Enlargement of Geographic Atrophy From First Diagnosis to End of Life

Abstract

IMPORTANCETreatments for geographic atrophy (GA), a late stage of age-related macular degeneration (AMD), are currently under development. Understanding the natural course is needed for optimal trial design. Although enlargement rates of GA and visual acuity (VA) in the short term are known from clinical studies, knowledge of enlargement in the long term, life expectancy, and visual course is lacking.OBJECTIVE To determine long-term enlargement of GA. DESIGN, SETTING, AND PARTICIPANTSIn this study, participant data were collected from 4 population-based cohort studies, with up to 25 years of follow-up and eye examinations at 5-year intervals: the Rotterdam Study cohorts 1, 2, and 3 and the Blue Mountains Eye Study. Data were collected from 1990 to 2015, and data were analyzed from January 2019 to November 2020.MAIN OUTCOMES AND MEASURES Area of GA was measured pixel by pixel using all available imaging. Area enlargement and enlargement of the square root-transformed area, time until GA reached the central fovea, and time until death were assessed, and best-corrected VA, smoking status, macular lesions according to the Three Continent AMD Consortium classification, a modified version of the Wisconsin age-related maculopathy grading system, and AMD genetic variants were covariates in Spearman, Pearson, or Mann-Whitney analyses. RESULTSOf 171 included patients, 106 (62.0%) were female, and the mean (SD) age at inclusion was 82.6 (7.1) years. A total of 147 of 242 eyes with GA (60.7%) were newly diagnosed in our study. The mean area of GA at first presentation was 3.74 mm 2 (95% CI,. Enlargement rate varied widely between persons (0.02 to 4.05 mm 2 per year), with a mean of 1.09 mm 2 per year (95% CI, 0.89-1.30). Stage of AMD in the other eye was correlated with GA enlargement (Spearman ρ = 0.34; P = .01). Foveal involvement was already present in incident GA in 55 of 147 eyes (37.4%); 23 of 42 eyes (55%) developed this after a mean (range) period of 5.6 (3-12) years, and foveal involvement did not develop before death in 11 of 42 eyes (26%). After first diagnosis, 121 of 171 patients with GA (70.8%) died after a mean (SD) period of 6.4 (5.4) years. Visual function was visually impaired (less than 20/63) in 47 of 107 patients (43.9%) at last visit before death. CONCLUSIONS AND RELEVANCEIn this study, enlargement of GA appeared to be highly variable in the general population. More than one-third of incident GA was foveal at first presentation; those with extrafoveal GA developed foveal GA after a mean of 5.6 years. Future intervention trials should focus on recruiting those patients who have a high chance of severe visual decline within their life expectancy.

Exploring patient acceptability of emerging intravitreal therapies for Geographic Atrophy: a mixed-methods study

“…Further work is required to develop precise and robust risk stratification tools and to determine the time-difference in progression that patients will perceive as meaningful. Data from Colijn and colleagues’ analysis of four population-based cohort studies 27 suggests that delaying progression to foveal involvement by at least 0.8 years could allow the average individual with non-foveal GA to retain central vision and avoid severe vision loss for the rest of their life. 45 As such, even a modest reduction in rate of progression would deliver clinically meaningful benefits to a large number of patients.…”

“…However, natural history studies demonstrate a progressive decline in vision over time, with almost two-thirds of eyes observed to have foveal involvement associated with moderate or severe sight loss within 4-5 years. 27,43 Additionally, the current treatments have been demonstrated to have higher efficacy the further the lesion is from the fovea, 18,44 thus extending time of foveal preservation. Therefore, there is a challenge here to accurately identify and robustly support patients at risk of foveal involvement in future whilst their visual acuity remains good, in order to maximise potential to preserve vision with these treatments if approved.…”

“…However, GA is different to wet AMD, being slower to progress, with well-documented variation in rates of progression across individuals, and asymptomatic in many patients until involving the fovea. 26,27 Therefore it is vital to understand whether patients with GA would find it acceptable to commence and adhere to frequent intravitreal treatments, in order to slow GA progression. Furthermore, identifying barriers and facilitators that influence the acceptability of such treatments – even prospectively before they are approved - could help to address modifiable factors, and thereby improve treatment delivery and service design.…”

Expanding the Understanding of Geographic Atrophy

“…In a study (N = 147) examining the long-term enlargement of GA, more than 30% of incident GA was within the foveal region at initial presentation, and patients with extrafoveal GA developed it within the fovea after approximately 5 years. 26 Structural abnormalities on OCT at the area of the junctional zone are associated with faster GA progression compared with smooth-margin lesions. 18 Perilesional patterns in FAF images may also indicate the rate of progression in GA; individuals with banded or diffuse patterns display greater GA progression than those with a focal pattern or no pattern at all.…”

Regulation of Rac1 Activation in Choroidal Endothelial Cells: Insights into Mechanisms in Age-Related Macular Degeneration

“…Vision loss occurs in the advanced forms, known as atrophic or neovascular AMD. However, early and intermediate AMD often manifest before symptoms are noted and progress to either or both advanced forms [2][3][4]. Loss of central vision from the progression of atrophy can take years, whereas that from neovascular AMD can occur within a few months [5][6][7].…”