65 - Pathogenesis of age-related macular degeneration

Abstract

Age-related macular degeneration is a common cause of central vision loss among older adults worldwide. Legal blindness develops as a result of the two end stages of disease: geographic atrophy and neovascularization, which were traditionally evaluated on the basis of color fundus photography and fluorescein angiography, respectively. More recently, atrophy can be graded with spectral domain optical coherence tomography (OCT) to identify complete outer retinal atrophy (cORA) and complete retinal pigment epithelial (RPE) and outer retinal atrophy (cRORA), the two most severe forms of nonneovascular AMD. New concepts emerge through the integration of information from imaging many chorioretinal layers, fortified by human eye pathology and epidemiology. Major risk factors for progression are extracellular deposits that aggregate on either side of the highly RPE: drusen basally in the sub-RPE-basal laminar space and subretinal drusenoid deposit (SDD) apically between RPE and photoreceptors. These two deposits are most prominent in the central macular and perifoveal regions, respectively, suggesting dysregulation of specialized physiologies of cone and rod photoreceptors, respectively, with lipid transfer a leading candidate pathway in this pathologic process. Soft drusen form because the retina and RPE are relatively functional and continue to export lipid, compared with Bruch’s membrane and the choriocapillaris, which together impede transport to the circulation. Drusen provide a cleavage plane and inflammatory nidus for neovascularization of choroidal origin. Atrophy initiates when RPE migrates anteriorly into the retina and Müller glia invade the denuded drusen. SDD is associated with neovascularization of retinal origin and a new end stage, outer retinal atrophy in which RPE is initially intact. SDD pathogenic factors are likely analogous to those initiating drusen and represent a new frontier in clinical and laboratory research. Pachydrusen may represent a variant on this theme in which choroidal outflow is blocked.