A Cross-Sectional and Longitudinal Study of Retinal Sensitivity in RPE65-Associated Leber Congenital Amaurosis

Neruban Kumaran, Gary S Rubin, Angelos Kalitzeos, Kaoru Fujinami, James W B Bainbridge, Richard G Weleber, Michel Michaelides, Neruban Kumaran, Gary S Rubin, Angelos Kalitzeos, Kaoru Fujinami, James W B Bainbridge, Richard G Weleber, Michel Michaelides

Abstract

Purpose: RPE65-associated Leber congenital amaurosis (RPE65-LCA) is an early-onset severe retinal dystrophy associated with progressive visual field loss. Phase I/II and III gene therapy trials have identified improved retinal sensitivity but little is known about the natural history of retinal sensitivity in RPE65-LCA.

Methods: A total of 19 subjects (aged 9 to 23 years) undertook monocular full-field static perimetry of which 13 subjects were monitored longitudinally. Retinal sensitivity was measured as mean sensitivity (MS) and volumetrically quantified (in decibel-steradian) using visual field modeling and analysis software for the total (VTOT), central 30° (V30) and central 15° (V15) visual field. Correlation was evaluated between retinal sensitivity and age, best-corrected visual acuity (BCVA), contrast sensitivity, vision-related quality of life, and genotype. Test-retest reliability was also investigated.

Results: V30 was identified to have a strong, weak, and moderate correlation with age, BCVA and contrast sensitivity respectively. Furthermore, V30 was identified as having a weak linear relationship with the mobility and independence domains of the vision-related quality of life questionnaire. Longitudinal analysis demonstrated a slow loss of retinal sensitivity in this cohort. Subjects with at least one RPE65 nonsense variant appeared to show greater progressive loss of retinal sensitivity in the second decade of life than those without.

Conclusions: Volumetric assessment of central 30° visual field sensitivity, V30, is a useful independent measure of retinal function and, in our data, represented the best metric to monitor deterioration of retinal sensitivity in RPE65-LCA. Furthermore, functional correlation with genotype may enable more informed prognostic counseling. (ClinicalTrials.gov number, NCT02714816.)

Figures

Figure 1
Figure 1
Visual field sensitivity against age. Shown are scatterplots (including both eyes of all patients, n = 37) of (A) VTOT, (B) V30, and (C) V15 against age, demonstrating a decline in retinal sensitivity with increasing age across all three metrics.
Figure 2
Figure 2
(A) V30 compared to age. Shown is a scatterplot of V30 of the left eyes (n = 18) of all patients against their age, with the corresponding linear regression line. Shaded area denotes confidence interval for regression line. This demonstrates a strong, negative linear correlation (r = −0.67) between central 30° visual field sensitivity and age. (B) V30 compared to age, in the three genotype groups. Shown is a scatterplot of V30 of the left eyes of all patients against age, with linear regression lines for those in the “mild” (n = 5, r = + 0.46, red), “intermediate” (n = 7, r = −0.95, blue), and “severe” (n = 6, r = −0.67, green) genotype groups. This demonstrates the relationship between the central 30° visual field sensitivity and age after separating out the three genotype groups.
Figure 3
Figure 3
V30 compared to vision-related quality of life (n = 10). Scatterplot and linear regression line of V30 against (A) reading and accessing information, r = −0.14, (B) mobility and independence, r = −0.34, and (C) emotional well-being, r = −0.16. This demonstrates a weak linear relationship between central 30° visual field sensitivity and the three domains of vision related quality of life. Shaded area denotes confidence interval for regression line.
Figure 4
Figure 4
Change in central 30° visual field sensitivity, V30, over time in a subset of 13 patients. Shown is a line graph of V30 measurements in subjects over time. Subjects have also been color-coded by genotype group (red: mild, blue: intermediate, and green: severe). This demonstrates the slow loss of V30 over time.

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