Spatially Resolved Association of Structural Biomarkers on Retinal Function in Non-Exudative Age-Related Macular Degeneration Over 4 Years.

Purpose: To longitudinally assess the impact of high-risk structural biomarkers for natural disease progression in non-exudative age-related macular degeneration (AMD) on spatially resolved mesopic and scotopic fundus-controlled perimetry testing. Methods: Multimodal retinal imaging data and fundus-controlled perimetry stimuli points were semiautomatically registered according to landmark correspondences at each annual visit over a period of up to 4 years. The presence of sub-RPE drusen, subretinal drusenoid deposits, pigment epithelium detachments (PEDs), hyper-reflective foci (HRF), vitelliform lesions, refractile deposits, and incomplete RPE and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) were graded at each stimulus position and visit. Localized retinal layer thicknesses were extracted. Mixed-effect models were used for structure-function correlation. Results: Fifty-four eyes of 49 patients with non-exudative AMD (mean age, 70.7 ± 9.1 years) and 27 eyes of 27 healthy controls (mean age, 63.4 ± 8.9 years) were included. During study course, presence of PED had the highest functional impact with a mean estimated loss of -1.30 dB (P < 0.001) for mesopic and -1.23 dB (P < 0.001) for scotopic testing, followed by HRF with -0.89 dB (mesopic, P = 0.001) and -0.87 dB (scotopic, P = 0.005). Subretinal drusenoid deposits were associated with a stronger visual impairment (mesopic, -0.38 dB; P = 0.128; scotopic, -0.37 dB; P = 0.172) compared with sub-RPE drusen (-0.22 dB, P = 0.0004; -0.18 dB, P = 0.006). With development of c-RORA, scotopic retinal sensitivity further significantly decreased (-2.15 dB; P = 0.02). Thickening of the RPE-drusen-complex and thinning of the outer nuclear layer negatively impacted spatially resolved retinal sensitivity. Conclusions: The presence of PED and HRF had the greatest prognostic impact on progressive point-wise sensitivity losses. Higher predominant rod than cone-mediated localized retinal sensitivity losses with early signs of retinal atrophy development indicate photoreceptor preservation as a potential therapeutic target for future interventional AMD trials.

Retinal drusen in patients with chronic myeloproliferative blood cancers are associated with an increased proportion of senescent T cells and signs of an aging immune system.

The cause of age-related macular degeneration (AMD) is unknown, but evidence indicates that both innate and adaptive immunity play a role in the pathogenesis. Our recent work has investigated AMD in patients with myeloproliferative neoplasms (MPNs) since they have increased drusen and AMD prevalence. We have previously found increased levels of chronic low-grade inflammation (CLI) in MPN patients with drusen (MPNd) compared to MPN patients with normal retinas (MPNn). CLI and AMD are both associated with aging, and we, therefore, wanted to study immunosenescence markers in MPNd, MPNn, and AMD. The purpose was to identify differences between MPNd and MPNn, which might reveal novel information relevant to drusen pathophysiology and thereby the AMD pathogenesis. Our results suggest that MPNd have a T cell differentiation profile resembling AMD and more effector memory T cells than MPNn. The senescence-associated-secretory-phenotype (SASP) is associated with effector T cells. SASP is thought to play a role in driving CLI seen with advancing age. Senescent cells with SASP may damage healthy tissue, including the eye tissues affected in AMD. The finding of increased effector cells in MPNd could implicate a role for adaptive immunity and senescent T cells together with increased CLI in drusen pathophysiology.

Assessment of macular function in patients with non-vascularized pigment epithelial detachment.

Non-vascularized pigment epithelial detachments (PED) are usually associated with dry age-related macular degeneration (AMD). In this study, we aimed to investigate the correlation between visual function and morphologic parameters. Seventeen eyes of eleven patients with non-vascularized AMD were enrolled. In addition to conventional optical coherence tomography (OCT), polarization-sensitive optical coherence tomography (PS-OCT) measurements were performed by evaluating the regularity of retinal pigment epithelium (RPE) entropy within the PED area. Retinal sensitivity was measured with MP-3 microperimetry, and retinal sensitivities within (RSin) and outside (RSout) the PED area were calculated. The relationship between OCT parameters and visual function was analyzed. As a result, there was a significant difference between the RSin and RSout (p < 0.001, Wilcoxon signed rank test). Moreover, RSin was significantly related to logMAR VA (p = 0.033, linear mixed model). The regularity of RPE entropy was significantly related to visual acuity and RSin (p = 0.00038, p = 0.031, linear mixed model), although neither the height nor area of PED correlated with visual function. Our results suggest that retinal sensitivity is significantly deteriorated within the PED area and RPE entropy measured with PS-OCT was closely related to visual function in eyes with non-vascularized PED.

Shared Features in Retinal Disorders With Involvement of Retinal Pigment Epithelium.

When using spectral domain optical coherence tomography (SD-OCT) to inform the status of outer retina, we have noted discrete hyperreflective lesions extending through photoreceptor-attributable bands that have a similar presentation in multiple retinal diseases. These lesions present as either corrugated thickenings of interdigitation zone and ellipsoid zone bands or in later stages as rectangular or pyramidal shaped foci that extend radially through photoreceptor cell-attributable bands. In ABCA4-related and peripherin-2/RDS-disease (PRPH2/RDS), monogenic forms of retinopathy caused by mutations in proteins expressed in photoreceptor cells, these punctate lesions colocalize with fundus flecks in en face images. In fundus albipunctatus and retinitis punctata albescens, diseases caused by mutations in genes (retinol dehydrogenase 5, RDH5; and retinaldehyde-binding protein 1, RLBP1) encoding proteins of the visual cycle, these lesions manifest as white dot-like puncta. Similar aberrations in photoreceptor cell-attributable SD-OCT reflectivity layers manifest as reticular pseudodrusen (RPD) in short-wavelength fundus autofluorescence and near-infrared fundus autofluorescence fundus images and are linked to age-related macular degeneration a complex disease. Despite differences in the etiologies of retinal diseases presenting as fundus flecks, dots and RPD, underlying degenerative processes in photoreceptor cells are signified in SD-OCT scans by the loss of structural features that would otherwise define healthy photoreceptor cells at these foci.

Scotopic thresholds on dark-adapted chromatic perimetry in healthy aging and age-related macular degeneration.

To evaluate the effect of aging, intra- and intersession repeatability and regional scotopic sensitivities in healthy and age-related macular degeneration (AMD) eyes. Intra- and intersession agreement and effect of age was measured in healthy individuals. The mean sensitivity (MS) and pointwise retinal sensitivities (PWS) within the central 24° with 505 nm (cyan) and 625 nm (red) stimuli were evaluated in 50 individuals (11 healthy and 39 AMD eyes). The overall intra- and intersession had excellent reliability (intraclass correlation coefficient, ICC > 0.90) and tests were highly correlated (Spearman rs = 0.75-0.86). Eyes with subretinal drusenoid deposit (SDD) had reduced PWS centrally, particularly at inferior and nasal retinal locations compared with controls and intermediate AMD (iAMD) without SDD. There was no difference in MS or PWS at any retinal location between iAMD without SDD and healthy individuals nor between iAMD with SDD and non-foveal atrophic AMD groups. Eyes with SDD have reduced rod function compared to iAMD without SDD and healthy eyes, but similar to eyes with non-foveal atrophy. Our results highlight rod dysfunction is not directly correlated with drusen load and SDD location.

Clustering of eyes with age-related macular degeneration or pachychoroid spectrum diseases based on choroidal thickness profile.

Choroidal changes have been suggested to be involved in the pathophysiology of both age-related macular degeneration (AMD) and pachychoroid spectrum diseases (PSD). To find out the choroidal characteristics of each disease groups, various groups of AMD and PSD were classified into several clusters according to choroidal profiles based on subfoveal choroidal thickness (CT), peripapillary CT, the ratio of subfoveal CT to peripapillary CT and age. We retrospectively analyzed 661 eyes, including 190 normal controls and 471 with AMD or PSDs. In the AMD groups, eyes with soft drusen or reticular pseudodrusen were belonged to the same cluster as those with classic exudative AMD (all p < 0.001). However, eyes with pachydrusen were not clustered with eyes from other AMD groups; instead, they were classified in the same cluster as eyes from the PSD group (all p < 0.001). In the PSD group, eyes with pachychoroid neovasculopathy were grouped in the same cluster of those with polypoidal choroidal vasculopathy (p < 0.001). The cluster analysis based on the CT profiles, including subfoveal CT, peripapillary CT, and their ratio, revealed a clustering pattern of eyes with AMD and PSDs. These findings support the suggestion that pachydrusen has the common pathogenesis as PSD.

BASELINE PREDICTORS ASSOCIATED WITH 3-YEAR CHANGES IN DARK ADAPTATION IN AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To assess the relationship between baseline age-related macular degeneration (AMD) and disease stage, as well as optical coherence tomography features seen in AMD, with 3-year changes in dark adaptation (DA). METHODS: Prospective longitudinal study including patients with AMD and a comparison group (n = 42 eyes, 27 patients). At baseline and 3 years, we obtained color fundus photographs, spectral-domain optical coherence tomography, and rod-mediated DA (20 minutes protocol). Multilevel mixed-effect models were used for analyses, with changes in rod intercept time at 3 years as the primary outcome. As some eyes (n = 11) reached the DA testing ceiling value at baseline, we used 3-year changes in area under the DA curve as an additional outcome. RESULTS: Baseline AMD, AMD stage, and hyperreflective foci on optical coherence tomography were associated with larger changes in rod intercept time at 3 years. When change in area under the DA curve was used as an outcome, in addition to these features, the presence of retinal atrophy and drusenoid pigment epithelial detachment had significant associations. New subretinal drusenoid deposits at 3 years were also associated with more pronounced changes in rod intercept time and area under the DA curve. CONCLUSION: Specific optical coherence tomography features are associated with DA impairments over time, which supports that structural changes predict functional loss over 3 years.

Quantification of Key Retinal Features in Early and Late Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: We sought to develop and validate a deep learning model for segmentation of 13 features associated with neovascular and atrophic age-related macular degeneration (AMD). DESIGN: Development and validation of a deep-learning model for feature segmentation. METHODS: Data for model development were obtained from 307 optical coherence tomography volumes. Eight experienced graders manually delineated all abnormalities in 2712 B-scans. A deep neural network was trained with these data to perform voxel-level segmentation of the 13 most common abnormalities (features). For evaluation, 112 B-scans from 112 patients with a diagnosis of neovascular AMD were annotated by 4 independent observers. The main outcome measures were Dice score, intraclass correlation coefficient, and free-response receiver operating characteristic curve. RESULTS: On 11 of 13 features, the model obtained a mean Dice score of 0.63 ± 0.15, compared with 0.61 ± 0.17 for the observers. The mean intraclass correlation coefficient for the model was 0.66 ± 0.22, compared with 0.62 ± 0.21 for the observers. Two features were not evaluated quantitatively because of a lack of data. Free-response receiver operating characteristic analysis demonstrated that the model scored similar or higher sensitivity per false positives compared with the observers. CONCLUSIONS: The quality of the automatic segmentation matches that of experienced graders for most features, exceeding human performance for some features. The quantified parameters provided by the model can be used in the current clinical routine and open possibilities for further research into treatment response outside clinical trials.

Visual Function in Eyes with Intermediate AMD with and without Retinal Pigment Abnormalities.

SIGNIFICANCE: In intermediate AMD, a simple, clinically feasible vision test of sensitivity to radial deformation is significantly more impaired in eyes with hyperpigmentation than in eyes with large drusen but normal retinal pigmentation, consistent with the former's increased risk of progression to advanced AMD. This ongoing longitudinal study will determine whether this vision measure is predictive of progression to advanced AMD. PURPOSE: This study aimed to determine whether simple, clinically feasible psychophysical measures distinguish between two levels of intermediate AMD that differ in their risk of progression to advanced AMD: eyes with large macular drusen and retinal pigment abnormalities versus eyes with large macular drusen without pigment abnormalities. Abnormal pigmentation in the presence of large drusen is associated with a higher risk of development of advanced AMD. METHODS: Each eye of 39 individuals with the same form of intermediate AMD in both eyes was tested monocularly on a battery of vision tests. The measures (photopic optotype contrast sensitivity, discrimination of desaturated colors, and sensitivity to radial deformation [shape discrimination hyperacuity]) were compared for both dominant and nondominant eyes. ANOVA with eye (dominant or nondominant) as a within-subject factor and retinal status (pigmentary abnormalities present or absent from the macula) as a between-subject factor was used to determine statistical significance. RESULTS: Sensitivity to radial deformation was significantly reduced in eyes with large drusen and pigment changes compared with eyes with large drusen and normal retinal pigmentation (-0.40 ± 0.04 vs. -0.61 ± 0.02, respectively; F = 13.31, P = .001). CONCLUSIONS: In the presence of large macular drusen, performance on a shape discrimination task is related to the presence versus absence of abnormal retinal pigmentation, being poorer in the higher-risk group, supportive of the measure's potential to predict progression to advanced AMD.

TOPOGRAPHIC ASSESSMENT OF CHORIOCAPILLARIS FLOW DEFICITS IN THE INTERMEDIATE AGE-RELATED MACULAR DEGENERATION EYES WITH HYPOREFLECTIVE CORES INSIDE DRUSEN.

PURPOSE: To evaluate the choriocapillaris (CC) flow deficit (FD) in eyes with hyporeflective cores (HCs) inside drusen in eyes with intermediate age-related macular degeneration. METHODS: Intermediate age-related macular degeneration subjects underwent optical coherence tomography and optical coherence tomography angiography using a Cirrus HD-optical coherence tomography (Carl Zeiss Meditec, Dublin, CA). All B-scans were inspected for the presence of drusen with an HC that was defined as dark, condense materials inside drusen. Drusen regions delineated in the manufactures advanced retinal pigment epithelium elevation map were superimposed to the compensated CC optical coherence tomography angiography images. Quantitative analysis of CC FD% was performed under drusen with and without HCs, 150-µm-wide ring region around drusen with and without HCs, drusen-free region, and whole macula. RESULTS: Fifty eyes were included in this cross-sectional study. Twenty eyes had drusen with HCs. Thirty eyes without HCs were matched for age and sex. The CC FD% of whole macula was significantly greater in eyes with an HC than those without it (46.3% vs. 42.9%; P = 0.001). In eyes with HCs, regional CC FD% was the greater under drusen (59.8%) and in a 150-µm-wide ring surrounding drusen with HCs (53.0%) than corresponding regions for drusen without HCs (52.5% and 47.3%, respectively) (P < 0.005 in all, Bonferroni correction). The CC FD% in macular regions remote from drusen was 43.2%. CONCLUSION: Intermediate age-related macular degeneration eyes with HCs demonstrated more impaired CC flow, compared with those without this featured. The CC was also more severely impaired directly below these drusen with HCs. These findings highlight that the appearance of HCs may be an indicator of a more advanced disease phenotype.

Subthreshold laser treatment for reticular pseudodrusen secondary to age-related macular degeneration.

There is a lack of treatment aimed at the regression of reticular pseudodrusen (RPD) secondary to age-related macular degeneration (AMD). The aim of this prospective, pilot study is to evaluate the safety and short-term efficacy of subthreshold laser treatment (SLT) in patients affected by RPD secondary to dry AMD (dAMD). Twenty eyes of 20 patients (mean age 78.4 ± 6.8 years) with RPD secondary to dAMD were prospectively enrolled. All patients were treated in an extrafoveal area of 1.27 mm2 using end-point management yellow subthreshold laser and followed for 3 months. Best-corrected visual acuity was 0.140 ± 0.09 LogMAR at the baseline and no changes were observed during the follow-up (p = 0.232). No significant worsening was disclosed before and after the treatment analyzing the macular sensitivity of the treated area (p = 0.152). No topical and/or systemic side effects were disclosed during the 3-month follow-up. The distribution among the RPD stages changed after the treatment (p < 0.001). In detail, in the treated area, we observed a significant increase in the number of Stage 1 RPD during the follow-up (p = 0.002), associated with a significant decrease of Stage 3 RPD (p = 0.020). Outer nuclear layer (ONL) thickness analysis showed a significant increase after the treatment associated with RPD regression (p = 0.001). End-point management SLT appears a safe treatment for RPD secondary to dAMD, showing short-term safety outcomes. Our results suggest that SLT could be effective in inducing a RPD regression in terms of RPD stage and ONL thickening.

Longitudinal Analysis of Structural and Functional Changes in Presence of Reticular Pseudodrusen Associated With Age-Related Macular Degeneration.

Purpose: To examine longitudinal changes of retinal thickness and retinal sensitivity in patients with intermediate age-related macular degeneration (iAMD) and predominantly reticular pseudodrusen (RPD). Methods: At baseline 30 eyes of 25 iAMD patients underwent optical coherence tomography imaging, mesopic and scotopic fundus-controlled perimetry (FCP) with follow-up examinations at month 12 (20 eyes), 24 (12 eyes), and 36 (11 eyes). Thicknesses of different retinal layers and results of FCP testing (n = 56 stimuli) were spatially and longitudinally analyzed using linear mixed-effects models. Results: At baseline, the thickness of the partial outer retinal layer (pORL, 70.21 vs. 77.47 µm) and both mesopic (16.60 vs. 18.72 dB) and scotopic (12.14 vs. 18.67 dB) retinal sensitivity were decreased in areas with RPD compared with unremarkable areas (P < 0.001). Over three years, mean change of pORL was -0.66 normative standard deviation (SD; i.e., z-score, P < 0.001) for regions with existing RPD, -0.40 SD (P < 0.001) for regions with new occurring RPD, and -0.17 SD (P = 0.041) in unremarkable regions. Decrease of scotopic and mesopic sensitivity over three years was more pronounced in areas with existing (-3.51 and -7.76 dB) and new occurring RPD (-2.06 and -5.97 dB). Structure-function analysis revealed that 1 SD decrease of pORL thickness was associated with a sensitivity reduction of 3.47 dB in scotopic and 0.79 dB in mesopic testing. Conclusions: This study demonstrates progressive outer retinal degeneration and impairment of photoreceptor function in eyes with iAMD and RPD over three years. Preservation of outer retinal thickness and reduction of RPD formation may constitute meaningful surrogate endpoints in interventional trials on eyes with AMD and RPD aiming to slow outer retinal degeneration.

Validation of a Compensation Strategy Used to Detect Choriocapillaris Flow Deficits Under Drusen With Swept Source OCT Angiography.

PURPOSE: A compensation strategy that was developed to measure the choriocapillaris (CC) flow deficits (FDs) under drusen was tested in eyes with large drusen from age-related macular degeneration (AMD) before and after the drusen spontaneously resolved without evidence of disease progression. DESIGN: Prospective, observational consecutive case series. METHODS: Patients with AMD were enrolled in a prospective swept-source optical coherence tomography (SS-OCT) imaging study. Consecutive eyes with large drusen were followed, and eyes that underwent spontaneous collapse of drusen without evidence of disease progression were identified retrospectively. The drusen-resolved regions were manually outlined. CC FDs were measured using a previously published compensation strategy that adjusted for the decreased signal intensity underlying drusen. Both the percentage of FDs (FD%) and the mean FD sizes (MFDSs) were measured before and after drusen resolution. RESULTS: Resolution of drusen was identified in 8 eyes from 8 patients. The average interval between the 2 visits was 7.8 months. The average drusen volumes measured between visits were 0.23 and 0.04 mm3, respectively. After the drusen resolved, the average follow-up time without evidence of disease progression was 10.1 months. When the 2 visits were compared, there were no statistically significant differences in any of the CC parameters within the drusen resolved regions once the compensation strategy was applied (all P values >.22). CONCLUSIONS: In this naturally occurring experiment in which drusen collapsed without evidence of disease progression, the CC parameters were similar once our compensation strategy was applied both before and after the drusen resolved.

Association of Visual Function Measures with Drusen Volume in Early Stages of Age-Related Macular Degeneration.

Purpose: To assess which visual function measures are most strongly associated with overall retinal drusen volume in age-related macular degeneration (AMD). Methods: A total of 100 eyes (16 eyes with early AMD, 62 eyes with intermediate AMD, and 22 eyes from healthy controls) were recruited in this cross-sectional study. All subjects underwent several functional assessments: best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), visual acuity (VA) measured with the Moorfields Acuity Chart (MAC-VA), contrast sensitivity with the Pelli-Robson test, reading speed using the International Reading Speed texts, and mesopic and dark-adapted microperimetry. Drusen volume was automatically determined based on optical coherence tomography using an approach based on convolutional neural networks. The relationship between drusen volume and visual function was assessed with linear regressions controlling for confounders. Results: Mean drusen volume and MAC-VA differed significantly among all AMD stages and controls (P < 0.001). In univariate linear regression, LLVA, MAC-VA, contrast sensitivity, and mesopic and dark-adapted microperimetry were significantly negatively associated with the overall drusen volume (all P < 0.006). After controlling for AMD stage, age, and the presence of subretinal drusenoid deposits, MAC-VA and mesopic and dark-adapted microperimetry were still significantly associated with drusen volume (P = 0.008, P = 0.023, and P = 0.022, respectively). Conclusions: Our results suggest that MAC-VA, as well as mesopic and dark-adapted microperimetry, might indicate structural changes related to drusen volume in early stages of AMD.

Quantification of Choriocapillaris with Phansalkar Local Thresholding: Pitfalls to Avoid.

PURPOSE: To demonstrate the proper use of the Phansalkar local thresholding method (Phansalkar method) in choriocapillaris (CC) quantification with optical coherence tomography angiography (OCTA). DESIGN: Retrospective, observational case series. METHODS: Swept source OCTA imaging was performed using 3×3 mm and 6×6 mm scanning patterns. The CC slab was extracted after semiautomatic segmentation of the retinal pigment epithelium/Bruch membrane complex. Retinal projection artifacts were removed before further analysis, and CC OCTA images from drusen eyes were compensated using a previously published strategy. CC flow deficits (FDs) were segmented with 2 previously published algorithms: the fuzzy C-means approach (FCM method) and the Phansalkar method. With the Phansalkar method, different parameters were tested and a local window radius of 1 to 15 pixels was used. FD density, mean FD size, and FD number were calculated for comparison. RESULTS: Six normal eyes from 6 subjects and 6 eyes with drusen secondary to age-related macular degeneration from 6 subjects were analyzed. With both 3×3 mm and 6×6 mm scans from all eyes, the FD metrics were highly dependent on the selection of the local window radius when using the Phansalkar method. Larger window radii resulted in higher FD density values. FD number increased with the increase in the window radius but then decreased, with an inflection point at about 1 to 2 intercapillary distances. Mean FD size decreased then increased with increasing window radii. CONCLUSIONS: Multiple parameters, especially the local window radius, should be optimized before using the Phansalkar method for the quantification of CC FDs with OCTA imaging. It is recommended that the proper use of the Phansalkar method should include the selection of the window radius that is related to the expected intercapillary distance in normal eyes.

FEATURES OF THE MACULAR AND PERIPAPILLARY CHOROID AND CHORIOCAPILLARIS IN EYES WITH NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: We investigated macular and peripapillary choroidal thickness (CT) and flow voids in the choriocapillaris in eyes with nonexudative age-related macular degeneration. METHODS: We retrospectively reviewed the medical records of patients with nonexudative age-related macular degeneration and classified their eyes into three categories: pachydrusen, drusen, and subretinal drusenoid deposit. Mean macular and peripapillary CT and choriocapillaris flow void area were compared among the three groups. RESULTS: The three groups included 29, 33, and 33 patients, respectively. The mean macular and peripapillary CT findings were 260.64 ± 75.85 µm and 134.47 ± 46.28 µm for the pachydrusen group; 163.63 ± 64.08 µm and 93.47 ± 39.07 µm for the drusen group; and 95.33 ± 28.87 µm and 56.06 ± 11.64 µm for the subretinal drusenoid deposit group (all, P < 0.001). Mean macular and peripapillary flow void area varied among the subretinal drusenoid deposit group (57.07 ± 6.16% and 55.38 ± 6.65%), drusen group (58.30 ± 6.98% and 49.11 ± 9.11%) and pachydrusen group (50.09 ± 5.77% and 45.47 ± 8.06%) (all P < 0.001). CONCLUSION: The peripapillary CT and flow voids in the choriocapillaris varied according to the features of drusen in nonexudative age-related macular degeneration eyes. Greater flow voids and thinner CT in eyes with subretinal drusenoid deposits may suggest that these eyes have diffuse choroidal abnormalities both in and outside the macula.

Quantification of Choriocapillaris with Optical Coherence Tomography Angiography: A Comparison Study.

PURPOSE: To demonstrate the variation in quantitative choriocapillaris (CC) metrics with various binarization approaches using optical coherence tomography angiography (OCTA). DESIGN: Retrospective, observational, cross-sectional case series. METHODS: Macular OCTA scans, 3- × 3-mm and 6- × 6-mm, were obtained from normal eyes and from eyes with drusen secondary to age-related macular degeneration (AMD). The CC slab was extracted, and the CC flow deficits (FDs) were segmented with 2 previously published algorithms: the fuzzy C-means approach (FCM method) and Phansalkar's local thresholding (Phansalkar method). Four different values for the radius were used in order to investigate the effect on the FD segmentation when using the Phansalkar method. FD density (FDD), mean FD size (MFDS), FD number (FDN), FD area (FDA) and intercapillary distance (ICD) were calculated for comparison. Repeatability was assessed as coefficient of variation (CV), and Pearson's correlation analysis was conducted. RESULTS: Six eyes from 6 subjects with normal eyes and 6 eyes from 6 subjects with drusen secondary to AMD were scanned. The 3- × 3-mm scans resulted in higher repeatability than the 6- × 6-mm scans. For the Phansalkar method, larger values of the radius resulted in higher repeatability. ANOVA tests resulted in significant differences (P < 0.001) among the FCM method and the Phansalkar method with different radius options for all CC metrics and scan sizes investigated. In 3- × 3-mm scans, significant correlation was found between the FCM method and the Phansalkar method for all quantitative CC metrics other than FDN (all P < 0.001; 0.90 < r <0.99). CONCLUSIONS: Quantitative CC analysis with commercially available OCTA is complicated and researchers need to pay close attention to how they conduct such analyses.

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.

Longitudinal Assessment of Rod Function in Intermediate Age-Related Macular Degeneration With and Without Reticular Pseudodrusen.

Purpose: To evaluate rod function longitudinally in intermediate age-related macular degeneration subjects with reticular pseudodrusen (RPD) and without RPD (AMD). Methods: Retinal sensitivities (505 and 625 nm) during dark adaptation, at 14 locations within the central 12° macula were obtained after photobleaching at baseline and 12-month visits. Pointwise sensitivity differences between both stimuli were used to assess static rod function, while rod intercept time (RIT) and rod recovery rate (RRR) were used to evaluate dynamic function. Changes in function over time were compared between groups. Results: A total of 23 controls, 12 AMD, and 13 RPD cases were followed-up. At baseline, the RPD group had significantly worst static and dynamic rod function compared to AMD and control groups. Static function in AMD was similar to controls. Static and dynamic function across the central 12° was consistent in controls; however, it was most impaired at 4° compared to 12° eccentricity in disease groups. Over 12 months, no AMD cases progressed clinically and static function in AMD improved (P ≤ 0.04), but remained unchanged in control and RPD groups (P ≥ 0.17). The RRR for control and RPD groups remained stable, while the AMD group deteriorated, but only at 12° (P = 0.02). The RIT was stable in AMD (P = 0.75) and RPD (P = 0.71) groups but improved in the control group (P = 0.002). Conclusions: A decrease in RRR was detected over 12 months at 12° eccentricity in the AMD group. Evaluating changes in rod function requires testing at multiple locations including the peripheral macula.

Subthreshold Nanosecond Laser Intervention in Age-Related Macular Degeneration: The LEAD Randomized Controlled Clinical Trial.

PURPOSE: There is an urgent need for a more effective intervention to slow or prevent progression of age-related macular degeneration (AMD) from its early stages to vision-threatening late complications. Subthreshold nanosecond laser (SNL) treatment has shown promise in preclinical studies and a pilot study in intermediate AMD (iAMD) as a potential treatment. We aimed to evaluate the safety of SNL treatment in iAMD and its efficacy for slowing progression to late AMD. DESIGN: The Laser Intervention in Early Stages of Age-Related Macular Degeneration (LEAD) study is a 36-month, multicenter, randomized, sham-controlled trial. PARTICIPANTS: Two hundred ninety-two participants with bilateral large drusen and without OCT signs of atrophy. METHODS: Participants were assigned randomly to receive Retinal Rejuvenation Therapy (2RT®; Ellex Pty Ltd, Adelaide, Australia) SNL or sham treatment to the study eye at 6-monthly intervals. MAIN OUTCOME MEASURES: The primary efficacy outcome was the time to development of late AMD defined by multimodal imaging (MMI). Safety was assessed by adverse events. RESULTS: Overall, progression to late AMD was not slowed significantly with SNL treatment compared with sham treatment (adjusted hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.33-1.14; P = 0.122). However, a post hoc analysis showed evidence of effect modification based on the coexistence of reticular pseudodrusen (RPD; adjusted interaction P = 0.002), where progression was slowed for the 222 participants (76.0%) without coexistent RPD at baseline (adjusted HR, 0.23; 95% CI, 0.09-0.59; P = 0.002), whereas an increased progression rate (adjusted HR, 2.56; 95% CI, 0.80-8.18; P = 0.112) was observed for the 70 participants (24.0%) with RPD with SNL treatment. Differences between the groups in serious adverse events were not significant. CONCLUSIONS: In participants with iAMD without MMI-detected signs of late AMD, no significant difference in the overall progression rate to late AMD between those receiving SNL and sham treatment were observed. However, SNL treatment may have a role in slowing progression for those without coexistent RPD and may be inappropriate in those with RPD, warranting caution when considering treatment in clinical phenotypes with RPD. Our findings provide compelling evidence for further trials of the 2RT® laser, but they should not be extrapolated to other short-pulse lasers.