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Lim et al. Vessel Plus 2021;5:34 https://dx.doi.org/10.20517/2574-1209.2021.44 Page 3 of 9

The DWI lesion was thought initially to represent the region of restricted diffusion with failure of the
+
+
Na /K pump. Subsequently, the DWI lesion was found to represent both infarcted tissue and penumbra,
and visible perfusion abnormality also included regions of benign oligemia . These concepts have been
[14]
further refined: the current method of estimating infarcted tissue with MRI is by applying an apparent
diffusion coefficient threshold of ≤ 620 × 10 mm /s to identify core voxels . The revised definition of
2
-6
[15]
[16]
hypoperfused tissue is now T < 6 s . An issue with the use of MR imaging to define the ischemic
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penumbra is that the DWI and PWI images are acquired at different orientations. As such the mismatch
may be underestimated when using the formula PWI lesion minus DWI lesion. The so-called hidden
mismatch is revealed when the PWI and DWI images are registered to the same coordinates [17,18] . CTP can
produce perfusion maps with the same parameters as PWI. It has an advantage in that registration of the
images is not required in the calculation of the perfusion mismatch. CTP appears to be a viable alternative
and has been demonstrated to have similar accuracy [19,20] .
EARLY WORKS
Both the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET) and the Diffusion and Perfusion
Imaging Evaluation For Understanding Stroke Evolution (DEFUSE) studies demonstrated favorable
outcomes in stroke patients with a perfusion/diffusion mismatch treated with IV rtPA within 3-6 h of
symptom onset [21,22] . It is thought that the original EPITHET outcome was negative as it included oligemic
region in the analysis (T threshold 2 s). In subsequent analysis, changing the perfusion threshold (T 6 s)
max
max
resulted in positive trial outcome [16,23] . Furthermore, post-hoc analysis of the combined EPITHET-DEFUSE
dataset with the revised T threshold of > 6 s demonstrated reduced infarct growth and increased
max
[24]
reperfusion rates in the mismatch patients who received alteplase .
CT perfusion was also available at the time, but investigators were reading it visually, not quantitatively. The
double-blind, randomised, placebo-controlled phase 3 trial DIAS-3 (safety and efficacy of desmoteplase
given 3-9 h after ischemic stroke in patients with occlusion or high-grade stenosis in major cerebral arteries)
demonstrated no improvement in functional outcome with image-guided desmoteplase treatment . This
[25]
visual rather than quantitative analysis of perfusion data may be one of the reasons for the negative result, as
it has been demonstrated that volumetric calculation of mismatch is superior to visual assessment . Given
[26]
that visual assessment overestimates tissue at risk of infarction, there was a need for standardization of
lesion segmentation using objective criteria to strengthen methodology of further randomized trials. Fully
automated software packages were developed which were well validated in estimating ischemic core and
penumbra [27,28] .

With this in mind, the EXtending the time for Thrombolysis in Emergency Neurological Deficits
(EXTEND) trial was designed, building on these lessons. The investigators used automated perfusion
[29]
software (RAPID, iSchemaView) to aid treatment decision. The purpose was to test the use of perfusion
imaging selection of patients who presented 4.5 to 9 h after stroke onset or with wake-up stroke within 9 h
from the midpoint of sleep . Concurrently, a Multicenter, Randomized, Double-Blind, Placebo-Controlled
[29]
Trial to Test Efficacy and Safety of Magnetic Resonance Imaging-Based Thrombolysis in Wake-up Stroke
(WAKE-UP), was designed to test whether a different imaging approach (DWI-FLAIR mismatch) could be
[30]
used to select stroke patients with unknown time of onset e.g., waking up with symptoms .
Two endovascular thrombectomy trials also attempted to demonstrate the clinical benefit from selecting
patients with advanced imaging for endovascular clot retrieval in the late time window. The DAWN trial
(DWI or CTP Assessment With Clinical Mismatch in the Triage of Wake-Up and Late Presenting Strokes
Undergoing Neurointervention With Trevo) tested the concept of clinical-imaging mismatch to select their