Topographic Distribution and Progression of Soft Drusen Volume in Age-Related Macular Degeneration Implicate Neurobiology of Fovea.

Purpose: To refine estimates of macular soft drusen abundance in eyes with age-related macular degeneration (AMD) and evaluate hypotheses about drusen biogenesis, we investigated topographic distribution and growth rates of drusen by optical coherence tomography (OCT). We compared results to retinal features with similar topographies (cone density and macular pigment) in healthy eyes. Methods: In a prospective study, distribution and growth rates of soft drusen in eyes with AMD were identified by human observers in OCT volumes and analyzed with computer-assistance. Published histologic data for macular cone densities (n = 12 eyes) and in vivo macular pigment optical density (MPOD) measurements in older adults with unremarkable maculae (n = 31; 62 paired eyes, averaged) were revisited. All values were normalized to Early Treatment Diabetic Retinopathy Study (ETDRS) subfield areas. Results: Sixty-two eyes of 44 patients were imaged for periods up to 78 months. Soft drusen volume per unit volume at baseline is 24.6-fold and 2.3-fold higher in the central ETDRS subfield than in outer and inner rings, respectively, and grows most prominently there. Corresponding ratios (central versus inner and central versus outer) for cone density in donor eyes is 13.3-fold and 5.1-fold and for MPOD, 24.6 and 23.9-fold, and 3.6 and 3.6-fold. Conclusions: Normalized soft drusen volume in AMD eyes as assessed by OCT is ≥ 20-fold higher in central ETDRS subfields than in outer rings, paralleling MPOD distribution in healthy eyes. Data on drusen volume support this metric for AMD risk assessment and clinical trial outcome measure. Alignment of different data modalities support the ETDRS grid for standardizing retinal topography in mechanistic studies of drusen biogenesis.

Profiling neovascular age-related macular degeneration choroidal neovascularization lesion response to anti-vascular endothelial growth factor therapy using SSOCTA.

PURPOSE: To identify the changes in distinct vascular parameters of choroidal neovascularization (CNV) in eyes with treatment-naïve neovascular age-related macular degeneration (nAMD) during the primary response to anti-VEGF therapy using aflibercept. METHODS: Patients were prospectively followed during the first 3 months according to a standardized protocol with mandatory visits at days 7 and 14 after each anti-VEGF treatment up to day 90. Fourteen eyes were seen in addition at days 1 and 3 post-initial injection. Aflibercept was administered at baseline (BL), day 30 and 60. 6 × 6mm SSOCTA (PlexElite, Zeiss) images were acquired. Using the semi-automated AngioTool, CNV area, vessel area, vessel density (VD), the number of junctions, junctions density, total vessel length, average vessel length, total number of endpoints and lacunarity were assessed. RESULTS: Thirty-two consecutive patients presenting with treatment-naïve, SSOCTA-positive CNV lesions were included. Close follow-up showed a characteristic neovascular response curve with a dynamic decrease in lesion size within days and a reactive increase following 2 weeks after initial treatment. An undulating pattern was seen for all neovascular parameters except for vascular density, with variable statistical significance. Due to a flattening of the therapeutic response as early as after the second treatment, CNV lesion size and most of the related parameters had an increase in activity above baseline values at the end of the loading phase. Lesion size was the leading feature of reactivation by a mean increase of 19.3% after three monthly aflibercept injections. Subgroup analysis based on lesion size revealed a significant correlation between best-corrected visual acuity and quantitative change in lesion size over time, but not baseline size. CONCLUSIONS: Using SSOCTA, a morphologic neovascular response pattern can be identified in anti-VEGF treatment of CNV. A synchronized early decrease and consecutive reactivation in a large spectrum of neovascular biomarkers including size and internal structure are visualized in a qualitative and quantitative manner. SSOCTA analyses allow new insights in CNV morphology changes and therapeutic response.

LONGITUDINAL CHANGES IN QUANTITATIVE AUTOFLUORESCENCE DURING PROGRESSION FROM INTERMEDIATE TO LATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To prospectively investigate the development of quantitative autofluorescence (qAF) during progression from intermediate to late age-related macular degeneration (AMD). METHODS: Quantitative autofluorescence images from patients with intermediate AMD were acquired every three months with a Spectralis HRA + OCT (Heidelberg Engineering, Heidelberg, Germany) using a built-in autofluorescence reference. The association between changes in longitudinal qAF and progression toward late AMD was assessed using Cox regression models with time-dependent covariates. RESULTS: One hundred and twenty-one eyes of 71 patients were included, and 653 qAF images were acquired. Twenty-one eyes of 17 patients converted to late AMD (median follow-up: 21 months; 12 eyes: atrophic AMD; nine eyes: neovascular AMD). The converting patients' mean age was 74.6 ± 4.4 years. Eleven eyes in the converting group (52.4%) were pseudophakic. The presence of an intraocular lens did not affect the qAF regression slopes (P > 0.05). The median change for atrophic AMD was -2.34 qAF units/3 months and 0.78 qAF units/3 months for neovascular AMD. A stronger decline in qAF was significantly associated with an increased risk of developing atrophic AMD (hazard ratio = 1.022, P < 0.001). This association, however, was not present in the group progressing toward neovascular AMD (hazard ratio = 1.001, P = 0.875). CONCLUSION: The qAF signal declines with progression to atrophy, contrary to developing neovascularization. Quantitative autofluorescence may allow identification of patients at risk of progressing to late AMD and benefits individualized patient care in intermediate AMD.

SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY, FLUORESCEIN ANGIOGRAPHY, AND INDOCYANINE GREEN ANGIOGRAPHY COMPARISONS REVISITED: Using a Novel Deep-Learning-Assisted Approach for Image Registration.

PURPOSE: To compare area measurements between swept source optical coherence tomography angiography (SSOCTA), fluorescein angiography (FA), and indocyanine green angiography (ICGA) after applying a novel deep-learning-assisted algorithm for accurate image registration. METHODS: We applied an algorithm for the segmentation of blood vessels in FA, ICGA, and SSOCTA images of 24 eyes with treatment-naive neovascular age-related macular degeneration. We trained a model based on U-Net and Mask R-CNN for each imaging modality using vessel annotations and junctions to estimate scaling, translation, and rotation. For fine-tuning of the registration, vessels and the elastix framework were used. Area, perimeter, and circularity measurements were performed manually using ImageJ. RESULTS: Choroidal neovascularization lesion size, perimeter, and circularity delineations showed no significant difference between SSOCTA and ICGA (all P > 0.05). Choroidal neovascularization area showed excellent correlation between SSOCTA and ICGA (r = 0.992) and a Bland-Altman bias of -0.10 ± 0.24 mm. There was no significant difference in foveal avascular zone size between SSOCTA and FA (P = 0.96) and an extremely small bias of 0.0004 ± 0.04 mm and excellent correlation (r = 0.933). Foveal avascular zone perimeter was not significantly different, but foveal avascular zone circularity was significantly different (P = 0.047), indicating that some small cavities or gaps may be missed leading to higher circularity values representing a more round-shaped foveal avascular zone in FA. CONCLUSION: We found no statistically significant differences between SSOCTA and FA and ICGA area measurements in patients with treatment-naive neovascular age-related macular degeneration after applying a deep-learning-assisted approach for image registration. These findings encourage a paradigm shift to using SSOCTA as a first-line diagnostic tool in neovascular age-related macular degeneration.

Comparison of SD-Optical Coherence Tomography Angiography and Indocyanine Green Angiography in Type 1 and 2 Neovascular Age-related Macular Degeneration.

Purpose: The purpose of this study is to compare the ability of spectral domain optical coherence tomography angiography (SD-OCTA) and indocyanine green angiography (ICGA) to detect and measure lesion area in patients with type 1 and 2 choroidal neovascularization (CNV). Methods: Types 1 and 2 neovascular AMD (nAMD) were included in this prospective and observational case series. ETDRS best-corrected visual acuity (BCVA), ophthalmic examination with funduscopy, OCTA (AngioVue), fluorescein angiography (FA), ICGA, and OCT (Spectralis) were performed. CNV measurements were done manually by two experienced graders using the systems' innate region selection tools. Results: Forty eyes of 39 consecutive patients with nAMD were included. Mean age was 77 ± 6.4 years, ETDRS BCVA was 67 ± 13 letters, and 11 eyes were treatment naïve. Nineteen CNV lesions were classified as type 1 and 21 as type 2. ICGA was able to identify CNV in all eyes. By contrast, OCTA detected CNV in 95% of type 1 and 86% of type 2 nAMD eyes. Mean overall CNV area (CNV-A) was 2.8 ± 2.7 mm2 in ICGA and 2.1 ± 2.7 mm2 in OCTA. Both lesion types CNV-A appeared significantly smaller in OCTA compared with ICGA (P < 0.01). Bland-Altman plot revealed a mean difference (bias) between OCTA and ICGA CNV-A of 0.76 ± 1.74 mm2. Intraclass correlation coefficient (ICC) for CNV-A was 0.91 and 0.93 for ICGA and OCTA, respectively. ICGA CNV-A in the four OCTA-negative eyes (median 4.7 mm2) was not significantly different from the 36 OCTA-positive eyes (median 1.7 mm2). Conclusions: Type 1 and 2 CNV-A were significantly smaller in OCTA than in ICGA. OCTA was generally less successful in detecting CNV than ICGA in patients who were included into this study based on FA and OCT. However, OCTA detected all type 1 lesions except for one, indicating that the SD-OCTA signal is limited by detection limits of blood flow velocity rather than lesion type. Further efforts are needed pushing the limits of lowest detectable and fastest distinguishable flow until OCTA can deliver realistic qualitative and quantitative imaging of type 1 and 2 CNV for diagnosis and monitoring.

Retinal pigment epithelial features indicative of neovascular progression in age-related macular degeneration.

BACKGROUND/AIMS: To identify characteristic retinal pigment epithelium (RPE) changes in fellow eyes of patients with neovascular age-related macular degeneration (nAMD) using polarisation-sensitive optical coherence tomography (PS-OCT). METHODS: Thirty-one fellow eyes of 31 patients with unilateral nAMD were evaluated in this cohort study of a prospective interventional trial. PS-OCT as well as conventional imaging including spectral-domain (SD)-OCT and fluorescein angiography (FA) were performed using a standardised protocol. Monitoring visits were performed continuously at 1-month intervals. Morphological RPE features associated with the development of choroidal neovascularisation (CNV) were systematically analysed. RESULTS: Mean follow-up was 29 months (±17, SD). Thirteen (42%) of 31 eyes developed de novo CNV: 9 eyes type I CNV, 2 eyes type II CNV, 2 eyes a retinal angiomatous proliferation lesion. RPE thickening and reticular pseudodrusen (RPD) were observed significantly more often in eyes that developed CNV than in eyes without CNV development (p<0.01). Monthly increase in drusen volume was higher in the CNV group with a median increase of +2.2% in area and +2.9% in volume compared with +0.8% and +0.6% in the non-progressing group. RPE migration within the neurosensory retina and at the level of the RPE resulting in RPE thickening was seen topographically and chronologically associated with CNV development. CONCLUSIONS: Conversion to CNV is associated with RPE-related changes such as RPE migration, RPE thickening, drusen volume or the presence of RPD. Early detection of these features may allow more efficient screening in risk eyes and timely vision-preserving treatment in eyes developing neovascular disease.

Drusen volume development over time and its relevance to the course of age-related macular degeneration.

AIMS: To quantify the change in drusen volume over time and identify its prognostic value for individual risk assessment. METHODS: A prospective observational study over a minimum of 3 years and maximum of 5 years and follow-up examination every 3 months was conducted at the ophthalmology department of the Medical University of Vienna. 109 patients presenting early and intermediate age-related macular degeneration (AMD) were included, of which 30 patients concluded a regular follow-up for at least 3 years. 50 eyes of 30 patients were imaged every 3 months using spectral-domain and polarisation-sensitive optical coherence tomography (OCT). Drusen volume was measured using an automated algorithm. Data of a 6-month follow-up were segmented manually by expert graders. RESULTS: Gradings from 24 000 individual B-scans showed solid correlation between manual and automated segmentation with an initial mean drusen volume of 0.17 mm3. The increase in drusen volume was shown to be comparable among all eyes, and a model for long-term drusen volume development could be fitted as a cubic polynomial function and an R2=0.955. Spontaneous drusen regression was observed in 22 of 50 eyes. In this group, four eyes developed choroidal neovascularisation and three geographic atrophy. CONCLUSIONS: Drusen volume increase over time can be described by a cubic function. Spontaneous regression appears to precede conversion to advanced AMD. OCT might be a promising tool for predicting the individual risk of progression of AMD.

Identification of Drusen Characteristics in Age-Related Macular Degeneration by Polarization-Sensitive Optical Coherence Tomography.

PURPOSE: To describe qualitative characteristics of drusen in eyes with nonadvanced age-related macular degeneration (AMD) using polarization-sensitive optical coherence tomography (OCT). DESIGN: Cross-sectional study. METHODS: Twenty-five eyes of 25 patients with early to intermediate (nonadvanced) AMD were imaged with polarization-sensitive OCT using macular volume scans. All individual drusen in each B-scan were manually delineated by experts certified by a reading center and graded for 6 different morphologic characteristics based on a defined classification scheme, including the presence of internal depolarizing structures and associated depolarizing foci. With the use of a custom-made software, the central B-scan of each individual druse was selected and used to analyze its location, diameter, and characteristics and assess the prevalence of the different features and relations between them. RESULTS: Using the macular volume scans, 6224 individual drusen could be identified, including their position within the retina, their characteristics, and their association with any pigmentary alterations. The most common drusen type was a convex-shaped druse with homogeneous medium internal reflectivity and no depolarizing contents (55.3% of drusen). A total of 30.5% of the drusen exhibited internal depolarizing material; 0.3% presented overlying hyperreflective foci, and in 54.5% the foci were also depolarizing. Significant correlations were found between the diameter of the drusen and their distribution throughout the retina, shape, homogeneity of internal reflectivity, presence of internal depolarizing characteristics, and presence of overlying foci (P < .001 each). Significant relations were found between reflectivity, homogeneity, and polarization-sensitive internal characteristics (P < .001). CONCLUSIONS: Polarization-sensitive OCT reveals characteristic morphologic features of different druse types highlighting the pathophysiological spectrum of early to intermediate AMD.

Performance of automated drusen detection by polarization-sensitive optical coherence tomography.

PURPOSE: To estimate the potential of polarization-sensitive optical coherence tomography (PS-OCT) for quantitative assessment of drusen in patients with early age-related macular degeneration (AMD). METHODS: Fifteen eyes from 13 patients presenting drusen consistent with Age-Related Eye Disease Study classifications (grades 2 and 3) were examined ophthalmoscopically, followed by fundus photography, autofluorescence imaging, and three-dimensional scanning using a PS-OCT. For the automated evaluation of drusen location, area, and volume, a novel segmentation algorithm was developed based on the polarization scrambling characteristics of the retinal pigment epithelium (RPE) and applied to each complete data set. Subsequently, the drusen in each individual B-scan were identified by two independent expert graders. Concordance between manual and automated segmentation results was analyzed. Errors in the automated segmentation performance were classified as nonsignificant, moderate, or severe. RESULTS. In all, 2355 individual drusen, with a mean of 157 drusen per eye, were analyzed. Of drusen seen in the individual B-scans, 91.4% were detected manually by both expert graders. The automated segmentation algorithm identified 96.5% of all drusen without significant error. The mean difference in manual and automated drusen area (mean, 4.65 mm(2)) was 0.150. The number of detected drusen was significantly higher with automated than that with manual segmentation. PS-OCT segmentation was generally superior to fundus photography (P < 0.001). Particularly in nondetected drusen, a large variability in drusen morphology was noted. CONCLUSIONS: Automated drusen detection based on PS-OCT technology allows a fast and accurate determination of drusen location, number, and total area.

Performance of drusen detection by spectral-domain optical coherence tomography.

PURPOSE: To evaluate the performance of automated analyses integrated in three spectral-domain optical coherence tomography (SD-OCT) devices to identify drusen in eyes with early (i.e., nonatrophic and nonneovascular) age-related macular degeneration (AMD). METHODS: Twelve eyes of 12 AMD patients, classified as AREDS 2 and 3 and having a mean count of 113 drusen were examined with three clinical SD-OCT devices (Cirrus [Carl Zeiss Meditec, Dublin CA], 3DOCT-1000 [Topcon, Tokyo, Japan], and Spectralis [Heidelberg Engineering, GmbH, Heidelberg, Germany]) and five different scan patterns. After standard automated segmentation of the RPE was performed, every druse in each B-scan was identified and graded by two independent expert graders. Errors in the segmentation performance were classified as negligible, moderate, or severe. Correlations were based on the diameter and height of the druse and its automated segmentation. The overall drusen pattern identified by experts' detailed delineation was plotted with a custom-made computer program to compare automated to manual identification outcomes. RESULTS: A total of 1356 drusen were analyzed. The automated segmentation of the retinal pigment epithelium (RPE) by Cirrus made significantly fewer errors in detecting drusen than did the 3DOCT-1000 (P < 0.001). The Cirrus 200 × 200 scan pattern detected 30% of the drusen with negligible errors. Spectralis did not offer a true RPE segmentation. The drusen counts by expert graders were significantly higher in the scans than in the standard fundus photographs (P < 0.05). CONCLUSIONS: SD-OCT imaging proved an excellent performance in visualizing drusen-related RPE disease. However, the available automated segmentation algorithms showed distinct limitations to reliable identification of the amount of drusen, particularly smaller drusen, and the actual size.