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.

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.

Association of the Affordable Care Act with Eye-Related Emergency Department Utilization in the United States.

PURPOSE: To investigate the association of the Affordable Care Act (ACA) with nationwide eye-related emergency department (ED) use. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: All patients who presented to the ED with an eye-related primary diagnosis were eligible for inclusion. METHODS: Nationally representative data from the US Nationwide Emergency Department Sample were used to analyze eye-related ED visits before (2010-2013) and after (2014-2017) the ACA was mandated. All ED visits were categorized as emergent or nonemergent or could not be determined. MAIN OUTCOME MEASURES: The primary outcome was to compare the nationwide and regional incidence of eye-related ED visits per 100 000 US population before (2010-2013) and after (2014-2017) the ACA was mandated. Secondary outcome measures included change in payor status, proportion of urgent versus nonurgent visits, proportion of visits at teaching versus nonteaching hospitals, associated charges, and discharge disposition. RESULTS: A total of 16 808 343 eye-related ED visits occurred in the United States during the study period from 2010 to 2017. Of these, 8 088 203 ED visits occurred before the ACA was mandated (2010-2013), and 8 720 766 ED visits occurred after the ACA was mandated (2014-2017). After the ACA was mandated in 2014, there was an initial decline in incidence of eye-related ED visits from 652.4 per 100 000 population in 2013 to 593.0 per 100 000 population in 2014, followed by a rapid increase in incidence to 658.5 per 100 000 population in 2015, with a further increase to 746.6 per 100 000 population in 2016. The percentage of uninsured patients decreased from 19.0% to 14.3%. The increase in ED use was greatest for individuals in the lowest income quartile (895.1 per 100 000 population in 2013 to 964.0 per 100 000 in 2017). Overall, 44.8% of ED visits were due to nonemergent eye conditions. CONCLUSIONS: Although the ACA increased insurance coverage for Americans, theoretically increasing access to outpatient ophthalmic care, this did not decrease ED reliance for management of ophthalmic conditions. Additional measures beyond expanding insurance coverage may be necessary to provide high-quality, efficient, and equitable outpatient ophthalmic care to all Americans.

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.

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.

Topographic Variation of Retinal Vascular Density in Normal Eyes Using Optical Coherence Tomography Angiography.

Purpose: To establish a continuous topography of retinal vessel density in normal eyes using optical coherence tomography angiography (OCTA). Methods: A retrospective chart review was performed, and 8-mm × 8-mm OCTA images from 22 normal eyes were analyzed. Vessel density was plotted as a continuous function of distance from the foveal center (radial vessel density) and directional meridians (directional vessel density) for the superficial capillary plexus and deep capillary plexus. Results: Continuous radial and directional vessel density plots for the superficial and deep capillary plexus were generated. Radial vessel density analysis revealed transition points at 657 microns (95% confidence interval [CI], 619-696) and 950 microns (95% CI, 903-997) from the foveal center for the superficial plexus and deep plexus, respectively. Directional vessel density analysis demonstrated significant vessel density variations in these vascular layers and provided greater detail compared to traditional quadrant analysis. Conclusions: There are significant topographic variations of retinal vessel density in normal eyes. Continuous vessel density analysis offers greater sensitivity in detecting topographic vessel density changes compared to traditional methods of analysis. Translational Relevance: This study establishes a normative continuous vessel density topography that may help elucidate the role of the vascular bed in different chorioretinal diseases.

Local Progression Kinetics of Geographic Atrophy Depends Upon the Border Location.

Purpose: To assess the influence of lesion morphology and location on geographic atrophy (GA) growth rate. Methods: We manually delineated GA on color fundus photographs of 237 eyes in the Age-Related Eye Disease Study. We calculated local border expansion rate (BER) as the linear distance that a point on the GA border traveled over 1 year based on a Euclidean distance map. Eye-specific BER was defined as the mean local BER of all points on the GA border in an eye. The percentage area affected by GA was defined as the GA area divided by the total retinal area in the region. Results: GA enlarged 1.51 ± 1.96 mm2 in area and 0.13 ± 0.11 mm in distance over 1 year. The GA area growth rate (mm2/y) was associated with the baseline GA area (P < 0.001), perimeter (P < 0.001), lesion number (P < 0.001), and circularity index (P < 0.001); in contrast, eye-specific BER (mm/y) was not significantly associated with any of these factors. As the retinal eccentricity increased from 0 to 3.5 mm, the local BER increased from 0.10 to 0.24 mm/y (P < 0.001); in contrast, the percentage of area affected by GA decreased from 49.3% to 2.3%. Conclusions: Using distance-based measurements allows GA progression evaluation without significant confounding effects from baseline GA morphology. Local GA progression rates increased as a function of retinal eccentricity within the macula which is opposite of the trend for GA distribution, suggesting that GA initiation and enlargement may be mediated by different biological processes.

Altered transcriptome and disease-related phenotype emerge only after fibroblasts harvested from patients with age-related macular degeneration are differentiated into retinal pigment epithelium.

We have reported previously that retinal pigment epithelium (RPE) differentiated from induced pluripotent stem cells (iPSC) generated from fibroblasts of patients with age-related macular degeneration (AMD) exhibit a retinal degenerative disease phenotype and a distinct transcriptome compared to age-matched controls. Since the genetic composition of the iPSC and RPE are inherited from fibroblasts, we investigated whether differential behavior was present in the parental fibroblasts and iPSC prior to differentiation of the cell lines into RPE. Principal component analyses revealed significant overlap (essentially no differences) in the transcriptome of fibroblasts between AMD and controls. After reprogramming, there was no significant difference in the transcriptome of iPSC generated from AMD versus normal donors. In contrast, the transcriptome of RPE derived from iPSC segregated into two distinct clusters of AMD-derived cells versus controls. Interestingly, mitochondrial dysfunction in AMD-derived RPE was evident after approximately two months in culture. Moreover, these differences in mitochondrial dysfunction were not evident in the parental fibroblasts and iPSC. This study demonstrates an altered transcriptome and impaired mitochondrial function in RPE derived from AMD patients versus controls, and demonstrates these differences are not present in the original fibroblasts or iPSC. These results suggest that pathology in AMD is triggered upon differentiation of parent cells into RPE. More study of this phenomenon could advance the current understandings of the etiology of AMD and the development of novel therapeutic targets.

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.

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.

Geographic Atrophy Growth Is Strongly Related to Lesion Perimeter: Unifying Effects of Lesion Area, Number, and Circularity on Growth.

PURPOSE: To investigate the underlying reason for the previously observed impact of baseline lesion size, number, and circularity on geographic atrophy (GA) growth rate. DESIGN: Retrospective analysis of a multicenter, prospective, randomized controlled trial. PARTICIPANTS: Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. METHODS: We manually delineated atrophic lesions on color fundus photographs of 318 eyes with GA followed up over at least 2 visits (mean follow-up duration, 5.1 ± 3.0 years). We calculated GA area growth rate for each eye based on the first and last visit. GA perimeter-adjusted growth rate was defined as the ratio between GA area growth rate and mean GA perimeter between the first and last visit for each eye. MAIN OUTCOME MEASURES: GA area growth rate, growth rate of the square root of GA area, and GA perimeter-adjusted growth rate. RESULTS: GA area growth rate was correlated strongly with mean GA perimeter (r2 = 0.66). GA area growth rate was associated with baseline GA area (r2 = 0.39; P < 0.001), lesion number (r2 = 0.10; P < 0.001), and circularity index (r2 = 0.28; P < 0.001). The use of the square root of GA area reduced the influence of baseline GA area (but not lesion number or circularity) on GA growth rate. In comparison, GA perimeter-adjusted growth rate (0.098 ± 0.062 mm/year) was not correlated with baseline GA area (r2 = 0.005; P = 0.20), lesion number (r2 = 0.00009; P = 0.86), or circularity index (r2 = 0.007; P = 0.14). GA perimeter-adjusted growth rate was 50.0% higher in eyes whose fellow eyes showed GA at any visit (0.102 ± 0.062 mm/year) than in eyes whose fellow eyes never demonstrated GA during follow-up (0.068 ± 0.049 mm/year). CONCLUSIONS: The growth rate of GA area is associated strongly with lesion perimeter. This relationship explains the previously observed influences of baseline GA size, lesion number, and circularity on GA growth rate. GA perimeter-adjusted growth rate is uncorrelated with the 3 morphologic factors and may serve as a surrogate outcome measure to monitor GA progression in future studies.

Relationship of Topographic Distribution of Geographic Atrophy to Visual Acuity in Nonexudative Age-Related Macular Degeneration.

PURPOSE: To investigate the topographic distribution of geographic atrophy (GA) and to identify an anatomic endpoint that correlates with visual acuity (VA) in eyes with GA. DESIGN: Retrospective analysis of a multicenter, prospective, randomized controlled trial. PARTICIPANTS: The Age-Related Eye Disease Study participants with GA secondary to nonexudative age-related macular degeneration. METHODS: We manually delineated GA on 1654 fundus photographs of 365 eyes. We measured GA areas in 9 subfields on the Early Treatment Diabetic Retinopathy Study (ETDRS) grid and correlated them with VA via a mixed-effects model. We determined the optimal diameter for the central zone by varying the diameter from 0 to 10 mm until the highest r2 between GA area in the central zone and VA was achieved. We estimated the VA decline rate over 8 years using a linear mixed model. MAIN OUTCOME MEASURES: Geographic atrophy area in macular subfields and VA. RESULTS: The percentage of area affected by GA declined as a function of retinal eccentricity. GA area was higher in the temporal than the nasal region (1.30 ± 1.75 mm2 vs. 1.10 ± 1.62 mm2; P = 0.005) and in the superior than the inferior region (1.26 ± 1.73 mm2 vs. 1.03 ± 1.53 mm2; P < 0.001). Total GA area correlated poorly with VA (r2 = 0.07). Among GA areas in 9 subfields, only GA area in the central zone was associated independently with VA (P < 0.001). We determined 1 mm as the optimal diameter for the central zone in which GA area correlated best with VA (r2 = 0.45). On average, full GA coverage of the central 1-mm diameter zone corresponded to 34.8 letters' decline in VA. The VA decline rate was comparable between eyes with initial noncentral and central GA before GA covered the entire central 1-mm diameter zone (2.7 letters/year vs. 2.8 letters/year; P = 0.94). CONCLUSIONS: The prevalence of GA varies significantly across different macular regions. Although total GA area was associated poorly with VA, GA area in the central 1-mm diameter zone was correlated significantly with VA and may serve as a surrogate endpoint in clinical trials.

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.

Long-term Natural History of Atrophy in Eyes with Choroideremia-A Systematic Review and Meta-analysis of Individual-Level Data.

PURPOSE: To conduct a systematic review and meta-analysis of the natural history of atrophy secondary to choroideremia (CHM). CLINICAL RELEVANCE: A sensitive and reliable anatomic measure to monitor disease progression is needed in treatment trials for CHM. However, the long-term natural history of the residual retinal pigment epithelium (RPE) is unclear, with reported RPE area decline rates varying widely among patients. METHODS: We searched in 7 literature databases up through July 17, 2019, to identify studies that assessed the residual RPE area in untreated eyes with CHM using fundus autofluorescence (FAF). We sought individual-eye data and investigated the RPE decline pattern using 3 models: the area linear model (ALM), radius linear model (RLM), and area exponential model (AEM), in which the area, radius, and log-transformed area of RPE change linearly with time, respectively. To account for different eyes' entry times into the studies, we added a horizontal translation factor to each dataset. The RPE decline rate was estimated using a 2-stage random-effects meta-analysis. We assessed the risk of bias using the Quality In Prognosis Studies tool. RESULTS: Of 807 articles screened, we included 9 articles containing cross-sectional data (257 eyes) from 6 studies and longitudinal data (229 visits from 68 eyes) from 5 studies. The residual RPE area followed a trend of exponential decay as a function of patient age. After the introduction of horizontal translation factors to longitudinal datasets of individual eyes, the datasets fit along a straight line in the AEM over nearly 60 years (r2 = 0.997). The decline rate of log-transformed RPE area was 0.050 (95% confidence interval, 0.046-0.055) log(mm2)/year and was independent of the baseline RPE area (r = -0.18; P = 0.15) and age (r = 0.06; P = 0.63). In contrast, the decline rates of the area and effective radius of residual RPE strongly correlated with the baseline RPE area (r = 0.90 and 0.61, respectively; P < 0.001). CONCLUSIONS: The loss of residual RPE area in untreated eyes with CHM follows the AEM over approximately 60 years. Log-transformed residual RPE area measured by FAF can serve as an anatomic endpoint to monitor CHM.

Progression of Unifocal versus Multifocal Geographic Atrophy in Age-Related Macular Degeneration: A Systematic Review and Meta-analysis.

TOPIC: Determining the natural history of unifocal versus multifocal geographic atrophy (GA) secondary to nonexudative age-related macular degeneration. CLINICAL RELEVANCE: The association between GA focality (i.e., unifocal vs. multifocal lesions) and enlargement rate is inconsistent in the literature. Some studies report a comparable growth rate between unifocal and multifocal GA, whereas others suggest the growth rate varies widely between the 2 groups. METHODS: We searched 5 literature databases up to May 3, 2019, for studies that classified treatment-naïve GA patients based on lesion focality. We performed a random effects meta-analysis to determine the growth rates of GA. To account for different entry times among cohorts, we introduced a horizontal translation factor to the dataset of each cohort. Heterogeneity and study quality were assessed using the I2 statistic and Quality in Prognosis Studies tool, respectively. Publication bias was evaluated by funnel plots and the Egger test. RESULTS: We included 12 studies with 3489 eyes from 3001 patients. After the introduction of translation factors, the effective radius of unifocal and multifocal GA enlarged linearly over approximately 7 years. The effective radius growth rate of multifocal GA (0.199±0.012 mm/year) was 46.3% higher than the growth rate of unifocal GA (0.136±0.008 mm/year; P < 0.001). Interestingly, unifocal and multifocal GA lesions with the same total baseline area grew at vastly different rates, with an estimated ratio of the growth rate as 1.46 (between 2 and 3). This difference disappeared after we accounted for different baseline total perimeters between unifocal and multifocal groups. The measured GA growth rate was consistent across studies using color fundus photography, fundus autofluorescence, or OCT (P = 0.35-0.99). CONCLUSIONS: The effective radius of GA enlarges linearly and steadily over time in both unifocal and multifocal GA. The lesion focality is a significant prognostic factor for the GA effective radius growth rate. We propose that the growth rate of GA area is directly proportional to the total lesion perimeter (a measure of the number of retinal pigment epithelium cells exposed at the lesion border). Additional studies are needed to understand the cellular mechanisms underlying this relationship.