Worldwide, age-related macular degeneration (AMD) is a serious threat to vision loss in individuals over 50 years of age with a pooled prevalence of approximately 9%. For 2020, the number of people ...afflicted with this condition is estimated to reach 200 million. While AMD lesions presenting as geographic atrophy (GA) show high inter-individual variability, only little is known about prognostic factors. Here, we aimed to elucidate the contribution of clinical, demographic and genetic factors on GA progression. Analyzing the currently largest dataset on GA lesion growth (N = 388), our findings suggest a significant and independent contribution of three factors on GA lesion growth including at least two genetic factors (ARMS2_rs10490924 P < 0.00088 and C3_rs2230199 P < 0.00015) as well as one clinical component (presence of GA in the fellow eye P < 0.00023). These correlations jointly explain up to 7.2% of the observed inter-individual variance in GA lesion progression and should be considered in strategy planning of interventional clinical trials aimed at evaluating novel treatment options in advanced GA due to AMD.
To describe the directional kinetics of the spread of geographic atrophy (GA) spread in eyes with age-related macular degeneration and foveal sparing.
Prospective, noninterventional natural history ...study: Fundus Autofluorescence Imaging in Age-Related Macular Degeneration (FAM; clinicaltrials.gov identifier, NCT00393692).
Participants of the FAM study exhibiting foveal sparing of GA.
Eyes were examined longitudinally with fundus autofluorescence (FAF; excitation wavelength, 488 nm; emission wavelength, >500 nm) and near infrared (NIR) reflectance imaging (Spectralis HRA+OCT or HRA2; Heidelberg Engineering, Heidelberg, Germany). Areas of foveal sparing and GA were measured by 2 independent readers using a semiautomated software tool that allows for combined NIR reflectance and FAF image grading (RegionFinder; Heidelberg Engineering). A linear mixed effect model was used to model GA kinetics over time.
Change of GA lesion size over time (central vs. peripheral progression).
A total of 47 eyes of 36 patients (mean age, 73.8±7.5 years) met the inclusion criteria. Mean follow-up time was 25.2±16.9 months (range, 5.9-74.6 months). Interreader agreement for measurements of GA and foveal-sparing size were 0.995 and 0.946, respectively. Mean area progression of GA toward the periphery was 2.27±0.22 mm(2)/year and 0.25±0.03 mm(2)/year toward the center. Analysis of square root-transformed data revealed a 2.8-fold faster atrophy progression toward the periphery than toward the fovea. Faster atrophy progression toward the fovea correlated with faster progression toward the periphery in presence of marked interindividual differences.
The results demonstrate a significantly faster centrifugal than centripetal GA spread in eyes with GA and foveal sparing. Although the underlying pathomechanisms for differential GA progression remain unknown, local factors may be operative that protect the foveal retina-retinal pigment epithelial complex. Quantification of directional spread characteristics and modeling may be useful in the design of interventional clinical trials aiming to prolong foveal survival in eyes with GA.
To determine intraobserver and interobserver longitudinal measurement variability of novel semiautomated software for quantification of age-related macular degeneration-associated geographic atrophy ...(GA) based on confocal scanning laser ophthalmoscopy fundus autofluorescence (FAF) imaging.
Three-field FAF (excitation 488 nm, emission 500-700 nm), near-infrared reflectance (820 nm), and blue reflectance (488 nm) images of 30 GA subjects were recorded according to a standardized protocol at baseline after 6 and 12 months. At all visits, the GA area was analyzed on central FAF images by seven independent readers using semiautomated software. The software allows direct export of FAF images from the database and semiautomated detection of atrophic areas by shadow correction, vessel detection, and selection of seed points.
The mean size of atrophy at baseline and the mean progression rate were 5.96 mm² (range, 1.80-15.87) and 1.25 mm²/year (0.42-2.93), respectively. Mean difference of interobserver agreement (Bland-Altman statistics) ranged from -0.25 to 0.30 mm² for the baseline visit and from -0.14 to 0.11 mm²/year for the atrophy progression rate. Corresponding reflectance images were helpful for lesion boundary discrimination, particularly for evaluation of foveal GA involvement and when image quality was poor.
The new image processing software offers an accurate, reproducible, and time-efficient identification and quantification of outer retinal atrophy and its progression over time. It facilitates measurements both in natural history studies and in interventional trials to evaluate new pharmacologic agents designed to limit GA enlargement.
To analyse appearance, development over 2 years and characteristic patterns of reticular drusen (RDR) in eyes with high-risk characteristics for progression to late-stage age-related macular ...degeneration (AMD) (age-related eye disease study stages 3 and 4).
98 eyes of 98 patients (median age 73.4 years, IQR 69-78) participating in the Molecular Diagnostic of Age-related Macular Degeneration study were included. Simultaneous combined confocal scanning laser ophthalmoscopy (cSLO) and spectral-domain optical coherence tomography (SD-OCT) imaging as well as colour-fundus imaging was performed at baseline and at 24 months. Two independent graders determined the presence of different RDR phenotypes (cSLO modalities: 'dot', 'target', 'ribbon'; SD-OCT: 'spike' and 'wave') at both visits.
At baseline, RDR were detected in 44% (κ 0.96). They were always visible in near-infrared reflectance images. Detection rate was 42% using fundus autofluorescence (FAF), 39% on SD-OCT (waves: 100%; spikes: 90%) and 26% on blue reflectance (BR). 'Dots' were more frequently detected in all imaging compared with 'targets'. The 'ribbon' pattern was most frequently observed in colour images, BR images and FAF images. In 8 of the 48 eyes with no signs of RDR in any imaging modality at baseline, the development of RDR lesions was observed at 24 months (16.6%, κ 0.42).
Careful and meticulous analysis using three-dimensional in vivo imaging reveals distinct characteristic RDR patterns underlying detectable dynamic changes over a period of 2 years. RDR in eyes with early or intermediate AMD are a common observation but appear to be overall less common compared with eyes with geographic atrophy.
To analyze outer retinal changes within the atrophic lesion in patients with geographic atrophy (GA) secondary to age-related macular degeneration.
Twenty-one simultaneously obtained fundus ...autofluorescence (FAF, excitation, 488 nm; emission, 500-700 nm) and spectral-domain optical coherence tomography (SD-OCT) scans (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany) of 21 GA patients (mean age, 75.1 ± 7.4 years) were included and separately exported. Two readers independently graded the following parameters: width of the atrophic lesion on the FAF image at the site where the SD-OCT scan had been placed; and on the SD-OCT image, widths of the linear disruption of the outer nuclear layer, the external limiting membrane, and the inner and outer segments of the photoreceptor layer (IPRL) and width of the disruption of choroidal signal enhancement. Results. The mean width of the atrophic lesion by FAF imaging was 2.83 mm (95% confidence interval, 2.37-3.29). The linear disruption of choroidal hyperreflectivity showed the closest agreement with 2.83 mm (2.37-3.28), whereas the linear width of disrupted IPRL was larger (3.10 mm; 2.65-3.55). Overall, the width of the atrophic lesion correlated significantly with all five SD-OCT parameters (P < 0.0001, r = 0.96-0.99).
These findings demonstrate that the atrophic lesions identified with FAF represent irreversible underlying outer retinal damage. The observation that the width of the atrophic lesion identified with FAF, although significantly correlated but not identical with the width of disruption within the cellular layers of the retina, is consistent with the dynamic nature of the disease. (ClinicalTrials.gov numbers, NCT00393692, NCT00599846.).
To determine the topographic distribution and progression of geographic atrophy (GA) in patients with AMD.
Fundus autofluorescence images (excitation 488, emission 500-700 nm) from 413 eyes of 413 ...subjects (median age, 77.0 years; inter quartile range IQR, 72.0-82.0 years) of the Geographic Atrophy Progression (GAP) study were retrospectively analyzed. Using a modified Early Treatment Diabetic Retinopathy Study grid to divide the posterior pole into nine different subfields plus periphery, the localization, size, and progression of atrophic patches were determined. Subfields, zones (center, inner and outer), and slices (nasal, temporal, inferior, superior) were compared using the Friedman test.
The center and inner zones were involved in almost all eyes (>95%), while atrophy was less common in the outer zone subfields (76%). Inner zone atrophy size (median 4.00 mm(2)) and progression rate (0.67 mm(2)/year) were significantly greater than in the outer zone (0.60 mm(2) and 0.42 mm(2)/year; P < 0.001). There was a trend toward outer zone subfield and periphery involvement with increasing total size of atrophy. In addition, the superior outer subfield was significantly more affected by atrophy as compared with the other three outer subfields of the grid (P < 0.001).
Distribution and progression of existing GA patches depended both on the eccentricity from the center and total GA size. Central macular areas appeared most susceptible for the occurrence and expansion of GA. Refined analysis of distribution and directional spread is important to understand the natural history of the disease. This information will likely be helpful to design interventional GA clinical trials and associated anatomical outcome measures. (ClinicalTrials. gov number, NCT00599846.).
To evaluate the development of intraretinal cystoid lesions (ICLs) in eyes with intermediate age-related macular degeneration.
Serial multimodal retinal imaging data of 105 eyes from 87 age-related ...macular degeneration subjects (median age of 75.0 years) with no late age-related macular degeneration at baseline from the prospective longitudinal natural history "molecular diagnostic of age-related macular degeneration-study" were included. The presence of ICLs-defined as lacunar hyporeflective areas within the neurosensory retina-was determined by spectral-domain optical coherence tomography at Month 24. Both baseline and further follow-up data were additionally evaluated.
At Month 24, ICLs were identified in 12 of 105 (11.7%) eyes of which 4 had developed signs of choroidal neovascularization since baseline. Intraretinal cystoid lesions in these four eyes with choroidal neovascularization were mostly found at the level of the outer nuclear layer. Intraretinal cystoid lesions in the remaining 8 eyes occurred mainly at the level of the inner nuclear layer, showed smaller horizontal and vertical dimensions, and were not spatially confined to an increase in retinal thickness.
The results indicate that ICLs may develop also in the absence of active neovascularization. Distinctive morphologic features and localization of ICLs may be indicative of different underlying pathogenetic mechanisms. If no manifest choroidal neovascularization can be established in the presence of ICLs, close monitoring as well as awareness and self-monitoring seem to be advisable.
To determine the degree of concordance for progression rate, size of atrophy, and visual acuity in patients with bilateral geographic atrophy (GA) due to age-related macular degeneration (AMD).
...Analysis was performed in 156 eyes of 78 patients with bilateral GA. Best corrected visual acuity was determined with ETDRS charts. GA was quantified in digital fundus autofluorescence images (excitation, 488 nm; emission, >500 nm) by semiautomated imaging analysis. A linear, two-level, random-effects model was used to assess the natural course of disease. The concordance correlation coefficient (CCC) was calculated to assess the degree of agreement between disease characteristics of the left and right eyes. Bland-Altman plots were applied to compare measurements in the eyes.
CCC between the eyes was 0.310 (95% CI, 0.097-0.495) for visual acuity, 0.706 (95% CI, 0.575-0.801) for GA size, and 0.756 (95% CI, 0.644-0.837) for GA progression rate. Although Bland-Altman plots revealed high concordance for the progression rate, there was considerable discrepancy between both eyes for GA size. corrected
GA progression in bilateral atrophic AMD is a symmetrical process; however, GA size may differ substantially between the eyes. High concordance in intraindividual disease progression in the presence of a high degree of interindividual variability indicates an influence by genetic and/or environmental factors rather than nonspecific ageing changes. The relatively small concordance of GA size in this cohort may indicate asymmetric evolution of the disease in affected individuals. The results may be useful in the design of future clinical trials designed to slow the rate of GA progression (Clinical Trials.gov number, NCT00393692).
Purpose
To determine fundus autofluorescence (FAF) signal variations and corresponding microstructural alterations on spectral-domain optical coherence tomography (SD-OCT) in areas of funduscopically ...visible drusen associated with age-related macular degeneration (AMD).
Methods
Thirty eyes from 22 patients with geographic atrophy (GA) secondary to AMD (median age 74, range 64–87 years), who had undergone retinal imaging including color fundus photography (CFP), FAF and SD-OCT (Spectralis HRA+OCT; Heidelberg Engineering GmbH, Heidelberg, Germany) were retrospectively analyzed. In each eye, at least one druse (≥63 μm) in the perilesional zone of GA recorded on CFP was analyzed. Relative FAF intensities and alterations in SD-OCT bands at the site of each druse were evaluated.
Results
A total of 73 drusen were analyzed, which were associated with heterogeneous corresponding alterations on FAF and SD-OCT. The FAF signal was normal, increased, decreased or not evaluable in 32 (44 %), 27 (37 %), 12 (16 %), and 2 (3 %) drusen, respectively. Focal hyperreflectivity overlying drusen was most frequently spatially confined to increased FAF (present in 9 (33 %) of 27 drusen with increased FAF). Outer nuclear layer thinning and choroidal hyperreflectivity were associated with decreased FAF (present in 7 58 % of 12 and 6 50 % of 12 drusen with decreased FAF, respectively).
Conclusions
The appearance of soft drusen on CFP does not allow for differentiation between preserved and markedly compromised outer retinal integrity, including incipient atrophy and focal neurosensory alterations of reflectivity overlying extracellular sub-retinal pigment epithelium (RPE) deposits. Multimodal imaging reveals a broad spectrum of microstructural changes, which may reflect different stages in the evolution of drusen.
Advances in retinal imaging technology have largely contributed to the understanding of the natural history, prognostic markers and disease mechanisms of geographic atrophy (GA) due to age-related ...macular degeneration. There is still no therapy available to halt or slow the disease process. In order to evaluate potential therapeutic effects in interventional trials, there is a need for precise quantification of the GA progression rate. Fundus autofluorescence imaging allows for accurate identification and segmentation of atrophic areas and currently represents the gold standard for evaluating progressive GA enlargement. By means of high-resolution spectral-domain optical coherence tomography, distinct microstructural alterations related to GA can be visualized.
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