Molecular Vision 1999; 5:25 <http://www.molvis.org/molvis/v5/p25/> Received 24 May 1999 | Accepted 2 November 1999 | Published 3 November 1999

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The natural history of geographic atrophy, the advanced atrophic form of age-related macular degeneration

Janet S. Sunness
 
 

The Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, Baltimore, MD

Correspondence to: Janet S. Sunness, MD, The Wilmer Ophthalmological Institute, The Johns Hopkins University School of Medicine, 550 N. Broadway, 6th Floor, Baltimore, MD, 21205; Phone: (410) 955-5033; FAX: (410) 955-1829; email: jsunness@jhmi.edu

Abstract

Geographic atrophy is the advanced form of atrophic age-related macular degeneration. It is present in 3.5% of people age 75 and over in the United States. It progresses gradually over time, often sparing the fovea until late in the course of the disease. Forty to fifty percent of eyes with geographic atrophy and good visual acuity at baseline lose three or more lines of acuity by two years and 27% become worse than 20/200 by four years. This article discusses the information known about age-related geographic atrophy at the present time.

Introduction

Geographic atrophy (GA) of the retinal pigment epithelium is a form of advanced age-related macular degeneration (AMD) that, with choroidal neovascularization (CNV), is responsible for both severe and moderate central visual loss. GA is the natural endstage of the atrophic AMD process when CNV does not develop [1]. It will become increasingly prevalent as the population ages. Until recently, little attention has been focused on this relatively common disorder. Most of this symposium on age-related macular degeneration discusses CNV, because it is responsible for 80% of the legal blindness from AMD [2] and because there are treatments for some forms of choroidal neovascularization. At present, there is no treatment available for GA. As our knowledge of GA, factors that may be involved in retinal pigment epithelial cell death, genetics of AMD, new delivery systems of medications, and other aspects grows, it is hoped that interventions to prevent GA or slow its progression will be found.

Clinical and histopathologic description, and pathogenesis

Geographic atrophy is easily diagnosed clinically. It presents as a discrete area of loss of retinal pigment epithelium associated with loss of the overlying photoreceptors. This is seen clinically as an area of decreased retinal thickness which is lighter than the surrounding retina and through which the choroidal vessels may be seen more distinctly. On fluorescein angiography, GA appears as an area of discrete hyperfluorescence, representing a transmission defect and staining.

GA often develops first in the region near the fovea, but not involving the foveal center. It progresses gradually over time, sparing the fovea until late in the course of the disease [3-7]. It may develop following the fading of drusen, or in the context of an area of retinal pigment epithelial attenuation and pigmentary change. Several small areas may develop, and these tend to enlarge and coalesce over time. This may lead to a horseshoe of atrophy surrounding, but not involving the foveal center. The horseshoe may coalesce into a ring, still sparing the fovea. Finally, the fovea becomes atrophic. Not all cases of GA evolve in this way; it is difficult to know the evolution when one sees only a single solid area of GA, as was present in 39% of Sunness' patients at baseline [8]. Areas of GA have a dense scotoma (blind spot) [9]. Thus, in GA, the measured visual acuity, by reading a letter chart for example, is often preserved until late in the course of the disease. However, the visual impairment due to the scotomas near and surrounding fixation is significant and is more severe than measured visual acuity may indicate [10]. A patient with GA and good acuity may not be able to read or recognize faces because the word or face does not 'fit' into the spared central island of vision. Statistics that measure only the incidence of legal blindness significantly underestimate the visual impairment and disability associated with GA. Also, GA is bilateral in more than half of patients [4,5,11], so the condition leads to significant difficulty with visual tasks. GA may also develop following the flattening of a retinal pigment epithelial detachment [12-17].

Histopathologic examination reveals an absence of RPE in the area of GA, with a secondary loss of overlying photoreceptors [4]. The choriocapillaris may be absent. There is experimental evidence that when the RPE is absent the choriocapillaris involutes secondarily [18,19]. There is controversy as to whether GA could develop on a basis of choroidal vascular insufficiency. Green and others have argued that choroidal vascular insufficiency should cause degeneration of all the outer retinal layers, which is not seen in GA [4]. Friedman suggests that choroidal vascular resistance may be related to the development of AMD and GA [20]. GA is associated with deposits in and thickening of Bruch's membrane [1,21].

The incidence of geographic atrophy in eyes with drusen

In the Beaver Dam Eye Study, eight percent of eyes with drusen larger than 250 µm developed GA over a five-year period. All eyes that developed GA had pigmentary abnormalities and at least 0.2 Macular Photocoagulation Study (MPS) disc areas of drusen at baseline [22]. Holz found a 7.7% three-year cumulative incidence of GA in patients with bilateral drusen over 65 years of age in a retinal referral center [23].

The prevalence of geographic atrophy

GA is present in 3.5% of people over 75 years of age in the United States and other developed nations, based on two recent population-based studies [24,25]. This is half the prevalence of CNV. GA is relatively uncommon in blacks [26-28], as is CNV. The prevalence of GA increases with age, to 22% in the population over 90 years of age [29,30]. Forty-two percent of eyes with GA have acuity worse than 20/200 [31]. GA is responsible for 20% of the legal blindness from AMD [2].

Natural history

In a prospective natural history study of GA, 50% of eyes with GA that had visual acuity better than 20/50 at baseline lost three or more lines of acuity (doubling of the visual angle) by two years and 25% lost six or more lines of acuity (quadrupling of the visual angle) by two years [10]. Risk factors for more rapid loss of vision included GA within 250 µm of the foveal center and reduced visual function in dark-adapted testing [8,10]. Twenty-seven percent of the eyes with 20/50 or better at baseline had visual acuity of 20/200 or worse at four years [8]. Of those eyes with baseline visual acuities between 20/50 and 20/200, 20% lost three or more lines of acuity over two years.

GA continues to enlarge over time. The mean rate of enlargement over a two year period was 2.2 MPS disc areas (equivalent to 5.6 mm² on the retina) [8]. GA resulting from flattening of a retinal pigment epithelial detachment also continues to enlarge over time [8]. The rate of enlargement increases with increasing baseline size of atrophy up to about five MPS disc areas, after which the rate plateaus. There is evidence that reading rate is inversely related to the size of the atrophy when the fovea is already involved [32], so that an intervention that could slow the rate of enlargement of atrophy could have a significant positive impact on visual function even when a central scotoma is present.

In patients with bilateral GA, the size of the GA is very symmetrical between eyes and often the configuration of the atrophy is symmetrical [8]. However, the acuities may often be disparate, because one eye has an area of foveal sparing with good acuity while the fellow eye has no sparing and poor acuity [8].

The relationship between geographic atrophy and choroidal neovascularization

GA and CNV are both advanced stages of age-related macular degeneration. The GA discussed herein develops without evidence of the presence of CNV at any time during the course. But geographic atrophy can also develop following involution of CNV. Patients may have GA (without evidence of CNV) in one eye and CNV in the fellow eye; in these patients the eye with GA (without CNV) appears to follow a course that is essentially identical to that of patients with bilateral GA without evidence of CNV in either eye, in terms of foveal sparing, rates of acuity loss and rates of enlargement of atrophy [8]. However, the incidence of developing CNV in an eye with GA is significantly higher in patients whose fellow eye has CNV. In Sunness' prospective natural history study, those patients with bilateral GA and no evidence of CNV at baseline had a two-year cumulative incidence of developing CNV of 2%, and a four-year cumulative incidence of 11%. For patients with GA in one eye and CNV in the fellow eye, the cumulative incidence of developing CNV in the GA eye was 18% at two years and 34% at four years [33]. Those eyes that developed CNV had more rapid acuity loss. Two MPS papers reported on the patients with CNV in the study eye and GA without CNV in the fellow eye and found five-year cumulative incidence of developing CNV in the GA eye of 45% to 49% [34,35]. In Sunness' study, the CNV did not develop in areas of GA, but rather in areas of preserved retina surrounding the GA or in spared foveal regions [33]. Schatz reported that CNV did not develop in areas of GA when the choriocapillaris was absent [7]. Some histopathologic work likewise suggests that CNV does not develop where the choriocapillaris is absent [4].

GA generally does not cause the patient to note an abrupt loss of vision [36]. A complaint of abrupt visual loss should then raise the suspicion of choroidal neovascularization. However, the CNV that develops in GA is often evanescent, and may be difficult to detect given the hyperfluorescence already present from the GA [33]. Although GA can be associated with hemorrhages without evidence of CNV [33,37], the presence of a hemorrhage should trigger an investigation for the presence of CNV.

In Sunness' study, those patients who began with bilateral GA had a cumulative incidence of developing binocular legal blindness of 9% at two years and 17% at four years. The cumulative incidence of developing binocular legal blindness in the group with CNV in one eye and GA in the fellow eye at baseline was 18% at two years and 32% at four years [8].

Visual function abnormalities in geographic atrophy

In addition to central, ring, and paracentral scotomas, patients with GA have other visual function abnormalities that may be related to changes in the function of the retina that is not yet atrophic. Patients with GA have profound loss of function in dim environments and have delayed dark adaptation for both rods and cones [10,38-41]. They benefit greatly by increased lighting [10,42]. They have reduced contrast sensitivity [10,43-46] even in the presence of good acuity. (Some of these references refer to atrophic AMD in general [38,39,42-46]; the others refer specifically to GA [10,40,41].)

Reading is significantly impaired in GA, from a combination of limitations induced by the presence of a scotoma near or involving fixation, reduced contrast sensitivity, and need for adequate illumination [10].

Risk factors for developing geographic atrophy in eyes with drusen

As noted above, the presence of drusen larger than 250 µm and pigmentary abnormalities are risk factors for the development of GA. Within the group of patients with high risk drusen, other risk factors that have been identified include delayed choroidal filling on fluorescein angiography [47,48] and diminished foveal dark-adapted sensitivity [49].

Genetics

There is no doubt that there is a significant genetic component to AMD and to GA. GA has been found to be present in families with drusen and with CNV, and AMD has been found more commonly in monozygotic twins [50,51]. Dystrophies such as Zermatt's macular dystrophy (associated with a dominant mutation of the RDS/peripherin gene) have been identified which resemble GA [52]. Mutations of the ABCR gene have been associated with atrophic AMD [53,54]; these studies are being replicated.

Conditions resembling geographic atrophy

There are a number of conditions resembling GA. These are presented at somewhat greater length elsewhere [55]. Within the spectrum of AMD, involuted CNV, laser scars, and RPE rips can mimic GA. Patients with pattern dystrophy and vitelliform dystrophy may develop geographic atrophy [56]. Central areolar choroidal sclerosis is a hereditary condition that causes areas of chorioretinal atrophy similar to GA but occurring at a younger age. Other causes of central and ring scotomas include Stargardt disease, cone dystrophy, North Carolina macular dystrophies, other macular and retinal dystrophies, and toxic maculopathies [57].

Some unanswered questions regarding geographic atrophy

There are a number of intriguing questions in terms of the pathogenesis and course of GA, including:

What is the primary cause of GA?

What is responsible for the death of the RPE cells?

What is responsible for foveal sparing until late in the course of the disease?

What is responsible for dark adaptation abnormalities of both rods and cones? Why is there a need for markedly increased illumination?

Possible treatments for geographic atrophy

While there is currently no treatment to prevent GA or to slow its progression, there are several avenues of interest regarding possible treatments for GA.

Within the general notion of treating AMD, vitamins and minerals are being studied. There is no clear evidence at present of benefit of nutritional supplementation for GA. The National Institutes of Health-funded Age-Related Eye Disease Study, for example, is looking at whether vitamins or minerals affect the development of AMD.

Retinal pigment epithelial transplantation for GA is being attempted [58,59]. The ultimate goal would be to replace the senescent RPE with new RPE thus preserving photoreceptor function, but this is not achievable at the present time. A more limited goal is to determine whether transplanted RPE can produce a factor necessary for RPE survival, or inhibit a toxic influence, and thereby slow down or stop the progression of GA. Attempts at transplantation have been complicated by rejection of the transplanted cells [59]. Peripheral RPE may be tried, but many patients with GA have peripheral reticular degeneration of the RPE [8,60], evidence that the noncentral RPE is also not healthy.

As more is learned about growth factors and proteins expressed by the RPE, there will be attempts to replace missing factors.

Conclusion

GA is an important cause of visual loss from AMD. It is a degenerative process that progresses gradually over time. There is a large window of opportunity for introducing a potential treatment that could preserve a patient's vision at a mild to moderate level of impairment even after the disease has already begun. It is hoped that over time, more will be learned about GA, its prevention, management (both medical and low vision), and treatment.

Acknowledgements

This work was supported by NIH EY08552 and by Research to Prevent Blindness.

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