Pathophysiology of age-related macular degeneration

Clinical and pathological examination was performed on 378 eyes from 216 patients aged 43 to 97 years. This series represented eyes in which the fundi were normal or showed various manifestations of senile macular degeneration. The eyes were divided into six groups according to the histological appearance of a linear deposit at the base of the retinal pigment cells. Groups I and II were considered to represent normal ageing, Groups III and IV the progressive development of senile macular degeneration and Groups V and VI the end-results. Group I showed no basal linear deposit. Thickening and hyalinization of Bruch's membrane was noted as early as the fifth decade. Group II showed patchy development of the basal linear deposit in relation to thickened or basophilic segments of Bruch's membrane, or over intercapillary hyalinization extending to the level of the outer surface of the choriocapillaris. Almost all eyes in these two groups retained a normal fundus appearance but visual acuity declined with age even in the absence of other causes. In Group III the basal deposit formed a thin continuous layer associated with moderate degeneration of the retinal pigment epithelium. More than half the eyes had developed a clinical disturbance of pigmentation and in most vision was reduced. Group IV was characterized by thickening of the deposit and more pronounced disturbance of the pigment epithelium. Clinically most eyes showed coarse pigmentary changes and vision was in the order of 6/24. 14-3 per cent of eyes in this group showed early neovascularization from the choroid. In Group V the pigment epithelium disappeared to produce circumscribed areas of depigmentation. The basal linear deposit could be traced throughout the depigmented area in most eyes. Thin fibrovascular sheets were found beneath the pigment epithelium in 41-7 per cent of eyes. Group VI represented disciform degeneration. The basal linear deposit could often be demonstrated as a disrupted hyalinized layer incorporated into the scar. Disciform degeneration was an alternative end-result to geographical atrophy. In each group the clinical and histological findings may be modified by the presence of drusen or by atrophy of the choroid. The basal linear deposit consisted of banded fibres embedded in granular material lying between the plasma infoldings and the basement membrane of the retinal pigment epithelium. This deposit seems to be a manifestation of gradual failure of the pigment epithelium and proved to be the most suitable criterion by which to study the natural history of senile macular degeneration.

The renewal of retinal rod and cone outer segments has been studied by radioautography in rhesus monkeys examined 2 and 4 days after injection of leucine-3H. The cell outer segment consists of a stack of photosensitive, membranous discs. In both rods and cones some of the newly formed (radioactive) protein became distributed throughout the outer segment. Furthermore, in rods (but not in cones), there was a transverse band of concentrated radioactive protein slightly above the outer segment base 2 days after injection. This was due to the formation of new discs, into which labeled protein had been incorporated. At 4 days, these radioactive discs were located farther from the outer segment base. Repeated assembly of new discs had displaced them away from the basal assembly site and along the outer segment. Measurements of the displacement rate indicated that each retinal rod produces 80–90 discs per day, and that the entire complement of outer segment discs is replaced every 9–13 days. To compensate for the continual formation of new discs, groups of old discs are intermittently shed from the apical end of the cell and phagocytized by the pigment epithelium. Each pigment epithelial cell engulfs and destroys about 2000–4000 rod outer segment discs daily. The similarity between visual cells in the rhesus monkey and those in man suggests that the same renewal processes occur in the human retina.