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BLOG: Why is geographic atrophy often ring- or horseshoe-shaped?
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Geographic atrophy represents the end-result of nonexudative macular degeneration, a major cause of blindness in America. As clinicians, the finding can be frustrating, as options to prevent or slow the disease are limited at best.
Blindness can come quickly; as one study reports, the average rate of expansion is 139 microns/year – slightly more than the width of a retinal vein at the edge of the disc (Schatz et al.). This means if a patient develops a small spot of geographic atrophy (GA) in his or her perifoveal area, the fovea could be affected relatively quickly. But why do patients most often first develop GA in the perifoveal area? Why not in the arcades or in the fovea itself?
The answer to the mystery of the shape of GA, of course, lies in the reason of why it forms. We often first note GA as an annulus around the fovea, and sometimes as a horseshoe, sparing the temporal side of the ring. The reason this ring forms where it does is mostly due to the distribution pattern of lipofuscin in the posterior pole.
Lipofuscin accumulation parallels the distribution of rods in the retina. As we age, lipofuscin builds up in our retinal pigment epithelium (RPE) and is the reason why the RPE of older patients will glow more brightly in fundus autofluorescent photography than will that of a young patient.
Color fundus photograph of 75-year-old white male with horseshoe-shaped geographic atrophy.
Source: Rett D
Most of the lipofuscin in the RPE is derived from the phagocytosis of oxidatively damaged photoreceptor outer segments. Each RPE cell touches 30 to 50 rod outer segments, and as free radicals damage the photoreceptors, more phagocytosis occurs and thus more lipofuscin is accumulated in the RPE (Newsome).
Lipofuscin damages RPE cells in two ways: reducing cytoplasmic space, causing failure of typical metabolic processes, and acting as a detergent to lyse the cell membrane, causing cell death. The highest concentration of rods is 3 mm from the fovea; the quadrant with the most rods is superior to the fovea and the quadrant with the fewest is temporal to the fovea. Thus, the most likely area for GA to first appear is superior to the fovea, and the area for GA to last appear is temporal. Inter-patient variability explains why some patients have horseshoe-shaped GA and some have complete rings.
Infrared picture of 82-year-old white male with horseshoe-shaped geographic atrophy.
Source: Rett D
But why does lipofuscin not parallel cone distribution? Remember that while rod density peaks at 3 mm from the fovea (in a ring shape), cone density peaks directly at the foveola. Macular carotenoids like lutein and zeaxanthin function to decrease the oxidation of cone outer segments, and these pigments are in high concentration in the fovea, thus protecting cones and sparing the fovea from GA until the very end of the disease. Caucasians are at higher risk for GA because they have less melanin in their RPE compared to other races and, thus, higher free radical damage at the RPE level.
But there are other causes of GA in addition to lipofuscin deposition, and these account for the types of non-ring-shaped GA that some patients have.
RPE atrophy is usually more advanced directly above drusen and progresses to GA as the drusen (or drusenoid RPE detachments) regress. This drusen-centric formation of GA explains why some patients have more of a “scatter-shot” pattern of GA vs. a ring pattern. As an aside, there is a difference between small spots of dropout and true GA: to be called “geographic” an atrophic spot of the RPE has to be bigger than 175 microns in diameter (Bird et al.).
Autofluorescence picture of 81-year-old white male with horseshoe-shaped geographic atrophy.
Source: Rett D
In addition to lipofuscin and drusen, GA has a perfusion etiology. Bruch’s membrane collects debris and becomes thicker and denser with age, and this debris hinders the connection to the choroid. This causes a reduction in the permeability of Bruch’s membrane, making it more difficult for the choriocapillaris to perfuse the RPE and remove its waste. The horseshoe shape of some patients’ GA in the choroid-centric theory has to do with the variations of patient’s choroidal vasculature. The macula is a watershed zone for branches of the short posterior ciliary arteries and areas where multiple watershed zones meet are less perfused and, thus, can be thought of as the first place for GA to form.
Most clinicians reading this review have seen geographic atrophy before, and many of us have observed the annular or horseshoe shape. But when we stop to think about the reason this is happening, we can perhaps better understand the condition and spot the warning signs earlier.
References:
Age-Related Eye Disease Study Research Group. Arch Ophthalmol. 2001; 119:1417-1436.
Schatz H, et al. Ophthalmology. 1989;96:1541-1551.
Bird AC, et al. Surv Ophthalmol. 1995;39:367-374.
Curcio CA, et al. Invest Ophthalmol Vis Sci. 1993;34(12):3278-3296.
Delori FC, et al. Invest Ophthalmol Vis Sci. 2001;42:1855-1866.
Dorey CK, et al. Invest Ophthalmol Vis Sci. 1989;30(8):1691-1699.
Glaser BM. Arch Ophthalmol. 1985;106:603-607.
Kennedy CJ, et al. Eye. 1995;9:763-771.
McLeod DS, et al. Invest Ophthalmol Vis Sci. 1994;35:3799-3811.
Newsome DA. Trans Ophthalmol Soc UK. 1983;103:458-466.