The influence of the topographic location of geographic atrophy on vision-related quality of life in nonexudative age-related macular degeneration.

PURPOSE: To examine associations between the topographic distribution of geographic atrophy (GA) and vision-related quality of life (VRQoL). METHODS: This study included 237 eyes from 161 participants in the Age-Related Eye Disease Study (AREDS). GA lesions were manually delineated with color fundus photographs obtained by the AREDS Research Group and atrophic area was measured in an Early Treatment Diabetic Retinopathy Study (ETDRS) grid. VRQoL was measured using the National Eye Institute Visual Function Questionnaire (NEI-VFQ). Area of atrophy in the ETDRS grid subfields was correlated with VRQoL by linear regression modeling. RESULTS: The average area of atrophy in the better and worse eye was 3.43mm2 and 7.15mm2 respectively. In multivariable analysis, VRQoL was not associated with total area of atrophy in the better eye (ß, - 0.53; 95% confidence interval [CI], - 1.11 to 0.05; P = 0.07) or worse eye (ß, 0.12; 95% CI, - 0.32 to 0.55; P = 0.59). However, area of atrophy in the central 1-mm-diameter zone of the better eye was significantly associated with VRQoL when the ETDRS subfields were examined individually (ß, - 14.57; 95% CI, - 27.12 to - 2.02; P = 0.023), grouped into quadrants (ß, - 18.35; 95% CI, - 30.03 to - 6.67; P = 0.002), inner and outer zones (ß, - 17.26; 95% CI, - 29.38 to - 5.14; P = 0.006), or vertical and horizontal zones (ß, - 18.97; 95% CI, - 30.18 to - 7.77; P = 0.001). CONCLUSION: In patients with GA, greater area of atrophy in the central 1-mm-diameter zone of the better eye was independently associated with lower VRQoL, while total area of atrophy in the better or worse eye was not.

Central geographic atrophy vs. neovascular age-related macular degeneration: differences in longitudinal vision-related quality of life.

OBJECTIVE: Prior studies of vision-related quality of life (VRQoL) have examined advanced age-related macular degeneration (AMD) as a single group or focused on neovascular AMD (nAMD), even though advanced AMD can refer to either central geographic atrophy (GA) or nAMD. We compared the natural progression of VRQoL in central GA versus nAMD. METHODS: We included Age-Related Eye Disease Study (AREDS) participants with central GA (n = 206) or nAMD (n = 198) who completed the National Eye Institute Visual Function Questionnaire (NEI-VFQ) between 1997 and 2005. The rate of change of VRQoL was calculated as the slopes of linear models fit to longitudinal individual-level NEI-VFQ scores. Multivariable regressions identified factors associated with experiencing a decline in VRQoL during the study period and cross-sectional VRQoL score. RESULTS: There was a minor decline in VRQoL prior to the development of nAMD but a significantly steeper decline after progression to nAMD (0.49 ± 2.91 vs. 3.30 ± 5.58 NEI-VFQ units/year; p < 0.001). The rates of VRQoL decline were similar before and after the development of central GA (1.99 ± 4.97 vs. 1.68 ± 4.65 NEI-VFQ units/year; p = 0.66). Prior to the development of advanced AMD, the rate of VRQoL decline was greater for participants destined to develop central GA versus nAMD (p = 0.007), while postprogression to advanced disease, the rate was greater in nAMD compared with central GA (p = 0.012). Female gender (odds ratio [OR] 2.61, 95% confidence interval [CI] 1.38-5.06; p = 0.003) and higher baseline VRQoL score (OR 1.03, 95% CI 1.01-1.06; p = 0.006) were independently associated with experiencing a longitudinal decline in VRQoL. CONCLUSION: The natural progression of VRQoL differed in central GA versus nAMD, both before and after the development of advanced disease, suggesting that future studies should consider separating these phenotypes. Females and those with a higher baseline VRQoL were more likely to experience a longitudinal decline in VRQoL following progression to advanced AMD.

Geographic atrophy severity and mortality in age-related macular degeneration.

PURPOSE: To examine the association between geographic atrophy (GA) disease characteristics and mortality risk. METHODS: We manually delineated color fundus photographs of 209 Age-Related Eye Disease Study (AREDS) participants with GA secondary to age-related macular degeneration to identify total area of atrophy, GA effective radius growth rate, disease laterality, and the presence of foveal center involvement. Associations between GA characteristics and mortality were assessed with Cox proportional hazards models adjusted for health status indicators. RESULTS: During a median follow-up of 6.8 years, 48 (23.0%) participants with GA died. In adjusted models, accounting for age, sex, and health status, participants with total GA area in the highest quartile had a significantly increased risk of all-cause mortality compared to those with total GA area in the lowest quartile (hazard ratio [HR], 3.42; 95% confidence interval [CI], 1.32-8.86; P = 0.011). GA effective radius growth rate, bilateral disease, and the presence of foveal center involvement were not significantly associated with mortality. In a multivariable model, including health status indicators and all GA characteristics, total area of atrophy in the highest quartile remained significantly associated with mortality (HR, 4.65; 95% CI, 1.29-16.70; P = 0.019). CONCLUSIONS: More extensive GA, as indicated by a greater total area of atrophy, was associated with an increased risk of all-cause mortality in our cohort. The extent of GA may reflect the extent of underlying disease processes that contribute to greater mortality risk, further suggesting that GA may be part of a systemic rather than purely ocular disease process.

Natural History of Autosomal Recessive Stargardt Disease in Untreated Eyes: A Systematic Review and Meta-analysis of Study- and Individual-Level Data.

TOPIC: Systematic review and meta-analysis of the natural history of autosomal recessive Stargardt disease (STGD1). CLINICAL RELEVANCE: Controversy exists regarding the progression pattern of atrophic lesions secondary to STGD1, and the reported growth rates vary widely among studies. METHODS: We searched in 6 literature databases up through March 15, 2019, to identify studies that monitored atrophy progression by fundus autofluorescence in untreated eyes with STGD1 for 6 months or more. We analyzed both study- and individual-level data from the included studies using 3 models: the area linear model (ALM), radius linear model (RLM), and area exponential model (AEM), in which the area, radius, and natural log-transformed area changes linearly with time, respectively. A horizontal translation factor was added to each dataset to correct for different participants' entry times into the studies. The best model was determined by the predicted age of lesion onset and dependence of growth rates on baseline lesion sizes. The risk of bias was assessed using the Newcastle-Ottawa scale. RESULTS: Of 3158 articles screened, 7 studies (564 eyes) met our inclusion criteria. Cumulative study- and individual-level datasets fit along a straight line in the RLM after introducing horizontal translation factors to correct for different entry times (r2 = 0.99 and r2 = 0.93, respectively). The growth rate of effective lesion radius was 0.104 mm/year (95% confidence interval, 0.086-0.123 mm/year). The age of atrophy onset predicted by the RLM (22.7±5.0 years) was comparable to the reported age at onset of symptoms (22.1±3.1 years); in contrast, the predictions by the ALM and AEM deviated from this number by more than 5 years. Based on the individual-level data, the effective radius growth rate was independent of the baseline lesion size (r = 0.06); in comparison, the growth rates of area and natural log-transformed area were significantly dependent on the baseline lesion size (r = 0.47 and r = -0.33, respectively). CONCLUSIONS: The progression of STGD1 lesions followed the RLM in both study- and individual-level data. The effective radius growth rate of atrophic lesions could serve as a reliable outcome measure to monitor STGD1 progression.

RECLASSIFICATION OF FUNDUS AUTOFLUORESCENCE PATTERNS SURROUNDING GEOGRAPHIC ATROPHY BASED ON PROGRESSION RATE: A Systematic Review and Meta-Analysis.

PURPOSE: To reclassify fundus autofluorescence (FAF) patterns around geographic atrophy (GA) based on GA progression rates. METHODS: MEDLINE, EMBASE, Cochrane Library, Clinicaltrials.gov, and PubMed were searched for studies reporting GA progression rates among different FAF patterns, such as "None," "Focal," "Banded," "Patchy," "Diffuse Nontrickling," and "Diffuse Trickling." The GA radius growth rate among different FAF patterns was compared, and a GA growth function for each group was derived. To account for the patients' different entry times, a horizontal translation factor was introduced to shift each data subset from "time after enrollment" to "duration of GA." RESULTS: Seven studies with 496 eyes were included. Based on GA radius growth rates, the six FAF patterns were clustered into four groups with a high correlation coefficient within each group: Group 1, None, 0.061 mm/year (r = 0.996), Group 2, Focal, 0.105 mm/year (r = 0.987), Group 3, Banded, Patchy, and Diffuse Nontrickling, 0.149 mm/year (r = 0.993), and Group 4, "Diffuse Trickling, 0.245 mm/year (r = 0.997). CONCLUSION: This meta-analysis suggested that the six FAF patterns can be coalesced into four groups based on lesion progression rates. Simplification of the reclassified FAF patterns may shed light on the GA natural history and assist in the design of clinical trials.

Geographic Atrophy Natural History Versus Treatment: Time to Fovea.

BACKGROUND AND OBJECTIVE: The Food and Drug Administration recently approved treatments of geographic atrophy (GA). Our study aims to quantify the time for a lesion to reach the central fovea based on reduction of GA growth rates from therapeutics compared to the natural history. PATIENTS AND METHODS: A previously published study calculates local border expansion rate of GA lesions at varying retinal eccentricities. In this study, we use these rates to model GA expansion toward the fovea and the effects of treatments that reduce growth in GA area by 15% to 45% on lesions of varying sizes with posterior margin 250, 500, 750, 1000, 1250, 1500, and 3000 µm from the fovea. RESULTS: Lesions with an area 8 mm2 and posterior edge 500 µm from the fovea will reach the fovea in 5.08 years with no treatment, but the same lesions will reach the fovea in 5.85, 6.52, 7.36, and 8.46 years with a treatment that reduces growth in GA area by 15%, 25%, 35%, and 45%, respectively. CONCLUSIONS: Distance of the posterior edge of the lesion was the primary factor in GA growth toward the fovea, and lesion size only minimally affects growth rates of GA. Based on the efficacy of current and future therapeutics and distance of GA to the fovea, our study provides the marginal time benefit of treatment to guide patients and clinicians, placing both the natural history of GA and the effects of current and future treatments into clinical context. [Ophthalmic Surg Lasers Imaging Retina 2024;55:XX-XX.].

Longitudinal Choroidal Development in Preterm Infants.

Purpose: To characterize changes in subfoveal choroidal thickness in preterm infants from 30 to 60 weeks' postmenstrual age (PMA). Design: The prospective, observational Study of Eye Imaging in Preterm infantS (BabySTEPS) enrolled infants eligible for retinopathy of prematurity screening per the American Association of Pediatrics guidelines. Subjects: Infants imaged with an investigational, handheld OCT at ≥ 4 distinct imaging sessions between 30 to 60 weeks' PMA as part of BabySTEPS. Methods: Average choroidal thickness across the central subfoveal 1 mm in each eye at each time point was measured using custom segmentation software, and errors were manually corrected by a trained grader. We prospectively collected birth history data. A segmented mixed model was used to analyze the change in choroidal thickness as a function of PMA, birth weight, and gestational age (GA). Main Outcome Measures: Characterization of normative subfoveal choroidal thickness values and choroidal growth rate between 30 to 60 weeks' PMA. Results: We included 592 imaging sessions of 79 preterm infants (152 eyes). Mean (± standard deviation) GA was 27.5 ± 2.5 weeks. Mean choroidal thickness was 141.4 ± 34.5 µm at 30 weeks, 272.2 ± 83.9 µm at 38 weeks, and 306.2 ± 77.4 µm between 56 and 60 weeks. Between 30 and 60 weeks' PMA, choroidal growth followed a biphasic model, with a linear growth rate of 14.8 µm per week (95% confidence interval [CI], 13.6-16.0) from 30 until 38.4 weeks, then cessation of growth, with a growth rate of 0.3 µm per week (95% CI, -1.1 to 1.6) from 38.4 to 60 weeks. Infants with extremely low birth weight (ELBW; < 1000 g) and extremely preterm (GA < 28 weeks) infants had significantly slower initial growth rates compared with very low and low birth weight and very preterm and preterm infants (ELBW 13.0 vs. 21.0 µm per week; P < 0.0001 and extremely preterm 13.2 vs. 18.0 µm per week; P = 0.003). Conclusions: Preterm infant choroidal thickness experiences rapid linear growth from 30 to 38 weeks' PMA, at which time growth nearly stops. These foundational measurements and identification of the impact of extremes of low birth weight and prematurity on choroidal development will be essential as researchers begin to understand the role of choroidal development in ocular and retinal health in human infants. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

METformin for the MINimization of Geographic Atrophy Progression (METforMIN): A Randomized Trial.

Purpose: Metformin use has been associated with a decreased risk of age-related macular degeneration (AMD) progression in observational studies. We aimed to evaluate the efficacy of oral metformin for slowing geographic atrophy (GA) progression. Design: Parallel-group, multicenter, randomized phase II clinical trial. Participants: Participants aged ≥ 55 years without diabetes who had GA from atrophic AMD in ≥ 1 eye. Methods: We enrolled participants across 12 clinical centers and randomized participants in a 1:1 ratio to receive oral metformin (2000 mg daily) or observation for 18 months. Fundus autofluorescence imaging was obtained at baseline and every 6 months. Main Outcome Measures: The primary efficacy endpoint was the annualized enlargement rate of the square root-transformed GA area. Secondary endpoints included best-corrected visual acuity (BCVA) and low luminance visual acuity (LLVA) at each visit. Results: Of 66 enrolled participants, 34 (57 eyes) were randomized to the observation group and 32 (53 eyes) were randomized to the treatment group. The median follow-up duration was 13.9 and 12.6 months in the observation and metformin groups, respectively. The mean ± standard error annualized enlargement rate of square root transformed GA area was 0.35 ± 0.04 mm/year in the observation group and 0.42 ± 0.04 mm/year in the treatment group (risk difference = 0.07 mm/year, 95% confidence interval = -0.05 to 0.18 mm/year; P = 0.26). The mean ± standard error decline in BCVA was 4.8 ± 1.7 letters/year in the observation group and 3.4 ± 1.1 letters/year in the treatment group (P = 0.56). The mean ± standard error decline in LLVA was 7.3 ± 2.5 letters/year in the observation group and 0.8 ± 2.2 letters/year in the treatment group (P = 0.06). Fourteen participants in the metformin group experienced nonserious adverse events related to metformin, with gastrointestinal side effects as the most common. No serious adverse events were attributed to metformin. Conclusions: The results of this trial as conducted do not support oral metformin having effects on reducing the progression of GA. Additional placebo-controlled trials are needed to explore the role of metformin for AMD, especially for earlier stages of the disease. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Local progression kinetics of macular atrophy in recessive Stargardt disease.

BACKGROUND: To determine the effect of lesion topography on progression in Stargardt disease (STGD1). METHODS: Fundus autofluoresence (excitation 488 nm) images of 193 eyes in patients with proven ABCA4 mutation were semi-automatically segmented for autofluoresence changes: (DDAF) and questionably decreased autofluoresence (QDAF), which are proxies for retinal pigment epithelial (RPE) atrophy. We calculated topographic incidence of DDAF and DDAF + QDAF, as well as velocity of progression of the border of lesions using Euclidean distance mapping. RESULTS: Incidence of atrophy was highest near the fovea, then decreased in incidence with increased foveal eccentricity. However, the rate of atrophy progression followed the opposite pattern; rate of atrophy increased with distance from foveal center. The mean growth rate 500 microns from the foveal center for DDAF + QDAF was 39 microns per year (95% CI = 28-49), whereas the mean growth rate 3000 microns from the foveal center was 342 microns per year (95% CI = 194-522). No difference in growth rate was noted by axis around the fovea. CONCLUSIONS: Incidence and progression of atrophy by fundus autofluorescence follow opposite patterns in STGD1. Further, atrophy progression increases significantly with distance from foveal center, which should be taken into consideration in clinical trials.

Associations of systemic health and medication use with the enlargement rate of geographic atrophy in age-related macular degeneration.

BACKGROUND: The associations of geographic atrophy (GA) progression with systemic health status and medication use are unclear. METHODS: We manually delineated GA in 318 eyes in the Age-Related Eye Disease Study. We calculated GA perimeter-adjusted growth rate as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye (mean follow-up=5.3 years). Patients' history of systemic health and medications was collected through questionnaires administered at study enrolment. We evaluated the associations between GA perimeter-adjusted growth rate and 27 systemic health factors using univariable and multivariable linear mixed-effects regression models. RESULTS: In the univariable model, GA perimeter-adjusted growth rate was associated with GA in the fellow eye at any visit (p=0.002), hypertension history (p=0.03), cholesterol-lowering medication use (p<0.001), beta-blocker use (p=0.02), diuretic use (p<0.001) and thyroid hormone use (p=0.03). Among the six factors, GA in the fellow eye at any visit (p=0.008), cholesterol-lowering medication use (p=0.002), and diuretic use (p<0.001) were independently associated with higher GA perimeter-adjusted growth rate in the multivariable model. GA perimeter-adjusted growth rate was 51.1% higher in patients with versus without cholesterol-lowering medication use history and was 37.8% higher in patients with versus without diuretic use history. CONCLUSIONS: GA growth rate may be associated with the fellow eye status, cholesterol-lowering medication use, and diuretic use. These possible associations do not infer causal relationships, and future prospective studies are required to investigate the relationships further.

Biphasic change in retinal nerve fibre layer thickness from 30 to 60 weeks postmenstrual age in preterm infants.

BACKGROUND/AIMS: The optic nerve development during the critical postnatal weeks of preterm infants is unclear. We aimed to investigate the change of retinal nerve fibre layer (RNFL) in preterm infants. METHODS: We used an investigational handheld optical coherence tomography (OCT) system to serially image awake preterm infants between 30 and 60 weeks postmenstrual age (PMA) at the bedside. We assessed RNFL thickness in the papillomacular bundle and nasal macular ganglion cell layer+inner plexiform layer (GCL+IPL) thickness. We applied a segmented mixed model to analyse the change in the thickness of RNFL and GCL+IPL as a function of PMA. RESULTS: From 631 OCT imaging sessions of 101 infants (201 eyes), RNFL thickness followed a biphasic model between 30 and 60 weeks, with an estimated transition at 37.8 weeks PMA (95% CI: 37.0 to 38.6). RNFL thickness increased at 1.8 µm/week (95% CI: 1.6 to 2.1) before 37.8 weeks and decreased at -0.3 µm/week (95% CI: -0.5 to -0.2) afterwards. GCL+IPL thickness followed a similar biphasic model, in which the thickness increased at 2.9 µm/week (95% CI: 2.5 to 3.2) before 39.5 weeks PMA (95% CI: 38.8 to 40.1) and then decreased at -0.8 µm/week (95% CI: -0.9 to -0.6). CONCLUSION: We demonstrate the feasibility of monitoring RNFL and GCL+IPL thickness from OCT during the postnatal weeks of preterm infants. Thicknesses follow a biphasic model with a transition age at 37.8 and 39.5 weeks PMA, respectively. These findings may shed light on optic nerve development in preterm infants and assist future study designs.

Associations between systemic health and retinal nerve fibre layer thickness in preterm infants at 36 weeks postmenstrual age.

BACKGROUND/AIMS: Neonatal insults from systemic diseases have been implicated in the pathway of impaired neurodevelopment in preterm infants. We aimed to investigate the associations between systemic health factors and retinal nerve fibre layer (RNFL) thickness in preterm infants. METHODS: We prospectively enrolled infants and imaged both eyes at 36±1 weeks postmenstrual age (PMA) using a hand-held optical coherence tomography system at the bedside in the Duke intensive care nurseries. We evaluated associations between RNFL thickness and 29 systemic health factors using univariable and multivariable regression models. RESULTS: 83 infants with RNFL thickness measures were included in this study. Based on the multivariable model, RNFL thickness was positively associated with infant weight at imaging and was negatively associated with sepsis/necrotising enterocolitis (NEC). RNFL thickness was 10.4 µm (95% CI -15.9 to -4.9) lower in infants with than without sepsis/NEC in the univariable analysis (p<0.001). This difference remained statistically significant after adjustment for confounding variables in various combinations (birth weight, birthweight percentile, gestational age, infant weight at imaging and growth velocity). A 250 g increase in infant weight at imaging was associated with a 3.1 µm (95% CI 2.1 to 4.2) increase in RNFL thickness in the univariable analysis (p<0.001). CONCLUSIONS: Low infant weight and sepsis/NEC were independently associated with thinner RNFL in preterm infants at 36 weeks PMA. To our knowledge, this study is the first to suggest that sepsis/NEC may affect retinal neurodevelopment. Future longitudinal studies are needed to investigate this relationship further.

Subretinal Drusenoid Deposit Formation: Insights From Turing Patterns.

PURPOSE: The purpose of this study was to demonstrate that the organized formation of subretinal drusenoid deposits (SDDs) may be a Turing pattern. METHODS: A Java-based computational model of an inferred reaction-diffusion system using paired partial differential equations was used to create topographic images. Reaction kinetics were varied to illustrate a spectrum of pattern development, which were then compared to dot-like, reticular, and confluent SDD patterns observed clinically. RESULTS: A reaction-diffusion system using two agents, one an "activator" that increases its own production, and the other an "inhibitor" that decreases the activator's production, can create patterns that match the spectrum of topographic appearance of organized SDD. By varying a single parameter, the strength of the activator, the full spectrum of clinically observed SDD patterns can be generated. A new pattern, confluence with holes, is predicted and identified in one case example. CONCLUSIONS: The formation of clinically significant SDD and its different patterns can be explained using Turing patterns obtained by simulating a two-component reaction-diffusion system. TRANSLATIONAL RELEVANCE: This model may be able to guide future risk stratification for patients with SDD, and provide mechanistic insights into the cause of the disease.

A hierarchical Bayesian entry time realignment method to study the long-term natural history of diseases.

A major question in clinical science is how to study the natural course of a chronic disease from inception to end, which is challenging because it is impractical to follow patients over decades. Here, we developed BETR (Bayesian entry time realignment), a hierarchical Bayesian method for investigating the long-term natural history of diseases using data from patients followed over short durations. A simulation study shows that BETR outperforms an existing method that ignores patient-level variation in progression rates. BETR, when combined with a common Bayesian model comparison tool, can identify the correct disease progression function nearly 100% of the time, with high accuracy in estimating the individual disease durations and progression rates. Application of BETR in patients with geographic atrophy, a disease with a known natural history model, shows that it can identify the correct disease progression model. Applying BETR in patients with Huntington's disease demonstrates that the progression of motor symptoms follows a second order function over approximately 20 years.

Natural history of central sparing in geographic atrophy secondary to non-exudative age-related macular degeneration.

BACKGROUND: The macular central 1 mm diameter zone is crucial to patients' visual acuity, but the long-term natural history of central sparing in eyes with geographic atrophy (GA) is unknown. METHODS: We manually segmented GA in 210 eyes with GA involving central 1 mm diameter zone (mean follow-up=3.8 years) in the Age-Related Eye Disease Study. We measured the residual area in central 1 mm diameter zone and calculated central residual effective radius (CRER) as square root of (residual area/π). A linear mixed-effects model was used to model residual size over time. We added a horizontal translation factor to each data set to account for different durations of GA involving the central zone. RESULTS: The decline rate of central residual area was associated with baseline residual area (p=0.008), but a transformation from central residual area to CRER eliminated this relationship (p=0.51). After the introduction of horizontal translation factors to each data set, CRER declined linearly over approximately 13 years (r2=0.80). The growth rate of total GA effective radius was 0.14 mm/year (95% CI 0.12 to 0.15), 3.7-fold higher than the decline rate of CRER (0.038 mm/year, 95% CI 0.034 to 0.042). The decline rate of CRER was 53.3% higher in eyes with than without advanced age-related macular degeneration in the fellow eyes at any visit (p=0.007). CONCLUSIONS: CRER in eyes with GA declined linearly over approximately 13 years and may serve as an anatomic endpoint in future clinical trials aiming to preserve the central zone.

Association Between Retinal Microanatomy in Preterm Infants and 9-Month Visual Acuity.

Importance: Preterm infants are at risk for poor visual acuity (VA) outcomes, even without retinal problems on ophthalmoscopy. Infant retinal microanatomy may provide insight as to potential causes. Objective: To evaluate the association between preterm infant retinal microanatomy and VA at 9 months' corrected age. Design, Setting, and Participants: This prospective observational study took place from November 2016 and December 2019 at a single academic medical center and included preterm infants enrolled in Study of Eye Imaging in Preterm Infants (BabySTEPS). Infants were eligible for enrollment in BabySTEPS if they met criteria for retinopathy of prematurity (ROP) screening, were 35 weeks' postmenstrual age or older at the time of first OCT imaging, and a parent or guardian provided written informed consent. Of 118 infants enrolled in BabySTEPS, 61 were included in this analysis. Data were analyzed from March to April 2021. Exposures: Bedside optical coherence tomography (OCT) imaging at a mean (SD) 39.85 (0.79) weeks' postmenstrual age and monocular grating VA measurement at 9 months' corrected age. Main Outcomes and Measures: Presence and severity of macular edema and presence of ellipsoid zone at the fovea measured by extracting semiautomated thicknesses of inner nuclear layer, inner retina, and total retina at the foveal center; choroid across foveal 1 mm; and retinal nerve fiber layer (RNFL) across the papillomacular bundle (PMB). Pearson correlation coefficients were calculated and 95% CIs were bootstrapped for the association between retinal layer thicknesses and continuous logMAR VA. Associations were analyzed between retinal microanatomy and normal (3.70 cycles/degree or greater) vs subnormal grating VA at 9 months' corrected age using logistic regression and with logMAR VA using linear regression, adjusting for birth weight, gestational age, and ROP severity at the time of OCT imaging and accounting for intereye correlation using generalized estimating equations. Results: The mean (SD; range) gestational age of included infants was 27.6 (2.8; 23.0-34.6) weeks, and mean (SD; range) birth weight was 958.2 (293.7; 480-1580) g. In 122 eyes of 61 infants, the correlations between retinal layer thicknesses and logMAR VA were as follows: r, 0.01 (95% CI, -0.07 to -0.27) for inner nuclear layer; r, 0.19 (95% CI, 0.01 to 0.35) for inner retina; r, 0.15 (95% CI, -0.02 to 0.31) for total retina; r, -0.22 (95% CI, -0.38 to -0.03) for choroid; and r, -0.27 (95% CI, -0.45 to 0.10) for RNFL across the PMB. In multivariable analysis, thinner RNFL across the PMB (regression coefficient, -0.05 per 10-µm increase in RNFL thickness; 95% CI, -0.10 to -0.01; P = .046) and prior ROP treatment (regression coefficient, 0.33 for ROP treatment; 95% CI, 0.11 to 0.56; P = .003) were independently associated with poorer 9-month logMAR VA. Conclusions and Relevance: In preterm infants, RNFL thinning across the PMB was associated with poorer 9-month VA, independent of birth weight, gestational age, need for ROP treatment, and macular microanatomy. Evaluation of RNFL thickness using OCT may help identify preterm infants at risk for poor vision outcomes.

An In Silica Model for RPE Loss Patterns in Choroideremia.

Purpose: To use empirical data to develop a model of cell loss in choroideremia that predicts the known exponential rate of RPE loss and central, scalloped preservation pattern seen in this disease. Methods: A computational model of RPE loss was created in Python 3.7, which constructed an array of RPE cells clusters, binarized as either live or atrophic. Two rules were applied to this model: the background effect gave each cell a chance of dying defined by a background function, and the neighbor effect increased the chance of RPE cell death if a neighbor were dead. The known anatomic distribution of rods, RPE, choriocapillaris density, amacrine, ganglion, and cone cells were derived from the literature and applied to this model. Atrophy growth rates were measured over arbitrary time units and fit to the known exponential decay model. The main outcome measures: included topography of atrophy over time and fit of simulated residual RPE area to exponential decay. Results: A background effect alone can simulate exponential decay, but does not simulate the central island preservation seen in choroideremia. An additive neighbor effect alone does not simulate exponential decay. When the neighbor effect multiplies the background effect using the rod density function, our model follows an exponential decay, similar to previous observations. Also, our model predicts a residual island of RPE that resembles the topographic distribution of residual RPE seen in choroideremia. Conclusions: The pattern of RPE loss in choroideremia can be predicted by applying simple rules. The RPE preservation pattern typically seen in choroideremia may be related to the underlying pattern of rod density. Further studies are needed to validate these findings.

Long-term natural history of visual acuity in eyes with choroideremia: a systematic review and meta-analysis of data from 1004 individual eyes.

BACKGROUND/AIMS: Best-corrected visual acuity (BCVA) is the most common primary endpoint in treatment trials for choroideremia (CHM) but the long-term natural history of BCVA is unclear. METHODS: We searched in seven databases to identify studies that reported BCVA of untreated eyes with CHM. We sought individual-level data and performed segmented regression between BCVA and age. For eyes followed longitudinally, we introduced a horizontal translation factor to each dataset to account for different ages at onset of a rapid BCVA decline. RESULTS: We included 1004 eyes from 23 studies. BCVA of the right and left eyes was moderately correlated (r=0.60). BCVA as a function of age followed a 2-phase decline (slow followed by rapid decline), with an estimated transition age of 39.1 years (95% CI 33.5 to 44.7). After the introduction of horizontal translation factors to longitudinal datasets, BCVA followed a 2-phase decline until it reached 0 letters (r2=0.90). The BCVA decline rate was 0.33 letters/year (95% CI -0.38 to 1.05) before 39 years, and 1.23 letters/year (95% CI 0.55 to 1.92) after 39 years (p=0.004). CONCLUSION: BCVA in eyes with CHM follows a 2-phase linear decline with a transition age of approximately 39 years. Future trials enrolling young patients may not be able to use BCVA as a primary or sole endpoint, but rather, may need to employ additional disease biomarkers that change before age 39. BCVA may still have utility as a primary endpoint for patients older than 39 years who have measurable BCVA decline rates.