Prevalence and determinants of subretinal drusenoid deposits in patients' first-degree relatives.

PURPOSE: Subretinal drusenoid deposits (SDDs) are distinct extracellular alteration anterior to the retinal pigment epithelium (RPE). Given their commonly uniform phenotype, a hereditary predisposition seems likely. Hence, we aim to investigate prevalence and determinants in patients' first-degree relatives. METHODS: We recruited SDD outpatients at their visits to our clinic and invited their relatives. We performed a full ophthalmic examination including spectral domain-optical coherence tomography (SD-OCT) and graded presence, disease stage of SDD as well as percentage of infrared (IR) en face area affected by SDD. Moreover, we performed genetic sequencing and calculated a polygenic risk score (PRS) for AMD. We conducted multivariable regression models to assess potential determinants of SDD and associations of SDD with PRS. RESULTS: We included 195 participants, 123 patients (mean age 81.4 ± 7.2 years) and 72 relatives (mean age 52.2 ± 14.2 years), of which 7 presented SDD, resulting in a prevalence of 9.7%. We found older age to be associated with SDD presence and area in the total cohort and a borderline association of higher body mass index (BMI) with SDD presence in the relatives. Individuals with SDD tended to have a higher PRS, which, however, was not statistically significant in the multivariable regression. CONCLUSION: Our study indicates a potential hereditary aspect of SDD and confirms the strong association with age. Based on our results, relatives of SDD patients ought to be closely monitored for retinal alterations, particularly at an older age. Further longitudinal studies with larger sample size and older relatives are needed to confirm or refute our findings.

Retest variability and patient reliability indices of quantitative fundus autofluorescence in age-related macular degeneration: a MACUSTAR study report.

This study aimed to determine the retest variability of quantitative fundus autofluorescence (QAF) in patients with and without age-related macular degeneration (AMD) and evaluate the predictive value of patient reliability indices on retest reliability. A total of 132 eyes from 68 patients were examined, including healthy individuals and those with various stages of AMD. Duplicate QAF imaging was conducted at baseline and 2 weeks later across six study sites. Intraclass correlation (ICC) analysis was used to evaluate the consistency of imaging, and mean opinion scores (MOS) of image quality were generated by two researchers. The contribution of MOS and other factors to retest variation was assessed using mixed-effect linear models. Additionally, a Random Forest Regressor was trained to evaluate the extent to which manual image grading of image quality could be replaced by automated assessment (inferred MOS). The results showed that ICC values were high for all QAF images, with slightly lower values in AMD-affected eyes. The average inter-day ICC was found to be 0.77 for QAF segments within the QAF8 ring and 0.74 for peripheral segments. Image quality was predicted with a mean absolute error of 0.27 on a 5-point scale, and of all evaluated reliability indices, MOS/inferred MOS proved most important. The findings suggest that QAF allows for reliable testing of autofluorescence levels at the posterior pole in patients with AMD in a multicenter, multioperator setting. Patient reliability indices could serve as eligibility criteria for clinical trials, helping identify patients with adequate retest reliability.

Quantitative Fundus Autofluorescence in Systemic Chloroquine/Hydroxychloroquine Therapy: One Year Follow-Up.

Purpose: Systemic chloroquine/hydroxychloroquine (CQ/HCQ) can cause severe ocular side effects including bull's eye maculopathy (BEM). Recently, we reported higher quantitative autofluorescence (QAF) levels in patients with CQ/HCQ intake. Here, QAF in patients taking CQ/HCQ in a 1-year follow-up is reported. Methods: Fifty-eight patients currently or previously treated with CQ/HCQ (cumulative doses 94-2435 g) and 32 age- and sex-matched healthy subjects underwent multimodal retinal imaging (infrared, red free, fundus autofluorescence [FAF], QAF [488 nm], and spectral-domain optical coherence tomography (SD-OCT). For analysis, custom written FIJI plugins were used for image processing, multimodal image stacks assembling, and QAF calculation. Results: Thirty patients (28 without BEM and 2 with BEM, age range = 25-69 years) were followed up (370 ± 63 days). QAF values in patients taking CQ/HCQ showed a significant increase between baseline and follow-up examination: 282.0 ± 67.9 to 297.7 ± 70.0 (QAF a.u.), P = 0.002. An increase up to 10% was observed in the superior macular hemisphere. Eight individuals (including 1 patient with BEM) had a pronounced QAF increase of up to 25%. Compared to healthy controls, QAF levels in patients taking CQ/HCQ were significantly increased (P = 0.04). Conclusions: Our study confirms our previous finding of increased QAF in patients taking CQ/HCQ with a further significant QAF increase from baseline to follow-up. Whether pronounced QAF increase might predispose for rapid progression toward structural changes and BEM development is currently investigated in ongoing studies. Translational Relevance: In addition to standard screening tools during systemic CQ/HCQ treatment, QAF imaging might be useful in CQ/HCQ monitoring and could serve as a screening tool in the future.

Interreader Agreement and Longitudinal Progression of Incomplete/Complete Retinal Pigment Epithelium and Outer Retinal Atrophy in Age-Related Macular Degeneration.

OBJECTIVE: To analyze the ability to evaluate changes over time of individual lesions of incomplete or complete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA and cRORA, respectively) in patients with intermediate age-related macular degeneration (iAMD). DESIGN: OCT images from patients enrolled in Proxima B clinical trial (NCT02399072) were utilized. PARTICIPANTS: Patients enrolled in the Proxima B clinical trial, from the cohort with geographic atrophy (GA) in 1 eye and iAMD in the other eye at baseline, were included. METHODS: Junior and senior readers analyzed OCT images for the qualitative presence of 9 distinct early atrophic features (presence of zone of choroidal hypertransmission, attenuation and/or disruption of RPE, disruption of ellipsoid zone [EZ] and external limiting membrane [ELM], outer nuclear layer [ONL] thinning, outer plexiform layer [OPL]/inner nuclear layer [INL] subsidence, and hyporeflective wedge-shaped band). If deemed "present," 7 features were quantified with a predefined tolerance level of 50 µm (diameter for the zone of choroidal hypertransmission, zone of attenuation and/or disruption of the RPE, outer retinal thickness left/right vertical diameter, outer retinal thickness thinnest vertical diameter, annotation of EZ, and ELM disruption). MAIN OUTCOME MEASURES: Interreader agreements for qualitative assessments (κ-type statistics) and quantitative measurements (Bland-Altman statistics) were assessed. Progression of the lesion features over time was described. RESULTS: Moderate agreement was found for presence of choroidal hypertransmission (κ = 0.54), followed by ELM disruption (κ = 0.58), OPL/INL subsidence (κ = 0.46), and a hyporeflective wedge-shaped band (κ = 0.47). Quantification measurements showed that choroidal hypertransmission had the highest agreement, whereas RPE attenuation/disruption had the lowest agreement. Longitudinal adjudicated changes for quantitative measurements of lesion progression showed that choroidal hypertransmission and ELM disruption showed significant progression, whereas EZ disruption and RPE attenuation/disruption did not. CONCLUSIONS: The ability to evaluate changes over time for specific features of iRORA and cRORA was explored. The most robust biomarker was found to be choroidal hypertransmission, followed by ELM disruption and the qualitative markers of OPL/INL subsidence, as well as a wedge-shaped band. Disease progression over time could be assessed by some, but not all, spectral-domain OCT features that were explored. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Reticular Pseudodrusen: Interreader Agreement of Evaluation on OCT Imaging in Age-Related Macular Degeneration.

Purpose: To determine the interreader agreement for reticular pseudodrusen (RPD) assessment on combined infrared reflectance (IR) and OCT imaging in the early stages of age-related macular degeneration across a range of different criteria to define their presence. Design: Interreader agreement study. Participants: Twelve readers from 6 reading centers. Methods: All readers evaluated 100 eyes from individuals with bilateral large drusen for the following: (1) the presence of RPD across a range of different criteria and (2) the number of Stage 2 or 3 RPD lesions (from 0 to ≥ 5 lesions) on an entire OCT volume scan and on a selected OCT B-scan. Supportive information was available from the corresponding IR image. Main Outcome Measures: Interreader agreement, as assessed by Gwet's first-order agreement coefficient (AC1). Results: When evaluating an entire OCT volume scan, there was substantial interreader agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions, and ≥ 5 definite lesions on en face IR images corresponding to Stage 2 or 3 lesions (AC1 = 0.60-0.72). On selected OCT B-scans, there was also moderate-to-substantial agreement for the presence of any RPD, any or ≥ 5 Stage 2 or 3 lesions (AC1 = 0.58-0.65) and increasing levels of agreement with increasing RPD stage (AC1 = 0.08, 0.56, 0.78, and 0.99 for the presence of any Stage 1, 2, 3, and 4 lesions, respectively). There was substantial agreement regarding the number of Stage 2 or 3 lesions on an entire OCT volume scan (AC1 = 0.68), but only fair agreement for this evaluation on selected B-scans (AC1 = 0.30). Conclusions: There was generally substantial or near-substantial-but not near-perfect-agreement for assessing the presence of RPD on entire OCT volume scans or selected B-scans across a range of differing RPD criteria. These findings underscore how interreader variability would likely contribute to the variability of findings related to the clinical associations of RPD. The low levels of agreement for assessing RPD number on OCT B-scans underscore the likely challenges of quantifying RPD extent with manual grading. Financial Disclosures: Proprietary or commercial disclosure may be found after the references.

Reliability of Retinal Layer Annotation with a Novel, High-Resolution Optical Coherence Tomography Device: A Comparative Study.

Optical coherence tomography (OCT) enables in vivo diagnostics of individual retinal layers in the living human eye. However, improved imaging resolution could aid diagnosis and monitoring of retinal diseases and identify potential new imaging biomarkers. The investigational high-resolution OCT platform (High-Res OCT; 853 nm central wavelength, 3 µm axial-resolution) has an improved axial resolution by shifting the central wavelength and increasing the light source bandwidth compared to a conventional OCT device (880 nm central wavelength, 7 µm axial-resolution). To assess the possible benefit of a higher resolution, we compared the retest reliability of retinal layer annotation from conventional and High-Res OCT, evaluated the use of High-Res OCT in patients with age-related macular degeneration (AMD), and assessed differences of both devices on subjective image quality. Thirty eyes of 30 patients with early/intermediate AMD (iAMD; mean age 75 ± 8 years) and 30 eyes of 30 age-similar subjects without macular changes (62 ± 17 years) underwent identical OCT imaging on both devices. Inter- and intra-reader reliability were analyzed for manual retinal layer annotation using EyeLab. Central OCT B-scans were graded for image quality by two graders and a mean-opinion-score (MOS) was formed and evaluated. Inter- and intra-reader reliability were higher for High-Res OCT (greatest benefit for inter-reader reliability: ganglion cell layer; for intra-reader reliability: retinal nerve fiber layer). High-Res OCT was significantly associated with an improved MOS (MOS 9/8, Z-value = 5.4, p < 0.01) mainly due to improved subjective resolution (9/7, Z-Value 6.2, p < 0.01). The retinal pigment epithelium drusen complex showed a trend towards improved retest reliability in High-Res OCT in iAMD eyes but without statistical significance. Improved axial resolution of the High-Res OCT benefits retest reliability of retinal layer annotation and improves perceived image quality and resolution. Automated image analysis algorithms could also benefit from the increased image resolution.

Hyper-Reflective Foci in Intermediate Age-Related Macular Degeneration: Spatial Abundance and Impact on Retinal Morphology.

Purpose: The purpose of this study was to analyze spatially resolved structural changes at retinal locations in presence (+) or absence (-) of hyper-reflective foci (HRF) in eyes with subretinal pigment epithelium (RPE) drusen in intermediate age-related macular degeneration (iAMD). Methods: Patients with IAMD (n = 40; mean age = 69.7 ± 9.2 [SD] years) and healthy controls (n = 27; 64.2 ± 9.0) underwent spectral-domain optical-coherence-tomography imaging and fundus-controlled perimetry testing. After reviewing retinal layer segmentation, presence of HRF was annotated and retinal layer thicknesses (RLTs) extracted using ImageJ. Localized RLTs were compared between +HRF and -HRF positions. Univariate mixed linear models were used to investigate associations among RLT, HRF presence, and HRF size. Results: In iAMD eyes, a mean of 11.1 ± 12.5 HRF were detected with a peak abundance at 0.5 to 1.5 mm eccentricity to the fovea. At +HRF positions, outer nuclear layer (ONL; P = 0.0013, average difference = -12.4 µm) and retinal pigment epithelium drusen complex (RPEDC; P < 0.0001, +45.6 µm) thicknesses differed significantly compared to -HRF positions, even after correcting for accompanying drusen-related RPEDC layer thickening (P = 0.01). Mixed linear models revealed a significant association between increasing HRF area and decreasing ONL (association score = -0.17, P < 0.0001; 95% confidence interval [CI] = -0.22 to -0.11), and inner photoreceptor segments (IS) layer thicknesses (-0.08, P = 0.005; 95% CI = -0.14 to -0.03). Spearman rank correlation analysis yielded a significant correlation between total HRF area and mesopic (P = 0.015), but not scotopic (P = 0.305) retinal sensitivity losses. Conclusions: Descriptive analysis of this study demonstrated a predominant distribution of HRF at a foveal eccentricity of 0.5 to 1.5 mm, whereas further refined topographic analysis revealed a significant ONL layer thinning in presence of HRF even after correction for sub-RPE drusen presence compared to lesions in absence of HRF. Longitudinal studies are further needed to analyze the prognostic impact as well as the role of HRF presence in the context of iAMD.

Characteristics and Spatial Distribution of Structural Features in Age-Related Macular Degeneration: A MACUSTAR Study Report.

PURPOSE: To report the prevalence and topographic distribution of structural characteristics in study participants with age-related macular degeneration (AMD) and controls in the cross-sectional study part of the MACUSTAR study (ClinicalTrials.gov Identifier: NCT03349801). DESIGN: European, multicenter cohort study. SUBJECTS: Overall, 301 eyes of 301 subjects with early (n = 34), intermediate (n = 168), and late AMD (n = 43), as well as eyes without any AMD features (n = 56). METHODS: In study eyes with intermediate AMD (iAMD), the presence of structural AMD biomarkers, including pigmentary abnormalities (PAs), pigment epithelium detachment (PED), refractile deposits, reticular pseudodrusen (RPD), hyperreflective foci (HRF), incomplete/complete retinal pigment epithelium (RPE), and outer retinal atrophy (i/cRORA), and quiescent choroidal neovascularization (qCNV) was systematically determined in the prospectively acquired multimodal retinal imaging cross-sectional data set of MACUSTAR. Retinal layer thicknesses and the RPE drusen complex (RPEDC) volume were determined for the total study cohort in spectral-domain (SD) OCT imaging using a deep-learning-based algorithm. MAIN OUTCOME MEASURES: Prevalence and topographic distribution of structural iAMD features. RESULTS: A total of 301 study eyes of 301 subjects with a mean (± standard deviation) age of 71.2 ± 7.20 years (63.1% women) were included. Besides large drusen, the most prevalent structural feature in iAMD study eyes were PA (57.1%), followed by HRF (51.8%) and RPD (22.0%). Pigment epithelium detachment lesions were observed in 4.8%, vitelliform lesions in 4.2%, refractile deposits in 3.0%, and qCNV in 2.4%. Direct precursor lesions for manifest retinal atrophy were detected in 10.7% (iRORA) and 4.2% (cRORA) in iAMD eyes. Overall, the highest RPEDC volume with a median of 98.92 × 10-4 mm³ was found in iAMD study eyes. Spatial analysis demonstrated a predominant distribution of RPD in the superior and temporal subfields at a foveal eccentricity of 1.5 to 2 mm, whereas HRF and large drusen had a distinct topographic distribution involving the foveal center. CONCLUSIONS: Detailed knowledge of the prevalence and distribution of structural iAMD biomarkers is vital to identify reliable outcome measure for disease progression. Longitudinal analyses are needed to evaluate their prognostic value for conversion to advanced disease stages. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Comparability of automated drusen volume measurements in age-related macular degeneration: a MACUSTAR study report.

Drusen are hallmarks of early and intermediate age-related macular degeneration (AMD) but their quantification remains a challenge. We compared automated drusen volume measurements between different OCT devices. We included 380 eyes from 200 individuals with bilateral intermediate (iAMD, n = 126), early (eAMD, n = 25) or no AMD (n = 49) from the MACUSTAR study. We assessed OCT scans from Cirrus (200 × 200 macular cube, 6 × 6 mm; Zeiss Meditec, CA) and Spectralis (20° × 20°, 25 B-scans; 30° × 25°, 241 B-scans; Heidelberg Engineering, Germany) devices. Sensitivity and specificity for drusen detection and differences between modalities were assessed with intra-class correlation coefficients (ICCs) and mean difference in a 5 mm diameter fovea-centered circle. Specificity was > 90% in the three modalities. In eAMD, we observed highest sensitivity in the denser Spectralis scan (68.1). The two different Spectralis modalities showed a significantly higher agreement in quantifying drusen volume in iAMD (ICC 0.993 [0.991-0.994]) than the dense Spectralis with Cirrus scan (ICC 0.807 [0.757-0.847]). Formulae for drusen volume conversion in iAMD between the two devices are provided. Automated drusen volume measures are not interchangeable between devices and softwares and need to be interpreted with the used imaging devices and software in mind. Accounting for systematic difference between methods increases comparability and conversion formulae are provided. Less dense scans did not affect drusen volume measurements in iAMD but decreased sensitivity for medium drusen in eAMD.Trial registration: ClinicalTrials.gov NCT03349801. Registered on 22 November 2017.

Relative ellipsoid zone reflectivity and its association with disease severity in age-related macular degeneration: a MACUSTAR study report.

Quantification of the relative ellipsoid zone reflectivity (rEZR) might be a structural surrogate parameter for an early disease progression in the context of age-related macular degeneration (AMD). Within the European multicenter, cross-sectional MACUSTAR study, we have devised an automatic approach to determine the mean rEZR [arbitrary units, AU] at two independent visits in SD-OCT volume scans in study participants. Linear mixed-effects models were applied to analyze the association of AMD stage and AMD associated high-risk features including presence of pigmentary abnormalities, reticular pseudodrusen (RPD), volume of the retinal-pigment-epithelial-drusenoid-complex (RPEDC) with the rEZR. Intra-class correlation coefficients (ICC) were determined for rEZR reliability analysis. Within the overall study cohort (301 participants), we could observe decreased rEZR values (coefficient estimate ± standard error) of - 8.05 ± 2.44 AU (p = 0.0011) in the intermediate and of - 22.35 ± 3.28 AU (p < 0.0001) in the late AMD group. RPD presence was significantly associated with the rEZR in iAMD eyes (- 6.49 ± 3.14 AU; p = 0.0403), while there was a good ICC of 0.846 (95% confidence interval: 0.809; 0.876) in the overall study cohort. This study showed an association of rEZR with increasing disease severity and the presence of iAMD high-risk features. Further studies are necessary to evaluate the rEZR's value as a novel biomarker for AMD and disease progression.

Histologic Cell Shape Descriptors for the Retinal Pigment Epithelium in Age-Related Macular Degeneration: A Comparison to Unaffected Eyes.

Purpose: Phenotype alterations of the retinal pigment epithelium (RPE) are a main characteristic of age-related macular degeneration (AMD). Individual RPE cell shape descriptors may help to delineate healthy from AMD-affected cells in early disease stages. Methods: Twenty-two human RPE flatmounts (7 eyes with AMD [early, 3; geographic atrophy, 1; neovascular, 3); 15 unaffected eyes [8 aged ≤51 years; 7 aged >80 years)] were imaged at the fovea, perifovea, and near periphery (predefined sample locations) using a laser-scanning confocal fluorescence microscope. RPE cell boundaries were manually marked with computer assistance. For each cell, 11 shape descriptors were calculated and correlated with donor age, cell autofluorescence (AF) intensity, and retinal location. Statistical analysis was performed using an ensemble classifier based on logistic regression. Results: In AMD, RPE was altered at all locations (most pronounced at the fovea), with area, solidity, and form factor being the most discriminatory descriptors. In the unaffected macula, aging had no significant effect on cell shape factors; however, with increasing distance to the fovea, area, solidity, and convexity increased while form factor decreased. Reduced AF in AMD was significantly associated with decreased roundness and solidity. Conclusions: AMD results in an altered RPE with enlarged and deformed cells that could precede clinically visible lesions and thus serve as early biomarkers for AMD onset. Our data may also help guide the interpretation of RPE morphology in in vivo studies utilizing high-resolution single-cell imaging. Translational Relevance: Our histologic RPE cell shape data have the ability to identify robust biomarkers for the early detection of AMD-affected cells, which also could serve as a basis for automated segmentation of RPE sheets.

Intersession Repeatability of Structural Biomarkers in Early and Intermediate Age-Related Macular Degeneration: A MACUSTAR Study Report.

Purpose: To analyze the intersession repeatability of structural biomarkers in eyes with early and intermediate age-related macular degeneration (iAMD) within the cross-sectional part of the observational multicenter MACUSTAR study. Methods: Certified site personnel obtained multimodal imaging data at two visits (38 ± 20 [mean ± standard deviation] days apart), including spectral-domain optical coherence tomography (SD-OCT). One junior reader performed systematic and blinded grading at the central reading center, followed by senior reader review. Structural biomarkers included maximum drusen size classification (>63 to ≤125 µm vs. >125 µm), presence of large pigment epithelium detachments (PEDs), reticular pseudodrusen (RPD), vitelliform lesions, and refractile deposits. Intrasession variability was assessed using Cohen's κ statistics. Results: At the first visit, 202 study eyes of 202 participants were graded as manifesting with either early (n = 34) or intermediate (n = 168) AMD. Grading of imaging data between visits revealed perfect agreement for the maximum drusen size classification (κ = 0.817; 95% confidence interval, 0.70-0.94). In iAMD eyes, perfect to substantial agreement was determined for the presence of large PEDs (0.87; 0.69-1.00) and RPD (0.752; 0.63-0.87), while intersession agreement was lower for the presence of vitelliform lesions (0.649; 0.39-0.65) and refractile deposits (0.342; -0.029-0.713), respectively. Conclusions: Multimodal retinal imaging analysis between sessions showed a higher repeatability for structural biomarkers with predefined cutoff values than purely qualitative defined parameters. Translational Relevance: A high repeatability of retinal imaging biomarkers will be important to implement automatic grading approaches and to establish robust and meaningful structural clinical endpoints for future interventional clinical trials in patients with iAMD.

[Histological changes in keratoconus and wound healing after corneal cross-linking]. / Histologische Veränderungen beim Keratokonus und Wundheilung nach kornealem Crosslinking.

BACKGROUND: Keratoconus is classified as a corneal ectasia and is a multifactorial disease. In those affected, mostly adolescent patients visual deterioration occurs due to the development of irregular astigmatism. Treatment by corneal cross-linking (CXL) has been indicated in progressive disease for several years. OBJECTIVE: To present the pathophysiology and histological changes in keratoconus as well as wound healing processes after CXL and their potential complications. MATERIAL AND METHODS: Histological changes in keratoconus as well as wound healing processes after CXL and their potential complications are presented based on histological examination of corneal specimens with keratoconus with and without a condition after CXL. Relevant literature and own data are analyzed and discussed. RESULTS: Besides inflammatory processes, atopic and genetic dispositions play a role in the development of keratoconus. The histological characteristics of keratoconus include changes in the epithelium, Bowman's layer and stroma. Wound healing processes after CXL include healing of the surface epithelium and transient loss of keratocytes and nerve fibers. CONCLUSION: Keratoconus shows characteristic histopathological changes, such as epithelial irregularities, stromal thinning and breaks of Bowman's layer, whereas the endothelium and Descemet's membrane remain unchanged (apart from cases of corneal hydrops). After CXL wound healing processes can be followed primarily in vivo by confocal microscopy. Complications after CXL are rare. Persistent loss of keratocytes can be clinically manifested as a visually relevant scar.

Short-term real-world outcomes following intravitreal brolucizumab for neovascular AMD: SHIFT study.

BACKGROUND: Brolucizumab has recently been approved in Europe as a novel treatment for patients with neovascular age-related macular degeneration (nAMD). We report on early experiences with real-world outcomes of switch to brolucizumab therapy in previously anti-vascular endothelial growth factor (anti-VEGF)-treated patients. METHODS: Patients with recalcitrant nAMD were switched to brolucizumab therapy. Functional and structural parameters 4 weeks after first brolucizumab injection were evaluated including best-corrected visual acuity (BCVA (logMAR)), foveal centre point (FCP (µm)), central subfield retinal thickness (CSRT (µm)) and macular volume (mm³). RESULTS: Sixty-three eyes of 57 patients with nAMD (52.6% females) with a mean (±SD) age of 79.5±6.7 years were included. Mean change of BCVA was 0.03±0.14 logMAR (p=0.115). Significant reductions were recorded for FCP with a mean (±SD) change of -66.81±72.63 µm, -66.76±60.71 µm for CSRT and -0.27±0.24 mm³ for macular volume (all p<0.001). Intraocular inflammation was observed in seven eyes of seven patients, including one case of retinal vasculitis. CONCLUSIONS: The results of the SHIFT study indicate that switch to brolucizumab may represent a treatment option in patients with nAMD poorly responsive to other anti-VEGF agents. Further long-term analyses appear prudent to assess efficacy and safety of brolucizumab in a routine clinical setting.

OCT Signs of Early Atrophy in Age-Related Macular Degeneration: Interreader Agreement: Classification of Atrophy Meetings Report 6.

PURPOSE: To determine the interreader agreement for incomplete retinal pigment epithelium (RPE) and outer retinal atrophy (iRORA) and complete RPE and outer retinal atrophy (cRORA) and their related features in age-related macular degeneration (AMD). DESIGN: Interreader agreement study. PARTICIPANTS: Twelve readers from 6 reading centers. METHODS: After formal training, readers qualitatively assessed 60 OCT B-scans from 60 eyes with AMD for 9 individual features associated with early atrophy and performed 7 different annotations to quantify the spatial extent of OCT features within regions of interest. The qualitative and quantitative features were used to derive the presence of iRORA and cRORA and also in an exploratory analysis to examine if agreement could be improved using different combinations of features to define OCT atrophy. MAIN OUTCOME MEASURES: Interreader agreement based on Gwet's first-order agreement coefficient (AC1) for qualitatively graded OCT features and classification of iRORA and cRORA, and smallest real difference (SRD) for quantitatively graded OCT features. RESULTS: Substantial or better interreader agreement was observed for all qualitatively graded OCT features associated with atrophy (AC1 = 0.63-0.87), except for RPE attenuation (AC1 = 0.46) and disruption (AC1 = 0.26). The lowest SRD for the quantitatively graded horizontal features was observed for the zone of choroidal hypertransmission (± 190.8 µm). Moderate agreement was found for a 3-category classification of no atrophy, iRORA, and cRORA (AC1 = 0.53). Exploratory analyses suggested a significantly higher level of agreement for a 3-category classification using (1) no atrophy; (2) presence of inner nuclear layer and outer plexiform layer subsidence, or a hyporeflective wedge-shaped band, as a less severe atrophic grade; and (3) the latter plus an additional requirement of choroidal hypertransmission of 250 µm or more for a more severe atrophic grade (AC1 = 0.68; P = 0.013). CONCLUSIONS: Assessment of iRORA and cRORA, and most of their associated features, can be performed relatively consistently and robustly. A refined combination of features to define early atrophy could further improve interreader agreement.