A cross-sectional study to assess the clinical utility of modern visual function assessments in patients with inherited retinal disease: a mixed methods observational study protocol.

BACKGROUND: Treatment options for patients with inherited retinal disease are limited, although research into novel therapies is underway. To ensure the success of future clinical trials, appropriate visual function outcome measures that can assess changes resulting from therapeutic interventions are urgently required. Rod-cone degenerations are the most common type of inherited retinal disease. Visual acuity is a standard measure but is typically preserved until late disease stages, frequently making it an unsuitable visual function marker. Alternative measures are required. This study investigates the clinical utility of a range of carefully selected visual function tests and patient reported outcome measures. The aim is to identify suitable outcome measures for future clinical trials that could be considered for regulatory approval. METHODS: This cross-sectional study involves two participant groups, patients with inherited retinal disease (n = 40) and healthy controls (n = 40). The study has been designed to be flexible and run alongside NHS clinics. The study is split into two parts. Part one includes examining standard visual acuity, low luminance visual acuity, the Moorfields acuity chart visual acuity, mesopic microperimetry and three separate patient reported outcome measures. Part two involves 20 min of dark adaptation followed by two-colour scotopic microperimetry. Repeat testing will be undertaken where possible to enable repeatability analyses. A subset of patients with inherited retinal disease will be invited to participate in a semi-structured interview to gain awareness of participants' thoughts and feelings around the study and different study tests. DISCUSSION: The study highlights a need for reliable and sensitive validated visual function measures that can be used in future clinical trials. This work will build on work from other studies and be used to inform an outcome measure framework for rod-cone degenerations. The study is in keeping with the United Kingdom Department of Health and Social Care research initiatives and strategies for increasing research opportunities for NHS patients as part of their NHS care. TRIAL REGISTRATION: ISRCTN registry, ISRCTN24016133, Visual Function in Retinal Degeneration, registered on 18th August 2022.

Choroideremia: The Endpoint Endgame.

Choroideremia is an X-linked retinal degeneration resulting from the progressive, centripetal loss of photoreceptors and choriocapillaris, secondary to the degeneration of the retinal pigment epithelium. Affected individuals present in late childhood or early teenage years with nyctalopia and progressive peripheral visual loss. Typically, by the fourth decade, the macula and fovea also degenerate, resulting in advanced sight loss. Currently, there are no approved treatments for this condition. Gene therapy offers the most promising therapeutic modality for halting or regressing functional loss. The aims of the current review are to highlight the lessons learnt from clinical trials in choroideremia, review endpoints, and propose a future strategy for clinical trials.

A Network Meta-Analysis of Retreatment Rates following Bevacizumab, Ranibizumab, Aflibercept, and Laser for Retinopathy of Prematurity.

TOPIC: To compare bevacizumab, ranibizumab, aflibercept, and laser treatment as primary therapies for retinopathy of prematurity (ROP) in terms of retreatment rate. CLINICAL RELEVANCE: Anti-VEGF agents are increasingly used as primary treatment for ROP and may provide superior outcomes compared with laser in posterior disease. Head-to-head comparisons between different anti-VEGFs are lacking. METHODS: We searched CENTRAL, Embase, MEDLINE, and CINAHL databases for randomized controlled trials and nonrandomized comparative studies that had been reported as of March 2022. We included studies that used bevacizumab, ranibizumab, aflibercept or laser for ROP with comparable cohorts and treatment criteria. Studies were evaluated by the Grading of Recommendations, Assessment, Development and Evaluation framework, and those with biased case selection, nonrandomized case-control, or lack of control group were excluded. Frequentist meta-analyses of proportions determined the absolute primary retreatment rate of each modality and Bayesian network meta-analyses compared pairs of treatments in type 1 and Zone I ROP. RESULTS: In all, 30 studies (4686 eyes) were included in the network meta-analyses. For type 1 ROP, single-treatment success rates (i.e., likelihood of needing no further treatment) were 89.3% (95% confidence interval [CI]: 83.8%-93.8%; n = 1552) for laser, 87.0% (95% CI: 78.6%-93.8%; n = 2081) for bevacizumab, 80.7% (95% CI: 62.0%-94.4%; n = 326) for aflibercept, and 74.0% (95% CI: 62.7%-84.1%; n = 727) for ranibizumab. Bayesian network meta-analysis indicates that laser treatment is associated with a significant 62% (95% credible interval [CrI]: 16%-83%) reduction in retreatment risk compared with ranibizumab, while no significant difference was found among other pairwise comparisons. The mean ± standard error of the mean times to secondary treatment following primary aflibercept (12.96 ± 0.47 weeks) and bevacizumab (11.36 ± 0.54 weeks) therapy were significantly longer than that for primary ranibizumab (9.29 ± 0.43weeks) therapy (P = 7 × 10-7 and P = 9 × 10-3, respectively). For Zone I ROP, single-treatment success rates were 91.2% (95% CI: 83.6-96.9; n = 231) for bevacizumab, 78.3% (95% CI: 61.4-91.9; n = 100) for ranibizumab, and 65.9% (95% CI: 41.4-87.2; n = 158) for laser treatment. In this case, Bayesian network meta-analysis suggests that primary bevacizumab is associated with a significant 67% (95% CrI:10%-90%) reduction in retreatment risk compared with laser treatment. CONCLUSIONS: Laser was associated with a lower rate of retreatment than ranibizumab in type 1 ROP (Zones I and II combined), while bevacizumab was associated with a lower rate of retreatment than laser in Zone I ROP. Aflibercept and bevacizumab demonstrate longer duration of action than ranibizumab for ROP.

Low luminance visual acuity as a clinical measure and clinical trial outcome measure: a scoping review.

PURPOSE: The measurement of standard visual acuity (VA) is the most well-known part of any ophthalmic examination to indicate visual function. Despite this, it is insensitive in detecting early disease changes. Therefore, other visual function tests have been developed including low luminance VA (LLVA) and low luminance deficit (LLD). This scoping literature review aims to summarise the current published applications of LLVA and LLD assessments to evaluate their utility as clinical markers and research outcome measures in a variety of ophthalmic conditions. RECENT FINDINGS: Sixty-five peer-reviewed publications were included. LLVA was pioneered for use in geographic atrophy, a subtype of age-related macular degeneration, which remains the mainstay of its clinical application. However, other studies have reported additional useful applications in inherited retinal diseases including rare maculopathies and rod-cone dystrophies. Although there are some variations in testing methodology, use of the standard Early Treatment Diabetic Retinopathy Study (ETDRS) chart with a 2.0 log unit neutral density filter is the most popular approach. The optimal testing luminance is still to be defined. SUMMARY: Overall, LLVA is an earlier clinical marker of change in central retinal function than standard VA. It has been shown to be a risk factor for disease progression and a better indicator of a patient's level of everyday visual function. It is inexpensive and simple to implement using readily available standard ophthalmic equipment.

Microperimetry as an Outcome Measure in RPGR-associated Retinitis Pigmentosa Clinical Trials.

Purpose: To explore which microperimetry sensitivity index (pointwise sensitivity, mean sensitivity, and volume sensitivity) is suitable as a microperimetry outcome measure in patients with X-linked RPGR-associated retinitis pigmentosa (RP). Methods: Microperimetry data from patients with RPGR-associated RP were collected and analyzed retrospectively. Fourteen participants completed triplicate microperimetry testing, across 2 consecutive days for the repeatability analyses. Longitudinal data was obtained from 13 participants who completed microperimetry testing at two separate visits. Results: The test-retest coefficients of repeatability (CoR) for pointwise sensitivity were ±9.5 dB and ±9.3 dB, in the right and left eyes, respectively. The mean sensitivity CoR for the right and left eyes was ±0.7 dB and ±1.3 dB. Volume sensitivity CoR was ±144.5 dB*deg2 and ±324.2 dB*deg2 for the right and left eyes, respectively. The mean sensitivities were positively skewed toward zero in those with a high number of nonseeing points (arbitrarily assigned to -1.0 dB) and just seen points (0.0 dB). Volume sensitivities were unaffected by the averaging effects of skewed data. Conclusions: Clinical trials should report population-specific test-retest variability to determine a clinically significant change. Pointwise sensitivity indices should be used with caution as outcome measures in clinical trials owing to high levels of test-retest variability. Global indices seem to be less prone to variability. Volume sensitivity indices seem to be superior for use in RPGR-associated RP clinical trials compared with mean sensitivity because they are unaffected by the averaging effects of highly skewed data. Translational Relevance: Careful selection of sensitivity indices (VA) is required when using microperimetry as a clinical trial outcome measure.

Correlation Between Fundus Autofluorescence Pattern and Retinal Function on Microperimetry in Choroideremia.

Purpose: In patients with choroideremia, it is not known how smooth and mottled patterns on short-wavelength fundus autofluorescence (AF) imaging relate to retinal function. Methods: A retrospective case-note review was undertaken on 190 patients with choroideremia at two specialist centers for retinal genetics. Twenty patients with both smooth and mottled zones on short-wavelength AF imaging and concurrent mesopic microperimetry assessments were included. Mean retinal sensitivities within the smooth and mottled zones were compared between choroideremia patients, and identical points on mesopic microperimetry collected from 12 age-matched controls. Longitudinal analyses were undertaken at 2 and 5 years in a subset of patients. Results: In patients with choroideremia, mean retinal sensitivities at baseline were significantly greater in the smooth zone (26.1 ± 2.0 dB) versus the mottled zone (20.5 ± 4.2 dB) (P < 0.0001). Mean retinal sensitivities at baseline were similar in the smooth zone between choroideremia patients and controls (P = 0.054) but significantly impaired in the mottled zone in choroideremia compared to controls (P < 0.0001). The rate of decline in total sensitivity over 5 years was not significant in either the smooth or mottled zone in a small subset of choroideremia patients (n = 7; P = 0.344). Conclusions: In choroideremia, retinal sensitivity as determined by microperimetry correlates with patterns on AF imaging: retinal function in the smooth zone, where the retinal pigment epithelium is anatomically preserved, is similar to controls, but retinal sensitivity in the mottled zone is impaired. Translational Relevance: Patterns on AF imaging may represent a novel, objective outcome measure for clinical trials in choroideremia as a surrogate for retinal function.

Scotopic microperimetry: evolution, applications and future directions.

For many inherited and acquired retinal diseases, reduced night vision is a primary symptom. Despite this, the clinical testing options for spatially resolved scotopic vision have until recently been limited. Scotopic microperimetry is a relatively new visual function test that combines two-colour perimetry with fundus-controlled perimetry performed in scotopic luminance conditions. The technique enables spatially resolved mapping of central retinal sensitivity alongside the ability to distinguish between rod and cone photoreceptor sensitivities. Two companies produce commercially available scotopic microperimeters - Nidek (Nidek Technologies Srl, Padova, Italy) and CenterVue (CenterVue S.p.A., Padova, Italy). Scotopic microperimetry is a promising technology capable of detecting changes in retinal sensitivity before changes in other measures of visual function. Scotopic microperimetry is a promising functional biomarker that has the potential as a useful clinical trial outcome measure. This review summarises the evolution and applications of scotopic microperimetry, and discusses testing options, including testing grid selection, dark-adaptation time and threshold sensitivity analyses.

Low Luminance Visual Acuity and Low Luminance Deficit in Choroideremia and RPGR-Associated Retinitis Pigmentosa.

Introduction: Choroideremia and RPGR-associated retinitis pigmentosa (RP) are two distinct inherited rod-cone degenerations, where good visual acuity (VA) is maintained until late disease stages, limiting its usefulness as a disease marker. Low luminance VA and low luminance deficit (standard VA minus low luminance VA) may be more sensitive visual function measures. Methods: Standard VA was obtained using Early Treatment Diabetic Retinopathy Study letter charts (Precision Vision, Bloomington, IL, USA). Low luminance VA was assessed using a 2.0-log unit neutral density filter, with the same chart setup, without formal dark adaptation. Mean central retinal sensitivity was assessed using MAIA microperimetry (Centervue SpA, Padova, Italy). Optical coherence tomography imaging was attained with Heidelberg Eye Explorer software (Heidelberg Engineering, Heidelberg, Germany). Results: Twenty-four male participants with confirmed pathogenic RPGR mutations, 44 male participants with confirmed pathogenic CHM mutations, and 62 age-matched controls underwent clinical assessment prior to clinical trial recruitment. Low luminance VA was significantly reduced in both disease groups compared to controls. The low luminance deficit correlated with microperimetry retinal sensitivity and ellipsoid zone width. Eleven participants with moderate VA had poor low luminance VA (subsequently a large low luminance deficit), no detectable microperimetry sensitivity, and severely constricted ellipsoid zone widths. Conclusions: Low luminance VA and subsequently low luminance deficit are useful markers of central macular visual function in both choroideremia and RPGR-associated RP, when standard VA is preserved. Translational Relevance: Low luminance visual acuity and low luminance deficit are useful vision measures in two distinct rod-cone degenerations and may be useful in other retinal degenerations.

Structural and Functional Characteristics of Color Vision Changes in Choroideremia.

Color vision is considered a marker of cone function and its assessment in patients with retinal pathology is complementary to the assessments of spatial vision [best-corrected visual acuity (BCVA)] and contrast detection (perimetry). Rod-cone and chorioretinal dystrophies-such as choroideremia-typically cause alterations to color vision, making its assessment a potential outcome measure in clinical trials. However, clinical evaluation of color vision may be compromised by pathological changes to spatial vision and the visual field. The low vision Cambridge Color Test (lvCCT) was developed specifically to address these latter issues. We used the trivector version of the lvCCT to quantify color discrimination in a cohort of 53 patients with choroideremia. This test enables rapid and precise characterization of color discrimination along protan, deutan, and tritan axes more reliably than the historically preferred test for clinical trials, namely the Farnsworth Munsell 100 Hue test. The lvCCT demonstrates that color vision defects-particularly along the tritan axis-are seen early in choroideremia, and that this occurs independent of changes in visual acuity, pattern electroretinography and ellipsoid zone area on optical coherence tomography (OCT). We argue that the selective loss of tritan color discrimination can be explained by our current understanding of the machinery of color vision and the pathophysiology of choroideremia.