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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.

Purpose To examine the topographic correlation between retinal morphology and retinal sensitivity by mesopic and scotopic fundus-controlled perimetry (FCP) in eyes with intermediate AMD. Methods Thirty-five eyes from 32 patients (mean age 70.9 years) and 29 age-matched controls prospectively underwent spectral-domain optical coherence tomography (SD-OCT) imaging. Mesopic (Goldman III, 200 ms, 4-2 strategy) and scotopic (Goldman V, 200 ms, 4-2 strategy) FCP with a 56-stimulus point grid was performed in AMD patients with the MP-1S. Thickness values of different retinal layers were measured at each stimulus point and compared, topographically corresponding to values in controls of similar age for pointwise structural-functional analysis. Results The overall mean sensitivity in patients was 16.9 ± 3.0 dB for mesopic and 14.0 ± 3.7 dB for scotopic testing. Within the central 4° of the macula, reduced mesopic and scotopic sensitivity values were found (P < 0.0001). These findings correlated to central increasing retinal pigment epithelium-drusen complex (RPEDC) thickness and central decreasing outer nuclear layer (ONL) and photoreceptor (PR)-segments thickness (P < 0.0001, respectively). Structure-function correlations revealed that a reduction of mesopic and scotopic sensitivity was associated with increasing thickness of the total retina and the RPEDC and a decrease of the ONL and the PR-segments (P < 0.001, respectively). Conclusions Accumulation of sub-RPE material in patients with intermediate AMD is spatially associated to quantifiable structural alterations in various retinal layers and to corresponding retinal dysfunction. The topographic analysis of retinal thickness and retinal sensitivity will be helpful for a better understanding of the disease process and for the evaluation of new interventional approaches.

Purpose To develop and evaluate a software tool for automated detection of focal hyperpigmentary changes (FHC) in eyes with intermediate age-related macular degeneration (AMD). Methods Color fundus (CFP) and autofluorescence (AF) photographs of 33 eyes with FHC of 28 AMD patients (mean age 71 years) from the prospective longitudinal natural history MODIAMD-study were included. Fully automated to semiautomated registration of baseline to corresponding follow-up images was evaluated. Following the manual circumscription of individual FHC (four different readings by two readers), a machine-learning algorithm was evaluated for automatic FHC detection. Results The overall pixel distance error for the semiautomated (CFP follow-up to CFP baseline: median 5.7; CFP to AF images from the same visit: median 6.5) was larger as compared for the automated image registration (4.5 and 5.7; P < 0.001 and P < 0.001). The total number of manually circumscribed objects and the corresponding total size varied between 637 to 1163 and 520,848 pixels to 924,860 pixels, respectively. Performance of the learning algorithms showed a sensitivity of 96% at a specificity level of 98% using information from both CFP and AF images and defining small areas of FHC (“speckle appearance”) as “neutral.” Conclusions FHC as a high-risk feature for progression of AMD to late stages can be automatically assessed at different time points with similar sensitivity and specificity as compared to manual outlining. Upon further development of the research prototype, this approach may be useful both in natural history and interventional large-scale studies for a more refined classification and risk assessment of eyes with intermediate AMD. Translational Relevance Automated FHC detection opens the door for a more refined and detailed classification and risk assessment of eyes with intermediate AMD in both natural history and future interventional studies.

PURPOSE To analyze the central distribution of reticular drusen (RDR) in eyes with early and intermediate AMD without soft drusen or pigmentary changes within the central subfield using confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT). METHODS Fifty-two eyes of 46 subjects (median age: 76.3 years, interquartile range [IQR], 71-80) were examined by simultaneous combined near-infrared cSLO and raster SD-OCT imaging. The appearance and the topographic distribution of RDR were analyzed within the macula area using the Early Treatment Diabetic Retinopathy Study grid. In addition, longitudinal examinations during an observation period of at least 6 months were included (median observation time: 1.5 years, IQR, 0.9-2.8). RESULTS The RDR involvement within the central subfield (46%) was less compared with the surrounding subfields (62%-100%), slices (67%-100%), and zones (94%-100%) (P < 0.001). RDR were typically distributed as one continuous zone around the fovea in an incomplete or complete ring-shaped pattern, whereas the fovea itself was either spared or only a few lesions were present. Over time, the RDR density increased and new RDR lesions occurred at the border of the RDR zone toward a closure of the ring-shaped pattern. Within the fovea, development of RDR was observed in 8 of 28 eyes. CONCLUSIONS The fovea appears to be less vulnerable to RDR development as compared with peripheral macula areas. Factors for initial sparing of the foveal retina are yet unknown but may relate to topographic differences of choroidal blood flow and/or photoreceptor distribution.

Purpose To characterize longitudinal changes of reticular drusen (RDR) in subjects with geographic atrophy (GA) secondary to age-related macular degeneration in the multicenter, prospective natural history Geographic Atrophy Progression Study. Methods Three-field confocal scanning laser ophthalmoscopy fundus autofluorescence (cSLO FAF, excitation [exc.] = 488 nm; emission [em.] 500-800 nm, Heidelberg Retina Angiograph/Spectralis) of 44 eyes of 22 patients with RDR (median age 77.6 years; range, 61-90 years) at baseline were identified in the study population and included for further analysis. Two independent readers determined the presence, topographic distribution, and pattern of RDR at baseline and at 18 months. Furthermore, the convex hull of the extent of RDR as the minimum polygon encompassing the entire area of RDR involvement was quantified. Results RDR lesion boundaries were clearly detectable in all directions within three-field FAF composite images in 16 eyes of 10 patients at both baseline and final visits. Over time, RDR-affected retinal area and RDR density increased. Quantitative analysis showed a mean average RDR extent of 53.7 mm(2) (95% confidence interval [95% CI]; 40.7; 66.8) at baseline. The mean differences for intraobserver agreements were 2.4 mm(2) (95% CI; -0.1; 4.9) for reader 1 and -0.6 mm(2) (95% CI; -2.3; 1.1) for reader 2. The mean difference of interobserver agreement was 0.9 mm(2) (95% CI; -0.8; 2.7). A mean growth rate of the RDR extent within the three-field FAF composite image of 4.4 mm(2)/y (95% CI; 1.9; 6.9) was measured. Conclusions In vivo cSLO FAF imaging allows for both qualitative and quantitative mapping of longitudinal changes of RDR areas within a relatively short time period. Continuous enlargement of the affected retinal area indicates disease progression with regard to this phenotypic characteristic associated with GA in AMD. Systematic recordings of RDR progression appears warranted in future natural history and interventional studies in dry AMD. (ClinicalTrials.gov number, NCT00599846.).