Evaluating fingerprint-like patterns in the healthy Henle fiber layer using enface OCT imaging.

PURPOSE: Enface OCT may disclose a distinct "fingerprint-like' pattern within the HFL in various macular disorders. This study aims to investigate the frequency and characteristics of this pattern in healthy eyes and identify potential factors influencing its visibility. METHODS: Two, independent masked reading center graders evaluated for the presence and prominence of a fingerprint pattern in the Henle fiber layer (HFL) on enface OCT images from 33 healthy subjects (66 eyes). The prominence of the pattern was rated qualitatively using a 0-3 scale, with 3 indicating the strongest prominence. Tilt angles (relative to the normal/perpendicular at the center) of the retina were measured on horizontal and vertical B-scans, and the retinal curvature was assessed using ImageJ, in order to determine the impact of the incident light angle on the visibility and prominence of the fingerprint pattern. Inter-grader agreement using Cohen's kappa and the frequency and percentage of patterns in the entire enface image and in each quadrant were calculated and compared using the Friedman test with Dunn's post-test. A generalized estimating equation (GEE) was used to analyze the association between these metrics and fingerprint prominence. RESULTS: Substantial inter-grader agreement was observed (Cohen's kappa = 0.71) for assessing the prominence of the fingerprint pattern. Over 70% of eyes exhibited some evidence of the pattern (score ≥1). Significant difference in pattern prominence across quadrants was detected (p < 0.05), with lowest prominence in the temporal quadrant (p < 0.001 for pairwise comparisons against all other quadrants). The GEE analysis to account for the extent of the effect of scan tilt angle and RPE curvature was not able to predict the prominence of the fingerprint pattern, highlighting that angle of incidence (of the scanning laser light) alone could not explain the pattern. CONCLUSIONS: This study confirms that a fingerprint-like pattern within the HFL can also be observed in healthy eyes, challenging the notion that this finding is only manifest in the setting of disease. In addition, the lack of correlation with angle of incident light suggests that the pattern may be related to other intrinsic characteristics of the HFL.

Drusen morphometrics on optical coherence tomography in eyes with age-related macular degeneration and normal aging.

PURPOSE: To compare drusen size metrics (apical height and basal width) on optical coherence tomography (OCT) B-scans with their size assessed on color photos in eyes with age-related macular degeneration (AMD) and normal aging. METHODS: A total of 508 drusen were evaluated in this analysis. Flash color fundus photos (CFP), infrared reflectance (IR) images, and OCT B-scans obtained at the same visit were evaluated. Individual drusen were identified on CFPs and the diameters of the drusen were measured in planimetric grading software. CFPs were manually registered to the IR image with their corresponding OCT volume. After confirming correspondence between the CFP and OCT, the apical height and basal width of the same drusen were measured on OCT B-scans. RESULTS: Drusen were divided into small, medium, large, and very large categories based on their diameter on the CFP images (< 63, 63 to 124, 125 to 249, and [Formula: see text] 250 µm, respectively). The OCT apical height of small drusen on CFP ranged from 20 to 31 µm, while medium drusen ranged from 31 to 46 µm, large drusen ranged from 45 µm to 111 µm, and very large drusen ranged from 55 µm to 208 µm. The OCT basal width measured < 99 µm in small drusen, from 99 to 143 µm in medium drusen, from 141 to 407 µm in large drusen, and > 209 µm in very large drusen. CONCLUSION: Drusen of different size categories on color photographs may also be separated according to their apical height and basal width on OCT. The apical height and basal width ranges defined in this analysis may be of value in the design of an OCT-based grading scale for AMD.

Relationship between the distribution of intra-retinal hyper-reflective foci and the progression of intermediate age-related macular degeneration.

PURPOSE: To assess the relationship between the distribution of intra-retinal hyper-reflective foci (IHRF) on optical coherence tomography (OCT) and progression of intermediate age-related macular degeneration (iAMD) over 2 years. METHODS: Cirrus OCT volumes of the macula of subjects enrolled in the Amish Eye Study with 2 years of follow-up were evaluated for the presence of iAMD and IHRF at baseline. The IHRF were counted in a series of 5 sequential en face slabs from outer to inner retina. The number of IHRF in each slab at baseline and the change in IHRF from baseline to year 2 were correlated with progression to late AMD at 2 years. RESULTS: Among 120 eyes from 71 patients with iAMD, 52 eyes (43.3%) of 42 patients had evidence of both iAMD and IHRF at baseline. Twenty-three eyes (19.0%) showed progression to late AMD after 2 years. The total IHRF count increased from 243 at baseline to 604 at 2 years, with a significant increase in the IHRF number in each slab, except for the innermost slab 5 which had no IHRF at baseline or follow-up. The IHRF count increased from 121 to 340 in eyes that showed progression to late AMD. The presence of IHRF in the outermost retinal slabs 1 and 2 was independently associated with a significant risk of progression to late AMD. A greater increase in IHRF count over 2 years in these same slabs 1 and 2 was also associated with a higher risk of conversion to late AMD. CONCLUSIONS: The risk of progression to late AMD appears to be significantly associated with the distribution and extent of IHRF in the outermost retinal layers. This observation may point to significant pathophysiologic differences of IHRF in inner versus outer layers of the retina.

The relationship of diabetic retinopathy severity scales with frequency and surface area of diabetic retinopathy lesions.

PURPOSE: To assess the relationship between qualitative diabetic retinopathy (DR) scales with the precise numbers and surface area of DR lesions within the Early Treatment Diabetic Retinopathy Study (ETDRS) standard seven field (S7F) region on ultrawide-field (UWF) color fundus images. METHODS: In this study, we collected UWF images from adult patients with diabetes. Poor-quality images and eyes with any pathology precluding assessment of DR severity were excluded. The DR lesions were manually segmented. DR severity was graded according to the International Clinical Diabetic Retinopathy (ICDR) and AA protocol by two masked graders within the ETDRS S7F. These lesions' numbers and surface area were computed and correlated against the DR scores using the Kruskal-Wallis H test. Cohen's Kappa was performed to determine the agreement between two graders. RESULTS: One thousand five hundred and twenty eyes of 869 patients (294 females, 756 right eyes) with a mean age of 58.7 years were included. 47.4% were graded as no DR, 2.2% as mild non-proliferative DR (NPDR), 24.0% as moderate NPDR, 6.3% as severe NPDR, and 20.1% as proliferative DR (PDR). The area and number of DR lesions generally increased as the ICDR level increased up to severe NPDR, but decreased from severe NPDR to PDR. There was perfect intergrader agreement on the DR severity. CONCLUSION: A quantitative approach reveals that DR lesions' number and area generally correlate with ICDR-based categorical DR severity levels with an increasing trend in the number and area of DR lesions from mild to severe NPDR and a decrease from severe NPDR to PDR.

NEW BIOMARKER QUANTIFYING THE EFFECT OF ANTI-VEGF THERAPY IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY ON ULTRAWIDE FIELD FLUORESCEIN ANGIOGRAPHY: RECOVERY Study.

PURPOSE: To quantify changes of the retinal vascular bed area (RVBA) in mm2 on stereographically projected ultrawide field fluorescein angiography images in eyes with proliferative diabetic retinopathy after antivascular endothelial growth factor injection. METHODS: This is a prospective, observational study. The early-phase ultrawide field fluorescein angiography images (Optos 200Tx) of 40 eyes with proliferative diabetic retinopathy and significant nonperfusion obtained at baseline and after six months (NCT02863354) were stereographically projected by correcting peripheral distortion. The global retinal vasculature on ultrawide field fluorescein angiography was extracted for calculating RVBA by summing the real size (mm2) of all the pixels automatically. RESULTS: For the entire cohort, the global RVBA for the entire retina decreased from 67.1 ± 15.5 to 43.6 ± 18.8 mm2 after anti-VEGF treatment at six months (P < 0.001). In the subgroup receiving monthly anti-VEGF injections, the global RVBA decreased from 68.7 ± 16.2 to 33.9 ± 13.3 mm2 (P < 0.001). In the subgroup receiving anti-VEGF every three months, the global RVBA decreased from 65.6 ± 15.1 to 50.8 ± 19.3 mm2 (P = 0.004). CONCLUSION: RVBA seems to be a new biomarker to indicate efficiency of retinal vascular changes after anti-VEGF injection. Eyes with proliferative diabetic retinopathy and significant nonperfusion demonstrate reduced RVBA after anti-VEGF treatment.

COMPARISON OF SPECTRALIS AND CIRRUS OPTICAL COHERENCE TOMOGRAPHY FOR THE DETECTION OF INCOMPLETE AND COMPLETE RETINAL PIGMENT EPITHELIUM AND OUTER RETINAL ATROPHY.

PURPOSE: To evaluate and compare the detection of incomplete and complete retinal pigment epithelial and outer retinal atrophy (iRORA and cRORA) using Spectralis and Cirrus optical coherence tomography (OCT) devices. METHODS: Subjects with late age-related macular degeneration were imaged on the same day with Spectralis and Cirrus OCT. Two, masked, independent, and experienced retina specialist graders evaluated each case for the presence of cRORA and iRORA lesions. RESULTS: A significantly higher number of lesions were observed using Spectralis compared with Cirrus (239 vs. 226 and 223 vs. 209). Higher number of iRORA lesions were identified with Spectralis (105 vs. 90 and 96 vs. 82), and no significant difference was observed between devices for cRORA lesions (134 vs. 136 and 128 vs. 126). When considering the presence or absence of iRORA or cRORA, the agreement between devices for both graders was excellent for cRORA and good for iRORA. CONCLUSION: Spectralis and Cirrus OCT identified a similar number of cRORA lesions, although more iRORA lesions could be detected with Spectralis OCT. These findings may have implications for developing acquisition protocols for trials based on the intended atrophy targets and highlight the importance of using a consistent OCT instrument across a study.

CHORIOCAPILLARIS FLOW DEFICITS AS A RISK FACTOR FOR PROGRESSION OF AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To evaluate the association between choriocapillaris (CC) flow deficits and structural optical coherence tomography biomarkers and the progression of intermediate age-related macular degeneration (iAMD) to complete retinal pigment epithelial and outer retinal atrophy. METHODS: Retrospective analysis of consecutive patients with iAMD with a minimum follow-up of 12 months. Odds ratios of intraretinal hyperreflective foci, hyporeflective drusen cores, subretinal drusenoid deposits, the presence of drusen volume ≥0.03 mm3 within a central 3-mm circle, fellow eye with late stage of AMD, and CC flow deficits at baseline and months of follow-up were estimated from logistic regression. RESULTS: A total of 112 eyes with iAMD were included. Eyes that progressed were significantly more likely to show intraretinal hyperreflective foci, hyporeflective drusen cores, and drusen volume ≥0.03 mm3. The CC flow deficit was also significantly greater in eyes that developed complete retinal pigment epithelial and outer retinal atrophy. Intraretinal hyperreflective foci, hyporeflective drusen cores, drusen volume ≥0.03 mm3, and higher CC flow deficits were significantly and independently associated with the development of complete retinal pigment epithelial and outer retinal atrophy. CONCLUSION: The CC flow deficit was significantly greater in iAMD eyes that progressed to complete retinal pigment epithelial and outer retinal atrophy and remained an independent risk factor when structural optical coherence tomography biomarkers were considered. CC flow deficits may be useful for enhancing risk stratification and prognostication of patients with iAMD.

Reproducibility and agreement of four anterior segment-optical coherence tomography devices for anterior chamber angle measurements.

PURPOSE: To compare the reproducibility and agreement of anterior chamber angle (ACA) parameters and metrics obtained by four different anterior segment-optical coherence tomography (AS-OCT) devices. METHODS: In this prospective study, 30 eyes from 15 normal subjects underwent anterior segment angle scanning using the Spectralis, Cirrus, and Optovue spectral domain optical coherence tomography (SD-OCT), as well as the Visante time-domain optical coherence tomography (TD-OCT). For each eye, the scan line was performed perpendicularly on the inferior (270°) angle, and the inferior ACA image was acquired 2 times. Inter-instrument and intra-instrument, as well as inter-observer and intra-observer reproducibility of anterior chamber angle metrics, Schwalbe's line (SL) to scleral spur (SS) distance (TM-Span), angle opening distance (AOD), and trabecular iris space area (TISA) measurements, were evaluated by intraclass correlation coefficients (ICCs) and Bland-Altman plots with limits of agreement (LoA). RESULTS: For this cohort of 30 eyes of 15 normal subjects, the mean TM-Span, AOD, and TISA were 0.966 ± 0.198 mm, 0.750 ± 0.205 mm, and 0.286 ± 0.090 mm2 from the Spectralis; 0.929 ± 0.113 mm, 0.717 ± 0.120 mm, and 0.267 ± 0.095 mm2 from the Cirrus; 0.923 ± 0.191 mm, 0.683 ± 0.161 mm, and 0.265 ± 0.072 mm2 from the Optovue; and 0.970 ± 0.070 mm, 0.705 ± 0.150 mm, and 0.279 ± 0.065 mm2 from the Visante. The intra-instrument (ICCs > 0.838), intra-grader (ICCs > 0.910), and inter-grader (ICCs > 0.869) agreement were good. Agreement between the four instruments was also good with ICCs from 0.901 to 0.967 for TM-Span, 0.887 to 0.941 for AOD, and 0.923 to 0.961 for TISA. CONCLUSIONS: Consistent and reproducible ACA measurements could be obtained from multiple AS-OCT devices including both SD- and TD-OCT instruments. These findings have relevance when considering multiple imaging devices in future studies.

Relationship between proximity of choriocapillaris flow deficits and enlargement rate of geographic atrophy.

PURPOSE: To correlate choriocapillaris (CC) flow deficits (FD) in eyes with geographic atrophy (GA) at various distances from the border of the GA lesion with yearly enlargement rate (yER) of GA. METHODS: In this retrospective study, spectral domain optical coherence tomography (SD-OCT) and SD optical coherence tomography angiography (OCTA) images were collected from patients with GA, who were imaged at Doheny Eye Centers between 2016 and 2018, using the Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA). All enrolled patients had one baseline 6 × 6 mm OCTA scan and two 6 × 6 mm SD-OCT cubes, one at baseline and one at a follow-up visit at least 12 months later. The border of the GA was manually outlined on the en face OCT fundus image and the yER was calculated after square root transformation. A grid composed of 100-µm-wide successive concentric rings was created around the GA lesion on the OCTA CC slab using ImageJ and the FD% was calculated from the binarized image. FD% from each ring was correlated with the yER of GA. RESULTS: Thirty eyes of 22 patients were included in the study. The mean yER was 0.2 ± 0.15 mm. The FD% in the first five rings (from 0 to 500 µm from the border of GA) was significantly correlated with the yER. However, there was no statistically significant correlation between the yER and CC FD% beyond 500 µm from the GA lesion. CONCLUSIONS: Only the choriocapillaris FD% in the 500-µm region immediately surrounding GA lesions appears to predict the rate of enlargement of these lesions.

QUANTITATIVE ASSESSMENT OF CHORIOCAPILLARIS FLOW DEFICITS SURROUNDING CHOROIDAL NEOVASCULAR MEMBRANES.

PURPOSE: To quantify the regional variation in choriocapillaris (CC) flow deficits percentage (FD%) surrounding treatment-naïve Type 1 choroidal neovascularization (CNV) associated with age-related macular degeneration. METHODS: Patients were imaged with swept-source optical coherence tomography angiography system (Carl Zeiss PLEX Elite 9000; Carl Zeiss Meditec AG, Jena, Germany). Two 6 × 6-mm volume scans were acquired. Boundary-specific segmentation was used to isolate the Type 1 CNV. For CC assessment, both structural and optical coherence tomography angiography CC slabs (10-µm thick, starting 21 µm below the retinal pigment epithelium fit reference) were exported for signal compensation and averaging using ImageJ. The resultant CC image was binarized to calculate the FD%, for para-CNV and peri-CNV rings (each 500-µm wide). In a subgroup of 20 eyes, the FD% was compared with similar regions of age-matched controls. The FD% was also analyzed in small 500 × 500-µm squares equidistant from the fovea to compensate for regional variation of CC FD% as a potential confounding factor. RESULTS: Thirty-two eyes from 27 subjects were enrolled in this study. The CC FD% in the para-CNV ring was 26.58 ± 7.36, which was significantly higher than the peri-CNV ring (21.94 ± 6.31); P < 0.001. The FD% in para-CNV and peri-CNV rings was significantly greater than that of healthy controls (15.82 ± 1.29% and 15.53 ± 1.32%, respectively); P < 0.001. The FD% computed in the 500-µm squares equidistant from the fovea was also greater in the para-CNV ring (26.14 ± 7.11) than that in the peri-CNV ring (22.31 ± 6.21); P < 0.001. CONCLUSION: Choriocapillaris FD% is the highest in the region immediately surrounding the CNV.

CHOROIDAL VASCULARITY INDEX AND CHOROIDAL THICKNESS IN EYES WITH RETICULAR PSEUDODRUSEN.

PURPOSE: To evaluate choroidal vascularity index (CVI), choroidal thickness, choroidal volume, and choroidal intensity in subjects with nonneovascular age-related macular degeneration (NNVAMD) with and without reticular pseudodrusen (RPD). METHODS: We included 60 eyes of 35 subjects with NNVAMD (including 30 eyes of 18 subjects with RPD) and 30 eyes of 17 age-matched healthy individuals from the ongoing Amish Eye study. The choroid was segmented from dense volume spectral domain optical coherence tomography scans and choroidal thickness (microns), choroidal intensity (log units), and choroidal volume (mm) from the entire macula (6 × 6 mm) were computed. A central horizontal B-scan was binarized and the luminal and stromal portions of the choroid were segmented. Choroidal vascularity index (%) was calculated as the ratio of luminal area to total choroid area. Choroidal parameters were compared between the groups by pairwise comparisons using the Student's t-test. RESULTS: The CVI was significantly lower in healthy eyes compared to those with RPD (53.43 ± 8.51 vs. 54.76 ± 4.83, P < 0.001). The CVI was also significantly lower in NNVAMD eyes without RPD compared to those with RPD (50.09 ± 7.51 vs. 54.76 ± 4.83, P = 0.006). There was no difference in CVI between healthy eyes and NNVAMD eyes without RPD (P = 0.84). Choroidal thickness and choroidal volume were significantly higher in NNVAMD without RPD (P < 0.05); and significantly lower in NNVAMD with RPD (P < 0.05) when compared with normal eyes. Choroidal intensity was significantly higher in NNVAMD with RPD when compared with normal eyes (P = 0.02) and NNVAMD eyes without RPD (P = 0.001). CONCLUSION: Multiple choroidal parameters reflecting the status of the choroidal vasculature and stroma seem to be altered in eyes with RPD compared with both normal eyes and NNVAMD eyes without RPD. These findings may provide insights into the pathophysiology of RPD.

Choriocapillaris flow impairment predicts the development and enlargement of drusen.

PURPOSE: To evaluate the choriocapillaris flow in regions of enlarged or new incident drusen in patients with early and intermediate age-related macular degeneration (AMD). METHODS: We retrospectively reviewed and analyzed structural optical coherence tomography (OCT) and OCT angiography (OCTA) images of consecutive patients with early or intermediate AMD evaluated at the Doheny-UCLA Eye Centers between 2015 and 2018. All patients were imaged using a Cirrus OCT, and only one eye was included in the study. To be eligible for this analysis, patients were required to have a 3 × 3-mm OCTA scan acquired during the first visit (considered as baseline) and a fovea-centered 512 × 128 macular cube (6 × 6 mm) acquired at both the baseline visit and after a minimum of 1 year follow-up. The drusen maps generated from the macular cubes were used to generate a drusen area (DA) measurement and compute the difference between baseline and follow-up (ΔDA). After registering the structural OCTs to the baseline choriocapillaris (CC) OCTA, we analyzed and compared the baseline flow deficits (FD) within drusen-free region (FDDF), regions into which drusen enlarged or expanded at follow-up (FDEN), and regions in which new incident drusen (FDND) appeared at follow-up. RESULTS: Forty-six patients were eligible for the analysis and had a mean follow-up of 1.47 years. Twelve eyes of 12 subjects had a ΔDA < 0.1 mm2. In these eyes, only the FDDF was calculated (40.37 ± 2.29%) and it was not significantly different from the FDDF of eyes with ΔDA ≥ 0.1 mm2 (40.25 ± 4.37%, p = 0.849). When comparing the different regions within the eyes with ΔDA ≥ 0.1 mm2, there was no significant difference between FDED and FDND (43.61 ± 4.36% and 44.16 ± 2.38%, p = 528), but both were significantly higher than FDDF (p = 0.001 and p < 0.001, respectively). CONCLUSIONS: Significant CC flow impairment is present under regions of intact retinal pigment epithelium (RPE) where existing drusen will enlarge into or new drusen will appear within 2 years. These findings suggest that location of drusen may not be stochastic but may be driven by regional deficits in the choriocapillaris.

Directional kinetics analysis of the progression of geographic atrophy.

PURPOSE: To investigate the influence of baseline geographic atrophy (GA) size on the rate of GA progression by using both distance and area measurements. METHODS: Thirty-five eyes from 24 patients with GA due to age-related macular degeneration were obtained from anonymized datasets available at the Doheny Image Reading Center. Baseline and month 12 fundus autofluorescence (FAF) images were used for this analysis. Borders of GA lesions were semiautomatically segmented by certified reading center graders to create masks of the GA lesion. The masks from the two visits were registered and overlaid to allow the differences in area as well as the differences in the position of GA border between the visits to be computed. Distance measurements were performed using a Euclidean distance map. Sectoral (clock hour)/directional GA progression rates with respect to the foveal center were also calculated. RESULTS: GA progressed 1.6 ± 0.9 mm2 in area and 92.9 ± 64.9 µm in distance over the 12 months. Smaller GA lesions were associated with more rapid progression when measured using distance (P = 0.0004, R = - 0.554). In contrast, there was no significant correlation in this cohort between baseline GA area and the progression measured in area (P = 0.406). In the sectoral/directional GA progression analysis, progression speed differed among clockwise directions, when progression was evaluated by using area measurements. However, this difference was not found, when evaluated by using distance measurements. CONCLUSIONS: Use of linear distance-based measurements enables evaluation of GA progression which is not confounded by baseline lesion size.

Impact of segmentation density on spectral domain optical coherence tomography assessment in Stargardt disease.

PURPOSE: Automated spectral domain optical coherence tomography (SD-OCT) segmentation algorithms currently do not perform well in segmenting individual intraretinal layers in eyes with Stargardt disease (STGD). We compared selective B-scan segmentation strategies for generating mean retinal layer thickness and preserved area data from SD-OCT scans in patients with STGD1. METHODS: Forty-five eyes from 40 Stargardt patients were randomly selected from the ongoing Natural History of the Progression of Atrophy Secondary to Stargardt Disease (ProgStar) study. All eyes underwent SD-OCT using a standard macular volume consisting of 1024 × 49 equally spaced B-scans within a 20 × 20 degree field centered on the fovea. All 49 B-scans were segmented manually to quantify total retina, outer nuclear layer (ONL), photoreceptor inner segments, photoreceptor outer segments (OS), and retinal pigment epithelial layer (RPE). Mean thickness and total area were generated using all 49 B-scans (spaced 122 µm apart), 25 B-scans (every other B-scan, spaced 240 µm apart), 17 B-scans (every third scan, 353 µm apart), and 13 B-scans (every fourth scan, 462 µm apart), as well as by using an "adaptive" method where a subset (minimum 25 B-scans) of B-scans that the grader deemed as significantly different from adjacent B-scans were utilized. Mean absolute and percentage errors were calculated for macular thickness and area of different retinal layers for the different B-scan subset selection strategies relative to using all 49 B-scans, which was considered the reference or ground truth. RESULTS: Mean thickness and area measurements were significantly different for any regularly spaced reduction in B-scan density relative to the ground truth. When an adaptive approach was applied using a minimum of half the scans, the differences relative to ground truth were no longer significantly different. The mean percent differences for the area and thicknesses of the various layers ranged from 0.02 to 33.66 (p < 0.05 for all comparisons) and 0.44 to 7.24 (p > 0.05) respectively. CONCLUSION: Manual segmentation of a subset of B-scans using an adaptive strategy can yield thickness and area measurements of retinal sublayers comparable to the reference ground truth derived from using all B-scans in the volume. These results may have implications for increasing the efficiency of SD-OCT grading strategies in clinical trials for STGD and other related macular degenerative disorders.

AMISH EYE STUDY: Baseline Spectral Domain Optical Coherence Tomography Characteristics of Age-Related Macular Degeneration.

PURPOSE: To describe spectral domain optical coherence tomography (SD-OCT) findings in an Amish cohort to assess SD-OCT markers for early age-related macular degeneration (AMD). METHODS: The authors performed a family-based prospective cohort study of 1,146 elderly Amish subjects (age range 50-99 years) (2,292 eyes) who had a family history of at least 1 individual with AMD. All subjects underwent complete ophthalmic examinations, SD-OCT using both Cirrus and Spectralis (20 × 20° scan area) instruments, fundus autofluorescence, infrared imaging, and color fundus photography. Spectral domain optical coherence tomography characteristics were analyzed in subjects with AMD (with and without subretinal drusenoid deposits [SDDs]) and normal healthy cohorts. RESULTS: Participants' mean age was 65.2 years (SD ± 11). Color fundus photographic findings in 596 (53%) subjects (1,009 eyes) were consistent with AMD; the remaining 478 (43%) subjects showed no signs of AMD. The choroid was significantly thinner on OCT (242 ± 76 µm, P < 0.001) in those with AMD compared with those without (263 ± 63 µm). Subretinal drusenoid deposits were found in 143 eyes (7%); 11 of the 143 eyes (8%) had no other manifestations of AMD. Drusen volume (P < 0.001) and area of geographic atrophy (P < 0.001) were significantly greater, and choroid was significantly (P < 0.001) thinner in subjects with SDDs versus those without SDDs. CONCLUSION: The authors describe spectral domain optical coherence tomography characteristics in an elderly Amish population with and without AMD, including the frequency of SDD. Although relatively uncommon in this population, the authors confirmed that SDDs can be found in the absence of other features of AMD and that eyes with SDDs have thinner choroids.

CLASSIFICATION AND QUANTITATIVE ANALYSIS OF GEOGRAPHIC ATROPHY JUNCTIONAL ZONE USING SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: The junctional zone at the border of areas of geographic atrophy (GA) in eyes with nonneovascular age-related macular degeneration is an important target region for future therapeutic strategies. The goal of this study was to perform a detailed classification and quantitative characterization of the junctional zone using spectral domain optical coherence tomography. METHODS: Spectral domain optical coherence tomography volume cube scans (Spectralis OCT, 1024 × 37, Automatic Real Time > 9) were obtained from 15 eyes of 11 patients with GA because of nonneovascular age-related macular degeneration. Volume optical coherence tomography data were imported into previously described validated grading software (3D-OCTOR), and manual segmentation of the retinal pigment epithelium (RPE) and photoreceptor layers was performed on all B-scans (total of 555). Retinal pigment epithelium and photoreceptor defect maps were produced for each case. The borders of the photoreceptor defect area and RPE defect area were delineated individually on separate annotation layers. The two outlines were then superimposed to compare the areas of overlap and nonoverlap. The perimeter of the RPE defect area was calculated by the software in pixels. The superimposed outline of the photoreceptor defect area and the RPE defect area was scrutinized to classify the overlap configuration of the junctional zone into one of three categories: Type 0, exact correspondence between the edge of the RPE defect and photoreceptor defect; Type 1, loss of photoreceptors outside and beyond the edge of the RPE defect; Type 2, preservation of photoreceptors beyond the edge of the RPE defect. The relative proportion of the various border configurations was expressed as a percentage of the perimeter of the RPE defect. Each configuration was then classified into four subgroups according to irregularity of the RPE band and the presence of debris. RESULTS: Fifteen eyes of 11 patients (mean age: 79.3 ± 4.3 years; range: 79-94 years) were included in this study. Seventeen GA lesions were analyzed. Two hundred and thirty-two B-scans were found to pass through the GA lesions, yielding 612 individual GA borders which were separately analyzed and classified. The mean area of the RPE defect was 4.0 ± 4.4 mm, which was significantly smaller than that of the photoreceptor defect which measured 4.4 ± 4.1 mm (paired t test, P = 0.037). On average, 18.0 ± 9.6% (range, 2.3-36.6%) of the junctional zone was of the Type 0 configuration, 57.3 ± 19.0% (range, 21.3-96.8%) was Type 1, and 24.7 ± 18.0% (range, 0.9-64.4%) was Type 2. Type 1 was more prevalent than Type 0 and 2 (analysis of variance, P = 0.000). Debris was present at the margin of the defect in 24.3% (149 of 612) of all assessed junctional zones; 20.0% (14 of 70) of Type 0 junctions, 28.7% (120 of 418) of Type 1, and 12.1% (15 of 124) of Type 2. Debris was more common in Type 1 than Type 2 junctions (P < 0.001). Retinal pigment epithelial irregularity was present at the margin of the defect in 34.8% (213 of 612) of all assessed junctional zones; 52.9% (37 of 70) of Type 0 junctions, 38.0% (159 of 418) of Type 1, and 13.7% (17 of 124) of Type 2. Retinal pigment epithelial irregularity was present more often at Type 0 and Type 1 than at Type 2 junctions (P < 0.001 for both). CONCLUSION: The size of the optical coherence tomography-visible RPE and photoreceptor defect in GA lesions differ significantly. There were significant areas where the photoreceptor outer segments were preserved despite the absence of visible RPE cells, and also areas of photoreceptor outer segment loss despite apparent RPE preservation. These findings have implications for development of therapeutic strategies, particularly cell-replacement approaches.

QUANTIFICATION OF INTRARETINAL HARD EXUDATES IN EYES WITH DIABETIC RETINOPATHY BY OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate the reproducibility of intraretinal hard exudate (HE) quantification from spectral domain optical coherence tomography (SD-OCT) images of eyes with diabetic retinopathy (DR). METHODS: Cases with diabetic macular edema were enrolled. The area of HE obtained by B-scan segmentation was compared with the area obtained by en face segmentation. RESULTS: The mean ± SD for the HE area was 1.78 ± 1.37 mm with B-scan segmentation and 0.72 ± 0.82 mm with the automated en face analysis tool; the absolute difference was 1.01 ± 0.64 mm. There was excellent correlation in total HE area between the two methods (r = 0.95, P < 0.0001). The HE volume was 0.06 ± 0.07 mm. The correlation between HE volume and en face HE area was high (r = 0.95, P < 0.001). Intergrader reproducibility yielded excellent agreement with an intraclass correlation coefficient value of 0.99 (95% CI 0.994-0.999) for the en face approach and 0.99 (95% CI 0.977-0.997) for manual segmentation. CONCLUSION: Quantification of HE in eyes with diabetic retinopathy can be performed reliably using en face segmentation and, though the en face results are consistently lower, correlates well with HE measurements obtained by exhaustive segmentation of all B-scans in dense volume optical coherence tomography (OCT).

Automated Diabetic Retinopathy Image Assessment Software: Diagnostic Accuracy and Cost-Effectiveness Compared with Human Graders.

OBJECTIVE: With the increasing prevalence of diabetes, annual screening for diabetic retinopathy (DR) by expert human grading of retinal images is challenging. Automated DR image assessment systems (ARIAS) may provide clinically effective and cost-effective detection of retinopathy. We aimed to determine whether ARIAS can be safely introduced into DR screening pathways to replace human graders. DESIGN: Observational measurement comparison study of human graders following a national screening program for DR versus ARIAS. PARTICIPANTS: Retinal images from 20 258 consecutive patients attending routine annual diabetic eye screening between June 1, 2012, and November 4, 2013. METHODS: Retinal images were manually graded following a standard national protocol for DR screening and were processed by 3 ARIAS: iGradingM, Retmarker, and EyeArt. Discrepancies between manual grades and ARIAS results were sent to a reading center for arbitration. MAIN OUTCOME MEASURES: Screening performance (sensitivity, false-positive rate) and diagnostic accuracy (95% confidence intervals of screening-performance measures) were determined. Economic analysis estimated the cost per appropriate screening outcome. RESULTS: Sensitivity point estimates (95% confidence intervals) of the ARIAS were as follows: EyeArt 94.7% (94.2%-95.2%) for any retinopathy, 93.8% (92.9%-94.6%) for referable retinopathy (human graded as either ungradable, maculopathy, preproliferative, or proliferative), 99.6% (97.0%-99.9%) for proliferative retinopathy; Retmarker 73.0% (72.0 %-74.0%) for any retinopathy, 85.0% (83.6%-86.2%) for referable retinopathy, 97.9% (94.9%-99.1%) for proliferative retinopathy. iGradingM classified all images as either having disease or being ungradable. EyeArt and Retmarker saved costs compared with manual grading both as a replacement for initial human grading and as a filter prior to primary human grading, although the latter approach was less cost-effective. CONCLUSIONS: Retmarker and EyeArt systems achieved acceptable sensitivity for referable retinopathy when compared with that of human graders and had sufficient specificity to make them cost-effective alternatives to manual grading alone. ARIAS have the potential to reduce costs in developed-world health care economies and to aid delivery of DR screening in developing or remote health care settings.

Proposal of a simple optical coherence tomography-based scoring system for progression of age-related macular degeneration.

PURPOSE: To develop a simple, clinically practical, optical coherence tomography (OCT)-based scoring system for early age-related macular degeneration (AMD) to prognosticate risk for progression to late AMD. METHODS: We retrospectively reviewed OCT images (512 × 128 macular cube, Cirrus) from 138 patients diagnosed of early AMD in at least one eye and follow-up of at least 12 months. For patients with early AMD in both eyes, only the right eye was chosen as the study eye for longitudinal assessment. Scans were graded on four SD-OCT criteria associated with disease progression in previous studies: drusen volume within a central 3-mm circle ≥0.03 mm3, intraretinal hyperreflective foci (HRF), hyporeflective foci (hRF) within a drusenoid lesion (DL), and subretinal drusenoid deposits (SDD). Each criterion was assigned one point. For risk assessment of the study eye, the baseline status of the fellow eye was also considered, and thus these four features were also assessed in the fellow eye. The number of risk factors were summed for both eyes, yielding a total score (TS) of 0 to 8 for each patient. A fellow eye with evident choroidal neovascularization (CNV) or atrophy automatically received 4 points. Scores were then grouped into four categories to facilitate comparative analysis: I. (TS of 0, 1, 2), II. (TS of 3, 4), III. (TS of 5, 6) and IV. (TS of 7, 8). Correlation of baseline category assignment with progression to late AMD (defined as the presence of atrophy or CNV on OCT) by the last follow-up visit was evaluated with logistic regression analysis. RESULTS: The rate of progression to late AMD was 39.9% (55/138). Progression rates by category (I to IV) were 0, 14.3, 47.5, and 73.3%, respectively. Logistic regression analysis showed risk of progression to late AMD was 3.0 times (95% CI: 1.2-7.9) higher for an eye assigned to category IV than for an eye in category III and 16.4 (95% CI: 4.7-58.8) times higher than for an eye in category II. CONCLUSIONS: A simple scoring system relevant to prognosis for early AMD, and practical for use in a busy clinic, can be developed using SD-OCT criteria alone.

ASSESSMENT OF RETINAL BLOOD FLOW IN DIABETIC RETINOPATHY USING DOPPLER FOURIER-DOMAIN OPTICAL COHERENCE TOMOGRAPHY.

PURPOSE: To evaluate retinal blood flow measurements in normal eyes and eyes with varying levels of diabetic retinopathy (DR) using Doppler Fourier-domain optical coherence tomography (FD-OCT). METHODS: Twenty-two eyes of 19 subjects, 10 with severe nonproliferative DR (NPDR) and 12 with proliferative DR (PDR), were compared with 44 eyes of 40 healthy control subjects. All eyes were scanned by RTvue FD-OCT. Color disk photographs and cube/volume scans of the optic nerve head were obtained. Doppler OCT scans and accessory imaging data were imported into Doppler OCT of Retinal Circulation grading software to calculate TRBF and vascular parameters (e.g., venous and arterial cross-sectional area). Measurements were compared between cases and controls using independent t-tests. RESULTS: Mean TRBF was 44.98 ± 9.80 (range: 30.18-64.58) µL/minute for normal eyes, 35.80 ± 10.48 (range: 20.69-49.56) µL/minute for eyes with severe NPDR, and 34.79 ± 10.61 (range: 16.77-48.9) µL/minute for eyes with PDR. Mean TRBF was significantly lower in eyes with severe NPDR (P = 0.01) and PDR (P = 0.003) than in normal eyes. CONCLUSION: Total retinal blood flow was significantly lower in eyes with severe NPDR and PDR compared with normal eyes. Retinal blood flow determined by Doppler OCT may be a useful parameter for evaluating patients with DR.