Validating imaging biomarkers of cerebral edema in patients with severe ischemic stroke

Abstract

Background: There is no validated neuroimaging marker for quantifying brain edema. We sought to test whether magnetic resonance imaging (MRI)-based metrics would reliably change during the early subacute period in a manner consistent with edema and whether they would correlate with relevant clinical endpoints.

Methods: Serial MRI studies from patients in the Echoplanar Imaging Thrombolytic Evaluation Trial with initial diffusion-weighted imaging (DWI) lesion volume >82 cm(3) were analyzed. Two independent readers outlined the hemisphere and lateral ventricle on the involved side and calculated respective volumes at baseline and days 3 to 5. We assessed interrater agreement, volume change between scans, and the association of volume change with early neurologic deterioration (National Institutes of Health Stroke Scale score worsening of ≥ 4 points), a 90-day modified Rankin scale (mRS) score of 0 to 4, and mortality.

Results: Of 12 patients who met study criteria, average baseline and follow-up DWI lesion size was 138 cm(3) and 234 cm(3), respectively. The mean time to follow-up MRI was 62 hours. Concordance correlation coefficients between readers were >0.90 for both hemisphere and ventricle volume assessment. Mean percent hemisphere volume increase was 16.2 ± 8.3% (P < .0001), and the mean percent ventricle volume decrease was 45.6 ± 16.9% (P < .001). Percent hemisphere growth predicted early neurologic deterioration (area under the curve [AUC] 0.92; P = .0005) and 90-day mRS 0 to 4 (AUC 0.80; P = .02).

Conclusions: In this exploratory analysis of severe ischemic stroke patients, statistically significant changes in hemisphere and ventricular volumes within the first week are consistent with expected changes of cerebral edema. MRI-based analysis of hemisphere growth appears to be a suitable biomarker for edema formation.

Keywords: Acute ischemic stroke; biomarker subject codes 44 and 45; cerebral edema; magnetic resonance imaging; malignant stroke.

Figure 1

Examples of reader outlines on diffusion-weighted imaging for baseline hemisphere (a) and ventricle (b) volumes from one subject.

Figure 1

Examples of reader outlines on diffusion-weighted imaging for baseline hemisphere (a) and ventricle (b) volumes from one subject.

Figure 2

Scatter plots demonstrate the observed agreement between readers 1 and 2 for hemisphere volume measurements at (a) baseline and (b) follow up. On both graphs, data points approximate the identity line (slope=1) indicating strong agreement.

Figure 2

Scatter plots demonstrate the observed agreement between readers 1 and 2 for hemisphere volume measurements at (a) baseline and (b) follow up. On both graphs, data points approximate the identity line (slope=1) indicating strong agreement.

Figure 3

Bland-Altman plots of percent inter-rater difference for hemisphere volume measurements relative to average hemisphere volume for (a) baseline and (b) follow up.

Figure 3

Bland-Altman plots of percent inter-rater difference for hemisphere volume measurements relative to average hemisphere volume for (a) baseline and (b) follow up.