Lina Palaiodimou, MD

Cheng B, Boutitie F, Nickel A, Wouters A, Cho T-H, Ebinger M, et al. Quantitative Signal Intensity in Fluid-Attenuated Inversion Recovery and Treatment Effect in the WAKE-UP Trial. Stroke. 2019.

Advanced neuroimaging has already changed the scene in acute stroke treatment, allowing patients with unknown or extended time windows to receive recanalization therapies (intravenous thrombolysis, mechanical thrombectomy). The cornerstone of this recent breakthrough is the demonstration of viable brain tissue regardless of time elapsed since stroke onset. That was also the case in the WAKE-UP trial, which proved clinical benefit in alteplase-treated acute stroke patients with unknown time of onset, but clearly presenting salvageable brain tissue, as was demonstrated by diffusion-weighted imaging (DWI) – fluid-attenuated inversion recovery (FLAIR) mismatch.   

The study by Cheng et al. presents a post-hoc analysis of the WAKE-UP trial with the aim to associate quantitatively measured relative signal intensity in FLAIR (rSI-FLAIR) with the clinical outcomes of the treated patients. The objective of this study was rationalized by previous studies, which correlated rSI-FLAIR with time elapsed since stroke onset. That correlation was linear; higher rSI-FLAIR corresponded to longer time since stroke onset and, actually, when the clock was ticking, FLAIR was glowing. Consequently, Cheng et al. moved to the next logical reasoning that, since rSI-FLAIR is associated with time and time is associated with clinical outcomes, rSI-FLAIR may relate to clinical outcomes of alteplase-treated patients. 

In this post-hoc analysis, Cheng et al. selected patients from the WAKE-UP trial who presented with unilateral ischemic lesions only. This selection criterion was inevitable, since investigators had to compare signal intensity between the lesion and the “healthy” contra-lesional region. That was also the reason for excluding patients with extensive white matter hyperintensities in regions selected for reference measurement. With further exclusion of a subset of patients with imaging data of bad quality, the authors proceeded to the analysis of 443 patients. Imaging analysis was performed by a semi-automated procedure that measured signal intensity of FLAIR within stroke lesions, as were defined by maps of apparent diffusion coefficient (ADC), and the mirror-regions of the stroke lesions, as were designed through a 3-dimensional plane. FLAIR-rSI was calculated as the ratio between FLAIR-SI of stroke lesion to FLAIR-SI of mirror-regions. Outcomes of interest were favorable outcome at 90 days after stroke as defined by modified Rankin Scale (mRS) of 0-1, shift analysis of mRS with desire for lower scores at 90 days after stroke and independent outcome as defined by mRS of 0-2 at 90 days after stroke. Analysis was adjusted for National Institutes of Health Stroke Scale (NIHSS) at symptom onset and for stroke lesion volume.

After successfully quantified FLAIR-rSI in all 443 patients, the authors concluded that the interaction between FLAIR-rSI and treatment effect of alteplase was not significant for favorable outcome (mRS 0-1) or for lower scores of mRS (shift analysis) at 90 days. Nevertheless, a trend was noticed towards a continuous association of higher FLAIR-rSI and decreased treatment effect regarding those two outcomes of interest. Statistical significance was reached regarding the relationship between independent outcome (mRS 0-2) at 90 days and FLAIR-rSI, also demonstrating a negative continuous association. These results led the authors to conclude that higher FLAIR-rSI of stroke lesions was associated with decreased treatment effects of intravenous thrombolysis and consequently can be considered as “a valuable factor in multivariate and imaging-based individualized approaches for treatment of patients with acute stroke.”

Certain limitations exist in the study. First, this is a post-hoc analysis, and the results should be interpreted with caution. Twelve percent of WAKE-UP trial patients were excluded from the analysis, and no data exist in the article about baseline and outcome differences between patients included and excluded. Furthermore, the WAKE-UP trial was designed with the outcomes of interest of the favorable outcome (mRS 0-1) and the shift analysis of mRS at 90 days. Independent outcome (mRS 0-2) was further added for the sake of this post-hoc analysis, and it was the only outcome that reached statistical significance. Finally, there are no data about how many patients, who were included in the analysis, presented with infratentorial stroke and whether measuring FLAIR-rSI in small lesions located in the brainstem is feasible.

Despite the limitations, Cheng et al. presented a well-designed post-hoc analysis using robust and innovative neuroimaging methodology. However, the association of FLAIR-rSI with clinical outcomes in stroke patients should be investigated in adjusted models for more confounding factors, such as collateral status, or even for the time elapsed since stroke onset. Further studies are needed in order to prove an independent association of FLAIR-rSI and treatment efficacy, regardless of time and other factors, in verification and validation cohorts.