Subretinal hyperreflective material in regions of atrophy and fibrosis in eyes with neovascular age-related macular degeneration.

BACKGROUND: Subretinal hyperreflective material (SHRM) is a significant biomarker for poor visual outcomes in neovascular age-related macular degeneration (nAMD); however, its relationship with fibrosis and atrophy is not well understood. This study aims to evaluate the relationship between SHRM, atrophy, and fibrosis in eyes receiving antivascular endothelial growth factor therapy for nAMD. METHODS: Post-hoc analysis of the 65 patients enrolled in the SEVEN-UP study, a multicenter cross-sectional study of patients originally enrolled in the ANCHOR and MARINA trials of ranibizumab. Color fundus photographs (CFP) were reviewed and manually segmented to define regions of atrophy and fibrosis. SHRM borders on OCT volume scans were manually delineated, and thickness measurements were computed and compared in corresponding regions of atrophy and fibrosis on the CFPs. RESULTS: Of the 65 subjects, 51 eyes showed atrophy and/or fibrosis on CFP and were included in the final analysis. Both atrophy and fibrosis regions exhibited SHRM on OCT. The mean SHRM thickness on OCT was significantly greater in CFP-fibrosis regions (44.19 ± 46.95 µm) compared with CFP-atrophy regions (14.28 ± 13.35 µm; p < 0.001). Additionally, the average maximum height of SHRM in fibrotic regions (268.04 ± 130.05 µm) was significantly thicker than in atrophic regions (121.95 ± 51.17 µm; p < 0.001). CONCLUSIONS: Although atrophy and fibrosis are thought to be different end-stage outcomes in eyes with nAMD, they both demonstrate SHRM on OCT; the main distinction being thickness. Given these similarities, these regions of nAMD-associated atrophy may be better-termed "atrosis" to distinguish these lesions from typical atrophy in the absence of neovascular disease.

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 (3 eyes [5.7%] 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.

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.

Impact of slab selection on the relationship between choriocapillaris flow deficits and enlargement rate of geographic atrophy.

OBJECTIVE: To evaluate the effect of changing slab position on the correlation between choriocapillaris (CC) flow deficits (FD) in eyes with geographic atrophy (GA) and yearly enlargement rate (yER) of GA. METHODS: OCT and OCTA images obtained on Cirrus HD-OCT device were collected from patients with GA. Each patient underwent OCTA scan at baseline and two OCT scans, one at baseline and one after at least 12 months. GA was delineated on en-face fundus image to calculate yER. OCTA images were generated from three 10 µm thick slabs 11, 21 and 31 µm posterior to RPE-fit line. 100 µm-wide concentric rings were generated around GA to calculate FD% in each ring which was correlated with yER. RESULTS: For the 11-21 µm slab, FD% was not significantly correlated with yER for any of the rings (p > 0.05). For the 21-31 and 31-41 µm slab, FD% of rings located in the 600 µm region around GA was significantly correlated with yER (p < 0.05). However, in all slab locations, there was no significant correlation between yER and CC FD% of rings located beyond the 600 µm region (p > 0.05). CONCLUSIONS: Slab selection for quantification of CC FD% may have a significant impact on quantitative results in eyes with GA.

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.

SLIViT: a general AI framework for clinical-feature diagnosis from limited 3D biomedical-imaging data.

We present SLIViT, a deep-learning framework that accurately measures disease-related risk factors in volumetric biomedical imaging, such as magnetic resonance imaging (MRI) scans, optical coherence tomography (OCT) scans, and ultrasound videos. To evaluate SLIViT, we applied it to five different datasets of these three different data modalities tackling seven learning tasks (including both classification and regression) and found that it consistently and significantly outperforms domain-specific state-of-the-art models, typically improving performance (ROC AUC or correlation) by 0.1-0.4. Notably, compared to existing approaches, SLIViT can be applied even when only a small number of annotated training samples is available, which is often a constraint in medical applications. When trained on less than 700 annotated volumes, SLIViT obtained accuracy comparable to trained clinical specialists while reducing annotation time by a factor of 5,000 demonstrating its utility to automate and expedite ongoing research and other practical clinical scenarios.

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.

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.

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.

Comparison of diabetic retinopathy severity grading on ETDRS 7-field versus ultrawide-field assessment.

OBJECTIVES: To compare the diabetic retinopathy (DR) severity level determined when considering only the ETDRS 7-field region versus the entire ultrawidefield (UWF) image. METHODS: In this retrospective, cross-sectional study, UWF pseudocolor images were graded on the Eyenuk image viewing, grading, and annotation platform for the severity of DR considering only the regions within the ETDRS 7-fields as well as the entire UWF image using two different protocols: 1) the simple International Classification of Diabetic Retinopathy (ICDR) scale and 2) the more complex DRCR.net Protocol AA grading scale. RESULTS: A total of 250 eyes from 157 patients were included in this analysis. Six eyes (2.4%) demonstrated a discrepancy in severity level between the ETDRS 7-field region and the entire UWF image when using the ICDR classification system. The discrepancies were due to the presence of lesions [intraretinal haemorrhage (n = 2), neovascular disease (n = 4)] in the peripheral fields which were not identified in the ETDRS 7-fields. Fourteen eyes (5.6%) had a discrepancy in severity level between the ETDRS 7-field region and the entire UWF image when using the ETDRS DRSS Protocol AA grading scale. The discrepancies were due to the presence of a higher level of disease [intraretinal haemorrhage (n = 4), neovascularization (n = 4), preretinal haemorrhage (n = 2), scatter laser scars (n = 4)] in the peripheral fields. CONCLUSION: Although considering regions outside of the ETDRS 7-fields altered the DR severity level assessment in <5% of cases in this cohort, significant and potentially vision-threatening lesions including neovascularization and preretinal haemorrhage were identified in these peripheral regions. This highlights the importance of evaluating the entire UWF region when assessing patients with diabetic retinopathy.

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.

Risk Factors for Progression of Age-Related Macular Degeneration: Population-Based Amish Eye Study.

Objective: To evaluate the optical coherence tomography (OCT)-based risk factors for progression to late age-related macular degeneration (AMD) in a population-based study of elderly Amish. Methods: A total of 1332 eyes of 666 consecutive subjects who completed a 2-year follow-up visit were included in this multicenter, prospective, longitudinal, observational study. Imaging features were correlated with 2-year incidence of late AMD development. Odds ratios for imaging features were estimated from logistic regression. Baseline OCT images were reviewed for the presence of drusen volume ≥0.03 mm3 in the central 3 mm ring, intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), subretinal drusenoid deposits (SDD), and drusenoid pigment epithelium detachment (PED). Subfoveal choroidal thickness, drusen area, and drusen volume within 3 and 5 mm circles centered on the fovea were also assessed. Results: Twenty-one (1.5%) of 1332 eyes progressed to late AMD by 2 years. The mean age of the study subjects was 65 ± 10.17 (±SD) years and 410 subjects were female. Univariate logistic regression showed that drusen area and volume in both 3 mm and 5 mm circles, subfoveal choroidal thickness, drusen volume ≥ 0.03 mm3 in the 3 mm ring, SDD, IHRF, and hDC were all associated with an increased risk for development of late AMD. The multivariate regression model identified that drusen volume in the 3 mm ring (OR: 2.59, p = 0.049) and presence of IHRF (OR: 57.06, p < 0.001) remained as independent and significant risk factors for progression to late AMD. Conclusions: This population-based study confirms previous findings from clinic-based studies that high central drusen volume and IHRF are associated with an increased risk of progression to late AMD. These findings may be of value in risk-stratifying patients in clinical practice or identifying subjects for early intervention clinical trials.

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.

Pentosan Polysulfate Maculopathy: Prevalence, Spectrum of Disease, and Choroidal Imaging Analysis Based on Prospective Screening.

PURPOSE: To describe the prevalence and spectrum of disease of pentosan polysulfate (PPS) maculopathy in a large multimodal retinal imaging study and to report the results of choroidal vascularity index (CVI) analysis. DESIGN: Prospective cohort study Methods: Of 741 patients prescribed PPS within a large university database, 100 (13.4%) with any consumption agreed to participate in a prospective screening investigation. Multimodal retinal imaging including near-infrared reflectance (NIR), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SD-OCT) was performed in all patients. Characteristic findings of affected patients were identified, and affected and unaffected cohorts were compared. CVI, defined as stromal choroidal area (SCA) divided by the total choroidal area, was analyzed. RESULTS: The prevalence of PPS maculopathy was 16%. NIR illustrated punctate hyperreflective lesions with early presentation. FAF illustrated a speckled macular network of hypo- and hyperautofluorescence colocalized with multifocal hyperreflective retinal pigment epithelial lesions on SD-OCT. Advanced cases demonstrated varying degrees of atrophy. The affected cohort exhibited significantly greater mean PPS therapy duration, mean daily dosage, and mean cumulative dosage (19.5±5.5 years, 433.9±137.6 mg, 3,103.1±1,402.2 g) compared with the unaffected cohort (7.1±6.6 years, 291.6±177.6 mg, 768.4±754.8 g). SCA was significantly lower and CVI was significantly greater in the affected vs the unaffected group. CONCLUSIONS: This prospective cohort study identified a prevalence of PPS maculopathy of 15%-20% among PPS users who agreed to participate. A spectrum of findings may be observed with multimodal retinal imaging. Significant choroidal abnormalities associated with this characteristic maculopathy may provide surrogate markers of macular toxicity.

Automated identification of clinical features from sparsely annotated 3-dimensional medical imaging.

One of the core challenges in applying machine learning and artificial intelligence to medicine is the limited availability of annotated medical data. Unlike in other applications of machine learning, where an abundance of labeled data is available, the labeling and annotation of medical data and images require a major effort of manual work by expert clinicians who do not have the time to annotate manually. In this work, we propose a new deep learning technique (SLIVER-net), to predict clinical features from 3-dimensional volumes using a limited number of manually annotated examples. SLIVER-net is based on transfer learning, where we borrow information about the structure and parameters of the network from publicly available large datasets. Since public volume data are scarce, we use 2D images and account for the 3-dimensional structure using a novel deep learning method which tiles the volume scans, and then adds layers that leverage the 3D structure. In order to illustrate its utility, we apply SLIVER-net to predict risk factors for progression of age-related macular degeneration (AMD), a leading cause of blindness, from optical coherence tomography (OCT) volumes acquired from multiple sites. SLIVER-net successfully predicts these factors despite being trained with a relatively small number of annotated volumes (hundreds) and only dozens of positive training examples. Our empirical evaluation demonstrates that SLIVER-net significantly outperforms standard state-of-the-art deep learning techniques used for medical volumes, and its performance is generalizable as it was validated on an external testing set. In a direct comparison with a clinician panel, we find that SLIVER-net also outperforms junior specialists, and identifies AMD progression risk factors similarly to expert retina specialists.