Cell loss in geographic atrophy
Authors: BIRD A 
Published: November 2010

Purpose Geographic atrophy (GA) of the retinal pigment epithelium (RPE) is a term used by Gass to designate one form of late age‐related macular disease (AMD).1 It is a major cause of visual loss in Western communities, although, with few exceptions, less common that choroidal neovascularization. 2‐4 Concepts as to the pathological processes leading to GA are incompletely understood, and sequence of events has been debated for some years. On the basis of histological studies, Hogan took the view that the target cell of disease was the photoreceptor cell and that cell loss was consequent upon RPE dysfunction.5 Sarks and co‐workers undertook meticulous morphological studies on donor eyes and supported this view.6,7 Clinical studies using autofluorescence have supported these general conclusions. The observation that GA is preceded by excess autofluorescence implies that that accumulation of lipofuscin in the retinal pigment epithelium (RPE) is intrinsic to the evolution of GA.8,9 High quality imaging using OCT implies that in the area of GA there is complete or almost complete loss of photoreceptor cells.10,11 The alternatives that RPE may be absent, or thinned and depigmented could be distinguished one from the other. Beyond the edge of GA the RPE may or may not be hyper‐autofluorescent. In areas of abnormal autofluorescence, the images were interpreted as implying that the outer nuclear layer may be thinner than normal, but there was great variation from one patient to another. In those cases with homogeneous autofluorescence beyond the edge of atrophy, there tended to be an abrupt transition from normal outer nuclear thickness, and therefore photoreceptor cell population. In these cases, some change in the bands, interpreted as being derived from the outer limiting membrane and inner/outer segment junction, were recorded beyond the edge of the GA. This suggested that there may be abnormalities of the inner and outer segments in ophthalmoscopically normal retina. The reliability of autofluorescence as an indicator of integrity of the photoreceptor cells is not reported in either of these two studies. In addition the relative frequency of normal and abnormal outer nuclear layer beyond the margin of atrophy is not documented. However both indicate that there may be major loss of photoreceptor cells in retina that may appear normal by ophthalmoscopy. Functional testing also gives some clues as to the state of the outer retina in AMD. In early disease slow acquisition of fluorescence on fluorescein angiography is seen in about 25% of eyes.12 In such cases there is consistent loss of scotopic function by as much as 3.5 log units whereas photopic function is normal or near normal. In addition loss of sensitivity has been recorded over areas of abnormal autofluorescence.13 Whether these losses are due to cell death or cell dysfunction is unknown. In an attempt establish the extent of cell loss in cases of GA we examined 38 pairs of donor eyes in which GA had been documented clinically. In the area of GA there was no RPE and the outer retina was reduced to scattered cone nuclei with no outer or inner segment. Beyond the edge of GA in 4 eyes there was a sharp transition to an outer retina that was intact with several rows of photoreceptor nuclei with outer and inner segments. In the remaining eyes there was major loss of photoreceptor cells to one row of cones for up to 1,400 microns from the edge with some inner segments but no outer segments. The state of the outer retina did not correspond well with age changes in the RPE.

Conclusion 1. Photoreceptor cells are the target cell of disease. 2. The area of GA as assessed clinically does not indicate accurately the state of the outer retina. 3. The sensory loss measured in early AMD is due in part or completely to photoreceptor cell death 4. That autofluorescence is not a reliable indicator of the state of the outer retina.