Early localized alterations of the retinal inner plexiform layer in association with visual field worsening in glaucoma patients

Abstract

Glaucoma is a chronic neurodegenerative disease of the optic nerve and a leading cause of irreversible blindness, worldwide. While the experimental research using animal models provides growing information about cellular and molecular processes, parallel analysis of the clinical presentation of glaucoma accelerates the translational progress towards improved understanding, treatment, and clinical testing of glaucoma. Optic nerve axon injury triggers early alterations of retinal ganglion cell (RGC) synapses with function deficits prior to manifest RGC loss in animal models of glaucoma. For testing the clinical relevance of experimental observations, this study analyzed the functional correlation of localized alterations in the inner plexiform layer (IPL), where RGCs establish synaptic connections with retinal bipolar and amacrine cells. Participants of the study included a retrospective cohort of 36 eyes with glaucoma and a control group of 18 non-glaucomatous subjects followed for two-years. The IPL was analyzed on consecutively collected macular SD-OCT scans, and functional correlations with corresponding 10–2 visual field scores were tested using generalized estimating equations (GEE) models. The GEE-estimated rate of decrease in IPL thickness (R = 0.36, P<0.001) and IPL density (R = 0.36, P<0.001), as opposed to unchanged or increased IPL thickness or density, was significantly associated with visual field worsening at corresponding analysis locations. Based on multivariate logistic regression analysis, this association was independent from the patients’ age, the baseline visual field scores, or the baseline thickness or alterations of retinal nerve fiber or RGC layers (P>0.05). These findings support early localized IPL alterations in correlation with progressing visual field defects in glaucomatous eyes. Considering the experimental data, glaucoma-related increase in IPL thickness/density might reflect dendritic remodeling, mitochondrial redistribution, and glial responses for synapse maintenance, but decreased IPL thickness/density might correspond to dendrite atrophy. The bridging of experimental data with clinical findings encourages further research along the translational path.

High sampling resolution optical coherence tomography reveals potential concurrent reductions in ganglion cell‐inner plexiform and inner nuclear layer thickness but not in outer retinal thickness in glaucoma

“…Given the links between retinal cell parameters and retinal thickness measurements acquired using OCT, 52,72 understanding of retinal circuitry via histological studies provides a theoretical basis for the observed interactions between GCIPL and INL thickness measurements. In animal models of glaucoma, reductions in retinal ganglion cell dendrite density have been previously identified, 5,6 and reductions in IPL thickness in human OCT‐based studies similarly suggest that retinal ganglion cell‐INL connections are disrupted in glaucoma 73–75 . Furthermore, in ischaemia/reperfusion studies of the rat retina, both retinal ganglion cell and bipolar cell loss have been reported, 76,77 indicating potential concurrent or consecutive processes impact viability of both cell types.…”

“…In animal models of glaucoma, reductions in retinal ganglion cell dendrite density have been previously identified, 5,6 and reductions in IPL thickness in human OCT-based studies similarly suggest that retinal ganglion cell-INL connections are disrupted in glaucoma. [73][74][75] Furthermore, in ischaemia/reperfusion studies of the rat retina, both retinal ganglion cell and bipolar cell loss have been reported, 76,77 indicating potential concurrent or consecutive processes impact viability of both cell types. There are a multitude of synaptic targets onto retinal ganglion cells, including cone bipolar cells and various amacrine cells.…”