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Purpose: To evaluate functional and structural assessments as endpoints for clinical trials for USH2A-related retinal degeneration., Methods: People with biallelic disease-causing variants in USH2A, visual acuity ≥ 20/80, and visual field ≥ 10° diameter were enrolled in a 4-year, natural history study. Participants underwent static perimetry, microperimetry, visual acuity, fullfield stimulus testing (FST), and optical coherence tomography annually. Rates of change estimated from mixed-effects linear models and percentages of eyes with changes exceeding the coefficient of repeatability (CoR) or thresholds conforming with U.S. Food and Drug Administration (FDA) guidelines were evaluated., Results: Rates of change were generally more sensitive to change than proportions of eyes exceeding a threshold such as the CoR. Baseline ellipsoid zone area ≥ 3 mm2 was necessary to detect change. Mean sensitivity and volumetric hill of vision measures on static perimetry had similar properties and were the most sensitive to changes of the continuous measures. The highest 4-year proportions of eyes exceeding the CoR were from FST testing (47%) and microperimetry (32%). Specification of loci as functional transition points (FTPs) resulted in 45% (static perimetry) and 46% (microperimetry) at 4 years, meeting FDA guidelines for progression., Conclusions: Rate of change of mean sensitivity on static perimetry was a sensitive perimetric continuous measure. Percentages of within-eye change were largest with FST testing and microperimetry. FTPs appear to be particularly sensitive to change. These results affect clinical trial design for USH2A-related retinal degeneration., Translational Relevance: Analyses of natural history data from the Rate of Progression in USH2A-Related Retinal Degeneration (RUSH2A) study can inform eligibility criteria and endpoints for clinical trials.

Purpose: We determine the feasibility of using a dark-adapted chromatic (DAC) perimeter to obtain dark-adapted static and dynamic rod function at multiple retinal locations, and compare these functional parameters between subjects with intermediate age-related macular degeneration (AMD) and normal controls., Methods: Perimetric dark-adapted retinal sensitivities for the 505 and 620 nm stimuli across 7 retinal locations within the central 12° were repeatedly measured after exposing to a single photobleach in 22 intermediate AMD subjects and 8 controls. The sensitivities for each stimulus at 20 minutes after bleach and the sensitivity difference between the stimuli were used to determine static rod function. Sensitivities for the 505 nm stimulus at various times within the initial 20 minutes after bleach were used to estimate the rod criterion time to determine rod function dynamics. The static and dynamic rod functional parameters were compared between AMD and control eyes., Results: Compared to the control eyes, AMD eyes had a reduction in retinal sensitivities for the 505 nm (P < 0.001) and 620 nm (P < 0.001) stimuli, a reduction in sensitivity difference (P < 0.001), and an increased in rod criterion time (P < 0.001). Region within the central 6° appeared to be the most defective and AMD eyes with reticular pseudodrusen (RPD) seemed to have worse function than eyes without RPD., Conclusions: It is feasible to use a DAC perimeter to study dark-adapted static and dynamic rod-mediated function at multiple retinal loci. Static and dynamic rod function were abnormal in intermediate AMD and more so in eyes with RPD, particularly within the central 6° retina.

Importance: There is a need for more sensitive measures of disease in intermediate age-related macular degeneration (AMD) to evaluate novel interventions more effectively and expediently., Objective: To determine if microperimetry and low luminance visual acuity can detect functional changes over a short duration of follow-up., Design, Setting, and Participants: Prospective longitudinal examination of 49 participants with consecutive AMD and 10 healthy participants in a research clinic from May 1, 2012, to December 31, 2013. Forty-one participants had intermediate AMD, 8 had nonfoveal geographic atrophy due to AMD. Participants underwent microperimetry examinations in 1 eye during a 12-month period at 6-month intervals for participants with AMD and at baseline and 12 months for control participants; low luminance visual acuity was performed at baseline and at 12 months for all participants. Changes in pathological features of intermediate AMD eyes were determined using side-by-side comparisons of color fundus photographs from the initial and final visit as remaining stable, progressed, or improved., Main Outcomes and Measures: Microperimetric sensitivity and low luminance visual acuity., Results: A reduction in mean (SE) microperimetric pointwise sensitivity was identified at 12 months compared with the baseline for intermediate AMD eyes graded as stable (-0.31 dB [0.10 dB]; P = .003) or worsened (-0.42 dB [0.12 dB]; P < .001) and an improvement in mean (SE) pointwise sensitivity was identified in eyes graded as improved (1.13 dB [0.23 dB]; P < .001). A reduction in mean (SE) pointwise sensitivity was identified in eyes with nonfoveal geographic atrophy at both 6 months (-1.41 dB [0.22 dB]; P < .001) and 12 months compared with the baseline (-2.56 dB [0.22 dB]; P < .001) while a change in mean (SE) pointwise sensitivity was not identified over the 12-month period for control participants (-0.11 dB [0.11 dB]; P = .34). No changes in best-corrected visual acuity or low luminance visual acuity were identified in all groups over the 12-month period (P ≥ .07)., Conclusions and Relevance: Microperimetry detected subtle changes in visual function over a 12-month period in eyes with intermediate AMD but visual acuity measures did not identify any such changes. These findings suggest that microperimetry is worth exploring as a method for assessing the efficacy of novel interventions for intermediate AMD potentially requiring a shorter duration of follow-up.

Purpose: The purpose of this study was to examine the test-retest repeatability of microperimetric sensitivity at the border of deep scotomas., Methods: Thirty normal participants underwent two examinations, each on the Macular Integrity Assessment (MAIA) microperimeter and on the MP-1 microperimeter (four examinations in total). A customized stimulus pattern allowed microperimetric sensitivity to be measured at the border of the optic nerve head (ONH), which acted as a model for the border of a deep scotoma-and also at the macular and peripapillary region., Results: There were no significant changes in average point-wise sensitivity (PWS) values between the two examinations for all three regions using the MAIA microperimeter (P ≥ 0.262). The PWS coefficient of repeatability (CoR) was ±12.99 dB at the border of the ONH, which was significantly larger than points in the macular and peripapillary regions (P > 0.001). A significant decrease in average PWS, using the MP-1 microperimeter at the macular and peripapillary region (P < 0.001), meant that the PWS CoR could not be determined in these regions. No significant changes in average PWS were observed at the border of the ONH (P = 0.223), and the PWS CoR was ±7.52 dB in this region., Conclusions: Microperimetric test-retest repeatability at the border of a deep scotoma was worse than at other areas of normal retina, and this highlights the limitation of applying a single estimate of test-retest repeatability to determine whether significant functional decline has occurred at the border of a deep scotoma.

Purpose: To correlate and compare retinal function measured using multifocal electroretinography (mfERG) with microperimetry in intermediate age-related macular degeneration (AMD)., Methods: Sixty AMD participants underwent multifocal electroretinography (mfERG) and microperimetry testing in one eye, and 44 control participants were included to provide normative values for each test. Thirteen hexagons in the central three rings of a 103-hexagon stimulus grid for mfERG and retinotopically matched points on microperimetry were chosen and converted into standard deviations (SDs) away from that of normal participants (Z-score) to represent the magnitude of measured functional deficit and to allow a comparison of the two measures., Results: For the average of all points on mfERG and microperimetry, mfERG N1 to P1 response amplitude and microperimetric retinal sensitivity was significantly lower (P = 0.013 and P < 0.001, respectively) and mfERG P1 implicit time was significantly increased (P < 0.001) in the AMD participants compared to those in the control participants. Considering retinotopically matched points, there was no significant correlation between the average Z-scores of the microperimetric retinal sensitivity and mfERG implicit time (correlation coefficient, R = 0.254, P = 0.051), nor response amplitudes (R = 0.006, P = 0.965), and the measured functional deficit with microperimetry was consistently greater than both mfERG parameters (P < 0.001)., Conclusions: The measured functional deficit with microperimetry was greater than mfERG parameters in eyes with intermediate AMD. The absence of correlations between these two measures suggests that mfERG may be capturing unique aspects of retinal dysfunction. These findings are important when considering the use of these functional measures in intermediate AMD., (Copyright 2014 The Association for Research in Vision and Ophthalmology, Inc.)

Purpose: To determine the relationship between structural parameters of the outer retina on spectral-domain optical coherence tomography (SD-OCT) and microperimetric retinal sensitivity in early stages of age-related macular degeneration (AMD)., Design: Prospective, observational study., Participants: Seventy-five eyes of 75 participants with early stages of AMD (drusen ≥ 125 μm, with/without pigmentary abnormalities) and 25 control participants of a similar age., Methods: Participants underwent microperimetry testing and high-resolution SD-OCT scans. Structural parameters at 5 central points (0°, 1°, and 2.33° nasal and temporal to the fovea along the horizontal axis) corresponding to areas tested by microperimetry were compared. Structural parameters included outer segment (OS) length, thickness and elevation of the retinal pigment epithelium (RPE) band, grading of the inner-segment ellipsoid (ISe) band integrity, and presence of hyperreflective foci (HF)., Main Outcome Measures: Relationship between structural parameters and retinal sensitivity., Results: Retinal sensitivity was significantly correlated with RPE elevation (P<0.001), ISe grading (P<0.001), and presence of HF (P ≤ 0.018) at all test points, but not with OS length (P ≥ 0.093) or RPE thickness (P ≥ 0.125). However, multiple linear regression analyses revealed that only ISe grading (P ≤ 0.011) and RPE elevation (P ≤ 0.030) remained significantly associated with retinal sensitivity at all points. By using a simple linear model incorporating ISe grading and RPE elevation to predict values of retinal sensitivity, the 95% limits of agreement between the predicted and the actual value was ± 3.83 dB., Conclusions: The integrity of the ISe band and drusen-associated RPE elevation are significant independent predictors of microperimetric retinal sensitivity. Our findings imply that these 2 structural parameters may be surrogate markers of retinal function in the early stages of AMD., (Copyright © 2014 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Purpose: To determine the intrasession test-retest variability of microperimetry in participants with age-related macular degeneration (AMD)., Methods: This study consisted of two separate groups of subjects who had not performed microperimetry previously. In group 1, 30 AMD and 14 control participants performed three microperimetry examinations of a selected eye within one session (test 1 and 2, first pair; test 2 and 3, second pair). Follow-up examination at 6 months was available in 20 AMD participants in group 1, who performed two microperimetry examinations. In group 2, 71 AMD participants performed a short practice examination, then two microperimetry examinations of the right eye (test 1 and 2, first pair) and two of the left eye (test 3 and 4, second pair)., Results: There was a significant improvement in average point-wise sensitivity (PWS) between the first pair of examination in both groups (P < 0.001), but not in the subsequent pair (P ≥ 0.774). This improvement was not observed at the follow-up visit in the subset of AMD participants in group 1 (P = 0.433). The PWS coefficient of repeatability (CoR) for the second pair of examinations was ± 4.12 dB and ± 4.37 dB for AMD participants for group 1 and 2 respectively., Conclusions: A significant increase in sensitivity between the first and second test, but not in the subsequent tests, was found for participants who had not performed microperimetry previously. Intrasession test-retest variability can therefore be minimized by discarding the first examination to avoid the influence of a learning effect.

Purpose: The relationship between clinical severity of age-related macular degeneration (AMD) and macular function has not been well established. In this study, we investigated the correlation between clinical severity and functional deficits as detected by static and flicker perimetry., Methods: This cross-sectional study consisted of 279 AMD subjects and 24 control participants. AMD subjects were allocated into 1 of 10 AMD severity groups depending on the status of the designated study eye and the fellow eye, as assessed by color fundus photographs. Visual acuity, and static and flicker perimetry were tested on one eye during the same session. The geometric means, SDs, and percentage of abnormal eyes of static and flicker sensitivity of each AMD severity group were determined and compared., Results: The pattern of change in sensitivity and percentage of abnormal eyes for static perimetry across all AMD severity groups were similar to flicker perimetry. Eyes with drusen > 125 μm (P[static] = 0.018, P[flicker] = 0.024), drusenoid epithelial detachment (P[static and flicker] < 0.001) and noncentral geographic atrophy (GA; P[static and flicker] < 0.001) had significant reductions in static and flicker sensitivities compared to normal eyes. Static (β-coefficient -1.59, 95% confidence interval [CI] -4.78-1.60) and flicker (β-coefficient -1.29, 95% CI -4.66-2.08) sensitivities declined at a similar rate in eyes that showed clinical signs of progression., Conclusions: Static and flicker perimetry were affected similarly across the spectrum of AMD severity, and methods appeared to be valid techniques for assessing retinal sensitivity in AMD once drusen > 125 μm are present, but before the development of late AMD.