Julia S. Steinberg

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 Bruchs 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.

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.)

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.

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 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.

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 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.

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.

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.

[Reticular drusen over time with SD-OCT].

AIM The aim of the study was the analysis of reticular drusen (RDR) in patients with age-related macular degeneration using simultaneous confocal scanning laser ophthalmoscopy (cSLO) and spectral domain optical coherence tomography (SD-OCT) at different time points. METHODS Included in this retrospective analysis were 47 eyes from 32 patients (median age 80.1 years, range 66-89 years) with RDR at baseline and at least one follow-up visit. Registration of the cSLO near-infrared reflectance image and the SD-OCT B-scan (Spectralis HRA + OCT, Heidelberg Engineering, Heidelberg) at different time points was carried out using the AutoRescan tool. RESULTS While either no alterations or increase in the RDR area (n=19 eyes) or RDR density (n=15) were seen by cSLO imaging, the analysis of the SD-OCT B-scans at different time points revealed a more complex picture. An increase in two well visible lesions at the baseline visit was detected in 8 eyes at the first follow-up and in 3 eyes at the second follow-up examination. A regression was seen in 5 eyes at the first follow-up and in 3 eyes at the second follow-up visit. In most eyes (n=23), an increase of one with a parallel decrease of the second RDR lesion in the identical B-scan was identified at the first follow-up visit, whereas individual RDR showed an increase at the second follow-up examination that had initially shown a decrease in size at the first follow-up visit. CONCLUSIONS The results indicate underlying dynamic processes in the development and changes of RDR over time. For a more accurate analysis, the exact registration of SD-OCT B-scans at different time points and the use of high-resolution very dense volume scans would be helpful in order to assess such discrete changes of miniscule intraretinal lesions over time.