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.

Mesopic and dark-adapted two-color fundus-controlled perimetry in patients with cuticular, reticular, and soft drusen.

PURPOSE: To examine the feasibility and utility of dark-adapted two-color fundus-controlled perimetry (FCP) in patients with cuticular, reticular, and soft drusen, and to compare FCP data to microstructural spectral-domain optical coherence tomography (SD-OCT) data. METHODS: Forty-four eyes (24 eyes of 24 patients with drusen, age 69.4 ± 12.6 years; 20 normal eyes of 16 subjects, 61.7 ± 12.4 years) underwent duplicate mesopic, dark-adapted cyan and dark-adapted red FCP within 14° of the central retina (total of 12 936 threshold tests) using the Scotopic Macular Integrity Assessment (S-MAIA, CenterVue, Padova, Italy) device. FCP data were registered to SD-OCT data to obtain outer nuclear layer, inner and outer photoreceptor segment, and retinal pigment epithelium drusen complex (RPEDC) thickness data spatially corresponding to the stimulus location and area (0.43°). Structure-function correlations were assessed using mixed-effects models. RESULTS: Mean deviation values for eyes with cuticular, soft, and reticular drusen were similar for mesopic (-2.1, -3.4, and -3.6 dB) and dark-adapted red (-1.4, -2.6, and -3.3 dB) FCP. For the dark-adapted cyan FCP (0.1, -1.9, and -5.0 dB) and for the cyan-red sensitivity difference (+1.0, +0.5, and -2.4 dB), the mean deviation values differed significantly in dependence of the predominant drusen type (one-way ANOVA; p < 0.05). RPEDC thickness was associated with reduction of mesopic sensitivity (-0.34 dB/10 µm RPEDC thickening; p < 0.001), dark-adapted cyan sensitivity (-0.11 dB/10 µm RPEDC thickening; p = 0.003), and dark-adapted red sensitivity (-0.26 dB/10 µm RPEDC thickening; p < 0.001). CONCLUSIONS: In contrast to mesopic FCP, dark-adapted two-color FCP allowed for meaningful differential testing of rod and cone function in patients with drusen indicating predominant cone dysfunction in eyes with cuticular drusen and predominant rod dysfunction in eyes with reticular drusen. RPEDC thickness was the strongest predictor of the evaluated SD-OCT biomarkers for point-wise sensitivity.

Structure-Function Analysis in Patients With Intermediate Age-Related Macular 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.

Visual field indices and patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry in macular diseases.

BACKGROUND/AIMS: To analyse the retest reliability of visual field indices and to describe patterns of visual field deficits in mesopic and dark-adapted two-colour fundus-controlled perimetry (FCP) in macular diseases. METHODS: Seventy-seven eyes (30 eyes with macular diseases and 47 normal eyes) underwent duplicate mesopic and dark-adapted two-colour FCP (Scotopic Macular Integrity Assessment, CenterVue). Non-weighted (mean defect, loss variance), variability-weighted (mean deviation, pattern standard deviation (PSD)) and graphical (cumulative defect (Bebie) curves) indices were computed. Reproducibility (coefficient of repeatability, CoR) of these indices was assessed. Cluster analysis was carried out to identify patterns of visual field deficits. RESULTS: The intrasession reproducibility was lower for the mean defect as compared with the mean deviation (CoR (dB) 2.67 vs 2.57 for mesopic, 1.71 vs 1.45 for dark-adapted cyan, 1.94 vs 1.87 for dark-adapted red testing) and lower for the square-root loss variance as compared with the PSD (CoR (dB) 1.48 vs 1.34, 0.77 vs 0.65, 1.23 vs 1.03). Hierarchical cluster analysis of the indices disclosed six patterns of visual field deficits (approximately unbiased P value>0.95) with varying degrees of global versus focal defect and rod versus cone dysfunction. These were also reflected by the cumulative defect curves. CONCLUSION: FCP with mesopic and dark-adapted two-colour testing allows for reproducible assessment of different types of retinal sensitivity, whereby mean deviation and PSD exhibited the better retest reliability of the tested indices. Distinct patterns of retinal dysfunction can be identified using this setup, reflecting variable degrees of rod and cone dysfunction in different macular diseases. Dark-adapted two-colour FCP provides additional diagnostic information and allows for refined structure-function correlation in macular diseases.

Evaluation of Two Systems for Fundus-Controlled Scotopic and Mesopic Perimetry in Eye with Age-Related Macular Degeneration.

PURPOSE: The purpose of this study was to evaluate and compare the MP-1S (Nidek Technologies, Padova, Italy) and the S-MAIA (CenterVue, Padova, Italy) for mesopic and scotopic fundus-controlled perimetry (FCP) in age-related macular degeneration (AMD). METHODS: Eleven eyes from 11 patients underwent mesopic and, after 30 minutes of dark adaptation, scotopic (MP-1S: Goldmann V, 200 ms, background luminance 0.0032 cd/m2; S-MAIA: Goldman III, 200 ms, background luminance <0.0001 cd/m2) FCP. For the S-MAIA device, cyan (505 nm) and red (627 nm) scotopic FCP were performed. For both devices, a grid of 56 stimulus points covering 16° of the central macula was used. Examination time, fixation stability, and threshold values were analyzed. RESULTS: The upper end of the dynamic range (≤4 dB of lowest threshold) was frequently reached by the MP-1S for mesopic testing (median 34 of 56 stimuli), while threshold values within the lower 4 dB of the dynamic range were occasionally found with the S-MAIA for scotopic testing (median 3 for cyan, median 2 for red). After correction of the stimulus intensity for the S-MAIA results, the median difference for all stimuli between both devices for mesopic testing was -2.0 dB (interquartile range [-4;0], range -14 to 6). CONCLUSIONS: The results indicate that robust testing of mesopic and scotopic function is feasible with both devices in patients with AMD, although both devices are susceptible to floor and ceiling effects. TRANSLATIONAL RELEVANCE: The interpretation and particularly the comparison of both scotopic and mesopic FCP results between the MP-1S and the S-MAIA in AMD eyes need to consider variable susceptibility of floor and ceiling effects. Further software updates are desirable as FCP captures visual functional loss that is not noted with best-corrected central visual acuity and is important for clinical trials in AMD.

OCT Angiography-Based Detection and Quantification of the Neovascular Network in Exudative AMD.

Purpose: To investigate the potential of optical coherence tomography (OCT) angiography to detect and quantify the neovascular network in exudative AMD. Methods: Treatment-naïve eyes that were diagnosed with exudative AMD were prospectively examined by OCT angiography (OCT-A). The extent of the neovascular network was measured by three independent readers. Interclass-correlation coefficient and area overlap coefficients (OC) were calculated to assess locally precise agreement between measurements. As a reference for interreader agreement, the extent of the neovascular network was further measured on fluorescein angiography (FA) images. Results: A total of 31 eyes (27 patients, mean age 82.5 years, 15 female) were included in the study. Neovascularization subtype was classified as type I in 5, type II in 11, type III in 9, and mixed in 6 eyes, respectively. Interreader agreement for measurements of the neovascular network was 0.884 for OCT-A and 0.636 for FA. Overlap coefficient was 0.705 (interquartile [IQR]: 0.450-0.76) for OCT-A and 0.704 (IQR: 0.673-0.750) for FA, respectively. Area agreement was weaker in type III and mixed lesions. Conclusions: Optical coherence tomography angiography-based measurements of the new vessel complex in neovascular AMD are feasible with interreader agreement comparable with the values obtained for FA. The results underscore the potential of OCT-A as a noninvasive diagnostic tool in neovascular AMD. Yet, further studies will be required to reveal the origin of poor agreement observed in single eyes and to advance OCT-A toward dependable use (e.g., in a reading center context).

Correlation of Partial Outer Retinal Thickness With Scotopic and Mesopic Fundus-Controlled Perimetry in Patients With Reticular Drusen.

PURPOSE: To correlate partial outer retinal thickness with scotopic and mesopic fundus-controlled perimetry in patients with reticular drusen (RDR). DESIGN: Observational case series with controls of similar age. METHODS: Twenty eyes from 18 patients with RDR (mean age 75.8 years) and 20 eyes from 20 healthy controls (mean age 75.5 years) were included. Scotopic and mesopic fundus-controlled perimetry was performed in patients. The localized partial outer retinal thickness at the site of test stimuli was determined as the distance between the outer border of the outer plexiform layer and the inner border of the ellipsoid zone and topographically corrected according to measurements in controls. RESULTS: The mean partial outer retinal thickness in patients was 65.8 µm over areas with RDR and 76.4 µm (P < .0001) over nonaffected retinal areas. Mesopic and scotopic sensitivity were reduced corresponding to areas with RDR (mean scotopic 12.8 dB and mean mesopic 17.2 dB) as compared to nonaffected retinal areas (18.2 dB and 18.4 dB) (P < .001, P = .001). On average, a reduction of partial outer retinal thickness by 1 µm was associated with a decrease of scotopic function of 0.96 dB. CONCLUSIONS: The extent of outer retinal thinning in the presence of RDR is spatially associated with the extent of impairment in scotopic retinal function, indicating a direct structural-functional correlation of structural changes to loss of rod function. High-resolution retinal imaging in combination with scotopic fundus-controlled perimetry allows for a more refined structure-function correlation in diseases with a presumed higher vulnerability of rod compared with cone function.

Automated Retinal Image Analysis for Evaluation of Focal Hyperpigmentary Changes in Intermediate Age-Related Macular Degeneration.

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.

DEVELOPMENT OF INTRARETINAL CYSTOID LESIONS IN EYES WITH INTERMEDIATE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the development of intraretinal cystoid lesions (ICLs) in eyes with intermediate age-related macular degeneration. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Long-Term Follow-Up of Fundus Autofluorescence Imaging Using Wide-Field Scanning Laser Ophthalmoscopy.

AIM: To evaluate the variation of peripheral alterations in different retinal diseases over a period of >3 years by using wide-field fundus autofluorescence (FAF) scanning laser ophthalmoscopy (SLO). METHODS: A total of 26 eyes from 13 patients (median age 66 years, range 19-80) with age-related macular degeneration and other retinal degenerations were examined. In 2009, the Optos P200CAF prototype and from 2012 onwards, the Optos 200Tx (Optos plc, Scotland) were used for wide-field FAF SLO (excitation 532 nm). RESULTS: The area involvement in outer retinal pathological alterations, such as atrophy and mottling of the retinal pigment epithelium far beyond the vascular arcades, was readily and better visualized within one image frame using wide-field FAF as compared to pseudocolor SLO of the same device. Over time, progression of existing and the development of de novo peripheral lesions were recorded with a concomitant enlargement of central lesions. In two cases (unilateral paravenous pigmented choroidal atrophy and suspected phenocopy of retinal dystrophy), no longitudinal changes of the topographic distribution of peripheral FAF intensities were noted. CONCLUSIONS: Wide-field FAF SLO allows the mapping of dynamic changes at the outer retina far beyond the vascular arcades. While its ability to detect and monitor these changes appears to be better than that of pseudocolor imaging, wide-field FAF SLO may not only be helpful to assess more widespread retinal dysfunction, but may also be useful for longitudinal assessments in natural history studies and interventional clinical trials.

Foveal Sparing of Reticular Drusen in Eyes With Early and Intermediate Age-Related Macular Degeneration.

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.

Scotopic and Photopic Microperimetry in Patients With Reticular Drusen and Age-Related Macular Degeneration.

IMPORTANCE: Clinical observations suggest that patients with age-related macular degeneration (AMD) have vision problems, particularly in dim light conditions. Previous studies on structural-functional analysis in patients with AMD with reticular drusen (RDR) have focused on photopic sensitivity testing but have not specifically assessed scotopic function. OBJECTIVE: To evaluate retinal function by scotopic and photopic microperimetry in patients with AMD and a well-demarcated area of RDR. DESIGN, SETTING, AND PARTICIPANTS: Prospective case series in a referral center of 22 eyes from 18 patients (mean age, 74.7 years; range, 62-87 years). The study was conducted from June 1, 2014, to October 31, 2014. INTERVENTIONS: With the use of combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging, retinal areas with RDR (category 1) and no visible pathologic alterations (category 2) were identified in each eye. Scotopic and photopic microperimetry (MP-1S; Nidek Technologies) was performed using a grid with 56 stimulus points. MAIN OUTCOMES AND MEASURES: Comparison of mean threshold sensitivities for each category for scotopic and photopic microperimetry. RESULTS: In all eyes, areas of category 1 showed a relative and sharply demarcated reduction of scotopic threshold values compared with areas of category 2, but only less-pronounced differences were seen for photopic testing. Statistical analysis in the 18 eyes in which the 1.0-log unit neutral density filter was applied revealed a difference of scotopic threshold values in areas of category 1 (mean, 13.5 dB [95% CI, 12.1-15.0]) vs category 2 (mean, 18.3 dB; [95% CI, 17.4-19.3] (P ≤ .001). For photopic testing, the mean threshold values were 16.8 dB (95% CI, 15.5-18.2) in category 1 and 18.4 dB (95% CI, 17.1-19.6) in category 2 (P = .03). CONCLUSIONS AND RELEVANCE: The results of this study suggest that rod function is more severely affected than cone function in retinal areas with RDR. This differential structural-functional correlation underscores the functional relevance of RDR in patients with AMD.

Reticular drusen in eyes with high-risk characteristics for progression to late-stage age-related macular degeneration.

BACKGROUND/AIMS: 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). METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Longitudinal analysis of reticular drusen associated with age-related macular degeneration using combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging.

PURPOSE: To evaluate longitudinal variations of reticular drusen (RDR) in age-related macular degeneration using confocal scanning laser ophthalmoscopy (cSLO), near-infrared reflectance (NIR) and spectral-domain optical coherence tomography (SD-OCT) imaging. METHODS: Eighteen eyes of 12 patients with RDR (median observational time 5 months, range 3-10) were included. Changes over time in the en face cSLO NIR images, the identical SD-OCT B scan (simple approach) and the dense SD-OCT volume scans (11 µm between B scans, detailed approach) for 5 preselected RDR lesions were analysed, respectively. RESULTS: Nineteen of 90 (21%) lesions were no longer detectable at the follow-up examination with the simple SD-OCT approach (increase 7/decrease 48/unchanged 15/not gradable 1). By contrast, no disappearance of single lesions was noted for both cSLO (3/8/61/18) and detailed SD-OCT image analysis (67/22/1/0). Within the dense SD-OCT volume scan, a median change of individual lesion height of 10 µm/year was determined. CONCLUSIONS: The findings indicate a recordable progression of RDR lesions in lateral and vertical dimensions. Using dense SD-OCT volume scans, individual RDR lesion progression can be quantified and may be applied in future longitudinal studies.

Fundus autofluorescence imaging in dry AMD: 2014 Jules Gonin lecture of the Retina Research Foundation.

Fundus autofluorescence (FAF) imaging allows for topographic mapping of intrisnic fluorophores in the retinal pigment epithelial cell monolayer, as well as mapping of other fluorophores that may occur with disease in the outer retina and the sub-neurosensory space. FAF imaging provides information not obtainable with other imaging modalities. Near-infrared fundus autofluorescence images can also be obtained in vivo, and may be largely melanin-derived. FAF imaging has been shown to be useful in a wide spectrum of macular and retinal diseases. The scope of applications now includes identification of diseased RPE in macular/retinal diseases, elucidating pathophysiological mechanisms, identification of early disease stages, refined phenotyping, identification of prognostic markers for disease progression, monitoring disease progression in the context of both natural history and interventional therapeutic studies, and objective assessment of luteal pigment distribution and density as well as RPE melanin distribution. Here, we review the use of FAF imaging in various phenotypic manifestations of dry AMD.

Longitudinal analysis of reticular drusen associated with geographic atrophy in age-related macular degeneration.

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.).

Reticular drusen associated with geographic atrophy in age-related macular degeneration.

PURPOSE: To characterize reticular drusen (RDR) in patients with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) in a prospective, multicenter, natural history study. METHODS: Confocal scanning laser ophthalmoscopy (cSLO) three-field fundus autofluorescence (FAF; exc., 488; em., 500-700 nm), near-infrared reflectance (IR; 820 nm), and blue reflectance (BR; 488 nm) images as well as red-free (RF) and color fundus (CF) camera photographs were recorded in 458 GA patients. The digital images were evaluated by two independent readers with subsequent senior reader arbitration for prevalence and topographic distribution of RDR using a modified Early Treatment Diabetic Retinopathy Study grid. RESULTS: RDR were detected with at least one cSLO modality in 286 of 458 (62%) patients in either eye (bilateral 207 [45%]) and were visible in fundus camera photographs in 66 of 371 (18%) patients (bilateral 48 [13%]). Prevalence of RDR by cSLO imaging was associated with increasing age (P = 0.007) and female sex (P = 0.007), but not with GA total lesion area (P = 0.38). Cohen kappa statistics showed good interobserver agreement for FAF (0.81) and IR (0.82) imaging modes, and moderate agreement was found for BR (0.48), RF (0.48), and CF (0.40). On three-field FAF images RDR were present most frequently superior to the fovea (99%). CONCLUSIONS: RDR represent a common phenotypic hallmark in GA eyes. RDR are readily identified using cSLO imaging technology. These observations may explain the high prevalence determined herein, in contrast to previous reports based on fundus photographs. Incorporation of these novel imaging modalities in future natural history studies may facilitate efforts aimed at defining the role and predictive value of RDR in the progression of AMD. (ClinicalTrials.gov number, NCT00599846.)

Combined confocal scanning laser ophthalmoscopy and spectral-domain optical coherence tomography imaging of reticular drusen associated with age-related macular degeneration.

PURPOSE: To determine microstructural retinal alterations associated with reticular drusen in patients with age-related macular degeneration (AMD) using high-resolution in vivo imaging techniques. DESIGN: Retrospective case series. PARTICIPANTS: A total of 116 eyes of 78 AMD patients with reticular drusen were examined. METHODS: Simultaneous spectral-domain optical coherence tomography (SD OCT; 870 nm, 40,000 A-scans/sec) and near-infrared confocal scanning laser ophthalmoscopy (cSLO; 830 nm) were performed using a combined imaging instrument (Spectralis HRA+OCT, Heidelberg Engineering, Heidelberg, Germany). Individual anatomic layers in SD OCT were evaluated and correlated to en face cSLO fundus imaging. MAIN OUTCOME MEASURES: Description of corresponding structural changes in areas of reticular drusen. RESULTS: Reticular drusen appeared as an interlacing network of round or oval irregularities by near-infrared cSLO reflectance imaging. On SD OCT, reticular drusen corresponded to marked changes at a level anterior to the retinal pigment epithelium (RPE) and Bruch's membrane complex to the interface of inner and outer photoreceptor segment layer (IPRL). Individual reticular drusen correlated to focal elevations of the IPRL, accumulation of highly reflective material below the IPRL, and an increased distance between the IPRL and RPE. CONCLUSIONS: The findings indicate that the morphologic substrate of reticular drusen is the accumulation of highly reflective material within outer retinal layers anterior to the RPE. This is in contrast to previous assumptions pointing toward a localization of abnormal material at the level of the inner choroid. Although the origin of the material is unknown, the results may indicate a role for primary abnormalities in the neurosensory retina. Because reticular drusen represent high-risk markers for the progression of AMD, their ready identification is relevant both for natural history studies as well as for interventional trials.