Asymmetric Functional Impairment of ON and OFF Retinal Pathways in Glaucoma

Purpose: To investigate ON-pathway versus OFF-pathway dysfunction in glaucoma using handheld elec-troretinography (ERG) with a temporally modulated sinusoidal flicker stimulus.Design: Cross-sectional study.Participants: Fifty-nine participants accounting for 104 eyes, comprised of 19 control eyes, 26 glaucoma suspect eyes, and 59 glaucoma eyes.Methods: Participants underwent portable ERG testing, which included the photopic flash, photopic flicker, photopic negative response stimulus, ON-OFF stimulus, and a custom-written sinusoidal flicker stimulus that was modulated from 50 to 0.3 Hz.Main Outcome and Measures: The ERG response amplitudes were measured by the handheld ERG. For the custom-written sinusoidal flicker stimulus, we derived and compared the log10 first harmonic frequency response amplitudes. Patient discomfort and fatigue after ERG testing were rated on a scale from 1 to 5Results: Baseline demographics were not significantly different between groups, except for ocular charac-teristics. Analysis was performed adjusting for participant age, sex, race, and dilation status, and the sinusoidal frequency responses were stratified at 10 Hz because higher frequencies are associated with the OFF-pathway, whereas lower frequencies are associated with the ON-pathway. After stratification, glaucoma eyes showed an adjusted decrease of 32.1% at frequencies of more than 10 Hz (95% confidence interval [CI], -51.8% to -4.1%; P = 0.03). For 10 Hz stimulus frequencies or less, an adjusted 11.5% reduction was found (95% CI, -39.5% to 29.1%; P = 0.50). Glaucoma suspect eyes did show a decreased response, but this was not significant at either frequency range. When comparing handheld ERG with traditional visual field assessments, participants found the handheld ERG to result in much less discomfort and fatigue.Conclusions: Our finding that glaucoma participants showed greater decreases in ERG response at higher frequencies supports the hypothesis that the OFF-pathway may be more vulnerable in human glaucoma. Using a handheld ERG device with a sinusoidal flicker stimulus may provide an objective assessment of visual function in glaucoma. Ophthalmology Science 2021;1:100026 & COPY; 2021 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).