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Li, Miaoling, MD, PhD*,†; Huisingh, Carrie, MSPH*; Messinger, Jeffrey, DC*; Dolz-Marco, Rosa, MD, PhD‡,§,¶; Ferrara, Daniela, MD, PhD**; Freund, K. Bailey, MD‡,§,††; Curcio, Christine A., PhD*

doi: 10.1097/IAE.0000000000002182
Original Study: PDF Only

Purpose: To systematically characterize histologic features of multiple chorioretinal layers in eyes with geographic atrophy, or complete retinal pigment epithelium (RPE) and outer retinal atrophy, secondary to age-related macular degeneration, including Henle fiber layer and outer nuclear layer; and to compare these changes to those in the underlying RPE-Bruch membranechoriocapillaris complex and associated extracellular deposits.

Methods: Geographic atrophy was delimited by the external limiting membrane (ELM) descent towards Bruch membrane. In 13 eyes, histologic phenotypes and/or thicknesses of Henle fiber layer, outer nuclear layer, underlying supporting tissues, and extracellular deposits at four defined locations on the non-atrophic and atrophic sides of the ELM descent were assessed and compared across other tissue layers, with generalized estimating equations and logit models.

Results: On the non-atrophic side of the ELM descent, distinct Henle fiber layer and outer nuclear layer became dyslaminated, cone photoreceptor inner segment myoids shortened, photoreceptor nuclei and mitochondria translocated inward, and RPE was dysmorphic. On the atrophic side of the ELM descent, all measures of photoreceptor health declined to zero. Henle fiber layer/outer nuclear layer thickness halved, and only Müller cells remained, in the absence of photoreceptors. Sub-RPE deposits remained, Bruch membrane thinned, and choriocapillaris density decreased.

Conclusion: The ELM descent sharply delimits an area of marked gliosis and near-total photoreceptor depletion clinically defined as Geographic atrophy (or outer retinal atrophy), indicating severe and potentially irreversible tissue damage. Degeneration of supporting tissues across this boundary is gradual, consistent with steady age-related change and suggesting that RPE and Müller cells subsequently respond to a threshold of stress. Novel clinical trial endpoints should be sought at age-related macular degeneration stages before intense gliosis and thick deposits impede therapeutic intervention.

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High-resolution histology at the border of geographic atrophy (or complete retinal pigment epithelium and outer retinal atrophy) secondary to age-related macular degeneration reveals marked gliosis and near-total photoreceptor depletion, abundant extracellular deposits, and long-standing abnormalities of Bruch membrane and choriocapillaris, indicating severe and potentially irreversible tissue damage at this stage of the disease.

*Department of Ophthalmology, School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;

State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China;

Vitreous Retina Macula Consultants of New York, New York;

§LuEsther T Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, New York;

Oftalvist Clinic, Valencia, Spain;

**Genentech, South San Francisco, California; and

††Department of Ophthalmology, New York University School of Medicine, New York, New York.

Reprint requests: Christine A. Curcio, PhD, Department of Ophthalmology, EyeSight Foundation of Alabama Vision Research Laboratories, University of Alabama School of Medicine, 1670 University Boulevard Room 360, Birmingham, AL 35294-0099; e-mail:

Supported by Hoffman LaRoche, the Macula Foundation, Inc, and unrestricted funds to the Department of Ophthalmology from Research to Prevent Blindness, Inc, and EyeSight Foundation of Alabama. Project MACULA tissue acquisition and website construction was supported by NIH grants EY06109 (C.A.C.), International Retinal Research Foundation, Edward N. and Della L. Thome Foundation, Arnold and Mabel Beckman Initiative for Macular Research, and NEI Core grant P30 EY003039.

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