Evidence of Müller glial dysfunction in patients with aquaporin-4 immunoglobulin G–positive neuromyelitis optica spectrum disorder

Purpose To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Design Cross-sectional study; biochemical study of human retinas. Participants A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. Methods Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Muller glial distribution were analyzed using Western blotting and immunohistochemistry. Main Outcome Measures Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. Results The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Muller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction ( P  = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Muller cell–specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Muller glial distribution in the human macula. Conclusions This study provides in vivo structural and functional evidence of Muller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Muller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD.