Quantitative signal intensity in Fluid-Attenuated Inversion Recovery and treatment effect in the WAKE-UP trial

Background and Purpose: Relative signal intensity of acute ischemic stroke lesions in fluid-attenuated inversion recovery (fluid-attenuated inversion recovery relative signal intensity [FLAIR-rSI]) magnetic resonance imaging is associated with time elapsed since stroke onset with higher intensities signifying longer time intervals. In the randomized controlled WAKE-UP trial (Efficacy and Safety of MRI-Based Thrombolysis in Wake-Up Stroke Trial), intravenous alteplase was effective in patients with unknown onset stroke selected by visual assessment of diffusion weighted imaging fluid-attenuated inversion recovery mismatch, that is, in those with no marked fluid-attenuated inversion recovery hyperintensity in the region of the acute diffusion weighted imaging lesion. In this post hoc analysis, we investigated whether quantitatively measured FLAIR-rSI modifies treatment effect of intravenous alteplase. Methods: FLAIR-rSI of stroke lesions was measured relative to signal intensity in a mirrored region in the contralesional hemisphere. The relationship between FLAIR-rSI and treatment effect on functional outcome assessed by the modified Rankin Scale (mRS) after 90 days was analyzed by binary logistic regression using different end points, that is, favorable outcome defined as mRS score of 0 to 1, independent outcome defined as mRS score of 0 to 2, ordinal analysis of mRS scores (shift analysis). All models were adjusted for National Institutes of Health Stroke Scale at symptom onset and stroke lesion volume. Results: FLAIR-rSI was successfully quantified in stroke lesions in 433 patients (86% of 503 patients included in WAKE-UP). Mean FLAIR-rSI was 1.06 (SD, 0.09). Interaction of FLAIR-rSI and treatment effect was not significant for mRS score of 0 to 1 (P=0.169) and shift analysis (P=0.086) but reached significance for mRS score of 0 to 2 (P=0.004). We observed a smooth continuing trend of decreasing treatment effects in relation to clinical end points with increasing FLAIR-rSI. Conclusions: In patients in whom no marked parenchymal fluid-attenuated inversion recovery hyperintensity was detected by visual judgement in the WAKE-UP trial, higher FLAIR-rSI of diffusion weighted imaging lesions was associated with decreased treatment effects of intravenous thrombolysis. This parallels the known association of treatment effect and elapsing time of stroke onset

Advanced imaging in acute ischemic stroke of unknown onset

Stroke of unknown onset accounts for up to 20% of all acute ischemic stroke. Prior to the successful completion of the Efficacy and Safety of MRI-Based Thrombolysis in WAKE UP Stroke (WAKE UP) trial, these patients were typically excluded from treatment with IV tPA as this therapy was only approved for cases within 4.5 hours of known symptom onset. WAKE UP utilized a novel imaging biomarker of lesion age, the DWI-FLAIR mismatch (acute stroke visible on DWI but not yet visible on FLAIR), to allocate patients into the early time window for which thrombolysis has been proven safe and efficient; a concept which became known as “tissue clocking”. As a multicenter and imaging-heavy trial, WAKE UP relied upon a homogeneous understanding and interpretation of its imaging criteria by all of its many investigators, a process that was safeguarded by dedicated training developed especially for the study’s purposes. The study was successful and, upon its completion in 2017, together with two smaller and similar trials that were completed at comparable time points, WAKE UP generated enough high quality evidence to influence a change in official guidelines, now recommending thrombolysis for patients with stroke of unknown onset who satisfy WAKE UP criteria. Various sub-analyses conducted since on the WAKE UP cohort further cemented the credibility of tissue clocking as a patient selection paradigm. But it is not the only such model. In addition to tissue clocking another concept, dubbed penumbral imaging and used as a biomarker of tissue at risk of infarction, has also been investigated in large clinical trials such as EXTEND and ECASS-4, as a way to offer treatment to patients with unknown symptom onset. Both of these methods fall under the umbrella of advanced imaging because they necessitate hardware and/or software as well as expertise in image interpretation that is not routinely available in the majority of the world’s hospitals. Tissue clocking (using magnetic resonance imaging and the DWI-FLAIR mismatch) as well as penumbral imaging (using MR or CT based perfusion imaging) offer a lot of additional information, and through it, assurance to the treating physician that potential risks have been minimized and possible benefits of therapy enhanced. In this sense, advanced brain imaging should definitely be considered as part of state of the art, evidence based stroke treatment. Especially in the unknown time window, and due to its ability to perform both tissue clocking and penumbral imaging, MRI as a modality has been proposed as the most inclusive approach to screening ischemic stroke patients in hopes of identifying those still eligible for thrombolytic treatment. However, this approach clearly suffers the drawback of limited availability in everyday clinical practice. Further, well-designed and well-conducted prospective, randomized, controlled trials should be performed to evaluate the exact scope of (advanced) imaging needed for an as-inclusive-as-possible and successful patient selection in the unknown time window