Relative Ellipsoid Zone Reflectivity in Macular Telangiectasia Type 2.

Purpose: The relative ellipsoid zone reflectivity (rEZR) has been proposed as an innovative biomarker for photoreceptor integrity. This study evaluates the rEZR in macular telangiectasia type 2 (MacTel) eyes of different disease stages. Methods: The mean rEZR (ratio ellipsoid zone [EZ]/external limiting membrane [ELM] reflectivity [arbitrary units {AUs}], grey level range = 0-1) was analyzed for an entire spectral domain optical coherence tomography volume scan (global) and for each subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid (topographic) in patients with MacTel and controls. MacTel disease severity was classified according to Gass and Blodi. Results: Linear mixed-model analysis of 145 eyes of 74 patients and 50 eyes of 25 controls revealed globally lower, yet not statistically significant, rEZR values in MacTel eyes. Topographically, most pronounced decreases were found in stages 3 and 4/5 for the temporal inner (coefficient estimates [CEs] = -25.4 [-38.2; -12.6] and -34.1 [-48.7; -19.6] AU, both: P < 0.001), the inferior inner (-29.9 [-44.6; -15.6] and -35.3 [-52.1; -18.5] AU, both: P < 0.001), the nasal inner (-21.5 [-35.52; -7.4] and -31.6 [-47.6; -15.6] AU, P = 0,003 and P < 0.001), and in the superior inner subfield of stage 4/5 (-25.0 [-42.0; -7.9] AU, P = 0.004). Conclusions: The rEZR showed association with disease severity and the predilection area of MacTel. Given the current understanding of the pathophysiological concept of MacTel, these findings underscore the value of the rEZR as a potential novel biomarker for outer retinal integrity. Longitudinal studies are demanded to better characterize its value as a biomarker for early photoreceptor alterations and disease progression in MacTel.

Reticular Pseudodrusen: Interreader Agreement of Evaluation on OCT Imaging in Age-Related Macular Degeneration.

Purpose: To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence. Design: Interreader agreement study. Participants: Twelve readers from 6 reading centers. Methods: All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image. Main Outcome Measures: Interreader agreement, as assessed by Gwet's first-order agreement coefficient (AC1). Results: When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC1 = 0.60-0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC1 = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 0.30). Conclusions: There was generally substantial or near-substantial-but not near-perfect-agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Characteristics and Spatial Distribution of Structural Features in Age-Related Macular Degeneration: A MACUSTAR Study Report.

PURPOSE: To report the prevalence and topographic distribution of structural characteristics in study participants with age-related macular degeneration (AMD) and controls in the cross-sectional study part of the MACUSTAR study (ClinicalTrials.gov Identifier: NCT03349801). DESIGN: European, multicenter cohort study. SUBJECTS: Overall, 301 eyes of 301 subjects with early (n = 34), intermediate (n = 168), and late AMD (n = 43), as well as eyes without any AMD features (n = 56). METHODS: In study eyes with intermediate AMD (iAMD), the presence of structural AMD biomarkers, including pigmentary abnormalities (PAs), pigment epithelium detachment (PED), refractile deposits, reticular pseudodrusen (RPD), hyperreflective foci (HRF), incomplete/complete retinal pigment epithelium (RPE), and outer retinal atrophy (i/cRORA), and quiescent choroidal neovascularization (qCNV) was systematically determined in the prospectively acquired multimodal retinal imaging cross-sectional data set of MACUSTAR. Retinal layer thicknesses and the RPE drusen complex (RPEDC) volume were determined for the total study cohort in spectral-domain (SD) OCT imaging using a deep-learning-based algorithm. MAIN OUTCOME MEASURES: Prevalence and topographic distribution of structural iAMD features. RESULTS: A total of 301 study eyes of 301 subjects with a mean (± standard deviation) age of 71.2 ± 7.20 years (63.1% women) were included. Besides large drusen, the most prevalent structural feature in iAMD study eyes were PA (57.1%), followed by HRF (51.8%) and RPD (22.0%). Pigment epithelium detachment lesions were observed in 4.8%, vitelliform lesions in 4.2%, refractile deposits in 3.0%, and qCNV in 2.4%. Direct precursor lesions for manifest retinal atrophy were detected in 10.7% (iRORA) and 4.2% (cRORA) in iAMD eyes. Overall, the highest RPEDC volume with a median of 98.92 × 10-4 mm³ was found in iAMD study eyes. Spatial analysis demonstrated a predominant distribution of RPD in the superior and temporal subfields at a foveal eccentricity of 1.5 to 2 mm, whereas HRF and large drusen had a distinct topographic distribution involving the foveal center. CONCLUSIONS: Detailed knowledge of the prevalence and distribution of structural iAMD biomarkers is vital to identify reliable outcome measure for disease progression. Longitudinal analyses are needed to evaluate their prognostic value for conversion to advanced disease stages. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Comparability of automated drusen volume measurements in age-related macular degeneration: a MACUSTAR study report.

Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991-0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757-0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD.Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017.

Relative ellipsoid zone reflectivity and its association with disease severity in age-related macular degeneration: a MACUSTAR study report.

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p < 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression.

Natural History of the Relative Ellipsoid Zone Reflectivity in Age-Related Macular Degeneration.

PURPOSE: Relative ellipsoid zone reflectivity (rEZR) has been reported to be reduced in intermediate age-related macular degeneration (iAMD). However, longitudinal changes in rEZR remain unknown. This study investigated the natural history of rEZR in iAMD and its association with risk factors for disease progression, including the presence or extent of drusen volume, reticular pseudodrusen (RPD), and pigmentary abnormalities (PAs). DESIGN: Longitudinal observational study. PARTICIPANTS: Subjects with bilateral large drusen. METHODS: Spectral-domain (SD) OCT images of both eyes from each participant were obtained every 6 months for 3 years. Using an automated rEZR determination approach, the average rEZR of the central 20° macula was determined for each SD-OCT volume scan. Linear mixed models were used to determine the rate of change in rEZR with age (using the cross-sectional data at baseline) and over time (longitudinal data) and the interactions between the rate of rEZR changes with AMD risk factors at baseline. MAIN OUTCOME MEASURES: Relative ellipsoid zone reflectivity and its rate of change with age and over time. RESULTS: A total of 280 eyes from 140 individuals with bilateral large drusen were included in this study. Cross-sectional data showed that rEZR reduced with increasing age (-8.4 arbitrary units [AUs] per decade; 95% confidence interval [CI], -11.5 to -5.2; P < 0.001). Longitudinal data showed that, on average, rEZR declined at a rate of -2.1 AU per year (95% CI, -2.6 to -1.6 AU per year; P < 0.001). Larger RPD area (P = 0.042) at baseline was associated with a faster rate of rEZR decline over time, whereas the presence of PAs and the drusen volume at baseline showed no significant association with rEZR decline over time (P = 0.068 and P = 0.529, respectively). CONCLUSIONS: The rEZR significantly reduces over 3 years in subjects with iAMD, and both the presence and increasing extent of coexistent RPD at baseline are associated with a faster rate of decline. These findings warrant further studies to understand the value of rEZR as a biomarker of AMD progression.

Intersession Repeatability of Structural Biomarkers in Early and Intermediate Age-Related Macular Degeneration: A MACUSTAR Study Report.

Purpose: To analyze the intersession repeatability of structural biomarkers in eyes with early and intermediate age-related macular degeneration (iAMD) within the cross-sectional part of the observational multicenter MACUSTAR study. Methods: Certified site personnel obtained multimodal imaging data at two visits (38 ± 20 [mean ± standard deviation] days apart), including spectral-domain optical coherence tomography (SD-OCT). One junior reader performed systematic and blinded grading at the central reading center, followed by senior reader review. Structural biomarkers included maximum drusen size classification (>63 to ≤125 µm vs. >125 µm), presence of large pigment epithelium detachments (PEDs), reticular pseudodrusen (RPD), vitelliform lesions, and refractile deposits. Intrasession variability was assessed using Cohen's κ statistics. Results: At the first visit, 202 study eyes of 202 participants were graded as manifesting with either early (n = 34) or intermediate (n = 168) AMD. Grading of imaging data between visits revealed perfect agreement for the maximum drusen size classification (κ = 0.817; 95% confidence interval, 0.70-0.94). In iAMD eyes, perfect to substantial agreement was determined for the presence of large PEDs (0.87; 0.69-1.00) and RPD (0.752; 0.63-0.87), while intersession agreement was lower for the presence of vitelliform lesions (0.649; 0.39-0.65) and refractile deposits (0.342; -0.029-0.713), respectively. Conclusions: Multimodal retinal imaging analysis between sessions showed a higher repeatability for structural biomarkers with predefined cutoff values than purely qualitative defined parameters. Translational Relevance: A high repeatability of retinal imaging biomarkers will be important to implement automatic grading approaches and to establish robust and meaningful structural clinical endpoints for future interventional clinical trials in patients with iAMD.

Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study.

BACKGROUND: Brolucizumab has recently been approved in Europe as a novel treatment for patients with neovascular age-related macular degeneration (nAMD). We report on early experiences with real-world outcomes of switch to brolucizumab therapy in previously anti-vascular endothelial growth factor (anti-VEGF)-treated patients. METHODS: Patients with recalcitrant nAMD were switched to brolucizumab therapy. Functional and structural parameters 4 weeks after first brolucizumab injection were evaluated including best-corrected visual acuity (BCVA (logMAR)), foveal centre point (FCP (µm)), central subfield retinal thickness (CSRT (µm)) and macular volume (mm³). RESULTS: Sixty-three eyes of 57 patients with nAMD (52.6% females) with a mean (±SD) age of 79.5±6.7 years were included. Mean change of BCVA was 0.03±0.14 logMAR (p=0.115). Significant reductions were recorded for FCP with a mean (±SD) change of -66.81±72.63 µm, -66.76±60.71 µm for CSRT and -0.27±0.24 mm³ for macular volume (all p<0.001). Intraocular inflammation was observed in seven eyes of seven patients, including one case of retinal vasculitis. CONCLUSIONS: The results of the SHIFT study indicate that switch to brolucizumab may represent a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents. Further long-term analyses appear prudent to assess efficacy and safety of brolucizumab in a routine clinical setting.

OCT Signs of Early Atrophy in Age-Related Macular Degeneration: Interreader Agreement: Classification of Atrophy Meetings Report 6.

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 µm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 µm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.

Effect of subthreshold nanosecond laser on retinal structure and function in intermediate age-related macular degeneration.

BACKGROUND: Subthreshold nanosecond laser (SNL) treatment has been studied as a potential intervention in intermediate age-related macular degeneration (iAMD). This study investigated the effect of 100 SNL treatment spots on retinal structure and function. METHODS: A prospective single-arm interventional pilot study. SNL treatment was delivered as 100 spots around the retinal vascular arcades of the study eye (worst visual acuity) in a single session in subjects with iAMD. Multimodal retinal imaging and dark-adapted chromatic perimetry were performed at baseline and at 0.5, 3, 6 and 12 months post treatment. Post treatment changes in best corrected visual acuity (BCVA), retinal thickness, relative ellipsoid zone reflectivity (rEZR) and rod-mediated functional parameters were compared to baseline. RESULTS: Twenty-one subjects with iAMD were recruited. SNL treatment was associated with an increase in retinal thickness (p = 0.008) and decrease in rEZR (p < 0.001) at 2 weeks post laser. Recovery of retinal thickness and rEZR was observed at the 3-month post laser visit. A gradual improvement in BCVA was observed after laser treatment. The mean change in BCVA between baseline and 12-month visit was +1.9 ± 3.3 letters for the SNL treated eyes, compared to -0.4 ± 3.0 letters for the fellow eyes (p = 0.027). Rod-mediated function improved at 3 months post laser (p < 0.001) and returned to the baseline levels at 12 months post treatment. CONCLUSIONS: A single treatment with 100 SNL spots causes a short-term change in retinal structure and improvement in retinal function that are apparent at 3 months post treatment.

Conversion from Intermediate Age-Related Macular Degeneration to Geographic Atrophy in a Proxima B Subcohort Using a Multimodal Approach.

INTRODUCTION: This retrospective analysis assessed geographic atrophy (GA) progression in fellow eyes from the Proxima B trial intermediate age-related macular degeneration (iAMD) subcohort using high-resolution multimodal imaging anchored on optical coherence tomography (OCT). METHODS: Thirty-two patients from the Proxima B iAMD subcohort were assessed; all had GA with no macular neovascularization (MNV) in the contralateral eye. Imaging data, including color fundus photography, fluorescein angiography, near-infrared reflectance, fundus autofluorescence (FAF), and spectral-domain OCT, were obtained. Features preceding progression/conversion to advanced AMD (drusen, reticular pseudodrusen [RPD], MNV, incomplete/complete retinal pigment epithelium and outer retinal atrophy [iRORA/cRORA]) were assessed. RESULTS: Of 30 fellow eyes with available follow-up images, 12 converted to GA (FAF), 2 converted to MNV, and 16 were nonconverters during the review period (median: 17.8 months). iRORA/cRORA features (present in all converters at baseline) were identified on OCT in eyes that progressed to GA. Median time interval from iRORA to cRORA and from cRORA to GA was 7 months each. GA development/progression was either drusen- or RPD-associated (n = 6 each). Eyes with baseline RPD showed faster GA progression versus eyes with drusen (1.49 vs. 0.38 mm2/year). CONCLUSIONS: RPD presence was associated with rapid GA lesion enlargement and may provide an early indication of faster GA progression.

Right-angled vessels in macular telangiectasia type 2.

PURPOSE: To evaluate the role of right-angled vessels (RAVs) during disease progression in macular telangiectasia type 2 (MacTel). METHODS: In this study, 100 eyes of 52 patients and 52 eyes of 26 age-related controls were examined using fundus photography, spectral-domain optical coherence tomography (SD-OCT), OCT angiography (OCT-A) and fundus fluorescein angiography (FFA). Two masked readers graded fundus photographs of patients' eyes into five disease stages according to Gass and Blodi, and evaluated all eyes for the presence of RAVs. If RAVs were present, their course and origin (arterial vs venous) was evaluated with OCT-A and FFA, respectively. Additionally, we looked for morphological correlates of these vessels on SD-OCT scans. Neovascular eyes were analysed for the presence of RAVs and for morphological changes on formation of neovascularisations (NVs). RESULTS: In OCT-A, RAVs were already detectable in eyes with early stages (1 to 2), could be tracked from superficial to outer retinal layers and were shown to form anastomoses in the outer retina with disease progression. These vessels were of both arterial and venous origin as shown by early phase FFA. Dilated capillaries and RAVs in OCT-A corresponded to hyper-reflective alterations of the outer retina on SD-OCT scans. In 19/19 eyes, NVs were associated with the presence of RAVs, and RAVs were shown to directly connect to neovascular complexes and to undergo morphological changes upon NV formation. CONCLUSIONS: The results emphasise the role of RAVs during disease progression from an early stage on and demonstrate their involvement in the development of secondary NVs in MacTel.

Longitudinal Analysis of Retinal Thickness and Retinal Function in Eyes with Large Drusen Secondary to Intermediate Age-Related Macular Degeneration.

PURPOSE: To assess the longitudinal association between outer retinal microstructure and mesopic as well as scotopic retinal sensitivity in patients with drusen secondary to intermediate age-related macular degeneration (iAMD). DESIGN: Prospective, longitudinal natural history study. PARTICIPANTS: Fifty-nine eyes of 54 patients with large drusen (> 125 µm) associated with iAMD and 27 age-matched healthy control eyes. METHODS: Participants underwent spectral-domain OCT and both mesopic and scotopic fundus-controlled perimetry (FCP). Annual follow-up visits were performed over a 3-year period. MAIN OUTCOME MEASURES: Pointwise correlation of retinal sensitivity stimuli to corresponding standardized (Z score) pointwise retinal thickness. Linear mixed-effect models were applied to analyze longitudinally the association of pointwise retinal thickness changes, follow-up time, or both with retinal function. RESULTS: At baseline, mean pointwise sensitivity in patients was reduced by -1.67 dB (95% confidence interval [CI], -2.22 to -1.12) for mesopic and by -2.34 dB (95% CI, -2.85 to -1.84) for scotopic testing compared with controls with a pointwise sensitivity change of -0.35 dB/year (95% CI, -0.43 to -0.28) for mesopic and +0.20 dB/year (95% CI, 0.12-0.29) for scotopic testing, respectively (P < 0.001). Retinal thickness analysis in patients revealed a significantly thinner outer nuclear layer (ONL) by -0.49 standard deviation (SD; 95% CI, -0.70 to -0.28 SD) and a significant thicker retinal pigment epithelium-drusen complex (RPEDC) by +3.22 SD (95% CI, 2.27-4.17 SD) at baseline, respectively (P < 0.001). During follow-up, retinal thickness thickened further by +0.51 SD/year (RPEDC) and thinned by -0.03 SD/year (ONL; P = 0.045) and -0.34 SD/year (inner and outer photoreceptor segments) in patients, respectively (P < 0.001). Structure-function analysis showed a significant association of the ONL and the RPEDC thickness change with both types of FCP sensitivity testing (P < 0.001). Besides, follow-up time had a significant (independent) effect on mesopic and scotopic retinal sensitivity (P < 0.001). CONCLUSIONS: The longitudinal structure-function correlation demonstrated a progressive quantifiable degeneration of the outer retina in iAMD associated with photoreceptor dysfunction. Because longitudinal sensitivity changes could not be explained by structural changes alone, an unmet need remains for additional refined parameters on retinal structure to predict retinal function.

Non-neovascular age-related macular degeneration with subretinal fluid.

PURPOSE: To evaluate the various patterns of subretinal fluid (SRF) in eyes with age-related macular degeneration (AMD) in the absence of macular neovascularisation (MNV) and to assess the long-term outcomes in these eyes. METHODS: This retrospective study included only eyes with non-neovascular AMD and associated SRF. Eyes with evidence of MNV were excluded. Spectral-domain optical coherence tomography (SD-OCT) was obtained at baseline and at follow-up, and qualitative and quantitative SD-OCT analysis of macular drusen including drusenoid pigment epithelial detachment (PED) and associated SRF was performed to determine anatomic outcomes. RESULTS: Forty-five eyes (45 patients) were included in this analysis. Mean duration of follow-up was 49.7±36.7 months. SRF exhibited three different morphologies: crest of fluid over the apex of the drusenoid PED, pocket of fluid at the angle of a large druse or in the crypt of confluent drusen or drape of low-lying fluid over confluent drusen. Twenty-seven (60%) of the 45 eyes with fluid displayed collapse of the associated druse or drusenoid PED and 24 (53%) of the 45 eyes developed evidence of complete or incomplete retinal pigment epithelial and outer retinal atrophy. CONCLUSION: Non-neovascular AMD with SRF is an important clinical entity to recognise to avoid unnecessary anti-vascular endothelial growth factor therapy. Clinicians should be aware that SRF can be associated with drusen or drusenoid PED in the absence of MNV and may be the result of retinal pigment epithelial (RPE) decompensation and RPE pump failure.

Prognostic value of intermediate age-related macular degeneration phenotypes for geographic atrophy progression.

BACKGROUND: To characterise early stages of geographic atrophy (GA) development in age-related macular degeneration (AMD) and to determine the prognostic value of structural precursor lesions in eyes with intermediate (i) AMD on the subsequent GA progression. METHODS: Structural precursor lesions for atrophic areas (lesion size at least 0.5 mm² in fundus autofluorescence images) were retrospectively identified based on multimodal imaging and evaluated for association with the subsequent GA enlargement rates (square-root transformed, sqrt). A linear mixed-effects model was used to account for the hierarchical nature of the data with a Tukey post hoc test to assess the impact of the local precursor on the subsequent GA progression rate. RESULTS: A total of 39 eyes with GA of 34 patients with a mean age of 74.4±6.7 (±SD) years were included in this study. Five precursor lesions (phenotypes 1-5) preceding GA development were identified: large, sub-retinal pigment epithelial drusen (n=19), reticular pseudodrusen (RPD, n=10), refractile deposits (n=4), pigment epithelial detachment (n=4) and vitelliform lesions (n=2). Precursor lesions exhibited a significant association with the subsequent (sqrt) GA progression rates (p=0.0018) with RPD (phenotype 2) being associated with the fastest GA enlargement (2.29±0.52 (±SE) mm/year. CONCLUSIONS: The results indicate the prognostic relevance of iAMD phenotyping for subsequent GA progression highlighting the role of structural AMD features across different AMD stages.

Validation of an Automated Quantification of Relative Ellipsoid Zone Reflectivity on Spectral Domain-Optical Coherence Tomography Images.

Purpose: Relative ellipsoid zone reflectivity (rEZR) represents a potential biomarker of photoreceptor health on spectral-domain optical coherence tomography (SD-OCT). Because manual quantification of rEZR is laborious and lacks of spatial resolution, automated quantification of the rEZR would be beneficial. The purpose of this study was to evaluate the reliability and reproducibility of an automated rEZR quantification method. Methods: The rEZR was acquired using a manual and an automated approach in eyes with age-related macular degeneration (AMD) and healthy controls. The rEZR obtained from both methods was compared and the agreement between the methods and their reproducibility assessed. Results: Forty eyes of 40 participants with a mean (± standard deviation) age of 65.2 ± 7.8 years were included. Both the manual and automated method showed that control eyes exhibit a greater rEZR than AMD eyes (P < 0.001). Overall, the limits of agreement between the manual and automated method were -7.5 to 7.3 arbitrary units (AU) and 95% of the data points had a difference in the rEZR between the methods of ±8.2%. An expected perfect reproducibility was observed for the automated method, whereas the manual method had a coefficient of repeatability of 6.3 arbitrary units. Conclusions: The automated quantification of rEZR method is reliable and reproducible. Further studies of the rEZR as a novel biomarker for AMD severity and progression are warranted. Translational Relevance: Automated quantification of SD-OCT-based rEZR allows for its comprehensive and longitudinal characterization evaluating its relevance as an in vivo biomarker of photoreceptor function and its prognostic value for AMD progression.

Longitudinal Analysis of Structural and Functional Changes in Presence of Reticular Pseudodrusen Associated With Age-Related Macular Degeneration.

Purpose: To examine longitudinal changes of retinal thickness and retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD) and predominantly reticular pseudodrusen (RPD). Methods: At baseline 30 eyes of 25 iAMD patients underwent optical coherence tomography imaging, mesopic and scotopic fundus-controlled perimetry (FCP) with follow-up examinations at month 12 (20 eyes), 24 (12 eyes), and 36 (11 eyes). Thicknesses of different retinal layers and results of FCP testing (n = 56 stimuli) were spatially and longitudinally analyzed using linear mixed-effects models. Results: At baseline, the thickness of the partial outer retinal layer (pORL, 70.21 vs. 77.47 µm) and both mesopic (16.60 vs. 18.72 dB) and scotopic (12.14 vs. 18.67 dB) retinal sensitivity were decreased in areas with RPD compared with unremarkable areas (P < 0.001). Over three years, mean change of pORL was -0.66 normative standard deviation (SD; i.e., z-score, P < 0.001) for regions with existing RPD, -0.40 SD (P < 0.001) for regions with new occurring RPD, and -0.17 SD (P = 0.041) in unremarkable regions. Decrease of scotopic and mesopic sensitivity over three years was more pronounced in areas with existing (-3.51 and -7.76 dB) and new occurring RPD (-2.06 and -5.97 dB). Structure-function analysis revealed that 1 SD decrease of pORL thickness was associated with a sensitivity reduction of 3.47 dB in scotopic and 0.79 dB in mesopic testing. Conclusions: This study demonstrates progressive outer retinal degeneration and impairment of photoreceptor function in eyes with iAMD and RPD over three years. Preservation of outer retinal thickness and reduction of RPD formation may constitute meaningful surrogate endpoints in interventional trials on eyes with AMD and RPD aiming to slow outer retinal degeneration.