News & VIews

STROKE
the total number of

Can imaging extend the patients with stroke for whom

the EXTEND criteria will apply

thrombolytic time window is probably low

after stroke?
excluded — the median core volume was
4.6 ml in the alteplase group and 2.4 ml in
the placebo group. Ultimately, the size of the
Min Lou    core determines the outcome of reperfusion
therapy, and even the influence of penumbral
A new trial has demonstrated the benefits of intravenous thrombolysis, reperfusion on clinical outcome depends on
baseline core volume4. Theoretically, in areas
guided by perfusion imaging, 4.5–9.0 h after stroke onset and in individuals
of severe ischaemia, delayed reperfusion leads
with wake-up stroke. In addition to extending the time window for to less tissue salvage than does early reper­
thrombolysis after acute ischaemic stroke, these findings could aid the fusion; thus, the exclusion of patients with large
refinement of imaging and thrombolytic protocols. cores might have lessened the effect of time
on the outcome. Special care needs to be taken
Refers to Ma, H. et al. Thrombolysis guided by perfusion imaging up to 9 hours after onset of stroke. N. Engl. J. Med. 380, with CT perfusion (CTP) maps that reflect the
1795–1803 (2019). haemodynamics at baseline, as CTP ischae­
mic core thresholds can be influenced by time
Intravenous thrombolysis (IVT) is known to placebo, administered within the 4.5–9.0 h time to reperfusion5.
be effective for the treatment of acute ischae­ window after stroke onset or to patients with Despite the success of the EXTEND trial
mic stroke up to 4.5 h after onset, but debate wake-up stroke1. All participants were judged in terms of the use of perfusion mismatch
continues about its use beyond this time win­ to have salvageable brain tissue on the basis of to select patients, it is important to be aware
dow. Over the past two decades, a consider­ a mismatch between the volumes of the perfu­ that the total number of patients with stroke
able effort has been made to determine the sion lesion and the ischaemic core. The primary for whom the EXTEND criteria will apply is
extent to which treatment delay diminishes outcome — a modified Rankin scale (mRS) probably low. Between 2010 and 2018, only
the beneficial effects of IVT. Strategies for score of 0 or 1 — was achieved in 35.4% of the 79 patients who were known to be within the
delayed intervention with IVT are based on alteplase group and 29.5% of the placebo group. 4.5–9.0 h time window were recruited from
the principle of arterial recanalization and The design of the EXTEND trial was based 28 centres, and many patients were excluded
rapid reperfusion of the ischaemic penumbra, on a previous trial from the same group and from IVT owing to a large ischaemic core
which is physiologically defined as the region incorporated subsequent refinements in mis­ or lack of salvageable tissue, or because they
of critically hypoperfused tissue that can match definition. A Tmax threshold of >6 s was were candidates for endovascular thrombec­
potentially be rescued by rapid reperfusion. used to discriminate penumbra from oligemic tomy (EVT). In our centre, the proportion
Accordingly, multimodal imaging proto­cols tissue, that is, tissue that was underperfused of patients with acute ischaemic stroke who
have emerged to identify this tissue and select but not at risk of infarction. This threshold — met the EXTEND criteria was 6.3% in 2018.
the patients who are most likely to bene­fit a measure of the time taken for arterial blood Imaging-based selection has enabled a greater
from delayed intervention. The EXTEND to reach the brain — was important for the number of patients who are ideal candidates
trial, the results of which were announced in success of the trial, and was selected according for IVT in the later time window to receive
May 2019, has helped to increase confidence to previous studies that compared differen­ this treatment, although these individuals are
in the concept of physiological guidance for tial infarct growth between patients who did still relatively rare. Furthermore, a substantial
thrombolytic intervention1. and did not achieve reperfusion. One study proportion of patients with wake-up stroke
The EXTEND trial was a phase III rando­ using quantitative 15O-PET showed that a Tmax might still be in the time window, as evidence
mized trial of intravenous alteplase versus >5.6 s outperformed other perfusion-weighted suggests that wake-up strokes tend to occur
imaging parameters in detecting penum­ shortly before awakening6.
bral tissue up to 48 h after stroke onset2. These issues raise important questions
EXTEND … has helped However, Tmax maps are sensitive to delayed regarding further refinements of imaging-
to increase confidence in contrast arrival, which might not imply criti­ based selection to enable more patients to
cal hypoperfusion in some circumstances, receive IVT beyond 4.5 h. In addition to lesion
the concept of physiological such as a chronic carotid occlusion3. volume, lesion location affects the out­come.
guidance for thrombolytic Another possible reason for the success For example, involvement of the corticospinal
intervention of the trial was that patients with a base­ tract, which is associated with motor function,
line ischaemic core volume of ≥70 ml were was shown to predict poor outcomes of IVT in

Nature Reviews | NeuRology

News & Views

patients with small perfusion lesions7. Indeed, unresolved9 — should the later time window time window after stroke. The use of multi-
in individual patients, fixed voxel-wise thres­ now be factored into this debate? Of note, dimensional, data-driven individu­a lized
holding, as used by the automated tool RAPID, possibly owing to good collaterals, 67.3% of imaging solutions to select patients, together
might be inaccurate owing to the variability of patients in the EXTEND trial achieved recan­ with an increased probability of recanali­
spatial arrangement of lesion voxels, as well as alization at 24 h after IVT (compared with zation by novel thrombolytic agents, might
to the complexity of the underlying cerebral 39.4% in the placebo group), and 49.6% of enable more patients with stroke to benefit
haemodynamics. Neural networks are now IVT-treated patients attained an mRS score from IVT beyond the standard time window
being employed to predict tissue fate, allow­ of 0–2. The high recanalization response to in the future.
ing predictive features to be learned directly alteplase might explain the clinical benefit, Min Lou   
from training data based on the combination suggesting that the predictive ability of reca­ Department of Neurology, The 2nd Affiliated Hospital
of clinical data, imaging information and nalization after IVT could potentially influ­ of Zhejiang University, School of Medicine, Hangzhou,
response to treatment8. These novel deep ence the decision to proceed with EVT. Given Zhejiang, China.
learning architectures might aid the develop­ that several characteristics of the thrombus, e-mail: lm99@zju.edu.cn
ment of innovative tools with the potential to including location, length and morphology, https://doi.org/10.1038/s41582-019-0232-y
further explore the risks and benefits related could influence the likelihood of recanaliza­
to reperfusion therapy. tion (Fig. 1) and can be reconstructed with­ 1. Ma, H. et al. Thrombolysis guided by perfusion imaging
up to 9 hours after onset of stroke. N. Engl. J. Med.
Approximately 70% of the patients who out extra images, visualization of clot could 380, 1795–1803 (2019).
were enrolled in the EXTEND trial had readily be added to the triage protocol for 2. Zaro-Weber, O. et al. Penumbra detection in acute
stroke with perfusion magnetic resonance imaging:
large-vessel occlusions, and the results suggest stroke10. In addition, it is anticipated that a validation with 15O-positron emission tomography.
that imaging-guided IVT within the 4.5–9.0 h later window — possibly up to 24 h — will Ann. Neurol. 85, 875–886 (2019).
3. Albers, G. W. Use of imaging to select patients for late
time window could reduce the need for EVT open up for pharmacological IVT, especially window endovascular therapy. Stroke 49, 2256–2260
among these patients1. Primary stroke centres with new thrombolytic agents that have a high (2018).
4. Vogt, G. et al. Initial lesion volume is an independent
might need to develop expertise in multi­ recanalization rate. predictor of clinical stroke outcome at day 90:
modal imaging to identify more patients who In conclusion, refinement of imaging- an analysis of the Virtual International Stroke Trials
Archive (VISTA) database. Stroke 43, 1266–1272
are eligible for IVT. Moreover, the debate based patient selection could enable throm­ (2012).
regarding the utility of IVT as a bridging bolytic intervention to be offered as an 5. Bivard, A. et al. Ischemic core thresholds change with
time to reperfusion: a case control study. Ann. Neurol.
therapy to EVT within 4.5 h after stroke is still alternative to thrombectomy in the 4.5–9.0 h 82, 995–1003 (2017).
6. Wouters, A. et al. Wake-up stroke and stroke of
unknown onset: a critical review. Front. Neurol. 5,
153 (2014).
a b c d 7. Zhou, Y. et al. Identification of corticospinal tract
lesion for predicting outcome in small perfusion stroke.
Stroke 49, 2683–2691 (2018).
8. Pinto, A. et al. Stroke lesion outcome prediction based
on MRI imaging combined with clinical information.
Front. Neurol. 9, 1060 (2018).
9. Katsanos, A. H. & Tsivgoulis, G. Is intravenous
thrombolysis still necessary in patients who undergo
mechanical thrombectomy? Curr. Opin. Neurol. 32,
3–12 (2019).
10. Shi, F. et al. Presence of multi-segment clot sign
on dynamic CT angiography: a predictive imaging
marker of recanalisation and good outcome in
acute ischaemic stroke patients. Eur. Radiol. 28,
3413–3421 (2018).
Fig. 1 | Reperfusion therapy in the late time window. Images from a patient with middle
cerebral artery (MCA) occlusion treated at our centre. a | Pretreatment perfusion CT showed a small Acknowledgements
ischaemic core (red) and a large volume of salvageable tissue (green). b | CT angiography revealed a M.L. is supported by the National Natural Science Foundation
of China (grant number 81622017), the National Key
multi-segment clot — a potential predictive imaging marker of recanalization — in the occluded Research and Development Program of China (grant number
MCA (arrows). c,d | Intravenous thrombolysis (IVT) 340 min after stroke onset contributed to 2016YFC1301503) and the Science Technology Department
recanalization (part c) and a small final infarct (part d). The likelihood of recanalization, estimated of Zhejiang Province (grant number 2018C04011).

from clot characteristics, could aid triaging of patients with acute large-vessel occlusions who are Competing interests
eligible for both IVT and endovascular therapy. The author declares no competing interests.

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