Alterations of the Ganglion Cell Complex in Age-Related Macular Degeneration: An Amish Eye Study Analysis.

PURPOSE: To compare the ganglion cell complex (GCC) thickness in eyes with age-related macular degeneration (AMD) vs healthy controls in an elderly Amish population. DESIGN: Prospective cross-sectional study. METHODS: This is a post hoc analysis of the family-based prospective study of Amish subjects. Study subjects underwent imaging with the Cirrus HD-OCT (Carl Zeiss Meditec Inc) using a macular cube protocol of 512 × 128 scans (128 horizontal B-scans, each comprising 512 A-scans) over a 6 mm × 6 mm region centered on the fovea. The ganglion cell analysis algorithm calculated the GCC thickness by segmenting the outer boundaries of the retinal nerve fiber layer (RNFL) and inner plexiform layer (IPL) in all B-scans of the volume, with the region between these boundaries representing the combined thickness of the ganglion cell layer (GCL) and the IPL. A number of parameters were used to evaluate the GCC thickness: the average GCC thickness, minimum (lowest GCC thickness at a single meridian crossing the elliptical annulus), and sectoral (within each of 6 sectoral areas: superior, superotemporal, superonasal, inferior, inferonasal, and inferotemporal). The stage of AMD was graded on color fundus photographs in accordance with the Beckman Initiative for Macular Research classification system. RESULTS: Of 1339 subjects enrolled in the Amish eye study, a total of 1294 eyes of 1294 subjects had all required imaging studies of sufficient quality and were included in the final analysis. Of these, 798 (62%) were female. Following age adjustment, the average GCC thickness was significantly (P < .001) thinner in AMD subjects (73.71 ± SD; 13.77 µm) compared to normals (77.97 ± 10.42 µm). An independent t test showed that the early AMD (75.03 ± 12.45 µm) and late AMD (61.64 ± 21.18 µm) groups (among which eyes with geographic atrophy [GA] had the lowest thickness, of 58.10 ± 20.27 µm) had a statistically significant lower GCC thickness compared to eyes without AMD. There was no significant differences in average GCC thickness between early AMD and intermediate AMD (76.36 ± 9.25 µm) eyes. CONCLUSIONS: The GCC thickness in AMD eyes is reduced compared to normal eyes; however, the relationship is complex, with the greatest reduction in late AMD eyes (particularly eyes with GA) but no difference between early and intermediate AMD eyes.

OCT outcomes as biomarkers for disease status, visual function, and prognosis in diabetic macular edema.

OBJECTIVE: To evaluate disorganization of retinal inner layers (DRIL), as detected on spectral-domain optical coherence tomography (OCT) images, as a biomarker for diabetic macular edema (DME) activity, visual function, and prognosis in eyes with DME. DESIGN: Longitudinal prospective. METHODS: Post hoc correlation analyses were performed on data from a phase 2 clinical trial. Seventy-one eyes of 71 patients with treatment-naive DME received either suprachoroidally administered CLS-TA (proprietary formulation of a triamcinolone acetonide injectable suspension) combined with intravitreal aflibercept or intravitreal aflibercept with a sham suprachoroidal injection procedure. DRIL area, maximum horizontal extent of DRIL, ellipsoid zone (EZ) integrity, and the presence and location of subretinal (SRF) and intraretinal fluid (IRF) were evaluated at baseline and week 24 by certified reading centre graders. RESULTS: At baseline, the area and maximum horizontal extent of DRIL were negatively correlated with best-corrected visual acuity (BCVA; r = -0.25, p = 0.05 and r = -0.32, p =0.01, respectively). Mean baseline BCVA progressively worsened with each ordinal drop in EZ integrity, improved with the presence of SRF, and was invariant to the presence of IRF. DRIL area and maximum extent were significantly decreased at week 24 (-3.0 mm2 [p < 0.001] and -775.8 mm [p < 0.001], respectively. At week 24, decreases in the area and maximum horizontal extent of DRIL were positively correlated with increases in BCVA (r = -0.40, p = 0.003 and r = -0.30, p = 0.04). Improvements in BCVA at week 24 were no different between patients showing improvement in EZ, SRF, or IRF and those showing no improvement or worsening from baseline. CONCLUSIONS: DRIL area and DRIL maximum horizontal extent were demonstrated to be novel biomarkers for macular edema status, visual function, and prognosis in eyes with treatment-naive DME.

Longitudinal evaluation of the distribution of intraretinal hyper-reflective foci in eyes with intermediate age-related macular degeneration.

Purpose: Intraretinal hyper-reflective foci (IHRF) are optical coherence tomography (OCT) risk factors for progression of age-related macular degeneration (AMD). In this study we assess the change in the number and distribution of IHRF over two years. Methods: The axial distribution of IHRF were quantified in eyes with intermediate AMD (iAMD) at baseline and 24 months, using a series of 5 sequential equidistant en face OCT retinal slabs generated between the outer border of the internal limiting membrane (ILM) and the inner border of the retinal pigment epithelium (RPE). Following thresholding and binarization, IHRF were quantified in each retinal slab using ImageJ. The change in IHRF number in each slab between baseline and month 24 was calculated. Results: Fifty-two eyes showed evidence of IHRF at baseline, and all continued to show evidence of IHRF at 24 months (M24). The total average IHRF count/eye increased significantly from 4.67 ± 0.63 at baseline to 11.62 ± 13.86 at M24 (p<0.001) with a mean increase of 6.94 ± 11.12 (range: - 9 to + 60). Overall, at M24, 76.9% eyes showed an increase in IHRF whereas 15.4% of eyes showed a decrease (4 eyes [7.6%] showed no change). There was a greater number of IHRF and a greater increase in IHRF over M24 in the outer slabs. Conclusions: IHRF are most common in the outer retinal layers and tend to increase in number over time. The impact of the distribution and frequency of these IHRF on the overall progression of AMD requires further study.

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.

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.

Ethnic Variation in Diabetic Retinopathy Lesion Distribution on Ultra-widefield Imaging.

PURPOSE: To evaluate whether the distribution of diabetic retinopathy (DR) lesions differs among various ethnicities. DESIGN: Multi-center, retrospective cohort study. METHODS: We accrued a cohort of 226 eyes with DR consisting of 51 East Asian eyes, 102 South Asian eyes, 30 Caucasian eyes, and 43 Latino eyes, all evaluated with ultrawide field pseudocolor images. Images were manually annotated for DR lesions and were classified as having predominantly peripheral lesions (PPL) or predominantly central lesions (PCL) using 4 quantitative methods. The percent distribution of PCL to PPL was compared among different ethnicities. RESULTS: Using a single-field lesion frequency-based method, East Asian eyes more frequently demonstrated a PPL distribution (86.3%), whereas South Asian eyes more frequently demonstrated a PCL distribution (64.7%). These findings were also observed when considering only the subset of treatment-naïve eyes. Furthermore, in treatment-naïve eyes without proliferative DR, the percent distribution of PPL to PCL in East Asian eyes was significantly different when compared to other ethnicities (P < .0001 South Asian, P = .035 Caucasian, P = .0003 Latino). The majority of patients (60%-78%) in all ethnic groups had moderate nonproliferative diabetic retinopathy(NPDR), and the same difference between East Asian and South Asian eyes was observed in this subgroup. CONCLUSIONS: The distribution of DR lesions appears to vary among different ethnicities. DR lesions tend to be distributed more peripherally in East Asian eyes compared to other ethnic groups, particularly South Asian eyes, which tend to have more central disease. The prognostic implications of these ethnic differences in DR lesion distribution require further investigation.

Effect of OCT B-Scan Density on Sensitivity for Detection of Intraretinal Hyperreflective Foci in Eyes with Age-Related Macular Degeneration.

PURPOSE: To evaluate the impact of reducing the density of B-scans in an optical coherence tomography (OCT) volume on the sensitivity for detecting intraretinal hyperreflective foci (IHRF) in eyes with intermediate age-related macular degeneration (AMD). METHODS: A total of 165 eyes with intermediate AMD and IHRF were evaluated in this retrospective analysis. For each case, Cirrus HD-OCT volumes were imported into the reading center 3 D-OCTOR software. The number of IHRF cases was assessed based on all 128 B-scans (spaced 47 µm apart), using a categorical scale (graded as 1-4, 5-9, 10-14, 15-19, and >20). Additionally, the B-scan densities in the volume were lowered to 64 B-scans (spaced 94 µm apart), 43 B-scans (spaced 140 µm apart), and 32 B-scans (spaced 188 µm apart). The number of eyes with any IHRF and the numerical category of IHRF in the eye were used to compare the sensitivity at each reduced B-scan density against the reference 128 B-scan volume. RESULTS: In the primary analysis for the qualitative presence or absence of any IHRF, the sensitivity decreased to 98.2% (p = .32) with 64 B-scans, 92.7% (p = .001) with 43 B-scans, and 75.2% (p = .001) with 32 B-scans, compared with the 128 B-scan reference. With regard to the number of IHRF per eye, there was a significant difference (with a lower level chosen on the scale) when the B-scan density was reduced to 43 or 32 B-scans (p = .002 and p < .001, respectively). CONCLUSION: Increasing the inter-B-scan spacing from 47 to 188 microns significantly reduced the ability to accurately determine whether IHRF were present in an eye. An increase in inter-B-scan spacing to 140 microns was associated with a significant misclassification of the IHRF quantity. These findings may be relevant in the design of OCT scanning protocols for studies utilizing these biomarkers for AMD progression.

Correlation between Fundus Autofluorescence and En Face OCT Measurements of Geographic Atrophy.

PURPOSE: To evaluate the correlation between fundus autofluorescence (FAF) and en face spectral-domain OCT (SD-OCT) measurements of geographic atrophy (GA) area associated with age-related macular degeneration. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: Two hundred seventy eyes from 172 subjects with GA associated with age-related macular degeneration. METHODS: Subjects with atrophic age-related macular degeneration who underwent both FAF (Heidelberg HRA + Spectralis) and dense volume (128 B-scans over 6 × 6 mm2) SD-OCT (Cirrus OCT) imaging were included in this retrospective analysis. The borders of all areas of definite decreased autofluorescence (DDAF) corresponding to GA were manually outlined on FAF images by certified graders at Doheny Image Reading Center using validated planimetric grading tools. Geographic atrophy was also automatically delineated using en face OCT (at the level of the choroid) using an instrument software (Cirrus v.6.2), and segmentation errors were manually corrected before the computation of the GA area. The fundus autofluorescence and SD-OCT-derived measurements were correlated. MAIN OUTCOME MEASURES: Correlation between the SD-OCT and FAF measurements of the GA area. RESULTS: The mean GA area measured from the FAF images was 8.1 ± 5.04 mm2, compared with an automated, uncorrected GA area of 6.82 ± 3.84 mm2 measured using SD-OCT. Despite the presence of apparent OCT segmentation errors, there was a significant correlation between the FAF and uncorrected SD-OCT measurements (r = 0.80; P < 0.001). After the manual correction of the SD-OCT GA segmentation errors, the measured GA area increased to 7.29 ± 4.18 mm2, and the correlation with the FAF-determined GA area significantly improved (r = 0.98; P < 0.001). CONCLUSIONS: Spectral-domain OCT-derived measurements of GA correlate well with areas of DDAF obtained from FAF images. The manual correction of SD-OCT segmentation errors can further improve this correlation. These observations may support the use of SD-OCT-based measurements of the GA area in clinical research and clinical trials.

Final Outcomes from the Randomized RECOVERY Trial of Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy.

PURPOSE: Retinal nonperfusion (RNP) is an important biomarker for diabetic retinopathy (DR). Data suggest that consistent anti-VEGF pharmacotherapy can slow RNP development. The RECOVERY trial evaluated the impact of aflibercept (Eylea, Regeneron) on RNP among eyes with proliferative DR (PDR). DESIGN: Prospective, randomized clinical trial with treatment crossover in the second year. SUBJECTS: Eyes with PDR and RNP. METHODS: At baseline, the subjects were randomized 1:1 to monthly (arm 1) or quarterly (arm 2) intravitreal 2 mg aflibercept. At the beginning of year 2, the treatment arms were crossed over so that the monthly-dosed subjects subsequently received quarterly dosing and the quarterly-dosed subjects subsequently received monthly dosing. MAIN OUTCOME MEASURES: Change in total RNP area (mm2) through year 2. Secondary outcomes included Diabetic Retinopathy Severity Scale (DRSS) scores; best-corrected visual acuity; central subfield thickness; additional measures of RNP, including ischemic index (ISI); and adverse event incidence. Means and 95% confidence intervals were calculated. RESULTS: Among all subjects, from baseline to year 2, the mean RNP increased from 235 mm2 to 402 mm2 (P < 0.0001), and the ISI increased from 25.8% to 50.4% (P < 0.0001). Increases in the mean RNP (P < 0.0001) and ISI (P < 0.0001) were also observed from year 1 to year 2. The mean total RNP increased from 264 mm2 at baseline to 386 mm2 (P < 0.0001) at year 2 in arm 1 and from 207 mm2 at baseline to 421 mm2 (P < 0.0001) at year 2 in arm 2 (P = 0.023, arm 1 vs. arm 2). Increases in the mean RNP for both treatment arms (P < 0.0001) were also specifically observed within year 2 (P = 0.32, arm 1 vs. arm 2). Compared with baseline, the DRSS scores at the end of year 2 improved in 82% (n = 27) of subjects and remained stable in 18% (n = 6), with no subjects experiencing worsening; at 2 years, the DRSS scores had improved by 2 or more steps in 65% (n = 11) and 81% (n = 13) of subjects in arms 1 and 2, respectively. CONCLUSIONS: Through year 2 of the RECOVERY trial, both treatment arms experienced significant increases in RNP. Despite the expansion of the RNP area in nearly all subjects, 82% of subjects demonstrated an improvement in DRSS levels from baseline, with no subjects experiencing worsening in DRSS scores.

Association of Pegcetacoplan With Progression of Incomplete Retinal Pigment Epithelium and Outer Retinal Atrophy in Age-Related Macular Degeneration: A Post Hoc Analysis of the FILLY Randomized Clinical Trial.

IMPORTANCE: Change in areas of incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) within eyes with geographic atrophy (GA) might reflect similar changes among eyes with drusen but no GA. OBJECTIVE: To evaluate the potential association of pegcetacoplan with progression of iRORA in eyes with GA secondary to AMD. DESIGN, SETTING, AND PARTICIPANTS: This post hoc analysis of the phase 2 multicenter, randomized, single-masked, sham-controlled FILLY trial of intravitreal pegcetacoplan for 12 months took place from February 2 to July 7, 2020. Participants comprised 167 patients with GA secondary to AMD who received pegcetacoplan monthly (n = 41) or every other month (n = 56) or a sham injection (n = 70) in the FILLY trial, completed the month 12 study visit, and did not develop exudative AMD. INTERVENTIONS: Intravitreal pegcetacoplan, 15 mg, or sham injection, monthly or every other month for 12 months. MAIN OUTCOMES AND MEASURES: Masked readers analyzed spectral-domain optical coherence tomography scans in regions beyond a perimeter of 500 µm from the GA border according to the Classification of Atrophy Meetings criteria. Primary outcome measures were progression from iRORA to complete RPE and outer retina atrophy (cRORA) from baseline to 6 and 12 months. RESULTS: Among the 167 patients in the study, at baseline, iRORA was present in 45.0% of study eyes (18 of 40) in the pegcetacoplan monthly group, 61.8% of study eyes (34 of 55) in the pegcetacoplan every other month group, and 50.7% of study eyes (34 of 67) in the sham group. At 12 months, progression from iRORA to cRORA occurred in 50.0% of study eyes (9 of 18) in the pegcetacoplan monthly group (P = .02 vs sham), 60.6% of study eyes (20 of 33) in the pegcetacoplan every other month group (P = .06 vs sham), and 81.8% of study eyes (27 of 33) in the sham group. Compared with sham treatment, the relative risk of progression at 12 months from iRORA to cRORA was 0.61 (95% CI, 0.37-1.00) for eyes in the pegcetacoplan monthly group and 0.74 (95% CI, 0.54-1.02) for eyes in the pegcetacoplan every other month group. CONCLUSIONS AND RELEVANCE: Eyes receiving intravitreal pegcetacoplan had lower rates of progression from iRORA to cRORA compared with controls, suggesting a potential role for pegcetacoplan therapy earlier in the progression of AMD prior to the development of GA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02503332.

Post hoc analysis of ellipsoid zone changes beyond the central subfield in symptomatic vitreomacular adhesion patients from the OASIS trial.

BACKGROUND/AIMS: OASIS is a Phase IIIb trial (NCT01429441) assessing long-term outcomes in subjects with symptomatic vitreomacular adhesion (VMA). The purpose of this study is to report on the frequency, severity, location and time course of ellipsoid zone (EZ) alterations in ocriplasmin-treated and sham control eyes in the OASIS study. METHODS: 220 patients (146 ocriplasmin, 74 sham) subjects with VMA were enrolled in this masked post hoc analysis phase IIIb, randomised, sham-controlled double-masked multicentre clinical trial. A masked post hoc analysis of OCT images was performed at the Doheny Image Reading Center from subjects enrolled in the OASIS trial. The status of the EZ band was assessed in three different macular regions: the central subfield (CS) (≤1 mm diameter), the parafoveal area (PAA) (>1 to ≤3 mm) and the perifoveal area (PEA) (>3 to ≤6 mm). The EZ band was rated as normal/intact, full thickness macular hole (FTMH), abnormal but continuous, discontinuous/disrupted or absent at visits from baseline (pretreatment) to week 1 (day 7), month 1 (day 28), month 3, month 6, month 12 and the final follow-up at month 24. EZ band status was compared in both study and control eyes. RESULTS: A total of 208 patients (138 ocriplasmin, 70 sham) were included in this analysis. At baseline, FTMH was present in 48.6%, 8.0%, 0% and 52.8%, 2.9%, 0% in the CS, PAA and PEA of the ocriplasmin and sham groups, respectively. The EZ was graded to be abnormal but continuous, discontinuous/disrupted or absent at Baseline in 21.0%, 4.3%, 2.8% in the CS, PAA and PEA, respectively, of the ocriplasmin group; and 12.9%, 10.0%, 4.3% in the CS, PAA and PEA of the sham group. For the ocriplasmin group in the PAA, this frequency increased to 6.6% at week 1, was 9.8% at month 1, but improved to 3.8% at month 3, and remained stable to 1.6% at month 24. These differences, however, were not statistically significant. CONCLUSIONS: Ocriplasmin treatment for symptomatic VMA was associated with EZ abnormalities in a small percentage of patients that was best assessed in regions (PEA) relatively unaffected by the VM interface disease at baseline. The EZ abnormalities were apparent by week 1, persisted at month 1, and appeared to resolve in the majority of cases by month 3. TRIAL REGISTRATION NUMBER: NCT01429441.

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.

Effect of Human Central Nervous System Stem Cell Subretinal Transplantation on Progression of Geographic Atrophy Secondary to Nonneovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the effect of subretinally transplanted human central nervous system stem cells (HuCNS-SC) on the progression of geographic atrophy (GA) in patients with nonneovascular age-related macular degeneration (AMD). DESIGN: Multicenter, prospective, phase 1 open-label clinical trial. PARTICIPANTS: Fifteen patients with bilateral GA solely the result of AMD. METHODS: The eye with the worst best-corrected visual acuity from each patient was selected for treatment and was considered the study eye; fellow eyes served as controls. A total of 0.25 × 106 or 1.0 × 106 HuCNS-SCs were infused directly into the subretinal space, superotemporal to the fovea near the junctional zone, outside the area of GA. All patients underwent spectral-domain OCT and fundus autofluorescence imaging using the Spectralis HRA+OCT (Heidelberg Engineering, Inc., Heidelberg, Germany). Total GA area in both eyes was measured at baseline and month 12 by certified reading center graders using the Spectralis Region Finder software. Sectoral (clock hour) per directional radial GA progression rates with respect to the foveal center in both eyes were calculated using the polar transformation method in Image J software (National Institutes of Health, Bethesda, MD). To facilitate comparative analysis across the cohort, all eyes were transformed to a right-eye orientation. MAIN OUTCOME MEASURES: Total GA area and sectoral per directional GA progression rates were compared in both study and control eyes. RESULTS: No statistically significant difference was found in mean change in total GA area at month 12 between study and fellow eyes (1.07 ± 0.84 mm2 vs. 2.08 ± 1.97 mm2; P = 0.08). However, the month 12 sectoral per directional radial GA growth rate for the superotemporal region (i.e., the location of HuCNS-SC transplantation) showed a significantly slower progression rate in study eyes than in fellow eyes (0.29 ± 0.58 mm vs. 1.08 ± 0.65 mm; P = 0.007). The progression rate in the superotemporal quadrant of the study eye was significantly slower than in the other 3 quadrants combined (P = 0.04). CONCLUSIONS: In this small pilot study, HuCNS-SC transplantation seems to be associated with slower expansion of the GA lesion in the transplanted quadrant. Larger confirmatory studies are required. Sectoral or directional analysis of growth rates of GA may be a useful approach for assessing the efficacy of locally delivered therapies.

Retinal Sensitivity Using Microperimetry in Age-Related Macular Degeneration in an Amish Population.

BACKGROUND AND OBJECTIVES: To evaluate retinal sensitivity (RS) by mesopic and scotopic microperimetry (MP-1S) in an elderly Amish population with age-related macular degeneration (AMD). PATIENTS AND METHODS: Mesopic and scotopic microperimetric testing was performed in 148 eyes of 77 elderly Amish subjects (age > 50 years) from Pennsylvania using a retinal function analyzer. Scotopic testing was performed using a 2.0 log unit neutral density filter following 30 minutes of dark adaptation. All subjects underwent complete ophthalmic examinations, including spectral-domain optical coherence tomography, fundus autofluorescence, infrared reflectance imaging, and flash color fundus photography. Certified graders at Doheny Image Reading Center identified subjects with evidence of AMD as defined by the Beckman classification and quantified drusen volume. RS in subjects with and without AMD was compared. Correlations between RS and drusen burden were analyzed. Ten eyes with incomplete MP-1S exams were excluded from the final analysis. RESULTS: Among the 138 eyes from 77 subjects included in the final analysis, 42 eyes from 29 subjects had evidence of early or intermediate AMD. The mean age of subjects with AMD was 69.65 years ± 13.81 years versus 63.04 years ± 12.69 years in those without AMD (P = .06). Mesopic RS was 18.8 dB ± 2.1 dB in subjects with AMD and 19.6 dB ± 1.4 dB in those without AMD (P = .07). Scotopic RS was significantly lower (P = .04) in subjects with AMD (15.9 dB ± 2.9 dB) compared with those without AMD (17.3 dB ± 2.4 dB). There was no relationship between mesopic RS and either drusen area (r = -0.06; P = .32) or drusen volume (r = -0.08; P = .30). There was a trend for an association between scotopic RS and both drusen area (r = -0.39; P = .24) and drusen volume (r = -0.36; P = .30). CONCLUSIONS: In an elderly Amish population, eyes with early or intermediate AMD show a greater reduction in scotopic RS than mesopic RS, suggesting that rod function is more severely affected than cone function. Drusen area and volume measurements better correlated with scotopic RS. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e236-e241.].

Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy: Outcomes from the Randomized RECOVERY Trial.

PURPOSE: Evaluate the impact of intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) on retinal nonperfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). DESIGN: Prospective, randomized clinical trial. PARTICIPANTS: Eyes with treatment-naïve PDR and extensive RNP without diabetic macular edema. METHODS: Patients were randomized 1:1 to intravitreal 2 mg aflibercept every 4 weeks (monthly) or every 12 weeks (quarterly). MAIN OUTCOME MEASURES: The primary outcome measure was change in total RNP area (in square millimeters) from baseline to year 1. Secondary outcomes included ischemic index (ISI), diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, and adverse events. The mean and 95% confidence interval were calculated for each outcome. RESULTS: Through 1 year, the monthly (n = 20) and quarterly (n = 20) cohorts received 11.0 and 3.95 mean aflibercept injections, and DRSS scores improved 2 steps or more in 74% and 67% of patients, respectively. Among all patients through 1 year, mean total area of RNP increased from 235 mm2 to 266 mm2 (P = 0.18) and ISI increased from 25.8% to 31.9% (P = 0.004). Retinal nonperfusion outcomes favored monthly dosing. Mean total RNP increased from 207 mm2 at baseline to 268 mm2 (P = 0.01) at 1 year in the quarterly cohort and remained stable at 264 mm2 at baseline and 1 year (P = 0.70) in the monthly cohort (P = 0.05, monthly vs. quarterly cohorts). Although many eyes demonstrated increased areas of RNP longitudinally (n = 24 [66.7%]), this was more common with quarterly dosing (n = 14 [77.8%]), and a proportion of eyes (n = 12 [33.3%]) demonstrated localized areas of apparent reperfusion of nonperfused retina, more commonly in the monthly cohort (n = 8 [44.4%]). CONCLUSIONS: Widespread evidence of retinal reperfusion with aflibercept dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of the current study was not met. Nevertheless, zones of apparent reperfusion were detected in some patients, and a dose response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.

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.

Changes in Retinal Layer Thickness in the Contralateral Eye of Patients with Unilateral Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate the thickness of the outer retinal layers and its relationship with visual function in fellow eyes of participants with unilateral neovascular age-related macular degeneration (AMD). DESIGN: Longitudinal study. PARTICIPANTS: We enrolled 105 subjects with unilateral neovascular AMD from 3 clinical centers in Europe. METHODS: The fellow eye, without advanced AMD, was selected for the study. Subjects were followed up with visits occurring every 6 months for 2 years. Spectral domain optical coherence tomography volume scans were collected at 3 clinical sites, in Belfast, Northern Ireland; Coimbra, Portugal; and Milan, Italy. Detailed manual segmentation of outer retinal layers was performed using the custom-designed and validated grading software 3D OCTOR. Thickness measurements for neurosensory retina, photoreceptor layer (PRL) outer segments, retinal pigment epithelium plus drusen (RPE+drusen) complex, and choroidal layers from each sector of the standard macular grid were obtained. Measures of vison were distance visual acuity, near visual acuity, Smith-Kettlewell Institute low-luminance acuity score, and reading speed. Subjects were grouped based on the presence or absence of subretinal drusenoid deposits (SDDs) for further analysis. MAIN OUTCOME MEASURES: Change in thickness of retinal layers and change in measures of vision. RESULTS: In all, 85 eyes were included in the analysis. The average duration of follow-up was 20.5 ± 5.8 months. By the final visit, the RPE+drusen complex was significantly thinner when compared with baseline (29.7 µm vs. 34.09 µm; P = 0.03). Low-luminance deficit was significantly worse at the final visit (P < 0.001) and correlated with PRL outer segment thickness (r = 0.33; P =0.02). The RPE+drusen complex was significantly thicker in eyes with SDDs compared with that in those without SDDs (30.67 µm vs. 28.64 µm; P = 0.02). PRL outer segments became significantly thinner over time in eyes with SDDs compared with those in eyes without SDDs. CONCLUSIONS: The RPE+drusen complex layer becomes thinner over time in fellow eyes of subjects with unilateral neovascular AMD. The rate of PRL outer segment thinning was higher in eyes with SDDs than in eyes without SDDs. These findings are preliminary steps in the identification of early biomarkers for detecting and monitoring the progression of AMD.

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.

Relationship Between Dry Retinal Volume and Visual Acuity in Diabetic Macular Edema.

BACKGROUND AND OBJECTIVE: To evaluate the relationship between a novel spectral-domain optical coherence tomography (SD-OCT) parameter, predicted dry retinal volume (DRV), and visual acuity (VA) in subjects with diabetic macular edema. PATIENTS AND METHODS: Twenty-eight eyes of 26 subjects with macular edema secondary to diabetic retinopathy (cases) and 10 healthy eyes of normal volunteers (controls) were included. Spectral-domain optical coherence tomography volume scans (512 × 128) were obtained before and 6 months to 12 months after anti-vascular endothelial growth factor therapy. The borders of the neurosensory retina, nerve fiber layer (NFL), and vitreous were manually defined using previously described grading software. NFL reflectivity was used to normalize the signal between eyes, allowing a normalized total retinal intensity to be computed for each eye by summing the brightness of every pixel in the retina on all B-scans. Using this normalized retinal intensity, a ratio of retinal intensity of cases over retinal intensity of normal was generated. The predicted DRV was computed by multiplying this calculated ratio with total retinal volume at baseline for each eye. Correlation analysis was performed between DRV at baseline and VA at baseline and final follow-up. RESULTS: The mean ± standard deviation age of the cohort was 69 years ± 9.8 years, and 28% were female. Mean best-corrected VA (logMAR) improved from 0.56 ± 0.36 at baseline to 0.44 ± 0.32 at follow-up (P = .001). The uncorrected ("wet") total retinal volume of 13.25 mm3 ± 2.73 mm3 at baseline declined significantly to a posttreatment retinal volume of 10.92 mm3 ± 1.42 mm3. The predicted DRV (10.79 mm3 ± 1.42 mm3) was statistically similar to the post-treatment, actual retinal volume. No significant correlation was observed between DRV and post-treatment VA. CONCLUSIONS: The predicted DRV at baseline showed good agreement with the actual observed posttreatment retinal volume. Thus, DRV may be a potentially useful parameter to estimate the extent of retinal tissue loss that may be obscured by the presence of concomitant edema. The lack of correlation between DRV and VA, however, suggests that other parameters, such as the integrity of the outer retinal bands, are likely important for visual outcome prediction. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:510-515.].

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.