Altered Cone Structure and Function in Subjects with Pentosan Polysulfate Sodium Toxicity

Abstract

Purpose : Recently approved FDA treatments and ongoing clinical trials to slow progression of complete retinal pigment epithelium and retinal atrophy (cRORA) and its formation (incomplete iRORA) has created a pressing need to predict changes in c/iRORA. Primary clinical biomarkers are structural measurements extracted from optical coherence tomography (OCT) images, but these are insufficiently sensitive to predict the evolution of c/iRORA. The change in c/iRORA dynamically varies over months to years and between eyes of the same individual. We hypothesize that measurements of cellular-level structure and function in retina at risk of c/iRORA encroachment could improve our ability to predict progression. In this study, we use adaptive optics (AO)OCT to measure changes to the cone outer segment (OS) and cone function (phase optoretinogram (ORG)) near i/cRORA in subjects with pentosan polysulfate sodium toxicity (PPST) as a disease model.

Methods : PPST subjects (n=4, 44-67 YO) and a control subject (40 YO) underwent ORG with AO-OCT in 1°x0.8° regions of interest (ROIs, n=5) ≥ 2° from an i/cRORA boundary. ORG responses from S cones then by M & L cones were elicited with a two-pulsed stimulus (434 and 568 nm) delivered 1 s apart. The inner segment/outer segment (IS/OS) reflection and reflections along the OS were automatically identified in the A-scan. ORG response amplitude was measured as the change in OS length (nm) after stimulation. The most posterior reflection associated with a cone-like ORG response was selected as the cone OS tip. Correlations between metrics was determined by Pearson's correlation coefficient.

Results : Cone metrics were not different between ROIs near iRORA (n=3) compared to those near cRORA (n=2). Cone density ranged from just within the 95% confidence interval of published norms specific to retinal eccentricity (n=3) to abnormal (n=2). Only one subject retained ORG responding S cones. For all ROIs with measurable ORG responses, the percent of functioning cones by ORG and the diminished mean L & M ORG response strongly trended with cone density loss (r=0.93, p=0.06 and r=0.92, p=0.07, n=4, respectively). One ROI did not have an appreciable ORG response. Individual cone OS length did not correlate with individual cone ORG amplitude.

Conclusions : Our study demonstrates a significant loss of ORG related cone function in PPST in areas surrounding i/cRORA.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.