Cell Swelling Contributes to Thickening of Low-dose N-methyl-D-aspartate-induced Retinal Edema

Purpose: The contribution of cell swelling versus vascular leakage in retinal edema remains largely undefined. The objective of this study was to use in vivo magnetic resonance imaging (MRI) to assess retinal cell swelling in the edematous mouse retina.

Methods: Inner retinal edema was induced by intravitreal injection of 2.5 nmol N-methyl-D-aspartate (NMDA). To assess retinal cell swelling, diffusion MRI was performed at baseline, 3-hours, 1 day, 3 days, and 7 days (n ≥ 5 at each time point) after NMDA injection. To detect retinal vascular leakage, gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) enhanced MRI was performed at baseline, 3 hours and 1 day (n = 5 for each group) after NMDA injection. Upon the completion of MRI, mouse eyes were enucleated, cryosectioned, and stained for assessing retinal layer thickness and cell death.

Results: Inner retinal cell swelling was hyperintense on diffusion-weighted images at 3 hours and 1 day after NMDA injection. The thickened inner retina was also seen in anatomic MRI and histology. Quantitatively, inner retinal apparent diffusion coefficient (ADC) decreased approximately 20% at 3 hours and 1 day after NMDA injection (P < 0.05 compared with baseline), suggesting cell swelling. Systematic injection of paramagnetic Gd-DTPA did not alter vitreous longitudinal relaxation time (T1) at baseline or at 3 hours after NMDA injection. In contrast, vitreous T1 in mice decreased 16 ± 6% (P < 0.05), reflecting retinal vascular leakage at 1 day after NMDA injection.

Conclusions: Noninvasive diffusion MRI was performed to detect retinal cell swelling in vivo. Our results demonstrated that retinal cell swelling could directly lead to retinal thickening independent of vascular leakage.