Correlation between ellipsoid zone thickness and the presence of subretinal drusenoid deposits in age-related macular degeneration.

PURPOSE: Subretinal drusenoid deposits (SDDs) in age-related macular degeneration (AMD) are associated with systemic vascular diseases that compromise ocular perfusion. We demonstrate that SDDs are associated with decreased ellipsoid zone (EZ) thickness, further evidence of hypoxic damage. METHODS: Post hoc analysis of a cross-sectional study. 165 AMD subjects (aged 51-100; 61% women). Spectral-domain optical coherence tomography was obtained in both eyes. Masked readers assigned subjects to three groups: drusen only, SDD+drusen (SDD+D) and SDD only. EZ thickness was measured subfoveally and 2000 µm nasally, temporally, superiorly and inferiorly from the fovea. Univariate testing was performed using two-tailed t-tests with Bonferroni correction. RESULTS: The mean EZ thickness differences between the SDD+D and drusen-only groups were (in µm) 1.10, 0.67, 1.21, 1.10 and 0.50 at the foveal, nasal, temporal, superior and inferior locations, respectively (p=0.08 inferiorly, otherwise p≤0.01); between the SDD-only and drusen-only groups, the differences were 3.48, 2.48, 2.42, 2.08 and 1.42 (p≤0.0002). Differences in EZ thicknesses across all subjects and between groups were not significantly different based on gender, race or age. CONCLUSION: Subjects with SDDs (±drusen) had thinner EZs than those with drusen only, and the inferior EZ was least affected. EZs were thinnest in SDD-only subjects. This thinning gradation is consistent with progressive destruction of highly oxygen-sensitive mitochondria in the EZ from hypoxia. These findings support the reduced ophthalmic perfusion hypothesis for the formation of SDDs secondary to high-risk systemic vasculopathy.

En Face Optical Coherence Tomography Illustrates the Trizonal Distribution of Drusen and Subretinal Drusenoid Deposits in the Macula.

PURPOSE: To analyze the topographic distribution of macular drusen and subretinal drusenoid deposits (SDDs) using single-capture en face spectral domain optical coherence tomography (SD-OCT) imaging. DESIGN: Retrospective case series. METHODS: Analysis of 33 eyes of 20 patients with evidence of SDDs. Structural en face OCT images were reconstructed using a 40-µm-thick slab positioned from 48 to 88 µm above the Bruch membrane. The Early Treatment of Diabetic Retinopathy Study (ETDRS) grid and a rod/cone density map were overlaid on the en face OCT images, and the distribution of different subtypes of SDDs and macular drusen were assessed. RESULTS: A total of 31 eyes (94%) showed a trizonal distribution pattern of drusen and SDDs. Whereas small to large drusen tended to aggregate in the central circle, dot SDDs predominated in the inner ring and the inner portion of the outer ring of the ETDRS grid and ribbon SDDs localized to the outer ring and outside the ETDRS grid. Of note, drusen colocalized to the region of greatest cone density, whereas ribbon SDDs colocalized to the area of greatest rod density. The dot SDDs mapped to the intermediate region with mixed rod and cone representation. CONCLUSION: Dot and ribbon subtypes of SDDs and macular drusen show a characteristic trizonal distribution. The locations of these lesions colocalize according to the different densities of the cones and rods in the retina and may reflect varying pathophysiological activities of these photoreceptor subtypes.

Retro-mode: a newer insight into dry age-related macular degeneration (AMD).

The purpose of this study is to study the role of retro-mode (RM) in early detection and to compare it with other preexisting available modalities on multimodal imaging system in dry AMD. A prospective observational cross-sectional study was done between November 2020 and October 2021 which included 409 eyes of 207 patients. For study purpose, eyes were divided into 3 groups according to the size and number of the drusen, viz, group 1: No AMD, group 2: early AMD and group 3: intermediate AMD which was further divided into 2 subgroups, viz, subgroup A: eyes with drusen size 63-125 µm and subgroup B: eyes with drusen size 125-250 µm. Patients with active or treated wet AMD, scarred choroidal neovascular membrane (CNVM), other maculopathies, other retinopathies, high myopia, trauma and glaucoma were excluded from the study. In cases of No AMD and early AMD, a number of drusens detected on RM were statistically not significant compared to fundus autofluorescence (FAF) and color photo (CF), but in intermediate AMD cases, it was statistically significant. While the area involved by drusens calculated by RM was statistically significant compared to both other modalities. When all modalities were compared with enhanced depth imaging-optical coherence tomography (EDI-OCT) at the choroid and chorio-capillary (CC) level and vessel density (VD) on optical coherence tomography angiography (OCTA) at the choroid, capillaries, deep retinal and superficial retinal plexus level; it was only RM which was found to be in sync with these proven modalities in terms of pattern and trend. In the present scenario, RM is found to be a better diagnostic modality in detecting early and a greater number of drusens with area of involvement than other existing modalities. Though superior, as found in this study, this mode cannot replace other modalities at present but only acts as a complementary investigation in early detection of this disease.

Accurate drusen segmentation in optical coherence tomography via order-constrained regression of retinal layer heights.

Drusen are an important biomarker for age-related macular degeneration (AMD). Their accurate segmentation based on optical coherence tomography (OCT) is therefore relevant to the detection, staging, and treatment of disease. Since manual OCT segmentation is resource-consuming and has low reproducibility, automatic techniques are required. In this work, we introduce a novel deep learning based architecture that directly predicts the position of layers in OCT and guarantees their correct order, achieving state-of-the-art results for retinal layer segmentation. In particular, the average absolute distance between our model's prediction and the ground truth layer segmentation in an AMD dataset is 0.63, 0.85, and 0.44 pixel for Bruch's membrane (BM), retinal pigment epithelium (RPE) and ellipsoid zone (EZ), respectively. Based on layer positions, we further quantify drusen load with excellent accuracy, achieving 0.994 and 0.988 Pearson correlation between drusen volumes estimated by our method and two human readers, and increasing the Dice score to 0.71 ± 0.16 (from 0.60 ± 0.23) and 0.62 ± 0.23 (from 0.53 ± 0.25), respectively, compared to a previous state-of-the-art method. Given its reproducible, accurate, and scalable results, our method can be used for the large-scale analysis of OCT data.

Six-year incidence of age-related macular degeneration and correlation to OCT-derived drusen volume measurements in a Chinese population.

AIMS: To report the 6-year incidence of optical coherence tomography (OCT)-derived age-related changes in drusen volume and related systemic and ocular associations. METHODS: Chinese adults aged 40 years and older were assessed at baseline and 6 years with colour fundus photography (CFP) and spectral domain (SD) OCT. CFPs were graded for age-related macular degeneration (AMD) features and drusen volume was generated using commercially available automated software. RESULTS: A total of 4172 eyes of 2580 participants (mean age 58.12±9.03 years; 51.12% women) had baseline and 6-year follow-up CFP for grading, of these, 2130 eyes of 1305 participants had gradable SD-OCT images, available for analysis. Based on CFP grading, 136 (3.39%) participants developed incident early AMD and 10 (0.25%) late AMD. Concurrently, retinal pigment epithelial-Bruch's membrane (RPE-BrC) volumes decreased, remained stable and increased in 6.8%, 78.5% and 14.7%, respectively, over 6 years. In eyes where RPE-BrC volumes were >0 mm3 at baseline, this was associated with two-fold higher prevalence rate of any AMD at baseline (p<0.001). Multivariable analysis showed that when compared with eyes where RPE-BrC volume was unchanged, volume decrease was significantly associated with older age (OR=1.30; p<0.001), smoking (OR=2.21; p=0.001) and chronic kidney disease (OR=3.4, p=0.008), while increase was associated with older age (OR=1.36; p<0.001) and hypertension (OR=1.43; p=0.016). CONCLUSION: AMD incidence detected at 6 years on CFP and correlated OCT-derived drusen volume measurement change is low. Older age and some systemic risk factors are associated with drusen volume change, and our data provide new insights into relationship between systemic risk factors and outer retinal morphology in Asian eyes.

Prevalence and risk factors for age-related macular degeneration in a population-based cohort study of older adults in Northern Ireland using multimodal imaging: NICOLA Study.

PURPOSE: To report prevalence and risk factor associations for age-related macular degeneration (AMD) and AMD features from multimodal retinal grading in a multidisciplinary longitudinal population-based study of aging in Northern Ireland. STUDY DESIGN: Population-based longitudinal cohort study. METHODS: Retinal imaging at the Norther Ireland Cohort for the Longitudinal Aging Study health assessment included stereo Colour Fundus Photography (CFP) (Canon CX-1, Tokyo, Japan) and Spectral-Domain Optical Coherence Tomography (SD-OCT) ((Heidelberg Retinal Angopgraph (HRA)+OCT; Heidelberg Engineering, Heidelberg, Germany). Medical history and demographic information was obtained during a home interview. Descriptive statistics were used to describe the prevalence of AMD and individual AMD features. Multiple imputation followed by multiple regression modelling was used to explore risk factor associations including relationships with AMD genetic risk score. RESULTS: Retinal images from 3386 participants were available for analysis. Mean age of the sample was 63.4 (SD 9.01, range: 36-99). Population weighted prevalence of AMD using colour grading in those over 55 years was: no drusen: 6 0.4%; drusen <63 µm: 15.9%; drusen 63-125 µm: 13.7%; drusen >125 µm or pigmentary changes: 8.3%; late AMD: 1.6%. Prevalence of AMD features in those over 55 years was: OCT drusen 27.5%, complete outer retinal pigment epithelium and outer retinal atrophy (cRORA) on OCT was 4.3%, reticular drusen 3.2% and subretinal drusenoid deposits 25.7%. The genetic risk score was significantly associated with drusen and cRORA but less so for SDD alone and non-significant for hyperpigmentation or vitelliform lesions. CONCLUSIONS: Multimodal imaging-based classification has provided evidence of some divergence of genetic risk associations between classical drusen and SDD. Our findings support an urgent review of current AMD severity classification systems.

Longitudinal change of reticular pseudodrusen area in ultrawide-field imaging.

This study aimed to investigate the longitudinal change in the reticular pseudodrusen (RPD) area in the fundus and its association with late age-related macular degeneration (AMD). 91 RPD eyes (55 patients; age 67.9 ± 7.3 years) with > 5 years' follow-up (6.8 ± 0.9 years) from a single medical center were enrolled. Ultrawide-field photography images were analyzed using the concentric rings method, and the RPD area was semi-quantitatively classified according to the affected segment number into central, intermediate, and extensive types. Correlations of longitudinal changes in the RPD area and late AMD risk were investigated. RPD area increased significantly during the follow-up (p < 0.001). The increase rate correlated with age (r = 0.207; p = 0.048), RPD area at first visit (r = - 0.222; p = 0.035), and the decrease rate of subfoveal choroidal thickness (SFCT) (r = 0.217; p = 0.039). Many central (18/49, 36.7%) and intermediate (15/23, 65.2%) types switched to the more advanced type during the follow-up. Macular neovascularization and geographic atrophy developed in 12.3% and 18.7% of patients by 7 years. Late AMD incidence was significantly higher in eyes with large than in those with small RPD areas (p = 0.002). Larger RPD area at baseline, faster increase in RPD area, thinner SFCT, rapid decrease in SFCT, and the presence of late AMD on fellow eye were associated with late AMD. All RPD areas progressively increase over time. The regular assessment of RPD area may help to predict late AMD risk in RPD eyes.

A Deep Learning Framework for the Detection and Quantification of Reticular Pseudodrusen and Drusen on Optical Coherence Tomography.

Purpose: The purpose of this study was to develop and validate a deep learning (DL) framework for the detection and quantification of reticular pseudodrusen (RPD) and drusen on optical coherence tomography (OCT) scans. Methods: A DL framework was developed consisting of a classification model and an out-of-distribution (OOD) detection model for the identification of ungradable scans; a classification model to identify scans with drusen or RPD; and an image segmentation model to independently segment lesions as RPD or drusen. Data were obtained from 1284 participants in the UK Biobank (UKBB) with a self-reported diagnosis of age-related macular degeneration (AMD) and 250 UKBB controls. Drusen and RPD were manually delineated by five retina specialists. The main outcome measures were sensitivity, specificity, area under the receiver operating characteristic (ROC) curve (AUC), kappa, accuracy, intraclass correlation coefficient (ICC), and free-response receiver operating characteristic (FROC) curves. Results: The classification models performed strongly at their respective tasks (0.95, 0.93, and 0.99 AUC, respectively, for the ungradable scans classifier, the OOD model, and the drusen and RPD classification models). The mean ICC for the drusen and RPD area versus graders was 0.74 and 0.61, respectively, compared with 0.69 and 0.68 for intergrader agreement. FROC curves showed that the model's sensitivity was close to human performance. Conclusions: The models achieved high classification and segmentation performance, similar to human performance. Translational Relevance: Application of this robust framework will further our understanding of RPD as a separate entity from drusen in both research and clinical settings.

Small hard drusen and associated factors in early seniority.

PURPOSE: The purpose of this study was to examine the ocular and systemic risk profile of the fundus phenotype ≥ 20 small hard (macular) drusen (< 63 µm in diameter). METHODS: This single-center, cross-sectional study of 176 same-sex twin pairs aged 30 to 80 (median 60) years was a component of a framework study of the transition from not having age-related macular degeneration to having early AMD. Drusen categories assessed using fundus photography and optical coherence tomography included small hard drusen (diameter < 63 µm), intermediate soft drusen (63-125 µm), and large soft drusen (> 125 µm), of which the soft drusen are compatible with a diagnosis of AMD. RESULTS: Having ≥ 20 small hard drusen within or outside the macula was associated with increasing age, lower body mass index, shorter axial length, hyperopia, female sex, increasing high-density lipoprotein (HDL), high alcohol consumption, and with the presence of soft drusen. CONCLUSIONS: Having ≥ 20 small hard drusen was associated with some AMD-related risk factors, but not with smoking, increasing body mass index, and higher blood pressure. Having ≥ 20 small hard drusen was also associated with soft drusen, in agreement with previous studies. These findings suggest that small hard drusen are not an early manifestation of AMD but the product of a distinct process of tissue alteration that promotes the development of AMD or some subtype thereof.

Evaluation of the microperimetry in eyes with cuticular drusen.

Retinal sensitivity may vary by subtypes of cuticular drusen. This retrospective study included 52 eyes of 32 patients with cuticular drusen. All the patients underwent assessment of best-corrected visual acuity (BCVA), spectral-domain optical coherence tomography (SD-OCT), color fundus photography, fluorescein angiography, fundus autofluorescence, and microperimetry. The area occupied by drusen was counted using microperimetry. The cuticular drusen subtype was classified into 3 groups based on the SD-OCT findings. Age, BCVA, pattern standard deviation, area occupied by drusen, pupil size, and the false-positive rate were not significantly different (p > 0.05) according to the cuticular drusen type. The mean retinal sensitivity (MRS) (p = 0.063) and mean deviation (MD) (p = 0.098) showed marginally significant differences among the groups. In the subgroup analyses, type 1 and type 3 cuticular drusen showed significant differences in the MD (- 1.8 ± 2.1 vs - 5.1 ± 5.3; p = 0.011) and MRS (25.1 ± 2.2 vs 21.3 ± 5.7; p = 0.016) without differences in age, BCVA, or the area occupied by drusen (p > 0.05). The results indicate that depending on the subtypes of cuticular drusen type, the deterioration of retinal sensitivity is more likely to occur than decreased vision.

Multispectral pattern recognition measures change in drusen area in age-related macular degeneration with high congruency to expert graders.

Drusen are a hallmark lesion of age-related macular degeneration (AMD) and changes in their area and/or volume are strongly associated with disease progression. Assessment of longitudinal change in drusen size in clinical practice however is limited to a single commercial tool or manual inspection by clinicians. In this study we analysed change in drusen area in 33 eyes with intermediate AMD across two separate visits using a novel technique known as multispectral pattern recognition for en face retinal images from various imaging modalities (infrared (815 nm), fundus autofluorescence (488 nm) and green (532 nm) scanning laser ophthalmoscopy). We found 91% (30/33 eyes) agreement in the direction of drusen change for multispectral pattern recognition relative to expert graders who graded eyes as having drusen progression, regression or being stable. Multispectral pattern recognition showed 100% sensitivity (22/22 eyes) and 73% specificity (8/11 eyes). In comparison, we found only 70% (23/33 eyes) agreement in the direction of drusen change with a commercially available change analysis software, the Cirrus Advanced RPE Analysis relative to expert graders, with a sensitivity 64% (14/22 eyes) and specificity of 82% (9/11 eyes). Total drusen area or amount of change between visits had no significant effect on agreement. This suggests multispectral pattern recognition can quantify longitudinal change in drusen area from multimodal imaging with greater congruency to expert graders than a commercially available platform based on a single imaging modality. Considering the association of drusen area and disease progression, this method could aid clinical assessment and monitoring of AMD.

Age-related macular degeneration eyes presenting with cuticular drusen and reticular pseudodrusen.

This study aimed to describe the clinical characteristics of age-related macular degeneration (AMD) eyes with both cuticular drusen (CD) and reticular pseudodrusen (RPD). Clinical records of patients diagnosed with CD or RPD with multimodal imaging was reviewed for patients diagnosed with both CD and RPD. The distribution patterns of CD (macular and diffuse type) and RPD (localized, intermediate, and diffuse type), presence of soft drusen, large drusen (> 200 µm), variant subretinal drusenoid deposits, and macular complications were investigated. Of the 220 eyes of 110 patients diagnosed with CD and 926 eyes of 463 patients diagnosed with RPD, 13 eyes of seven patients met the diagnostic criteria for both CD and RPD. The mean age at initial presentation was 71.4 ± 8.8 years and six patients were female. The mean subfoveal choroidal thickness was 143.8 ± 25.1 µm. The distribution of CD was of the macular type in all eyes. Distribution of RPD was localized in 11 eyes (84.6%) and intermediate in two eyes (15.4%). Soft drusen, large drusen, and variant subretinal drusenoid deposits were present in 13 (100%), 12 (92.3%) and, seven (53.8%) eyes, respectively. Macular neovascularization was observed in two eyes (15.4%). CD and RPD can coexist in eyes with AMD. Multimodal imaging should be used for AMD eyes with features suggestive of CD and RPD, considering the high likelihood of developing late AMD.

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.

Retinal pigment epithelium-specific CLIC4 mutant is a mouse model of dry age-related macular degeneration.

Age-related macular degeneration (AMD) is the leading cause of blindness among the elderly. Dry AMD has unclear etiology and no treatment. Lipid-rich drusen are the hallmark of dry AMD. An AMD mouse model and insights into drusenogenesis are keys to better understanding of this disease. Chloride intracellular channel 4 (CLIC4) is a pleomorphic protein regulating diverse biological functions. Here we show that retinal pigment epithelium (RPE)-specific Clic4 knockout mice exhibit a full spectrum of functional and pathological hallmarks of dry AMD. Multidisciplinary longitudinal studies of disease progression in these mice support a mechanistic model that links RPE cell-autonomous aberrant lipid metabolism and transport to drusen formation.

Choroidal structural changes in different intermediate AMD patterns.

PURPOSE: To report variation of choroidal thickness (CT) and choroidal vascularity index (CVI) in subjects with drusen and subjects with reticular pseudodrusen (RPD) compared with healthy individuals using the Spectral-domain (SD)-Optical Coherence Tomography with enhanced depth imaging (EDI) system. DESIGN: A prospective, observational, cross-sectional study. SUBJECTS: Eighty-four participants. METHODS: The patients were imaged using the Heidelberg Spectralis device (Heidelberg Engineering, Heidelberg, Germany) with EDI mode. EDI-OCT images were exported and then imported into image analysis ImageJ software (National Institutes of Health, Bethesda) and a semiautomated algorithm was used for subsequent quantitative analysis. MAIN OUTCOME MEASURES: This study evaluated two choroidal parameters: (i) choroidal thickness (CT); (ii) choroidal vascularity index (CVI). RESULTS: CT analysis was performed in three different regions: (i) foveal region, (ii) parafoveal region; (iii) perifoveal region. All the analyzed regions were significantly decreased in RPD pattern, as compared with both the drusen group (p < .005) and healthy eyes (p < .005). CVI was significantly decreased in the RPD pattern, as compared with healthy eyes (p < 0.001). However, the drusenoid pattern did not have statistical significance in comparison with the control group suggesting the lower incidence of this pattern on choroidal vasculopathy. CONCLUSIONS: We report CT and CVI difference in RPD and drusen eyes. The RPD pattern seems to be a consequence of an alteration in the choroidal vascularity resulting in severe ischemia and excessive hypoxia inducing an increased risk of late AMD compared to the drusenoid pattern.

Quantification of Early and Intermediate Age-related Macular Degeneration Using OCT "en face" Presentation. / Quantifizierung der frühen und intermediären altersabhängigen Makuladegeneration mittels OCT-"en-face"-Darstellung.

BACKGROUND: Early and intermediate age-related macular degeneration (AMD) results in drusen deposits under the retinal pigment epithelium (RPE). These early stages of AMD exhibit different risks of progressing to late AMD. To date, early AMD has been classified and quantified by fundus photography. This does not appear to be sensitive enough for clinical trials studying the impact on drusen. SD-OCT with two-dimensional rendering of the segmented slices analysed allows for en face imaging of the drusen. The present trial studied the potential of quantifying early and intermediate AMD by en-face optical coherence tomography (OCT). MATERIAL AND METHODS: Thirty-one eyes of 29 patients in different stages of early and intermediate AMD were studied. To this end, fundus photographs (Kowa VX-10i, Kowa, Tokyo, Japan) and en-face OCT images (RTVue XR Avanti, Optovue, Inc., Fremont, CA, USA) were taken. First, different segmentation levels (6 µm underneath the RPE, on the RPE, 6 µm and 9 µm above the RPE) and different layer thicknesses (5 µm, 10 µm, 20 µm and 30 µm) were analysed to determine the best segmentation for visualising drusen. Drusen were marked manually and their number and surface area calculated. This analysis was then compared with the standardised drusen analyses on fundus photography. Additional changes in early and intermediate AMD such as pigment epithelial detachments (PEDs) and subretinal drusenoid deposits (SDD) as well as small atrophies were also documented and compared. OUTCOMES: The best segmentation for delineating the drusen on the en-face OCT images was found to be a segmentation 6 µm underneath the RPE with a slice thickness of 20 µm. Comparison of drusen quantification on en-face OCT images with the standardised drusen analysis on fundus photography revealed particularly good similarity. Other changes in early and intermediate AMD, such as PEDs, SDD and small atrophies, were easier to assess on the en-face OCT images. CONCLUSIONS: The analysis and quantification of drusen from en-face OCT images with 20 µm segmentation at 6 µm underneath the RPE allows differentiated quantification of various drusen characteristics. Moreover, other changes in early and intermediate AMD can also be analysed. In future observational and clinical trials, this could help quantify drusen.

A New Method for Visualizing Drusen and Their Progression in Flood-Illumination Adaptive Optics Ophthalmoscopy.

Purpose: Drusen are dynamic sub-RPE deposits that are risk factors for late-stage age-related macular degeneration (AMD). Here we show a new imaging method using flood-illumination adaptive optics (FIAO) that reveal drusen with high contrast and resolution. Methods: A fovea-centered 4° × 4° FIAO image and eight surrounding images with gaze displaced by ±2° vertically and horizontally were acquired. Clinical color fundus and spectral-domain optical coherence tomography were acquired for clinical grading and comparison. Custom software registered overlapping FIAO images and fused the data statistically to generate a fovea-centered 4° × 4° gaze-dependent image. Our dataset included 15 controls (aged 31-72) and 182 eyes from 104 AMD patients (aged 56-92), graded as either normal aging (n = 7), and early (n = 12), intermediate (n = 108) and late AMD (n = 42); 27 had subretinal drusenoid deposits (SDDs), and 83 were imaged longitudinally. Results: No gaze varying structures were detected in young eyes. In aging eyes with no evidence of age-related changes, putative drusen <20 µm in diameter were visible. Gaze-dependent images revealed more drusen and many smaller drusen than visible in color fundus images. Longitudinal images showed expansion and fusion of drusen. SDDs were lower contrast, and RPE atrophy did not yield a consistent signal. Conclusions: Gaze-dependent imaging in a commercially available FIAO fundus camera combined with image registration and postprocessing permits visualization of drusen and their progression with high contrast and resolution. Translational Relevance: This new technique offers promise as a robust and sensitive method to detect, map, quantify, and monitor the dynamics of drusen in aging and AMD.

Macular neovascularization in eyes with pachydrusen.

The natural history and clinical significance of pachydrusen is unclear. This study aims to compare the longitudinal changes of eyes with pachydrusen and soft drusen and progression to exudative macular neovascularisation (MNV). Patients with a diagnosis of MNV in one eye only and the fellow eye was selected as the study eye. Study eyes were required to have pachydrusen or soft drusen on fundus photographs and follow up of at least 2 years or until exudative MNV occurred. Systematic grading was performed at baseline and change in drusen area and onset of exudative MNV recorded over the period of follow up. A total of 75 eyes from 75 patients (29 with pachydrusen and 46 with soft drusen) were included. There was no difference in the rate of progression to exudative MNV in the soft and pachydrusen groups (13.3% versus 24.1%, p = 0.38). Pachydrusen, as compared to soft drusen, was associated with polypoidal choroidal vasculopathy subtype (85.7% versus 16.7%, p < 0.01) and the location of exudation was co-localised with soft drusen but not with pachydrusen. There was a higher rate of increase in soft drusen area compared to pachydrusen area (27.7 ± 31.9%/year versus 8.7 ± 12.4%/year respectively, p < 0.01). We found no difference in the proportion of eyes that developed exudative MNV in this study however characterisation of drusen evolution patterns revealed a strong association with exudative MNV subtype.

Subthreshold laser treatment for reticular pseudodrusen secondary to age-related macular degeneration.

There is a lack of treatment aimed at the regression of reticular pseudodrusen (RPD) secondary to age-related macular degeneration (AMD). The aim of this prospective, pilot study is to evaluate the safety and short-term efficacy of subthreshold laser treatment (SLT) in patients affected by RPD secondary to dry AMD (dAMD). Twenty eyes of 20 patients (mean age 78.4 ± 6.8 years) with RPD secondary to dAMD were prospectively enrolled. All patients were treated in an extrafoveal area of 1.27 mm2 using end-point management yellow subthreshold laser and followed for 3 months. Best-corrected visual acuity was 0.140 ± 0.09 LogMAR at the baseline and no changes were observed during the follow-up (p = 0.232). No significant worsening was disclosed before and after the treatment analyzing the macular sensitivity of the treated area (p = 0.152). No topical and/or systemic side effects were disclosed during the 3-month follow-up. The distribution among the RPD stages changed after the treatment (p < 0.001). In detail, in the treated area, we observed a significant increase in the number of Stage 1 RPD during the follow-up (p = 0.002), associated with a significant decrease of Stage 3 RPD (p = 0.020). Outer nuclear layer (ONL) thickness analysis showed a significant increase after the treatment associated with RPD regression (p = 0.001). End-point management SLT appears a safe treatment for RPD secondary to dAMD, showing short-term safety outcomes. Our results suggest that SLT could be effective in inducing a RPD regression in terms of RPD stage and ONL thickening.