Test-retest repeatability of microperimetry in patients with retinitis pigmentosa caused by mutations in RPGR.

Abstract

RPGR-associated retinitis pigmentosa (RPGR-RP) is the most common cause of X-linked RP worldwide, accounting for the majority of molecularly confirmed cases.1 Because these patients possess good visual acuity until a late stage of the disease, alternative visual function measures are required to monitor disease progression. Macula sensitivity, as assessed by microperimetry, may be a more sensitive functional parameter. A phase I/II clinical trial has recently been reported, investigating the safety and efficacy of novel subretinal gene therapy, in which microperimetry gains have been reported.2 As the effects of interventions such as gene therapy are likely to be assessed against preoperative baseline values, it is important to ensure that the baseline measurement is both accurate and consistent. The goal of this study was to provide baseline test-retest repeatability values for mean sensitivity in RPGR-RP patients to determine thresholds for clinically significant changes. Patients were assessed as part of their routine clinical care and prior to recruitment into a phase I/II clinical trial of retinal gene therapy for RPGR-RP (ClinicalTrials.gov identifier NCT03116113) conducted at the Oxford Eye Hospital, UK. The cohort comprised 15 male patients with confirmed pathogenic mutations in the RPGR gene. Patients underwent measurements of macula sensitivity using the MAIA microperimeter (Centervue SpA, Padova, Italy) after 20 minutes of dark adaptation (light level <1 lx), but no pharmacological dilation,3 using a standard 10-2 grid with a 4-2 threshold strategy. The right eye was tested first, following local standard operating procedures.4 Patients underwent testing in triplicate across 2 days, with two tests on the first day and the final test being completed on the second day. The primary outcome was coefficient of repeatability in macula sensitivity, calculated as per the method by Bland and Altman.5 Secondary outcomes included coefficients of repeatability in individual point sensitivities and the size of the scotoma. The length of the border between the scotoma and sensate retinal island was assessed manually and recorded as the number of points. Fixation stability was assessed as the bivariate counter ellipse area (BCEA), which is a standard MAIA output. The average difference in the macula sensitivity was −1.0 dB in the right eye and −0.89 dB in the left eye, between tests 1 and 2. This reduced to 0.09 dB in the right eye and −0.01 dB in the left eye, between tests 2 and 3. There were statistically significant differences between time points (Wilcoxon signed-rank test, right eye P = .04, left eye P = .08), but not between eyes (Mann-Whitney U test, P > .05). Hence, the test-retest variability became more consistent from the second test onwards. The final coefficient of repeatability was 1.30 dB. The coefficient of repeatability for individual point sensitivity was 6 dB; the coefficient of repeatability for the scotoma size was 11 points, after data were removed for floor effects. The number of border points was significantly correlated with the individual subject coefficient of repeatability in the scotoma size (Spearman rank correlation coefficient, rs = 0.78, P ≤ .01). There was no correlation between the subject BCEA and their coefficient of repeatability in the mean sensitivity or scotoma size (P > .05 across all tests), nor between the variability in the scotoma and the variability in mean sensitivity (P > .05 across all tests). In conclusion, greater test-retest variability in mean sensitivity is seen between the first and second tests. Individual subject coefficient of repeatability is similar between eyes as well as their baseline macula sensitivity, supporting the use of the non-interventional eye as control in clinical trials. Subjects should undergo triplicate testing and the final macula sensitivity should be used as the baseline. All participants gave informed written consent to microperimetry testing as part of screening, but before potential recruitment, to the associated clinical trial (NCT03116113). Both the screening and clinical trial were reviewed and approved by the local research ethics committee and conducted in accordance with the tenets of the Declaration of Helsinki. Some patients who passed microperimetry screening were subsequently enrolled into a clinical trial sponsored by Nightstar Therapeutics (NCT03116113). The views expressed are those of the authors and not necessarily those of the NHS, NIHR or the Department of Health and Social Care. The sponsor and funding organization had no role in the design or conduct of this research. R. E. M. receives grant funding from Biogen Inc. R. E. M. is a consultant to Novartis, Biogen and Spark Therapeutics. These companies did not have any input into the work presented. No other authors have a conflict of interest.