Retinal Structure in RPE65-Associated Retinal Dystrophy

Neruban Kumaran, Michalis Georgiou, James W B Bainbridge, Mette Bertelsen, Michael Larsen, Fiona Blanco-Kelly, Carmen Ayuso, Hoai Viet Tran, Francis L Munier, Angelos Kalitzeos, Michel Michaelides, Neruban Kumaran, Michalis Georgiou, James W B Bainbridge, Mette Bertelsen, Michael Larsen, Fiona Blanco-Kelly, Carmen Ayuso, Hoai Viet Tran, Francis L Munier, Angelos Kalitzeos, Michel Michaelides

Abstract

Purpose: RPE65-associated retinal dystrophy (RPE65-RD) is an early onset, progressive, severe retinal dystrophy. We sought to characterize the natural history of retinal degeneration in affected individuals.

Methods: We performed cross-sectional and longitudinal quantitative and qualitative assessments of retinal architecture in RPE65-RD using spectral domain optical coherence tomography (SD-OCT) and fundus autofluorescence (FAF) imaging. Twenty-six subjects (mean age, 14.8 years, range, 5-24 years) with RPE65-RD underwent SD-OCT and FAF imaging, of whom 14 subjects were followed up over time. Foveal thickness (FT), outer nuclear layer thickness (ONLT), ellipsoid zone width (EZW), and ellipsoid zone area (EZA) were calculated where possible. These were correlated with age, best corrected visual acuity (BCVA), and central 30° retinal sensitivity (V30). Intra-observer agreement, test-retest repeatability, and interocular symmetry were also investigated.

Results: We identified structural interocular symmetry, the presence of autofluorescence in 46% (12/26) of subjects, and the presence of foveal hypoplasia (associated with significantly worse BCVA) in 50% of subjects. EZW and EZA were measurable in 67% (35/52) and 37% (19/52) of eyes, respectively, with both demonstrating good agreement on repeated measurement. The annual rate of progression using EZW was -300.63 µm/year, and -1.17 mm2/year in EZA. EZW was found to have a statistically significant correlation with BCVA and V30.

Conclusions: We identified the presence of autofluorescence in half of our subjects, with foveal hypoplasia also noted in half of our cohort. EZW, and to a lesser extent EZA, were robust measures of retinal degeneration and represent valuable metrics to determine the impact of intervention. (ClinicalTrials.gov number NCT02714816.).

Conflict of interest statement

Disclosure: N. Kumaran, MeiraGTx (C); M. Georgiou, MeiraGTx (C); J.W.B. Bainbridge, MeiraGTx (C); M. Bertelsen, None; M. Larsen, None; F. Blanco-Kelly, None; C. Ayuso, None; H.V. Tran, None; F.L. Munier, None; A. Kalitzeos, None; M. Michaelides, MeiraGTx (C)

Figures

Figure 1.
Figure 1.
Example of SD-OCT en-face analysis. Example of the demarcated boundary on the infrared image of subject MM_0289, used to calculate the ellipsoid zone area (EZA), measured here as 9.56 mm2. Edges of the demarcated boundary shown on one B-scan using calipers as an example. The same caliper tool was used for ellipsoid zone width (EZW) measurements, but notably this was done using the 1 µm: 1 µm setting.
Figure 2.
Figure 2.
Disease symmetry in subjects with RPE65-associated RD. Interocular symmetry was observed in all five subjects. The orange bars mark the width of the ellipsoid zone and the blue arrows indicate the borders of where it is lost. Two of the five subjects have foveal hypoplasia and two subjects have an ellipsoid zone extending beyond the width of the scan (D and E). All scans are to the same scale.
Figure 3.
Figure 3.
Combined stacked scatterplots and box plots for SD-OCT measurements. Shown are stacked scatterplots and box plots for (A) foveal thickness (FT, n = 26 eyes), (B) outer nuclear layer thickness (ONLT, n = 26 eyes), (C) ellipsoid zone width (EZW, n = 17 eyes), and (D) ellipsoid zone area (EZA, n = 9 eyes) for the left eyes of all patients, where measurable. Box plots with box spanning interquartile range with maximum and minimum values (excluding outliers) are provided. Solid and dashed lines represent median and mean, respectively.
Figure 4.
Figure 4.
Agreement of SD-OCT ellipsoid zone measurements. (A) Bland-Altman plot of ellipsoid zone width (EZW; µm) demonstrating the mean difference (dashed line, 108.9 µm) and upper and lower limits of agreement (shaded area, −485.82 µm to 703.69 µm). (B) Bland-Altman plot of ellipsoid zone area (EZA; mm2) demonstrating the mean difference (dashed line, −0.17 mm2) and upper and lower limits of agreement (shaded area, −0.87 mm2 to 0.53 mm2).
Figure 5.
Figure 5.
Ellipsoid zone width (EZW) progression. Demonstrated is an example of EZW progression in a 21-year-old subject (MM_0262) over 19 months.
Figure 6.
Figure 6.
Examples of fundus autofluorescence phenotypes and associated SD-OCT scans seen in RPE65-RD. (A–C) The demonstrated increased central autofluorescence seen in some subjects with RPE65-RD, (D) demonstrates findings in a healthy control for comparison. White lines indicate the position and extent of the SD-OCT B-scans.

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