Quantitative Markers of Neural Changes, Retinal Thickness, and Responses to Electrical Stimulation in Retinal Degeneration.

Purpose: Inherited retinal dystrophies demonstrate significant heterogeneity in the severity and distribution of photoreceptor loss. Current quantitative methodologies, however, do not account for this within-eye variation, which may explain conflicting findings regarding the efficacy of interventional strategies. Design: We developed an eccentricity-agnostic measure of photoreceptor loss and determined if accounting for localized changes in retinal degeneration could explain the performance of an implanted retinal prosthesis. Subjects: Hematoxylin and eosin stained, full thickness retinal cross sections of control eyes and eyes of an adenosine triphosphate-induced feline model of retinal degeneration (n = 4) were imaged. Methods: Individual regions of 250 μm length were quantified for localized photoreceptor degeneration using the Outer Retina ratio (ORr). Regions were categorized into no, mild, moderate, or severe degeneration groups. Main Outcome Measures: Outer Retina ratio was correlated to neural markers using 3,3'-diaminobenzidine or fluorescent immunohistochemistry to determine if localized remodeling occurred within ORr defined regions. Outer Retina ratio was also assessed against measures of cortical neural activity evoked by electrical stimulation through a suprachoroidally implanted electrode array. Results: Outer Retina ratio effectively correlated with changes in rhodopsin and cone opsin labeling in the outer retina as well as inner retinal changes in calbindin, protein kinase C alpha, and RNA-binding protein with multiple splicing labeling. Assessment of degenerative retina categorized using ORr also identified disease alterations missed via pooled analyses including the presence of reduced opsin immunoreactivity and retraction in regions yet to exhibit signs of photoreceptor loss. There were some differences in cortical measures between ORr groups and weak individual correlations ( Conclusions: These findings suggest that ORr is a valid estimator of heterogeneous degeneration in a retinal degeneration model and could be useful to identify areas with specific degenerative features in retinal degeneration. However, more work is needed to determine the quantitative remodeling metrics (and other nonretinal multi-factors) that best serve as estimates for the efficacy of therapeutic interventions. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.