Longitudinal changes in optoretinography provide an early and sensitive biomarker of outer retinal disease

Abstract

Objective: To examine whether optoretinography (ORG) can provide greater sensitivity for assessing the time-course of disease progression in Retinitis Pigmentosa compared to standard clinical imaging in a longitudinal study.

Design: Cohort, longitudinal study.

Participants: Five non-syndromic RP patients and eight control subjects participated in the study.

Methods: Clinical examination, imaging sessions and data analysis were all conducted at the University of Washington. Five eyes of 5 patients diagnosed with RP, comparing standard clinical imaging to ORG, were collected over a 21-month span between August 2022 and May 2024.

Main outcome and measures: ORG response to visual stimuli, ellipsoid zone (EZ) width and outer segment length (OS length) were evaluated for longitudinal changes as markers of disease progression.

Results: The reduction in cone function with ORG over time exceeds that observed in standard clinical markers of photoreceptor structure - EZ width and OS length. EZ width and OSL decreased by 4.5% ± 5.9% and 6.5% ± 1.4%, respectively, approximately 9.9 and 6.9 times less than the reduction noted in ORG, respectively. The most notable degradation was noted at the borders of the transition zone, where ORG showed progressive and sub-clinical losses in photoreceptor function whereas standard OCT showed healthy, unaffected outer retinal structure.

Conclusions: Optoretinography detects sub-clinical disease and reliably identifies longitudinal markers of progression with greater sensitivity compared to standard clinical imaging. The ability to detect functional changes in the outer retina prior to standard clinical measures underscores its potential as a sensitive, accelerated and clinically-relevant outcome measure to guide patient selection and their therapeutic response in future clinical trials.

Figure 1.

Overview of study design, illustrating the advanced structure-function assessment. OCT volumes along with the segmented en face image at the inner/outer segment-ellipsoid zone (ISOS-EZ) and outer segment tips (COST) help visualize the retinal structure (A). A zoomed-in view of OCT B-scans provides the outer retinal profile (red line) from which the OS length is obtained and plotted as a function of eccentricity in a color map (B). Warmer and cooler colors represent longer and shorter OS lengths respectively. Retinal function is assessed by measuring the change in outer segment optical path length (ΔOPL) evoked by a light stimulus (shaded green) – denoted as the ORG amplitude (D). The saturated ORG amplitude is obtained from the time evolution of the functional response, shown in (D) for a near-foveal (gray) and parafoveal (black) retinal location. The shaded areas around the solid lines indicate the standard-deviation of repeat measurements. The variation of the saturated ORG is plotted as a function of eccentricity in a color map (E). Test-retest (left) and Bland-Altman analysis (right) shows high repeatability for both OS length (C) and ORG (F).

Figure 2.

Example longitudinal study analysis pipeline for RP01. (A) Clinical OCT B-scans from baseline (top) and follow-up (bottom) visit. Red arrows indicate the fovea. Red & yellow dashed lines mark the EZ width boundaries at baseline and follow-up respectively. (B) Fundus autofluorescence (FAF) from baseline (top) and follow-up (bottom) visit. The white dashed ellipse outlines the EZ area, while the blue rectangle marks the region selected for further OCT-ORG analysis. (C) En face images for baseline (top) and follow-up (bottom), with the corresponding EZ area from (B) marked as a white dashed ellipse. The yellow ellipse highlights the area chosen for OSL and ORG analysis, based on the preservation of all outer retinal layers. Maps of (D) OS length and (E) ORG amplitude are shown for baseline (top) and follow-up (bottom). An outline is drawn in the OS length and ORG maps, as reference for comparison between baseline and follow-up visits.

Figure 3.

Longitudinal follow-up in RP03, RP04, and RP05, displaying the progression from the initial baseline visit to the most recent follow-up. (A) Baseline and follow-up en face images at the ISOS-EZ band and the corresponding ROIs (red) selected for OS length and ORG analysis. Maps of OS length and ORG are shown in (B) and (C) respectively. Their corresponding color bars denote the variation in OS length and ORG response amplitude. Yellow dashed lines and arrows indicate the same location for reference across follow-ups.

Figure 4.

Comparison of biomarkers for detecting RP disease progression. (A) The ORG maps are divided into regions-of-interest (ROIs) (white circles) to allow regional comparison of photoreceptor dysfunction. ORGedge and ORGcent are derived from ROIs at the border of the healthy island and in the central fovea, respectively, while ORGtot is obtained from the entire ORG map. The fovea is indicated by a red star. (B) Comparison of regional metrics derived from ORG, including ORGtot, ORGedge, and ORGcent. (C) Corresponding metrics from OS length, including OSLtot, OSLedge, and OSLcent in (C). (D) Scatter and bar plots showing the percentage reduction in ORGedge amplitude over time for the five RP patients, with pink and purple shades representing the first and second follow-up visits, respectively. Connecting lines illustrate ORG changes for the same imaged location across the different follow-ups. Statistical significance values obtained from the Wilcoxon signed-rank test are noted for (D).

Figure 5.

Comparison between ORGedge, OS length, and EZ-width for the five RP patients. Statistical significance values obtained from the Wilcoxon signed-rank test are noted in the plot.