Analysis of brain edema in RHAPSODY

Abstract

Background: Cerebral edema is a secondary complication of acute ischemic stroke, but its time course and imaging markers are not fully understood. Recently, net water uptake (NWU) has been proposed as a novel marker of edema.

Aims: Studying the RHAPSODY trial cohort, we sought to characterize the time course of edema and test the hypothesis that NWU provides distinct information when added to traditional markers of cerebral edema after stroke by examining its association with other markers.

Methods: A total of 65 patients had measurable supratentorial ischemic lesions. Patients underwent head computed tomography (CT), brain magnetic resonance imaging (MRI) scans, or both at the baseline visit and after 2, 7, 30, and 90 days following enrollment. CT and MRI scans were used to measure four imaging markers of edema: midline shift (MLS), hemisphere volume ratio (HVR), cerebrospinal fluid (CSF) volume, and NWU using semi-quantitative threshold analysis. Trajectories of the markers were summarized, as available. Correlations of the markers of edema were computed and the markers compared by clinical outcome. Regression models were used to examine the effect of 3K3A-activated protein C (APC) treatment.

Results: Two measures of mass effect, MLS and HVR, could be measured on all imaging modalities, and had values available across all time points. Accordingly, mass effect reached a maximum level by day 7, normalized by day 30, and then reversed by day 90 for both measures. In the first 2 days after stroke, the change in CSF volume was associated with MLS (ρ = -0.57, p = 0.0001) and HVR (ρ = -0.66, p < 0.0001). In contrast, the change in NWU was not associated with the other imaging markers (all p ⩾ 0.49). While being directionally consistent, we did not observe a difference in the edema markers by clinical outcome. In addition, baseline stroke volume was associated with all markers (MLS (p < 0.001), HVR (p < 0.001), change in CSF volume (p = 0.003)) with the exception of NWU (p = 0.5). Exploratory analysis did not reveal a difference in cerebral edema markers by treatment arm.

Conclusions: Existing cerebral edema imaging markers potentially describe two distinct processes, including lesional water concentration (i.e. NWU) and mass effect (MLS, HVR, and CSF volume). These two types of imaging markers may represent distinct aspects of cerebral edema, which could be useful for future trials targeting this process.

Keywords: Ischemic stroke; edema; imaging markers.

Figure 1.. Case examples for the measurement of imaging markers of edema.

(A) To measure NWU, lesional ROIs were measured on the CT scans. The ratio of Hounsfield units relative to a mirrored ROI on the contralateral hemisphere was calculated according to a previously published approach. In this example, $NWU=\frac{(35.14-29.52)}{35.14}\times 100=15.9\mathrm{\%}$ (B) Hemispheric volume was calculated on both left and right hemispheres, excluding the CSF spaces. The hemisphere volume ratio was then calculated as the ratio of the ischemic hemisphere volume to that of the contralateral hemisphere volume. (C) CSF volume was assessed including ventricular and sulcal CSF spaces.

Figure 2.. Edema formation and resolution over time by treatment group.

(A) NWU increases from the baseline to day 2 scan, representing an increase in water content. (B) CSF volume decreases over the same two timepoints. (C) MLS increases over the first 7 days before decreasing by day 90. This pattern occurs as the ischemic hemisphere swells, followed by a period of atrophy and hemisphere shrinkage at later timepoints. (D) Hemisphere volume ratio (HVR) shows a similar pattern to MLS, with an initial increase over the first 7 days followed by a decrease through day 90.