CLINICAL ENDPOINTS FOR THE STUDY OF GEOGRAPHIC ATROPHY SECONDARY TO AGE-RELATED MACULAR DEGENERATION

Abstract

Purpose: To summarize the recent literature describing the application of modern technologies in the study of patients with geographic atrophy (GA) secondary to age-related macular degeneration.

Methods: Review of the literature describing the terms and definitions used to describe GA, imaging modalities used to capture and measure GA, and the tests of visual function and functional deficits that occur in patients with GA.

Results: In this paper, we describe the evolution of the definitions used to describe GA. We compare imaging modalities used in the characterization of GA, report on the sensitivity and specificity of the techniques where data exist, and describe the correlations between these various modes of capturing the presence of GA. We review the functional tests that have been used in patients with GA, and critically examine their ability to detect and quantify visual deficits.

Conclusion: Ophthalmologists and retina specialists now have a wide range of assessments available for the functional and anatomic characterization of GA in patients with age-related macular degeneration. To date, studies have been limited by their unimodal approach, and we recommend that future studies of GA use multimodal imaging. We also suggest strategies for the optimal functional testing of patients with GA.

Conflict of interest statement

Conflict of Interest

SriniVas Sadda has served as a consultant to Genentech, Roche, Allergan, Novartis, Stem Cell Inc, Iconic, Avalanche, Optos, and Carl Zeiss Meditec. Usha Chakravarthy has attended advisory boards for Hoffmann-La Roche and Genentech. Her institution has received grants from Hoffmann-La Roche and she is principal investigator in trials sponsored by Roche. David G. Birch has been a consultant for AGTC, Acucela, Inc., Shire Pharmaceuticals, ISIS/GSK, QLT, and Thrombogenics. Giovanni Staurenghi is principal investigator in trials sponsored by Roche. He is also consultant for Heidelberg Engineering, Quantel Medical, Carl Zeiss Meditec, Alcon, Allergan, Bayer, Boheringer, Genentech, GSK, Novartis, Roche. His institution received grants from Optos, Optovue, Centervue, Heidelberg Engineering, Quantel Medical, Novartis, Carl Zeiss Meditec, Alcon, allergan. He has a patent with Ocular Instruments. Erin Henry is an employee of Genentech, Inc. Christopher Brittain is an employee of F. Hoffmann-La Roche, Ltd.

Figures

Fig 1

AREDS macular grid and Beckman AMD severity grading system using CFP. Brighter areas on CFP correspond to GA and loss of pigmented epithelium. Standardized circles C0 (63 μm) and C1 (125 μm) are used for determination of drusen size.

Fig 2

Assessment of GA using FAF. In a healthy retina, lipofuscin autofluorescence is distributed uniformly in a pattern that diminishes toward the fovea. In contrast, distinct dark areas are evident in the eye with GA, where death of lipofuscin-containing RPE cells leaves a region of hypofluorescence. Different FAF patterns in the junctional zone have been correlated with varying risk of GA progression. IQR, interquartile ratio.

Fig 3

Characterization of GA using SD-OCT. A. 2-D OCT of a healthy eye showing individual retinal layers. B. 2-D OCT of an eye with GA showing degradation of RPE and neural layers and enhancement of signal from the choroid. C. 2-D OCT for quantitation of GA progression. Highlighted green area corresponds to retina lost to atrophy from baseline to follow-up, allowing measurement of change in retinal thickness and GA lesion boundaries. RNFL, retina nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer (1 = external limiting membrane; 2 = inner photoreceptor layer; 3 = photoreceptor outer segment-RPE interdigitation; 4 = RPE-Bruch’s membrane complex; 5 = choriocapillaris and choroid).

Fig 4

Schematic illustration of the assessment of retinal function using mfERG in healthy retina (top) and in GA (bottom). When the mfERG map is superimposed on the CFP image, the color gradient of the mfERG grid shows the most intense signal in healthy retina at the fovea. In eyes with AMD, decreasing retinal function is shown as darker colors in areas corresponding to GA.

Fig 5

Measurement of retinal function in GA using microperimetry. Color-coded map of retinal sensitivity (top) shows loss of retinal function in darker areas that correspond to GA lesions as assessed by FAF (bottom). Worsening of retinal function is shown over time as lesion area expands from baseline (A), at 12 months (B), and at 24 months (C).