Aquaporin-4-IgG (AQP4-IgG) seropositive Neuromyelitis Optica Spectrum Disorder (NMOSD) typically presents with discrete attacks of optic neuritis (ON) and transverse myelitis, and insidious subclinical disease activity is considered a rare occurrence. Prior optical coherence tomography (OCT) studies have suggested that subclinical retinal abnormalities, including lower foveal thickness and altered foveal morphology, may be present in AQP4-IgG+ NMOSD in the absence of a clinical history of ON; however, existing studies were relatively small.
To compare retinal layer thicknesses at the fovea and surrounding macula between AQP4-IgG+ NMOSD eyes without a history of ON (AQP4-nonON) and healthy controls (HC).
In this single-center cross-sectional study, 83 AQP4-nonON and 153 HC eyes were studied with spectral-domain OCT. Statistical analyses were performed with generalized estimating equations (GEE) and were adjusted for age, sex and race.
Total foveal thickness did not differ between AQP4-nonON and HC eyes (-3.55±3.79μm, p=0.35). AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01±2.03μm, p=0.049; IS: -0.32±0.14μm, p=0.029) and surrounding macula (ONL: -1.98±0.95μm, p=0.037; IS: -0.16±0.07μm, p=0.023), compared to HC. Macular retinal nerve fiber layer (mRNFL: -1.34±0.51μm, p=0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44±0.93μm, p=0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. The magnitude of the estimated differences was similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye (n=33 patients; mRNFL: -1.33±0.60μm, p=0.026; GCIPL: -2.59±1.12μm, p=0.021; macular ONL: -2.01±1.04μm, p=0.052; macular IS: -0.16±0.08μm, p=0.031; foveal ONL: -3.78±2.28μm, p=0.10; foveal IS: -0.28±0.19μm, p=0.14).
AQP4-nonON eyes exhibited evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These results remained largely unaltered in analyses limited to patients who had never experienced ON, suggesting that they are likely related to processes that are independent of clinically overt ON attacks. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD, and may relate to a primary retinal process or subclinical optic neuropathy.