (2.4%) compared to LVO (1%); mortality after perforation was 50% at 3 months (Figs. 2 and 3).46
Hemorrhagic risks of EVT for DVO is demonstrated in the case of a 69-year-old man presented with right hemiparesis and aphasia (NIHSS-score 15 points) at 190 min after last-seen-well. Non-contrast CT showed an Alberta Stroke Program Early CT Score (ASPECTS) of 10 and CT angiography revealed a left distal M2-M3 MCA occlusion (Fig. 2A and 2B, white arrows). The patient was treated with intravenous thrombolysis using tenecteplase (0.25 mg/kg). Perfusion imaging revealed a limited area of 7 cc of tissue-at-risk without established infarction involving the motor cortex (Fig. 2A). The patient showed no clinical improvement and was further treated with endovascular therapy. DSA with injection of left ICA (lateral projection): the hypo-perfused area marked with red shaded area (Fig. 2B). Superselective injection of distal M1 (lateral projection): occlusion of distal M2-M3 branch of the superior trunk (red arrow) (Fig. 2C). After 2 attempts with a stent-retriever, recanalization of M2-M3 branch (white arrow) and Thrombolysis in cerebral infarction (TICI) 2b score was achieved. (Fig. 2D). No contrast extravasation was observed during the procedure. However, NCCT immediately after EVT revealed extensive right hemispheric subarachnoid hemorrhage and PH2 hematoma, possibly due hemorrhagic transformation or avulsion of the small perforators during stent retrieval (Fig. 2E). The patient received tranexamic acid intravenously but had rapid neurological deterioration and was intubated. Two hours later, NCCT showed a marked extension of the intracranial hemorrhage (Fig. 2F). The patient died two days later.
However, not all intracranial hemorrhages are symptomatic, as shown in the case of a 79-year-old woman that presented with left hemiparesis and left homonymous hemianopia (NIHSS score 8 points) at 505 min following symptom onset. Non-contrast CT revealed an ASPECTS of 7 and CT angiography showed a proximal right M2 Middle Cerebral Artery occlusion. Endovascular therapy was initiated at 543 min following symptom onset and achieved complete recanalization (TICI 3) at 32 min following groin puncture but microcatheter injection resulted in extravasation on DSA (Fig. 3A–3C). Post-EVT CT showed subarachnoid hemorrhage (Fig. 3D). Despite this complication, the patient had a favorable outcome and was discharged three days later with a NIHSS of 2. Her modified Rankin Scale score at 3 months was 1.
Since DVO patients have a more favorable natural course of disease with BMT compared to LVOs,29 it becomes clear that this complication weighs more in the risk-to-benefit ratio. There have been several suggestions as to the mechanism behind the perforation of vessels by microwires, microcatheters moving in vessels with small diameters, and retraction of stent retrievers/aspiration catheters. Mechanical shear stress caused by retraction of stent retrievers/aspiration catheters causes perforator branches to rupture or a pre-existing atherosclerotic lesion causes the main vessel to rupture. Intense aspiration within a non-occluded segment on an intracranial artery might lead to luminal collapse and consecutively inadvertent shear forces at the vessel wall, which might increase the risk of vessel perforation.47 Perforation rates of 8% for A2 ACA and 9% for M3 MCA occlusions have been reported in a multicenter retrospective study; they were associated with worse rates of recanalization, worse functional outcomes and higher mortality.48 Whether to choose first-line aspiration or stent-retriever or the combined approach is still a matter of debate. In a systematic review of mostly retrospective observational studies involving mainly M2 MCA occlusions, the combined approach resulted in higher rates of successful recanalization and functional independence at the cost of higher rates of subarachnoid hemorrhage.49
Third, the more distal the artery the smaller the volume of tissue-at-risk, thus the lesser potential clinical benefit from early reperfusion. Fourth, many interventionalists prefer general anesthesia to improve the quality of roadmap to access distal clots; despite equivalent outcomes with conscious sedation in the setting of LVOs, the prolonged procedural times and the potential deleterious effects of transient hypotension during the induction of anesthesia in the setting of DVOs requires further investigation.33
Fifth, mini stent retrievers with diameters ranging from 2.5 to 3 mm compared to 4–6 mm of early stent retrievers, 50-53 low-profile aspiration and distal access catheters54,55 and long microcatheters56 have been developed in recent years for DVOs but randomized data on their safety and efficacy is lacking. Novel techniques such as the blind exchange/mini-pinning or the QUATTRO technique may increase first-pass recanalization rates and lower hemorrhagic complications.57,58

EFFICACY OF EVT IN DVO WITH MINOR STROKE

EVT appears equivalent to BMT for patients with anterior circulation LVO AIS with low (≤6) baseline NIHSS scores, despite the increased risk for sICH according to a recent meta-analysis of available observational data.59 Consequently, the safety and efficacy of EVT in LVO patients with minor AIS has not been established. Moreover, the treatment effect of EVT in proximal versus distal occlusions was substantially different in a recent systematic review and meta-analysis: EVT was associated with a significantly lower rate of functional independence in patients with distal M2 MCA occlusions as compared to BMT.60 A similar treatment modification effect of clinical severity at presentation was recently reported for AIS with PCA occlusions, with patients with NIHSS-scores≤6 having higher rates of functional dependence and mortality when treated with EVT compared to BMT.61 Currently, both RCTs evaluating the safety and efficacy of EVT in patients with LVO and NIHSS<6 (ENDOLOW, ClinicalTrials.gov Identifier: NCT04167527 and MOSTE, ClinicalTrials.gov Identifier: NCT03796468) exclude patients with M2 MCA occlusions as well as DVO.

PATIENT SUBGROUPS THAT ARE MORE LIKELY TO BENEFIT FROM DVO EVT

Despite abundant individual case reports shared on social media platforms of angiographic images of fully recanalized DVOs, often devoid of significant scientific merit or educational value, it remains to be seen whether current clinical trials will solve the clinical equipoise of the safety and efficacy of EVT in DVO.62 Until their results are published, data from carefully designed observational studies suggest some subgroups of DVO patients are more likely to benefit from intervention. A recent study of 140 patients with M2 occlusions treated with EVT reported a significant treatment effect between recanalization and computed tomography perfusion-derived lesion volumes was observed in patients with >150 mL hypoperfusion volume (adjusted odds ratio, 1.02 [95% CI 1.00–1.03]; p=0.007) or >125 mL penumbral volumes (adjusted odds ratio, 1.02 [95% CI 1.01–1.03]; p=0.005), as well as for baseline ischemic core volume within the range of 15 to 40 mL (adjusted odds ratio, 1.11 [95% CI 1.01–1.22]; p=0.03). These preliminary findings highlight the need for more research to define perfusion parameter thresholds for tissue-at-risk, ischemic core definitions and hemorrhagic risk in distal occlusions.63 Equally importantly, this study showed treatment benefit in younger patients presenting with more severe deficit (NIHSS>10), emphasizing the importance of baseline characteristics and stroke severity at presentation for patient selection.

ONGOING RCTS INVESTIGATING THE SAFETY AND EFFICACY OF EVT IN DVO

There are 5 ongoing RCTs that were designed to robustly assess the safety and efficacy of EVT compared to BMT in AIS patients with DVO (Table 2). These trials need to overcome the challenges of EVT in patients with DVO including the limited net clinical benefit per patient and increased risk of complications compared to LVO, uncertainty about the definition of favorable clinical and angiographic outcomes and uncertainty regarding the inclusion of proximal M2MCA occlusions or not.64
The DISTAL trial (Endovascular Therapy Plus Best Medical Treatment [BMT] Versus BMT Alone for Medium Vessel Occlusion Stroke), aims to randomize AIS patients with DVO and NIHSS-score of ≥4 points; DVO detection will be based on CT/CTA or MR/MRA (perfusion imaging will be optional for some centers).65 The M2 MCA segment will be considered co-or non-dominant if it perfuses less than half of the M1 MCA territory (<100 cc of brain tissue on perfusion imaging for those sites that use perfusion imaging) or if the occluded M2 segment is smaller than the non-occluded M2 on DSA. Patients with co-dominant and non-dominant MCA occlusions will be included in the trial.
The ESCAPE-MeVO (Endovascular Treatment to Improve Outcomes for Medium Vessel Occlusions) trial, randomized AIS patients with DVO presenting with NIHSS-scores≥6 points or NIHSS-scores of 3–5 points with disabling neurological deficits to EVT and BMT.66 Patients will be eligible for randomization if imaging suggests salvageable brain tissue, depending on the imaging modality of the participating site: for CTA, whether multiphase or single phase, at least some collaterals have to be visible; CT perfusion indicating core/penumbra mismatch; or MR with or without perfusion. Proximal M2 occlusions, defined as MCA segments up to 1 cm distal to the MCA bifurcation/trifurcation, will be included. Apart from the standard clinical outcomes measured using mRS-score, scales of health-related quality of life (EQ-5D-5 L) and Lawton scale of instrumental activities of daily living score will be assessed at 3 months to overcome limitations of mRS-score. The rationale for measuring this score in DVO patients is that cortical neurological deficits (abulia, alexia, agraphia, quadranopia), as sometimes are seen in this subgroup of stroke patients, are hard to capture with the NIHSS and mRS scores. However, even if these scales may succeed in detecting changes in subjective quality of life (e.g., reduced anxiety, better ability to perform specific tasks), these deficits may not always correlate with substantial functional independence improvements. Even if statistically significant improvements could be demonstrated, it remains unclear whether the incremental improvements captured by more sensitive scales lead to substantial benefits regarding functional independence, return to work, or other important aspects of life to justify the use of a resource-intensive and potentially risky procedure like EVT for DVO. In other words, the health economics and ethical considerations of treatment must balance the potential for improved quality of life with the cost, procedural risks, and resource allocation in stroke care.67
The FRONTIER-AP (Randomized Controlled Trial of the Clinical Outcome and Safety of Endovascular Versus Standard Medical Therapy for Stroke With Medium Sized Vessel Occlusion) trial, is an Australian-led international clinical trial that will randomize AIS patients with DVO presenting with NIHSS-score of ≥5 points or 1–5 points with dysphasia to EVT or BMT.68 As the authors acknowledge that superiority of the EVT will impose significant restructuring of acute stroke care, they have designed an implementation phase, incorporating statistical analysis, health economics analysis, operational research and geospatial analysis. Patients with M2 MCA occlusions beyond the bifurcation/trifurcation will be included in this trial.
The DISCOUNT (Evaluation of Mechanical Thrombectomy in Acute Ischemic Stroke Related to a Distal Arterial Occlusion) is a French clinical trial that randomizes AIS patients with DVO presenting with NIHSS-scores of ≥5 points; only distal M2 occlusions (distal to the mid-height of the insula) will be included.69 As part of the trial, a cost/effectiveness ratio analysis will be performed.
The DISTALS (Distal Ischemic Stroke Treatment With Adjustable Low-Profile Stentriever) trial will randomize AIS patients with DVO presenting with NIHSS-scores of ≥4, or NIHSS-scores 2–3 due to aphasia and/or hemianopia. DVO is defined as any occluded distal vessel with diameter ≥1.5 mm as measured on CTA or MRA.70 Occlusions of dominant M2 branches will be excluded and advanced neuroimaging protocols will be used to include patients with favorable profile (perfusion lesion volume ≥10 cc on CT or MR perfusion and ischemic core lesion in ≤50% of the perfusion lesion volume).
Finally, the Combined Thrombectomy for Distal MediUm Vessel Occlusion StroKe (DUSK; ClinicalTrials.gov ID NCT05983757) trial has been suspended due to the slow recruitment and progress.

CONCLUSIONS

EVT has revolutionized LVO treatment and has rapidly proven to be effective in prolonged time windows, posterior circulation and large-core ischemia. This by no means proves that the next frontier, distal occlusions, will be promptly crossed. Lower clinical gains and increased risk of complications limit the net gain per patient and large RCTs or individual patient data meta-analyses from multiple RCTs may be needed to prove statistically significant benefits. However, DVO still affects a considerable number of stroke patients and IVT represents a partially effective treatment for these patients. Industry swiftly provided interventionalists with novel devices that promise to reduce complications for vessels of smaller diameter, but their improved profile remains to be tested in the ongoing RCTs. In the meantime, clinicians should probably treat patients with proximal (to the mid-Sylvian point) or dominant M2 occlusions with severe clinical deficit as LVOs, whereas distal occlusions with mild neurological deficit (NIHSS<6) should probably be treated with BMT or randomized if possible in the ongoing RCTs. These trials may eventually change the current treatment landscape, expanding EVT indications and providing a novel challenge for systems of care to expand EVT capabilities within stroke networks.

NOTES

Ethics Statement
A written informed consent was obtained from the patient or their families for their information on demographic data, medical condition, images, treatment, and outcome anonymously.
Availability of Data and Material
This is not applicable to this type of manuscript as it does not contain raw data.
Author Contributions
Apostolos Safouris, Lina Palaiodimou and Georgios Tsivgouli drafted the manuscript. Georgios Magoufis and Sandor Nardai provided the images included in the manuscript. Odysseas Kargiotis, Klearchos Psychogios, Aikaterini Theodorou, Tatiana Sidiropoulou, Frantzeska Frantzeskaki, Michail Mantatzis, Stavros Spiliopoulos, and Georgios Tsivgoulis provided critical comments and revisions. All authors reviewed the manuscript and approved the final version for submission.
Sources of Funding
None.
Conflicts of Interest
No potential conflicts of interest relevant to this article was reported.

Acknowledgments

None.

Fig. 1.
Illustrative case in which occlusion of M2 branches in the same patient would qualify as large vessel occlusion on the left and distal vessel occlusion on the right.
jnn-2024-00161f1.jpg
Fig. 2.
A case of detrimental symptomatic intracranial hemorrhage post EVT for DVO.
jnn-2024-00161f2.jpg
Fig. 3.
Parenchymal hemorrhage type 2 in a successful EVT of a right M2 middle cerebral artery occlusion.
jnn-2024-00161f3.jpg
Table 1.
Definitions of M2 Middle Cerebral Artery in Randomized Controlled Clinical Trials evaluating the safety and efficacy of endovascular therapy in acute ischemic stroke patients with large vessel occlusions of the anterior circulation
Trial, year M2 definition Number of patients with M2 Number of patients with DVO
MR CLEAN, 2014 - 39/499 A1/A2, 3/499
ESCAPE, 2015 from the site of bifurcation or trifurcation to the origin of the cortical branches 9/310*
EXTEND IA, 2015 - 10/70
SWIFT PRIME, 2015 Distal to the first bifurcation or trifurcation 18/191*
REVASCAT, 2015 First-order branch of the main trunk of the middle cerebral artery 18/203*

DVO, distal vessel occlusions.

* Centrally adjudicated; isolated M2 was an exclusion criterion of these trials.

Table 2.
Randomized controlled clinical trials evaluating the safety and efficacy of endovascular therapy (compared to best medical therapy) in acute ischemic stroke patients with distal vessel occlusions
Trial name Trial NCT Phase Sample* NIHSS-score M2MCA Time from last-known-well Imaging criteria EVT devices used
DISTAL 5029414 III 526 ≥4 points Inclusion of co-dominant or non-dominant M2MCA <24 h 6-24h: FLAIR-DWI mismatch Multiple
DISCOUNT 5030142 III 488 ≥5 points Inclusion of distal M2 occlusions (distal to the mid-height of the insula) <6 h Multiple
DISTALS 5152524 II 118 ≥4 points or Inclusion of co-dominant or non-dominant M2MCA <24 h Perfusion lesion >10 mL and Core <0.5 of perfusion lesion volume Single
2–3 points with aphasia or hemianopia
ESCAPE-MeVO 5151172 III 530 ≥6 points or Inclusion of proximal and distal M2MCA <12 h ASPECTS>5 and lack of salvageable brain tissue Single
3-5 points with disabling deficits
FRONTIER-AP Not available II 240 ≥5 points or Inclusion of M2MCA segment beyond bifurcation or trifurcation <9 h <4.5 h: hypodensity <50% of MCA or ACA 4.5–9 h: core<70 mL Single
1–5 with dysphasia

M2MCA, M2 middle cerebral artery occlusion; ACA, anterior cerebral artery; ASPECTS, Alberta Stroke Program Early CT Score.

* projected;

ACTRN12621001746820p

(a) Hypodensity in the majority of brain parenchyma supplied by the DVO or absence of collaterals on multiphase CTA (b) Lack of core:penumbra mismatch on CT Perfusion (c) Diffusion restriction in the majority of the brain parenchyma supplied by the DVO or lack of core:penumbra mismatch on MR perfusion.

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