Development of a Genotype Assay for Age-Related Macular Degeneration: The EYE-RISK Consortium.

PURPOSE: To develop a genotype assay to assess associations with common and rare age-related macular degeneration (AMD) risk variants, to calculate an overall genetic risk score (GRS), and to identify potential misdiagnoses with inherited macular dystrophies that mimic AMD. DESIGN: Case-control study. PARTICIPANTS: Individuals (n = 4740) from 5 European cohorts. METHODS: We designed single-molecule molecular inversion probes for target selection and used next generation sequencing to sequence 87 single nucleotide polymorphisms (SNPs), coding and splice-site regions of 10 AMD-(related) genes (ARMS2, C3, C9, CD46, CFB, CFH, CFI, HTRA1, TIMP3, and SLC16A8), and 3 genes that cause inherited macular dystrophies (ABCA4, CTNNA1, and PRPH2). Genetic risk scores for common AMD risk variants were calculated based on effect size and genotype of 52 AMD-associated variants. Frequency of rare variants was compared between late AMD patients and control individuals with logistic regression analysis. MAIN OUTCOME MEASURES: Genetic risk score, association of genetic variants with AMD, and genotype-phenotype correlations. RESULTS: We observed high concordance rates between our platform and other genotyping platforms for the 69 successfully genotyped SNPs (>96%) and for the rare variants (>99%). We observed a higher GRS for patients with late AMD compared with patients with early/intermediate AMD (P < 0.001) and individuals without AMD (P < 0.001). A higher proportion of pathogenic variants in the CFH (odds ratio [OR] = 2.88; P = 0.006), CFI (OR = 4.45; P = 0.005), and C3 (OR = 6.56; P = 0.0003) genes was observed in late AMD patients compared with control individuals. In 9 patients, we identified pathogenic variants in the PRPH2, ABCA4, and CTNNA1 genes, which allowed reclassification of these patients as having inherited macular dystrophy. CONCLUSIONS: This study reports a genotype assay for common and rare AMD genetic variants, which can identify individuals at intermediate to high genetic risk of late AMD and enables differential diagnosis of AMD-mimicking dystrophies. Our study supports sequencing of CFH, CFI, and C3 genes because they harbor rare high-risk variants. Carriers of these variants could be amendable for new treatments for AMD that currently are under development.

Twelve-month results of ab interno trabeculectomy with Kahook Dual Blade: an interventional, randomized, controlled clinical study.

PURPOSE: To evaluate the efficacy and safety profile of Kahook Dual Blade ab interno trabeculectomy combined with phacoemulsification compared to stand-alone conventional cataract surgery. METHODS: A single-center longitudinal, randomized controlled trial was conducted. Patients older than 18 years with coexisting cataract and open-angle glaucoma or ocular hypertension were invited to participate. Preoperative and postoperative clinical data were collected and analyzed preoperatively and at months 1, 3, 6, and 12 after the procedure. Main outcome measures included best corrected visual acuity, intraocular pressure, number of glaucoma medications, endothelial cell count, and standard automated perimetry. RESULTS: Forty-two eyes from 33 patients were randomly allocated to the combined cataract and KDB (treatment, n = 21) or cataract alone (control, n = 21) groups. Intraocular pressure decreased from 17.9 ± 3.5 to 16.0 ± 2.2 mmHg and from 17.3 ± 2.5 to 15 ± 3.2 mmHg at the last visit in the treatment and control groups (p = 0.47). The use of glaucoma medications was reduced from a median (IQR) 1 (1-2) to 0 (0-0) in the treatment group and from 1 (1-2) to 0 (0-1) in the control group, with no significant differences between groups at the 12-month visit (p = 0.47). Best corrected visual acuity, endothelial cell count, and standard automated perimetry remained similar during follow-up in both groups. CONCLUSIONS: In patients with well-controlled, mild-to-moderate glaucoma, adding ab interno trabeculectomy with KDB to phacoemulsification might not be more effective than phacoemulsification alone to reach mid-teens IOP values. Both procedures showed similar safety profiles. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04202562, December 17, 2019 retrospectively registered.

Transplantation of Human Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium in a Swine Model of Geographic Atrophy.

BACKGROUND: The aim of this study was to test the feasibility and safety of subretinal transplantation of human induced pluripotent stem cell (hiPSC)-derived retinal pigment epithelium (RPE) cells into the healthy margins and within areas of degenerative retina in a swine model of geographic atrophy (GA). METHODS: Well-delimited selective outer retinal damage was induced by subretinal injection of NaIO3 into one eye in minipigs (n = 10). Thirty days later, a suspension of hiPSC-derived RPE cells expressing green fluorescent protein was injected into the subretinal space, into the healthy margins, and within areas of degenerative retina. In vivo follow-up was performed by multimodal imaging. Post-mortem retinas were analyzed by immunohistochemistry and histology. RESULTS: In vitro differentiated hiPSC-RPE cells showed a typical epithelial morphology, expressed RPE-related genes, and had phagocytic ability. Engrafted hiPSC-RPE cells were detected in 60% of the eyes, forming mature epithelium in healthy retina extending towards the border of the atrophy. Histological analysis revealed RPE interaction with host photoreceptors in the healthy retina. Engrafted cells in the atrophic zone were found in a patchy distribution but failed to form an epithelial-like layer. CONCLUSIONS: These results might support the use of hiPSC-RPE cells to treat atrophic GA by providing a housekeeping function to aid the overwhelmed remnant RPE, which might improve its survival and therefore slow down the progression of GA.

Regression to the Mean in Measurements of Growth Rates in Geographic Atrophy.

INTRODUCTION: Comparison of patients with extremely high and low values of a given characteristic is a common strategy to gain insights into disease mechanisms, but this approach is particularly susceptible to regression to the mean (RTM). OBJECTIVE: The aim of this work was to determine RTM in growth rate measurements in patients with geographic atrophy (GA) secondary to age-related macular degeneration. METHODS: We conducted a retrospective analysis of the GAIN (NCT01694095) and its extension study, in which individuals 50 years or older with pure GA were followed for a minimum of 6 months. Two repeated and masked measurements of area of atrophy, both at baseline and final visits, were made, and growth rates were calculated for each. RTM was determined graphically and statistically, and the percentage of eyes misclassified as having fast and slow progression rates due to RTM was determined for different definitions of "fast" and "slow" growth. RESULTS: We included 112 eyes of 112 patients: 64.3% were females, the mean age was 78.1 (SD ±7.6) years, and the mean follow-up time was 3.2 (±2.2) years. There was RTM, which decreased when the mean of two measurements was used. The magnitude of RTM in growth rates ranged from 2 to 11 µm/year and led to misclassification of eyes considered to have fast and slow growth between 2.9 and 10.3% of the cases, depending on the definition of fast and slow growth. CONCLUSIONS: RTM was present in measurements of GA growth rate, but it had a modest impact on patient misclassification. Comparison of features between patients with extreme growth rates is a reasonable strategy, but RTM should be minimized by taking the mean of two measurements.

Performance characteristics of multicolor versus blue light and infrared imaging in the identification of reticular pseudodrusen.

PURPOSE: To describe the appearance of reticular pseudodrusen on multicolor imaging and to evaluate its diagnostic accuracy as compared with the two modalities that may be considered the current reference standard, blue light and infrared imaging. METHODS: Retrospective study in which all multicolor images (constructed from images acquired at 486 nm-blue, 518 nm-green and 815 nm-infrared) of 45 consecutive patients visited in a single center was reviewed. Inclusion criteria involved the presence of >1 reticular pseudodrusen on a 30° × 30° image centered on the fovea as seen with the blue light channel derived from the multicolor imaging. Three experienced observers, masked to each other's results with other imaging modalities, independently classified the number of reticular pseudodrusen with each modality. RESULTS: The median interobserver agreement (kappa) was 0.58 using blue light; 0.65 using infrared; and 0.64 using multicolor images. Multicolor and infrared modalities identified a higher number of reticular pseudodrusen than blue light modality in all fields for all observers (p < 0.0001). Results were not different when multicolor and infrared were compared (p ≥ 0.27). CONCLUSIONS: These results suggest that multicolor and infrared are more sensitive and reproducible than blue light in the identification of RPD. Multicolor did not appear to add a significant value to infrared in the evaluation of RDP. Clinicians using infrared do not need to incorporate multicolor for the identification and quantification of RPD.

Diagnostic Accuracy of Spectralis SD OCT Automated Macular Layers Segmentation to Discriminate Normal from Early Glaucomatous Eyes.

PURPOSE: To evaluate the accuracy of the macular retinal layer segmentation software of the Spectralis spectral-domain (SD) optical coherence tomography (OCT) device (Heidelberg Engineering, Inc., Heidelberg, Germany) to discriminate between healthy and early glaucoma (EG) eyes. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Forty EG eyes and 40 healthy controls were included. METHODS: All participants were examined using the standard posterior pole and the peripapillary retinal nerve fiber layer (pRNFL) protocols of the Spectralis OCT device. Using an Early Treatment Diagnostic Retinopathy Study circle at the macular level, the automated retinal segmentation software was applied to determine thicknesses of the following parameters: total retinal thickness, inner retinal layer (IRL), macular retinal nerve fiber layer (mRNFL), macular ganglion cell layer (mGCL), macular inner plexiform layer (mIPL), macular inner nuclear layer (mINL), macular outer plexiform layer (mOPL), macular outer nuclear layer (mONL), photoreceptors (PR), and retinal pigmentary epithelium (RPE). The ganglion cell complex (GCC) was determined by adding the mRNFL, mGCL, and mIPL parameters and the ganglion cell layer-inner plexiform layer (mGCL-IPL) was determined by combining the mGCL and mIPL parameters. Thickness of each layer was compared between the groups, and the layer and sector with the best area under the receiver operating characteristic curve (AUC) were identified. MAIN OUTCOME MEASURES: Comparison of pRNFL, IRL, mRNFL, mGCL, mIPL, mGCC, mGCL-IPL, mINL, mOPL, mONL, PR, and RPE parameters and total retinal thicknesses between groups for the different areas and their corresponding AUCs. RESULTS: Peripapillary RNFL was significantly thinner in the EG group globally and in all 6 sectors assessed (P < 0.0005). For the macular variables, retinal thickness was significantly reduced in the EG group for total retinal thickness, mIRL, mRNFL, mGCL, and mIPL. The 2 best isolated parameters to discriminate between the 2 groups were pRNFL (AUC, 0.956) and mRNFL (AUC, 0.906). When mRNFL, mGCL, and mIPL measurements were combined (mGCC and mGCL plus mIPL), then its diagnostic performance improved (AUC, 0.940 and 0.952, respectively). CONCLUSIONS: Macular RNFL, mGCL-IPL, and mGCC measurements showed a high diagnostic capability to discriminate between healthy and EG participants. However, macular intraretinal measurements still have not overcome standard pRNFL parameters.

Optical Coherence Tomography in Inherited Macular Dystrophies: A Review.

Macular dystrophies (MDs) constitute a collection of hereditary retina disorders leading to notable visual impairment, primarily due to progressive macular atrophy. These conditions are distinguished by bilateral and relatively symmetrical abnormalities in the macula that significantly impair central visual function. Recent strides in fundus imaging, especially optical coherence tomography (OCT), have enhanced our comprehension and diagnostic capabilities for MD. OCT enables the identification of neurosensory retinal disorganization patterns and the extent of damage to retinal pigment epithelium (RPE) and photoreceptor cells in the dystrophies before visible macular pathology appears on fundus examinations. It not only helps us in diagnostic retinal and choroidal pathologies but also guides us in monitoring the progression of, staging of, and response to treatment. In this review, we summarize the key findings on OCT in some of the most common MD.

Changes in vessel density patterns assessed with OCTA in patients with diabetic macular edema treated with anti-VEGF therapy.

AIMS: To determine the presence of sectoral changes in vessel density (VD) patterns induced by vascular endothelial growth factor inhibitors (anti-VEGF) in patients with diabetic macular edema (DME) using optical coherence tomography angiography (OCTA). METHODS: Prospective, interventional study. A total of 43 patients (63 eyes) were initially enrolled in the study. We performed swept source (SS) OCT and sectorial OCTA measurement to determine parafoveal VD at baseline and after six months of anti-VEGF treatment. In the locations with statistically significant differences in VD between baseline and month 6, we performed univariate and multivariate analyses to determine which, if any, of the baseline variables were associated with the observed changes. RESULTS: A total of 34 patients (48 eyes) were included in the final analysis. Mean VD decreased from baseline to month 6 (from 45.2 (± 3.5) to 44.6 (± 3.2) % in the SCP and from 50 (± 3.3) to 49 (± 3.9) % in the DCP). The only significant changes in VD were observed in the nasal sector of the deep capillary plexus, with a decrease of 2.9% (p = 0.001). On univariate and multivariate analyses, the only variable significantly associated with changes in VD in the nasal sector after 6 months of treatment was baseline VD in the same sector. CONCLUSIONS: Anti-VEGF therapy has a small impact on VD values over time. These variations observed after treatment seems to be related to changes over areas of vascular anomalies and displaced vessels adjacent to cystic areas, with no significant changes over ischemic areas. No correlation was observed between this trend and other clinical baseline features.

Classifying glaucoma exclusively with OCT: comparison of three clustering algorithms derived from machine learning.

BACKGROUND/AIMS: To objectively classify eyes as either healthy or glaucoma based exclusively on data provided by peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform (GCIPL) measurements derived from spectral-domain optical coherence tomography (SD-OCT) using machine learning algorithms. METHODS: Three clustering methods (k-means, hierarchical cluster analysis -HCA- and model-based clustering-MBC-) were used separately to classify a training sample of 109 eyes as either healthy or glaucomatous using solely 13 SD-OCT parameters: pRNFL average and sector thicknesses and GCIPL average and minimum values together with the six macular wedge-shaped regions. Then, the best-performing algorithm was applied to an independent test sample of 102 eyes to derive close estimates of its actual performance (external validation). RESULTS: In the training sample, accuracy was 91.7% for MBC, 81.7% for k-means and 78.9% for HCA (p value = 0.02). The best MBC model was that in which subgroups were allowed to have variable volume and shape and equal orientation. The MBC algorithm in the independent test sample correctly classified 98 out of 102 cases for an overall accuracy of 96.1% (95% CI, 92.3-99.8%), with a sensitivity of 94.3 and 100% specificity. The accuracy for pRNFL was 92.2% (95% CI, 86.9-97.4%) and for GCIPL 98.0% (95% CI, 95.3-100%). CONCLUSIONS: Clustering algorithms in general (and MBC in particular) seem promising methods to help discriminate between healthy and glaucomatous eyes using exclusively SD-OCT-derived parameters. Understanding the relative merits of one method over others may also provide insights into the nature of the disease.

Optical coherence tomography assessment of apparent foveal swelling in patients with foveal sparing secondary to geographic atrophy.

OBJECTIVE: To determine whether foveal swelling exists in patients with foveal sparing and geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD) and to establish the contribution of different foveal layers to this condition by use of spectral-domain optical coherence tomography (SD-OCT). DESIGN: Prospective comparative case series. PARTICIPANTS: We assessed patients from a longitudinal study with foveal sparing and GA secondary to AMD. Of an initial sample of 108 patients, 13 eyes of 10 patients complied with the inclusion criteria to study eyes in which apparent swelling would not be questionable. We used a control group of 13 healthy patients to compare the outcome measurements. METHODS: We acquired high-resolution SD-OCT horizontal and oblique B-scans centered at the umbo. Two retinal specialists (J.M., F.T.) independently classified the SD-OCT images. MAIN OUTCOME MEASURES: Difference in foveal center thickness, apparent outer nuclear layer (ONL) thickness, ONL thickness without Henle's fiber layer (HFL), sub-ONL thickness, and retinal thickness at 1000 µm and 3500 µm from the foveal center. RESULTS: The thickness at the foveal center was similar between patients with apparent foveal swelling (cases) and controls without AMD (226 vs. 227 µm; P = 0.56), but the apparent ONL was thicker in cases than in controls (125 vs. 114 µm; P = 0.02). However, when HFL was excluded from the measurements, there was little difference in the results (74 vs. 73 µm; P = 0.82). CONCLUSIONS: We found neither foveal nor ONL swelling in this study. We observed HFL thickening in foveal sparing secondary to GA, which might be related to swelling of the axons of the photoreceptors, or Müller's cells. We also observed thinning of the retina below the external limiting membrane. The clinical significance of these findings should be addressed by longitudinal studies and may have specific therapeutic implications.

Methodological Appraisal of Phase 3 Clinical Trials in Geographic Atrophy.

Geographic atrophy (GA) secondary to age-related macular degeneration is a common cause of blindness worldwide. Given the recent approval of the first therapy for GA, pegcetacoplan, we critically appraise methodological aspects of the phase 3 clinical trials published so far in this disease in relation to their design, analysis and interpretation. We reviewed some of the key attributes of all phase 3 clinical trials in GA available in the main public registry of clinical trials as of 20 May 2023. The topics discussed included types of endpoints, eligibility criteria, p-value and effect size, study power and sample size, the intention to treat principle, missing data, consistency of results, efficacy-safety balance and application of results. Five phase 3 clinical trials have reported results, either partially or completely: GATHER1, DERBY/OAKS, CHROMA/SPECTRI, SEATTLE and GATE. Although there are many similarities between these trials in terms of endpoints or broad eligibility criteria, they differ in several aspects (metric of the primary endpoint, sample size, type of adverse events, etc.) that can influence the results, which are discussed. Readers should understand key methodological aspects of clinical trials to improve their interpretation. On the other hand, authors should adhere to clinical trial reporting guidelines to communicate what was done and how it was done.

Correlation between Topographic Vessel Density and Retinal Thickness Changes in Patients with Diabetic Macular Edema Treated with Anti-VEGF Therapy: Is It a Suitable OCTA Biomarker?

The objective of this study was to determine the correlation between topographic vessel density (VD) and retinal thickness (RT) reductions induced by vascular endothelial growth factor inhibitors (anti-VEGF) in patients with diabetic macular edema (DME) using optical coherence tomography angiography (OCTA). This was a prospective, interventional case series. VD and RT measurements were separately taken in four parafoveal subfields at baseline and after six months of treatment. This correlation was statistically assessed using Spearman's rho correlation coefficient after adjustment for multiple comparisons. The study included a total of 48 eyes in the final analysis. Mean VD decreased from baseline to month 6 (from 45.2 (±3.5) to 44.6% (±3.2) in the superficial capillary plexus and from 50 (±3.3) to 49% (±3.9) in the deep capillary plexus). Statistically significant reductions in RT were observed in all ETDRS sectors (p < 0.0001). No significant association was found between RT and VD, even when analyzing responders and non-responders separately. After six months of anti-VEGF treatment, no significant correlation was observed between the topographic VD and RT values. These findings suggest that reductions in VD values may not solely result from a reduction in microaneurysms, also being affected by the repositioning of displaced vessels due to edema and a reduction in their caliber. Therefore, VD changes may not be a suitable indirect OCTA biomarker of microaneurysm turnover and treatment response.

Hyporeflective wedge-shaped band in geographic atrophy secondary to age-related macular degeneration: an underreported finding.

OBJECTIVE: To describe and interpret the frequently observed spectral-domain optical coherence tomography (SD-OCT) finding of a marked hyporeflective wedge-shaped structure at the boundaries of the areas of atrophy. DESIGN: A prospective, longitudinal follow-up study. PARTICIPANTS: Consecutive patients (n = 71) 50 years of age and older with geographic atrophy (GA) secondary to age-related macular degeneration (AMD) were examined between January 2010 and June 2011. METHODS: Patients were evaluated with the use of imaging techniques that included 35° fundus photography, infrared, fundus autofluorescence (FAF), and SD-OCT. Visualization of the fundus with FAF was done simultaneously with OCT. Two acquisition protocols were followed: a macular cube for coverage (19 horizontal B-scans centered on the fovea) and high-resolution horizontal B-scan for qualitative foveal detail. MAIN OUTCOMES MEASURES: Estimation of the prevalence of a hyporeflective wedge-shaped band among patients with GA. RESULTS: A marked hyporeflective wedge-shaped structure, with its base on Bruch's membrane and its apex pointing toward the inner limit of the outer plexiform layer (OPL) adjacent to the margin between the atrophied area and the preserved retina, was observed in 72.9% of eyes (70/96; 95% confidence interval, 63.9-82.0). This hyporeflective band appeared to be within the OPL. Using eccentric SD-OCT acquisition, the boundaries between the outer nuclear layer (ONL) and Henle's fiber layer (HFL) were well defined, showing that the ONL ends before the margin of atrophy of the retinal pigment epithelium (RPE). A narrow hyperreflective band separated the margin of the ONL and RPE from the hyporeflective band, already within the atrophic area. CONCLUSIONS: A hyporeflective wedge-shaped structure appears frequently within the boundaries of the OPL in patients with GA secondary to AMD, corresponding to an increase in the width of the HFL, presumably because of axonal swelling or interaxonal edema. This finding may improve the interpretation of SD-OCT images of the outer layers, may help in understanding better the interactions between photoreceptor cells and the RPE, and may help in the development of monitoring techniques and therapies for GA secondary to AMD.

FUSION regimen: ranibizumab in treatment-naïve patients with exudative age-related macular degeneration and relatively good baseline visual acuity.

BACKGROUND: To investigate the safety and efficacy of a combined fixed-interval and pro re nata regimen of ranibizumab (FUSION regimen) for treatment of exudative age-related macular degeneration in patients with good visual acuity at baseline. To establish whether similar efficacy to monthly regimens can be achieved with fewer injections, even in patients with good visual acuity. METHODS: This was a prospective, open-label, consecutive interventional case series in treatment-naïve patients with exudative age-related macular degeneration. The FUSION regimen consists of three phases: 1) a loading phase of two or three injections, depending on presence or absence of choroidal neovascularization activity at first follow-up, 2) administration of one injection on disappearance of exudation, and 3) subsequent administration of two separate injections at intervals 2 months apart, and then an injection every 3 months. Endpoints included visual acuity, presence of fluid, adverse events and number of injections administered. RESULTS: Seventeen eyes of 17 Caucasian patients were included. Mean patient age was 76 years, and 15 patients were female. Mean baseline visual acuity was 67.5 letters (median 67), with Snellen equivalent 20/50++, ranged between 45 (20/125) and 83 (20/20--). At 3 months, mean change in best-corrected visual acuity (BCVA) was +2.3 letters (median +9) compared with baseline (p = 0.3). At 6 months, mean change in BCVA was +4.2 letters (median +9) compared with baseline (p = 0.02). At 12 months, one patient had discontinued the study. Mean change in BCVA was 5.6 (median +10) compared with baseline (p = 0.04). No patient lost ≥15 letters, and 14 patients (87.5%) lost <5 letters. The mean number of injections was 6.9. One patient experienced a retinal pigment epithelium tear; no other complications were observed. CONCLUSIONS: The FUSION regimen for ranibizumab has the potential to maintain visual gains achieved during the loading phase, as reported in studies with monthly injections, even in eyes with a relatively good visual acuity at baseline. These 12-month results warrant validation in a larger, randomized controlled trial.

Intra and interobserver agreement in the classification of fundus autofluorescence patterns in geographic atrophy secondary to age-related macular degeneration.

BACKGROUND: To describe the intra and interobserver agreement in the evaluation of fundus autofluorescence patterns in geographic atrophy secondary to age-related macular degeneration. METHODS: A consecutive series of patients with geographic atrophy and fundus autofluorescence images of a minimum acceptable quality for grading were included. Four observers with experience in the evaluation of autofluorescence images independently classified the randomly presented series of images on two occasions, at least 1 month apart from each other (intraobserver analysis). The second determination of each observer was used for evaluation of interobserver agreement. The kappa statistic and 95% confidence intervals, together with percentages of agreement, were used to analyze the results. RESULTS: The final sample included 69 eyes of 49 patients. Intraobserver agreement ranged from substantial to almost perfect (kappa between 0.51 and 0.83), while interobserver results ranged from poor to substantial (corresponding to kappa between 0.30 and 0.62). The use of more simple classifications improved reproducibility. CONCLUSIONS: Although intraobserver reproducibility was high, interobserver agreement was variable. Clear descriptions and a uniform set of criteria to classify these patients are needed if fundus autofluorescence imaging is used to evaluate patients with geographic atrophy.

Kinetics of Heterogeneous Background in Stargardt's Disease over Time.

Stargardt's disease (STGD1) is caused by mutations in the ABCA4 gene. Different lesions characterised by decreased autofluorescence levels are found in fundus autofluorescence (FAF) from STGD1 patients and could be used as outcome indicators for disease progression. We investigated the fate of foci with reduced autofluorescence (FRA) within the heterogeneous background of STGD1 patients using FAF imaging. Genetically confirmed STGD1 patients presenting heterogeneous background autofluorescence on high-quality FAF images at a minimum of two visits at least 12 months apart were chosen. A grid centred on the fovea was used to define five different zones. Within each zone, five FRA were randomly selected for each eye. The eccentricity of foci was determined at different time points for each patient. Analysis of 175 randomly chosen FRA showed consistent centrifugal displacement over time, most notably in eyes showing areas with definitely decreased autofluorescence. Interestingly, FRA did not leave an area of hypo-autofluorescence on FAF in locations where they were previously located. These findings may help to better understand STGD1 progression, improve FAF interpretation, and shed light on the nature of heterogeneous background.

External Validation and Clinical Applicability of Two Optical Coherence Tomography-Based Risk Calculators for Detecting Glaucoma.

Purpose: To clinically validate the diagnostic ability of two optical coherence tomography (OCT)-based glaucoma diagnostic calculators (GDCs). Methods: We conducted a retrospective, consecutive sampling of 76 patients with primary open-angle glaucoma, 107 glaucoma suspects, and 67 controls. Demographics, reliable visual field testing, and macular and optic disc OCT were collected. The reference diagnosis was compared against the probability of having glaucoma obtained from two GDCs derived from multivariate logistic regressions using quantitative and qualitative (GDC1) or only quantitative (GDC2) OCT data. The discrimination (area under the curve [AUC]) and calibration (calibration plots) were compared for both calculators and the best OCT parameters. Results: GDC2 was able to identify 46.9% more suspects and 14.7% more glaucomatous eyes than GDC1. Both GDCs obtained the highest discriminative ability in glaucomatous eyes (GDC1 AUC = 0.949; GDC2 = 0.943 vs inferior peripapillary retinal nerve fiber layer [pRNFL] = 0.931; P = 0.43). The discriminating ability was not as good for glaucoma suspects, but the GDCs were not inferior to pRNFL (GDC 1 AUC = 0.739; GDC2 = 0.730; inferior pRNFL = 0.760; P = 0.54) and GDC2 was still able to correctly identify up to 30.8% more cases than the conventional OCT classification. Calibration showed risk underestimation for both groups and calculators, but it was better in GDC2 and in patients with glaucoma. Conclusions: OCT-based calculators showed an excellent diagnostic performance in glaucomatous eyes. GDC2 was able to identify approximately 30% more cases than the conventional pRNFL inferior OCT classification in both groups, suggesting a potential role of these composite scores in clinical practice. Translational Relevance: These OCT-based calculators may improve glaucoma diagnosis in clinical care.

Update on geographic atrophy in age-related macular degeneration.

Age-related macular degeneration (AMD) is the main cause of legal blindness in older patients in developed countries, and geographic atrophy (GA) represents the advanced form of dry AMD. Although it accounts for one third of the cases of late AMD and is responsible for 20% of the cases of severe visual loss due to the disorder. GA currently lacks effective treatment, whereas antiangiogenic therapies have been shown to be successful in managing choroidal neovascularization, the other form of late AMD. Recent advances in GA epidemiology, etiology, genetics, and imaging techniques have renewed the interest in this entity, which is a cause of progressive visual loss even in treated patients with neovascular AMD. This knowledge has triggered many clinical trials targeting different molecules shown to be associated with the disease, and it is hoped that this research will translate into effective drugs for GA in the near future.