HYPERREFLECTIVE FOCI NOT SEEN AS HYPERPIGMENTARY ABNORMALITIES ON COLOR FUNDUS PHOTOGRAPHS IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To investigate the prognostic value of quantifying optical coherence tomography (OCT)-defined hyperreflective foci (HRF) that do not correspond to hyperpigmentary abnormalities (HPAs) on color fundus photographs (CFPs)-HRF (OCT+/CFP-) -when considered in addition to HPA extent, for predicting late age-related macular degeneration development. This study sought to understand the impact of HRF (OCT+/CFP-) extent on visual sensitivity. METHODS: Two hundred eighty eyes from 140 participants with bilateral large drusen underwent imaging and microperimetry at baseline, and then 6-monthly for 3-years. The extent of HPAs on CFPs and HRF (OCT+/CFP-) on OCT was quantified at baseline. Predictive models for progression to late age-related macular degeneration, accounting for drusen volume and age, were developed using HPA extent, with and without HRF (OCT+/CFP-) extent. The association between HPA and HRF (OCT+/CFP-) extent with sector-based visual sensitivity was also evaluated. RESULTS: Incorporating HRF (OCT+/CFP-) extent did not improve the predictive performance for late age-related macular degeneration development ( P ≥ 0.32). Increasing HPA and HRF (OCT+/CFP-) extent in each sector were independently and significantly associated with reduced sector-based visual sensitivity ( P ≤ 0.004). CONCLUSION: The addition of HRF (OCT+/CFP-) extent to HPA extent did not improve the prediction of late age-related macular degeneration development. HRF (OCT+/CFP-) extent was also independently associated with local reductions in visual sensitivity, after accounting for HPAs.

Visual Sensitivity Loss in Geographic Atrophy: Structure-Function Evaluation Using Defect-Mapping Microperimetry.

Purpose: To examine the structure-function relationship in eyes with geographic atrophy (GA) using defect-mapping microperimetry, a testing strategy optimized to quantify the spatial extent of deep visual sensitivity losses. Methods: Fifty participants with GA underwent defect-mapping microperimetry testing of the central 8°-radius region (208 locations tested once with a 10-decibel stimuli) and fundus autofluorescence imaging in one eye. The GA extent in the corresponding central 8°-radius was derived by manual annotations and image co-registration to examine the global structure-function relationship. The distance of each test location from the GA margin was also derived, and regions defined, to examine the local structure-function relationship. Results: GA extent in the central 8° explained a substantial proportion of variance in the percentage of locations missed (nonresponse) on microperimetry at the global level (R2 = 0.90). At a local level, the probability of missing stimuli at the outer junctional zone (0-500 µm outside the GA margin) and GA margin (probability = 7% and 34%, respectively) was higher than at the outer nonlesional zone (>500 µm outside the GA margin; probability = 2%; P < 0.001 for both). The probability of missing stimuli at the inner junctional zone (0-250 µm inside the GA margin) was also lower than at the inner lesional zone (>250 µm inside the GA margin; probability = 64% and 88%; P < 0.001). Conclusions: This study confirms the expected functional relevance of the region with GA on fundus autofluorescence imaging and underscores the potential effectiveness of defect-mapping microperimetry testing for capturing visual function changes when evaluating new GA treatments.

Reticular Pseudodrusen: Impact of Their Presence and Extent on Local Rod Function in Age-Related Macular Degeneration.

Purpose: To understand the spatial relationship between local rod-mediated visual function and reticular pseudodrusen (RPD) in eyes with large drusen. Design: Retrospective cross-sectional study. Participants: One eye with large drusen (>125 µm) each from 91 individuals with intermediate age-related macular degeneration, with and without RPD. Methods: All participants underwent dark adaptation testing using a dark-adapted chromatic perimeter, where visual sensitivities were measured over 30 minutes of dark adaptation after photobleach. The rod intercept time (RIT; a measure of dynamic rod function) and pointwise sensitivity difference (PWSD; a relative measure of rod- compared with cone-mediated function) was determined at multiple retinal locations, and their association with the overall (central 20° × 20° region) and local (2° diameter region centered on the location tested) extent of RPD and drusen (quantified using multimodal imaging) was examined. Main Outcome Measures: Association between overall and local extent of RPD and drusen with RIT and PWSD at each retinal location tested. Results: In a multivariable analysis, delayed RIT was associated with an increasing overall (P < 0.001), but not local (P = 0.884), extent of RPD. In contrast, the increasing local (P < 0.001), but not overall (P = 0.475), extent of drusen was associated with delayed RIT. Furthermore, only an increasing overall extent of RPD (P < 0.001) was associated with reduced PWSD (or worse rod compared with cone function), but not the local extent of RPD and drusen, or overall extent of drusen (P ≥ 0.344). Conclusions: Local rod-mediated function was associated with the overall, rather than local, extent of RPD in eyes with large drusen, suggesting that there may be widespread pathologic changes in eyes with RPD that account for this. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Deep Learning-Based Detection of Reticular Pseudodrusen in Age-Related Macular Degeneration on Optical Coherence Tomography.

Reticular pseudodrusen (RPD) signify a critical phenotype driving vision loss in age-related macular degeneration (AMD). Their detection is paramount in the clinical management of those with AMD, yet they remain challenging to reliably identify. We thus developed a deep learning (DL) model to segment RPD from 9,800 optical coherence tomography B-scans, and this model produced RPD segmentations that had higher agreement with four retinal specialists (Dice similarity coefficient [DSC]=0·76 [95% confidence interval [CI] 0·71-0·81]) than the agreement amongst the specialists (DSC=0·68, 95% CI=0·63-0·73; p <0·001). In five external test datasets consisting of 1,017 eyes from 812 individuals, the DL model detected RPD with a similar level of performance as two retinal specialists (area-under-the-curve of 0·94 [95% CI=0·92-0·97], 0·95 [95% CI=0·92-0·97] and 0·96 [95% CI=0·94-0·98] respectively; p ≥0·32). This DL model enables the automatic detection and quantification of RPD with expert-level performance, which we have made publicly available.

Systematic Underestimation of Visual Sensitivity Loss on Microperimetry: Implications for Testing Protocols in Clinical Trials.

Purpose: To examine whether systematic changes in visual sensitivity measurements on microperimetry occur over tests within the same session and whether these changes vary according to the level of visual sensitivity loss. Methods: Eighty individuals with glaucoma or atrophic age-related macular degeneration underwent three microperimetry tests in one eye during one session using the 4-2 staircase strategy. Changes in mean sensitivity (MS) and pointwise sensitivity (PWS) between the first and second test pairs were examined, with PWS was examined separately based on its average value across the three tests in 6-dB bins. The coefficient of repeatability (CoR) for MS between each sequential test pair was also calculated. Results: There was a significant decline in MS from the first to second test (P = 0.001), but no significant difference in MS was seen between the second and third tests (P = 0.562). This significant decline in the first test pair was observed in locations with an average PWS of <6 dB or between 6 to 12 dB and between 12 to 18 dB (P < 0.001), but not for all other average PWS bins (P ≥ 0.337). The CoR of MS was significantly lower in the second compared to the first test pair (1.4 dB and 2.5 dB, respectively; P < 0.001). Conclusions: The 4-2 staircase strategy conventionally used on microperimetry testing systematically underestimates visual sensitivity loss on the first test. Translational Relevance: The consistency and accuracy of visual sensitivity measurements on microperimetry in clinical trials could be markedly improved by using estimates from an initial test to seed subsequent tests and excluding this first test from analyses.

Hyporeflective Cores within Drusen: Association with Progression of Age-Related Macular Degeneration and Impact on Visual Sensitivity.

PURPOSE: To examine the association between hyporeflective cores within drusen (HCD) and disease progression in age-related macular degeneration (AMD) and with visual function. DESIGN: Longitudinal observational study. PARTICIPANTS: Two hundred and eighty eyes from 140 participants with bilateral large drusen, without late AMD. METHODS: Multimodal imaging and microperimetry were performed at baseline and subsequently every 6 months for up to 3 years. Baseline OCT scans were graded for the presence of HCD and used to calculate drusen volume. The total area of the drusenoid lesions containing hyporeflective cores (HCD extent) on color fundus photographs (CFPs) was calculated. CFPs were also graded for the presence of pigmentary abnormalities. The association between HCD extent with progression to late AMD (including OCT signs of atrophy) and visual sensitivity measured using microperimetry at baseline and its rate of change over time was evaluated with and without adjustment for confounders of drusen volume, pigmentary abnormalities, and age. MAIN OUTCOME MEASURES: Time to develop late AMD and visual sensitivity. RESULTS: Twenty (7%) eyes from 12 (9%) individuals were found to have HCD at baseline, which was associated with a nonsignificantly increased rate of progression to late AMD (unadjusted P = 0.050). HCD extent was significantly associated with an increased rate of progression to late AMD (unadjusted P = 0.034) and lower visual sensitivity at baseline (unadjusted P < 0.001). However, these associations were no longer significant (P ≥ 0.264 for both) after adjusting for known risk factors for AMD progression. HCD extent was also not associated with a faster rate of visual sensitivity decline before the development of late AMD, with or without adjustment (P ≥ 0.674 for both). Increasing age and larger drusen volume were associated with HCD extent (P ≤ 0.041). CONCLUSIONS: In a cohort with bilateral large drusen, HCD presence and extent were not independently associated with an increased rate of progression to late AMD over 3 years, nor with lower visual sensitivity or an increased rate of visual sensitivity decline before the development of late AMD, after adjusting for known risk factors for disease progression.

Hyperpigmentary abnormalities in age-related macular degeneration: association with progression and impact on visual sensitivity.

BACKGROUND/AIMS: To investigate the additional prognostic value of quantifying the extent of colour fundus photography (CFP)-defined hyperpigmentary abnormalities (HPAs) compared with their presence alone for predicting progression to late-stage age-related macular degeneration (AMD) and to understand their association with visual sensitivity in individuals with intermediate AMD. METHODS: 140 participants with bilateral large drusen underwent multimodal imaging and microperimetry at baseline and then every 6 months for up to 3 years. Baseline CFPs were graded for the presence of HPAs and their extent was quantified. Optical coherence tomography (OCT) scans were used to quantify drusen volume. Predictive models for progression to late AMD (including OCT signs of atrophy) were developed using either HPA presence or extent. The association between HPA extent with mean visual sensitivity (both overall and sector based) was also evaluated. All models were adjusted for the confounders of baseline age and drusen volume. RESULTS: The predictive performance for late AMD development was not significantly different for HPA presence or extent (p=0.92). Increasing HPA extent in each sector, but not its overall extent in an eye, was associated with reduced sector-based visual sensitivity (p<0.001 and p=0.671, respectively). CONCLUSION: In a cohort with bilateral large drusen, quantifying HPA extent did not improve the prediction of late AMD development compared with presence alone. HPA extent was associated with more local, rather than generalised, reductions in visual sensitivity. These findings suggest that quantification of HPA extent adds little to the prediction of AMD progression, but that it provides an imaging biomarker of visual dysfunction.