Thrombectomy for Distal, Medium Vessel Occlusions

Rapid EVT to restore cerebral perfusion is now the cornerstone of treatment for AIS due to PLVOs. Multiple randomized trials demonstrated dramatically improved patient outcomes with EVT among broadly selected patients within the first 6 hours and imaging-selected patients 6 to 24 hours after last known well. With PLVOs well established as a treatment target, DMVOs have emerged as a promising next potential frontier for EVT, for several reasons. First, the overwhelming benefit magnitude of EVT for PLVOs suggests thrombectomy would also be beneficial for DMVOs. Second, the advent of EVT as a standard PLVO therapy has triggered rapid, iterative advances in endovascular retriever and aspiration technology, leading to more navigable and smaller devices able to reach more distal, narrower vessels. Third, a recognized unintended event during EVT for PLVO is thrombus fragmentation and escape from retrieval devices, leading to emboli in distal arteries. For EVT of PLVO-AIS to achieve maximal benefits, effective rescue endovascular therapy for DMVOs arising from initial thrombus manipulation is desirable.

This consensus statement integrates recent research on DMVO stroke epidemiology, imaging, medical and endovascular therapy, and clinical trial design with classic understanding of the distal cerebral vasculature and its ischemic syndromes, to provide a statement of current understanding of the opportunities and limitations of EVT for DMVOs. Promising research directions and steps to promote collaborative, systematic investigation are delineated.

Key Distinctive Features and General Terminology

Two key distinctive anatomic features of distal, medium cerebral arteries profoundly affect endovascular procedure conduct and endovascular device design: (1) vessel distance/tortuosity and (2) vessel size.

Vessel Distance/Tortuosity

The distal cerebral arteries are distinguished by longer distances and more tortuous cumulative travel pathways from the arterial puncture site. Distal arteries have ≥1 additional branch steps than proximal arteries and also loop around neuroanatomic structures such as the corpus callosum (ACA), insula and temporal lobe (MCA), and temporal and occipital lobe (PCA). This tortuosity increases the difficulty of successful navigation to target occlusions and constrains the physical forces deliverable by a retrieval device separated from its manipulable end by multiple turns.^1,2

Vessel Size

The intermediate-size cerebral arterial tree is bounded by 2 vessel size ranges with well-established rubrics in the neurovascular literature. Above are the wide proximal intracranial arteries that, when obstructed, carry the label of “large vessel occlusions.” Below are the narrow penetrating arteries that, when stenotic or occluded, carry the label of “small vessel” disease in the classic neurovascular literature. Accordingly, small vessel occlusions (SVOs)are those occurring within penetrating arteries, currently far too small for endovascular targeting. Consequently, the intermediate, “medium vessels” can be operationally defined as cerebral arteries with lumen diameters between 0.75 and 2.0 mm. The upper 2.0-mm threshold places into the large vessel category the intracranial internal carotid artery (ICA; typical diameter, 3.8 mm), the M1 segment of the MCA (2.7 mm), the basilar artery (3.2 mm), and the vertebral artery (2.8 mm).^3–5 The lower 0.75-mm threshold places into the small vessel category deep penetrator arteries (typical lenticulostriate artery diameter, 0.5 mm), long pial penetrator arteries, and surface pial arteries (typical pial artery diameter, 0.2–0.7 mm).^6,7 Squarely in the medium vessel category are the M3 MCA arteries (typical diameters at origin, 1.1–1.5 mm), M4 MCA, A2 to A5 ACA, and P2 to P5 PCA.^2,8

Since distance tortuosity and size are each important aspects, the Summit group recommended adopting a general label that captures both—DMVOs. Where appropriate, the use of labels using either of the distinctive anatomic features alone was also endorsed: distal vessel occlusions (DVOs) or medium vessel occlusions (MVOs) (contrasted with proximal vessel occlusions [PVOs] or large vessel occlusions [LVOs], respectively).

It is important to note these 2 anatomic features may occur in a dissociated manner. For example, in a patient with a duplicate MCA stem, the M1 MCA segment may be proximal but medium in diameter (and an occlusion would be a proximal, medium vessel occlusion [PMVO]). Conversely, in a patient with an azygous ACA, the A2 segment may be distal but large in diameter (and an occlusion would be a distal, large vessel occlusion [DLVO]). Similarly, in a patient with a dominant M2 MCA division, an occlusion in the initial segment of the artery, exceeding 2 mm diameter, would be a DLVO.

There is wide agreement in the literature that the proximal, large artery category includes the intracranial ICA, M1 MCA segment, intracranial vertebral arteries, and basilar artery. Similarly, a general consensus recognizes the distal, middle artery category as including the M3 and M4 MCA segments, A2 to A5 ACA segments, P2 to P5 PCA segments, and PICA, AICA, and SCAs. However, categorization of M2 MCA, A1 ACA, and P1 PCA has varied.⁹ Positioning of the M2 MCA within any classification system is particularly challenging, as M2 MCA angioarchitecture is highly heterogenous across patients. M2 MCA branch patterns include bifurcation, trifurcation, tetrafurcation, and candelabra^8,10; M2 MCA vessel segments range in size from 1.1 to 2.1 mm in diameter¹¹; M2 MCA occlusions may occur in dominant segments that are similar to M1 in size (though still more distal and branched/tortuous to reach) or in nondominant segments that are similar to M3 and other much small arteries in size.¹² Accordingly, it seems ill advised to advance a fixed, inflexible naming system that places all segments of all M2 MCAs in all patients in one or another category. It is preferable to use the particular size and distalness of the involved M2 MCA segment to drive classification in an evidence-based, case-specific manner, and that is the approach here proposed.

A proposal has been advanced to resolve the mild approach differences between investigative groups when demarcating proximal large vessels versus distal medium vessels by conflating the two into a single category, defining any endovascularly accessible artery as a large vessel.¹³ However, the Consensus Group was concerned that such an approach would elide important anatomic differences in the vasculature that are relevant to clinical decision-making. In addition, the Consensus Group felt that definitions of anatomic terms (eg, large) should rest upon anatomic properties and be stable over time, rather than rest on evolving catheter technology properties and fluctuate over time.

Supporting the approach that we advance is that, subsequent to our international consensus conference and the framing of our proposals and subsequent to the first submission of the current manuscript, a single-center group published a perspective article similarly supporting formally distinguishing more distal, medium-size vessels from more proximal, larger size vessels, rather than conflating the two in a single category.¹⁴ There are differences in the new approaches recommended. Our international Consensus Group has proposed the terms DMVO and PLVO; the single-center group proposed the terms MeVO (medium vessel occlusion) and LVO. As noted above, we purposely selected a naming system that incorporates both, not just one, of the two most salient biopathophysiologic dimensions for EVT of the cerebral angioarchitecture: (1) distance-tortuosity and (2) size. Both of these target vessel properties have important implications for EVT device technology design and EVT procedure conduct. Also, as noted, we do additionally support, when appropriate, the use of single dimension terms, focused only on size (MVO and LVO) or only on distance tortuosity (DVO and PVO). Accordingly, our proposed nomenclature is the more comprehensive and subsumes the other proposal, while both demonstrate that the field recognizes the time is right to articulate an improved naming system.

Selected Aspects of the Anatomy of the Distal, Medium-Size Cerebral Arterial Tree

The distal, medium-size cerebral arterial vasculature encompasses all or portions of 6 arterial arbors: the ACA, MCA, PCA, PICA, AICA, and SCA.¹⁵ Altogether, these vessels typically have 25 anatomic segments and give rise to 34 distinct branch arteries. Their anatomic courses, distal territories supplied, and symptoms when occluded are shown in Figure 1. Verbal descriptions of segments, course, and branches are provided in Text I in the Data Supplement for the ACA, PCA, PICA, AICA, and SCA and in the next paragraphs for the largest, most frequently affected vascular arbor—the MCA.

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Middle Cerebral Artery

Two MCA anatomy classification schemes are widely used. Under arboreal trunk-division-branch terminology. the MCA arises from the ICA, courses laterally, and then divides generally according to 1 of 3 patterns: (1) bifurcation into superior and inferior divisions (78%), trifurcation into superior, middle, and inferior divisions (12%), and a candelabra directly giving off ≥4 trunks (10%). The MCA divisions give off 12 distal arterial branches: orbitofrontal, prefrontal, precentral, central, anterior parietal, posterior parietal, angular, temporo-occipital, posterior temporal, middle temporal, anterior temporal, and temporopolar.

Using angiography-based terminology, M1, M2, M3, and M4 segments are distinguished based on the MCA trajectory through the Sylvian triangle. The M1 or sphenoidal segment runs from the artery origin horizontally to the limen insulae. The M1 typically encompasses the entire MCA stem and initial short segments of the MCA divisions, although sometimes the MCA stem can extend into M2. At the insula, the MCA turns vertically as the M2 or insular segment, from which most MCA cortical branches arise. The M3 or opercular segment then courses inferolaterally to the lateral surface of the Sylvian fissure. The M4 or cortical segment begins as vessels exit the Sylvian fissure and fan over the convex surface of the cerebral hemispheres.

When the MCA stem bifurcates, the superior and inferior divisions at their origin average 2.4 mm in diameter,² placing a majority of initial M2 segments in the large vessel category, but division vessel size is smaller with trifurcations. The 12 cortical branch arteries range from 1.1 to 1.5 mm in diameter at their origin.⁸

Epidemiology, Outcomes, and Clinical Features of Spontaneous DMVOs

Available population-based and large clinical registry data indicate spontaneous (not procedure-related) DMVOs are a common cause of AIS and the source of substantial patient morbidity. The precise frequency of DMVOs has been incompletely delineated, as many epidemiologic studies have not systematically performed intracranial vessel imaging. However, useful ranging estimates can be obtained by process of elimination considerations. Broadly, population-based and large clinical registry studies suggest that AIS presentations are due to acute PLVOs in 35% to 40%, acute small vessel (deep and long pial penetrator) occlusions in 20% to 25%, hemodynamic watershed ischemia in 2% to 5%, and unusual and disseminated conditions (eg, reversible vasoconstriction syndrome, hyperviscocity, moyamoya) in 1% to 5%.^9,16–19 The remainder, it can be inferred, are preponderantly due to acute DMVOs, which must then account for 25% to 40% of AIS—an estimate that accords with available series data.^20–24 The exact frequencies of individual DMVO occlusion sites have varied with population studied, method of vessel imaging performed, and definition of LVO versus MVO used (Table 1).⁹

The outcome of DMVO-AIS under medical therapy is characterized by frequent disability and, among M2 but not other occlusion locations, high mortality. In the multicenter STOP Stroke study (Screening Technology and Outcome Project), at 6 m, M2 occlusions were associated with functional dependency/death (modified Rankin Scale [mRS] score, 3–6) in 60% of patients and mortality in 24%.²¹ Proximal ACA and PCA occlusions were associated with functional dependency/death (mRS score, 3–6) in 77% and mortality in 8%.

The clinical syndromes of hemispheric DMVOs reflect highly focal compromise of cognitive, motor, sensory, and visual function subserved by the cortex and superficial white matter. Common are partial rather than global aphasia, fractionated rather than complete hemiparesis or hemianesthesia, as well as partial or complete hemivisual field defects (Figure 1). While presenting deficits of more distal DMVOs can be subtle, more proximal DMVOs generally produce severe initial symptoms. In the multicenter STOP Stroke study, initial mean National Institutes of Health Stroke Scale scores were: M2–11.5, A1–8.5, A2–12.4, P1–16.3, and P2–10.4.²¹

Epidemiology, Outcomes, and Clinical Features of Emboli in New Territories and Emboli in Distal Territories Complicating EVT

During EVT procedures for PLVOs, fragmentation and distal embolization of target thrombi may occur during thrombus manipulation. Distal occlusions at procedure end can cause incomplete final reperfusion (Thrombolysis in Cerebral Infarction [TICI] 2a–2c rather than TICI 3), larger infarcts, and worse clinical outcome. Two general types of procedure-related distal occlusions may be distinguished: (1) ENTs affecting fields not previously compromised by ischemia, and (2) EDTs within the initial ischemic field. ENTs are typically due to fragmentation and loss of control of thrombus during pullback. EDTs are typically due to fragmentation and loss of control of thrombus during the initial engagement with the retrieval device. ENT and EDT rates have varied in different series, reflecting variations in target occlusion locations, thrombus composition, frequency of pre-EVT intravenous thrombolysis, and types of thrombectomy devices used.^25–30 Soft, erythrocyte-rich red clots are more vulnerable to fragmentation and embolization than hard, fibrin- and platelet-rich white clots.²⁷

The most common type of ENT is embolism to a previously unaffected ipsilateral ACA during EVT for a target MCA occlusion. Clinically, ACA ENT may present as new ACA-typical symptoms, including contralateral leg weakness and sensory loss, bladder dyscontrol, transcortical motor aphasia, apraxia, and abulia, added to preprocedural MCA-typical symptoms. Among 650 patients undergoing mechanical thrombectomy, 9.4% experienced ACA embolism and had more radiologic hemorrhage (65% versus 37%), less 90-day functional independence (25% versus 48%), and higher mortality (35% versus 20%).²⁸ In the ESCAPE multicenter trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times), infarct in new territory was observed in 5.0% of EVT patients (and 12% of patients evaluated with postprocedure magnetic resonance imaging) and was associated with worse clinical outcome.³¹

The most common types of EDT are emboli to MCA or ACA segments beyond an initial ICA target occlusion or emboli to M2 to M4 segments beyond an initial M1 target. EDT is a cause of incomplete reperfusion of the initial PLVO target occlusion. In HERMES (Highly Effective Reperfusion Evaluated in Multiple Endovascular Stroke trials) pooled randomized clinical trial data, among 801 EVT patients, partial reperfusion was frequent, present in 80% of patients, including expanded TICI (eTICI) 2a (1%–49% reperfusion) in 14%, eTICI 2b50 (50%–66% reperfusion) in 14%, eTICI 2b67 (67%–89% reperfusion) in 30%, and eTICI 2C (90%–99%) in 23%; complete reperfusion, eTICI 3 (100%), occurred in only 9%.³² Less reperfusion, from TICI 3 to TICI 2c to TICI 2b, was associated with worse outcomes, including reduced functional independence (60.1% versus 52.3% versus 46.6%) and increased mortality (8.3% versus 9.2% versus 12.6%).

In many EVT cases, the distal vascular tree is first imaged only after reperfusion of the proximal target occlusion, precluding determination of whether visualized distal occlusions were part of the initial occlusive event or arose as procedure-related EDTs. However, these mechanisms can be distinguished when the distal vasculature is imaged before/during procedure start, by magnetic resonance imaging susceptibility-weighted imaging or by catheter contrast injection beyond the target occlusion. In 2 series of magnetic resonance-imaged patients, EDTs were common, occurring in 22% to 23% of patients.^30,33

EDTs may be clinically covert when a large infarct evolves from the initial proximal vessel occlusion despite reperfusion. When clinically manifest, EDTs may present as persistent deficits related to the affected distal vascular field despite resolution/improvement of other initially presenting deficits.

Imaging Aspects of DMVOs

Current imaging techniques and rating scales, developed to characterize PLVOs, are of some value but require refinement and further development to optimally delineate DMVOs.

Computed Tomography/Magnetic Resonance Imaging

On noncontrast computed tomography, erythrocyte-rich distal occlusive thrombi will produce hyperdense vessel signs. With M3 to M4 occlusions, these appear as circular hyperdensities in the Sylvian triangle—the computed tomography dot sign.³⁴ However, systematic search for computed tomography dot signs is often not performed in clinical interpretations; similar findings in ACA, PCA, and cerebellar branch arteries have not been extensively described; and erythrocyte-poor, isodense occlusions will not be seen. Similarly, on routine magnetic resonance imaging, erythrocyte-rich distal occlusive thrombi will produce susceptibility vessel signs, evident as intravascular, tubular low-intensity signals on susceptibility-weighted sequences.^30,33,35 However, erythrocyte-poor, isointense occlusions will not be directly visualized, though local slow flow evidenced by fluid attenuation inversion recovery vascular hyperintensity may be suggestive.

Computed Tomography Angiography/Magnetic Resonance Angiography

On computed tomography angiography (CTA) and magnetic resonance angiography (MRA), distal occlusions are evident as sudden vessel cutoffs. CTA and MRA detect M2 MCA, A1 ACA, P1 PCA, and proximal cerebellar artery occlusions with high accuracy. However, they are less reliable for more distal branch occlusions, as reduced artery caliber and branch anatomy variability can make it difficult to determine whether loss of distal vessel signal is due to an occlusion or anatomic variation. Detection of distal occlusions is aided by CTA/MRA acquisitions that continue late into the passage of contrast through the cerebral vasculature, including multiphase, rather than single-phase, CTA, and time-resolved MRA. Spatial resolution and delineation of smaller vessels is improved by augmented signal-to-noise computed tomography analysis and higher magnetic resonance field strength; waveletCTA and 7T MRA show distal vessel occlusions clearly but are not widely available.^36,37

Computed Tomography Perfusion/Perfusion Weighted Imaging Magnetic Resonance

Perfusion imaging is helpful in indicating indirectly presence of DMVOs.³⁸ Hypoperfusion in a wedge-shaped region matching the typical territory of an ACA, MCA, PCA, or cerebellar distal branch artery strongly suggests occlusion of the feeding vessel. Artificial intelligence algorithms may help map focal hypoperfusion regions to individual arterial branches. Blood flow delays may be less beyond distal than proximal occlusions due to shorter collateral routes over the cerebral convexity; accordingly, a Tmax >6-s penumbral threshold may not have the same meaning for distal as proximal occlusions. Nonetheless, penumbral imaging via perfusion-core mismatch can be informative in distal occlusions, after adjusting lesion size thresholds for decision-making to the smaller fields at risk.

Catheter Angiography

Providing superior visualization of medium-size arteries and their sudden cutoff, catheter angiography remains the most sensitive technique for detecting DMVOs. However, characterizing collateral flow with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology grading system can be difficult, as the proportion of the territory with reduced collateral flow may be challenging to quantify, due to smaller field size and often faster collateral flow. Fine-grained TICI reperfusion grades can similarly be more difficult to assign.

Select DMVO imaging aspects meriting additional research are shown in Table 2.

Intravenous and Intra-Arterial Fibrinolytic Treatment for DMVOs

Pharmacologic fibrinolysis is more effective for the smaller clot burdens of DMVOs than the larger clot burdens of PLVOs.^39,40 For intravenous fibrinolysis, in a meta-analysis of 2063 patients across 26 studies, partial or complete recanalization with intravenous alteplase alone was achieved in 52% of M2/M3 MCA occlusions, compared with 35% for M1 MCA, 13% for ICA, and 13% for basilar.⁴¹ In the EVT era, in the INTERRSeCT study (Identifying New Approaches to Optimize Thrombus Characterization for Predicting Early Recanalization and Reperfusion With IV Alteplase and Other Treatments Using Serial CT Angiography), intravenous alteplase before endovascular intervention recanalized 43% of M3 MCA, ACA, or PCA occlusions and 37% of M2 MCA, compared with 22% for M1 MCA and 11% for ICA.⁴² Nonetheless, as these data attest, intravenous thrombolysis alone is imperfect for DMVOs, recanalizing only one-third to one-half of visualized thrombi.

Intra-arterial infusion of fibrinolytics permits delivery of higher drug concentration to the target thrombus and reduced systemic lytic exposure. Several studies have evaluated intra-arterial lysis as a primary therapy for DMVOs. In the PROACT-2 trial (Prourokinase in Acute Cerebral Thromboembolism 2), among 44 patients with isolated M2 occlusions, intra-arterial prourokinase increased partial or complete reperfusion rates (54% versus 17%) and tended to increase independent outcome (52% versus 29%).⁴³ In a large single-center study, intra-arterial urokinase achieved partial or complete recanalization in 76% of M2 and 33% of M3 occlusions.⁴⁴ As rescue therapy after incompletely successful endovascular mechanical thrombectomy, judicious intra-arterial fibrinolysis can increase reperfusion with minimal increased risk of hemorrhagic transformation.^45,46

Endovascular Mechanical Thrombectomy for DMVOs

Distal, medium vessels were not an initial target for endovascular mechanical thrombectomy procedures. Their longer, more tortuous access route and thinner arterial walls potentially increase risk of dissection, perforation, and vasospasm; and the smaller at-risk tissue volumes constrain potential reperfusion benefit. However, as DMVOs in strategic locations can be debilitating and EVT for PLVOs is overwhelmingly beneficial, it seems likely well-selected patients could be helped by extending EVT therapy further up the cerebral arterial tree. As catheter technology has improved, endovascular devices sufficiently small and navigable to be applied to DMVOs have iteratively advanced. While initial stent retrievers had radial diameters of 6 and 4 mm, smaller devices have recently been released, including 3 mm (eg, the Catch Mini, pREset LITE, Mindframe Capture LP, Trevo XP ProVue) and 2.5 mm (eg, the Tigertriever 13),^47–50 as well as devices that afford operator control over amount of radial opening using an adjustable slider (Figure 2).⁵¹ Similarly, technical advances in thromboaspiration devices have increased suitability for the distal vasculature, including increased flexibility, less traumatic tips, and appropriate suction force (Figure 3).^52,53 General anesthesia may have greater relative advantage compared with procedural sedation for EVT for DMVOs, as reduced patient movement facilitates catheter navigation to the more distal and fragile target arteries; however, concerns remain regarding the potential for general anesthesia to delay procedure start and lower blood pressure, impairing collaterals.

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Randomized trials of EVT have enrolled only a limited number of DMVO patients and preponderantly occlusions of M2 MCA rather than more distal, smaller arteries. Further, the enrolled M2 MCA occlusions have largely been in proximal, large M2 MCA divisions with size and accessibility similar to M1 MCA occlusions (M1-like M2 occlusions). Nonetheless, the M2 MCA randomized clinical trial evidence provides important initial perspective on potential benefit of EVT in the distal arterial tree. In a HERMES pooled analysis of 130 patients with M2 MCA occlusions in 7 randomized clinical trials, the target occlusion was in proximal M2 in 89% and distal M2 in 11% and in a dominant division in 56%, codominant in 38%, and nondominant in 5%.¹² Substantial reperfusion (modified Thrombolysis in Cerebral Infarction [mTICI] 2b–3) was achieved in 59%, and EVT compared with medical therapy alone increased 3-m functional independence (58% versus 40%; P=0.03). EVT benefit was greatest with proximal and dominant M2 MCA segment occlusions. Intriguingly, no symptomatic intracranial hemorrhage (0%) was observed in EVT-treated patients compared with 7.9% in controls. In the ASTER trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization) comparing EVT with contact aspiration versus stent retrievers, 79 enrolled patients had M2 occlusions.⁵⁴ Nominal differences in reperfusion rates did not reach statistical significance: after initial contact aspiration versus stent retriever: TICI 2b/3, 65% versus 68%; TICI 3, 29% versus 39%; after use of rescue devices: TICI 2b to 3, 90% versus 84%; TICI 3: 35% versus 42%. Functional independence at 90 days was similar between contact aspiration and stent retriever (54% versus 50%), though a trend toward increased mortality with contact aspiration was noted (20% versus 3%).

For other DMVOs, evidence is primarily from case series rather than randomized trials. In a large single-center series, EVT was performed in 69 patients with ACA (43%), M3 MCA (54%), or PCA (10%) occlusions, including 62% primary distal occlusions and 33% distal occlusions present after PLVO EVT.⁵⁵ Modalities were stent retrievers in 54%, intra-arterial alteplase in 52%, and thromboaspiration in 45%. Outcomes included substantial reperfusion (mTICI 2b–3) in 83%, parenchymal hematoma in the distal arterial field in 4%, 90-day functional independence in 30%, and mortality in 20%. At the Distal Summit, preliminary results were presented from Essen of EVT in 44 ACA occlusion patients, 77% EDT after intracranial ICA thrombectomy, 20% primary occlusions, and 2% ENT after MCA thrombectomy (Chapot, personal communication, 2019). Substantial reperfusion (TICI 2b–3) was achieved in 93% with complications of bleeding in 2% and ENT in 2%. These findings demonstrate EVT is now able to achieve high reperfusion rates in at least some DMVO targets with relatively few complications, indicating more formal, multicenter testing is warranted.

Designing Clinical Trials for Ischemic Strokes Due to DMVOs

DMVOs pose several challenges, none insuperable, to clinical trial design. The 3 mechanisms of DMVOs create heterogeneity in potential study populations. In primary distal occlusions, DMVO-related deficits appear in isolation; in ENT, added to those of the initial presenting occlusion; and in EDT, blended into those of the initial presenting occlusion. Further, while anterior circulation PLVOs yield fairly homogenous clinical deficits, DMVOs yield disparate deficits varying with the fractionated arterial territory compromised. Patients with isolated abulia due to ACA, alexia with agraphia due to MCA, quadrantanopia due to PCA, and unilateral ataxia due to PICA branch infarction differ radically in symptomatic manifestations. Moreover, their impairments are often not well captured by the National Institutes of Health Stroke Scale and the mRS—the standard acute stroke trial entry and outcome assessment scales.

Given this clinical heterogeneity, one approach would be to adopt as the primary efficacy end point the more homogenous technical outcome of vessel status/reperfusion. Comparison to randomized controls might not be required in an objective performance criterion trial, as immediate spontaneous reperfusion in distal occlusions is rare.⁵⁶ To ensure reperfusion had potential clinical benefit, entry criteria could require the compromised artery supply an eloquent territory (eg, a region subserving motor, visual, language, or memory function). Entry criteria could also or alternatively require presence of a disabling deficit, using the operationalized definition developed for the PRISMS mild stroke trial (Potential of rtPA for Ischemic Strokes With Mild Symptoms): a deficit that, if unchanged, would prevent the patient from performing basic activities of daily living (bathing, ambulating, toileting, hygiene, and eating) or returning to work.⁵⁷ Clinical outcomes, including 3-m mRS global disability, would be secondary end points. Branch-territory infarct volume and penumbra salvage could be useful additional biomarker secondary outcomes.⁵⁰ Using technical vessel outcomes as primary end points would replicate for DMVOs the rapid regulatory clearance path of the first PLVO retrieval device but also its drawback of not demonstrating for payors definite clinical, in addition to technical, benefit.⁵⁸

Modality-specific functional measures as primary end points are another potential approach. This strategy has been used in stroke recovery trials in which treatments target specific deficits, such as language therapy for aphasia or visual stimulation for visual-field defects.⁵⁹ A variety of modality-specific outcome measures are available, including for arm motor function (eg, the Action Research Arm Test), language (Stroke and Aphasia Quality of Life Scale), memory (Rivermead Behavioural Memory Test), and vision (visual fields). Of particular note is gait speed (10-m walk test) as a functional outcome measure reflecting lower extremity motor function in ACA infarcts.

But if appropriately analyzed, a global disability measure, such as the mRS, may prove responsive for DMVOs despite the heterogenous deficits they produce. Because the mRS assesses global, all-cause disability, it can capture functional limitations arising from different neurologic deficits. Inability to return to work (mRS level 2) is sensitive to walking difficulty from ACA, reading difficulty from MCA, and hemianopia from PCA branch infarcts. In the STOP Stroke study, dependency or death (mRS score, 3–6) in medically treated DMVO patients occurred frequently: 50% to 87% of A1, A2, M2, P1, and P2 occlusions.²¹ The mRS can be optimized to be informative in milder stroke patients by use of shift analysis with granular sampling of good outcomes (eg, mRS tetrachotomized at 0, 1, 2, 3–6 or trichotomized at 0–1, 2, 3–6) or of sliding dichotomy analysis using prognosis-adjusted modeling. With randomization stratified by location to ensure balance in treatment arms, global functional outcome measures could potentially be used in DMVO trials.

Conclusions

DMVOs produce 24% to 40% of AIS, arising as spontaneous thromboemboli and as unintended consequences of EVT for PLVOs. The 6 distal medium arterial arbors (ACA, M2–M4 MCA, PCA, PICA, AICA, and SCA) have 25 distinct anatomic segments and encompass 34 arterial branches that supply highly differentiated, largely superficial cerebral neuroanatomical regions. DMVOs engender clinical syndromes that are heterogenous and fractionated but frequently disabling. Though more effective for distal than proximal occlusions, intravenous fibrinolytics nonetheless fail to recanalize one-half to two-thirds of occlusions. Accordingly, there is an unmet need for treatment of DMVOs, and these territories are a promising next frontier for endovascular intervention. Initial clinical cohort studies of smaller, more navigable stent retriever and thromboaspiration devices suggest EVT for DMVOs is safe and technically effective. Sustained, collaborative investigations are desirable to advance imaging recognition of DMVOs, further iterate device designs and improve reperfusion efficacy, and conduct large registry studies and formal clinical trials using harmonized, common data elements to improve treatment of this common stroke subtype.

Acknowledgments

We are grateful to Bat-Orgil Bat-Erdene for expert scientific figure preparation.

Footnotes