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Page 4 of 9 Linger et al. Vessel Plus 2020;4:36 I http://dx.doi.org/10.20517/2574-1209.2020.51

Thrombolysis (without thrombectomy) in perfusion mismatch-selected patients has proven beneficial 4.5-
9 h after onset, including patients with wake-up stroke who were within 9 h of the midpoint of sleep [26,27] .
In practical terms this included wake-up stroke patients up to 16 h after the time they were last known to
be well, similar to the DEFUSE 3 trial time window. The potential for late-window thrombolysis to improve
outcomes in combination with thrombectomy is now being explored in randomized trials [Tenecteplase
in Stroke Patients Between 4.5 and 24 h (TIMELESS), NCT03785678 and Extending the time window
for Tenecteplase by Effective Reperfusion of peNumbrAL tissue in patients with Large Vessel Occlusion
(ETERNAL), NCT04454788].

ENDOVASCULAR THROMBECTOMY FOR PATIENTS PRESENTING WITH MILD STROKE
DEFICITS OR DISTAL OCCLUSIONS
The benefit of endovascular thrombectomy in patients presenting with anterior circulation LVO and mild
deficits is still unknown, with less than 1% of patients enrolled in recent thrombectomy trials having
[28]
a NIHSS ≤ 5 . Despite this cohort having only mild symptoms on first assessment, evidence suggests
that without reperfusion therapy, a substantial proportion subsequently deteriorate and are disabled
at 90 days (mRS 2-6; 29%) [29,30] . Patients with more proximal occlusions, particularly terminal internal
carotid artery occlusions, are at the highest risk of neurological deterioration. Deterioration is likely
[31]
due to leptomeningeal collateral circulation failure over time, in the absence of reperfusion . Recent
observational data indicate that immediate thrombectomy for the mild stroke patient (NIHSS ≤ 5) is safe
[28]
and may improve clinical outcomes . This is currently being assessed in two randomized controlled trials
[Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW), NCT04167527 and Exploration of
the limits of mechanical thrombectomy indications in a single action - MinOr Stroke Therapy Evaluation -
NIHSS 0-5 (IN EXTREMIS-MOSTE), NCT03796468].

In contrast to the unequivocal evidence for the effectiveness of thrombectomy in patients with proximal
occlusion, evidence of benefit beyond the M1 segment is less robust. Relatively few patients with M2
occlusions were included in randomized trials and the definition of M2 segments varied, with many
representing early bifurcation of the M1 segment. Anterior cerebral artery and posterior cerebral artery
occlusions were not included in trials, other than 3 patients in MR CLEAN. Hypothetically, the benefit
of thrombectomy should be reduced given the smaller territory supplied by more distal vessels and the
increased efficacy of thrombolysis in reperfusing more distal occlusions. Furthermore, the risk of arterial
injury may potentially be increased given the smaller vessel size and increased tortuosity. However, meta-
analyses have suggested benefit of thrombectomy in proximal M2 segments in carefully selected patients
with significant neurological deficits [15,32] . Advances in device technology are likely to improve the safety
and efficacy of distal thrombectomy. Further research is needed in this area.

ENDOVASCULAR THROMBECTOMY FOR PATIENTS PRESENTING WITH LARGE ISCHEMIC
CORE VOLUMES
Increasing ischemic core volume (estimated by diffusion restriction on MRI or critically reduced cerebral
[33]
blood flow on CT perfusion) is associated with lower likelihood of functional independence . Despite
this association, there is emerging evidence for the benefit of thrombectomy in selected patients with large
cores (> 70 mL), particularly within 6h of stroke onset [33,34] . These data suggest that even with large baseline
core volumes, there may be significant volumes of viable but critically hypoperfused tissue that can be
salvaged with intervention and translate to clinically meaningful benefit . Several randomized controlled
[34]
trials [Thrombectomy for Emergent Salvage of Large Anterior Circulation Ischemic Stroke (TESLA),
NCT03805308; Efficacy and Safety of Thrombectomy in Stroke With Extended Lesion and Extended Time
Window (TENSION), NCT03094715; Exploration of the limits of mechanical thrombectomy indications in
a single action - Large Stroke Therapy Evaluation - ASPECT 0-5 (IN EXTREMIS - LASTE), NCT03811769