Molecular Vision 1999; 5:25 <>
Received 24 May 1999 | Accepted 2 November 1999 | Published 3 November 1999

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:


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.


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].


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.


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.


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


1. Sarks SH. Changes in the region of the choriocapillaris in aging and degeneration. In: Shimizu K, Oosterhuis JA, editors. XXIII Concilium Ophthalmologicum: Kyoto 1978 Acta. Proceedings of the 23rd International Congress of Ophthalmology; 1978 May 14-20; Kyoto, Japan. Amsterdam: Excerpta Medica; 1979. p. 228-38.

2. Ferris FL 3rd, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. Arch Ophthalmol 1984; 102:1640-2.

3. Gass JD. Drusen and disciform macular detachment and degeneration. Arch Ophthalmol 1973; 90:206-17.

4. Green WR, Key SN 3rd. Senile macular degeneration: a histopathologic study. Trans Am Ophthalmol Soc 1977; 75:180-254.

5. Sarks JP, Sarks SH, Killingsworth MC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye 1988; 2:552-77.

6. Maguire P, Vine AK. Geographic atrophy of the retinal pigment epithelium. Am J Ophthalmol 1986; 102:621-5.

7. Schatz H, McDonald HR. Atrophic macular degeneration. Rate of spread of geographic atrophy and visual loss. Ophthalmology 1989; 96:1541-51.

8. Sunness JS, Gonzalez-Baron J, Applegate CA, Bressler NM, Tian Y, Hawkins B, Barron Y, Bergman A. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology. In press 1999.

9. Sunness JS, Schuchard RA, Shen N, Rubin GS, Dagnelie G, Haselwood DM. Landmark-driven fundus perimetry using the scanninglaser ophthalmoscope. Invest Ophthalmol Vis Sci 1995; 36:1863-74.

10. Sunness JS, Rubin GS, Applegate CA, Bressler NM, Marsh MJ, Hawkins BS, Haselwood D. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology 1997; 104:1677-91.

11. Potter JW, Thallemer JM. Geographic atrophy of the retinal pigment epithelium: diagnosis and vision rehabilitation. J Am Optom Assoc 1981; 52:503-8.

12. Blair CJ. Geographic atrophy of the retinal pigment epithelium. A manifestation of senile macular degeneration. Arch Ophthalmol 1975; 93:19-25.

13. Braunstein RA, Gass JD. Serous detachments of the retinal pigment epithelium in patients with senile macular disease. Am J Ophthalmol 1979; 88:652-60.

14. Casswell AG, Kohen D, Bird AC. Retinal pigment epithelial detachments in the elderly: classification and outcome. Br J Ophthalmol 1985; 69:397-403.

15. Elman MJ, Fine SL, Murphy RP, Patz A, Auer C. The natural history of serous retinal pigment epithelium detachment in patients with age-related macular degeneration. Ophthalmology 1986; 93:224-30.

16. Meredith TA, Braley RE, Aaberg TM. Natural history of serous detachments of the retinal pigment epithelium. Am J Ophthalmol 1979; 88:643-51.

17. Bird AC, Marshall J. Retinal pigment epithelial detachments in the elderly. Trans Ophthalmol Soc U K 1986; 105:674-82.

18. Korte GE, Reppucci V, Henkind P. RPE destruction causes choriocapillary atrophy. Invest Ophthalmol Vis Sci 1984; 25:1135-45.

19. Leonard DS, Zhang XG, Panozzo G, Sugino IK, Zarbin MA. Clinicopathologic correlation of localized retinal pigment epithelial debridement. Invest Ophthalmol Vis Sci 1997; 38:1094-109.

20. Friedman E, Krupsky S, Lane AM, Oak SS, Friedman ES, Egan K, Gragoudas ES. Ocular blood flow velocity in age-related macular degeneration. Ophthalmology 1995; 102:640-6.

21. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993; 100:1519-35.

22. Klein R, Klein BE, Jensen SC, Meuer SM. The five-year incidence and progression of age-related maculopathy: the Beaver Dam Eye Study. Ophthalmology 1997; 104:7-21.

23. Holz FG, Wolfensberger TJ, Piguet B, Gross-Jendroska M, Wells JA, Minassian DC, Chisholm IH, Bird AC. Bilateral macular drusen in age-related macular degeneration. Prognosis and risk factors. Ophthalmology 1994; 101:1522-8.

24. Klein R, Klein BE, Franke T. The relationship of cardiovascular disease and its risk factors to age-related maculopathy. The Beaver Dam Eye Study. Ophthalmology 1993; 100:406-14.

25. Vingerling JR, Dielemans I, Hofman A, Grobbee DE, Hijmering M, Kramer CF, de Jong PT. The prevalence of age-related maculopathy in the Rotterdam Study. Ophthalmology 1995; 102:205-10.

26. Schachat AP, Hyman L, Leske MC, Connell AM, Wu SY. Features of age-related macular degeneration in a black population. The Barbados Eye Study Group. Arch Ophthalmol 1995; 113:728-35.

27. Friedman DS, Katz J, Bressler NM, Rahmani B, Tielsch JM. The prevalence of age-related macular degeneration among blacks and whites in an urban population. Invest Ophthalmol Vis Sci 1998; 39:S463.

28. Bressler SB, Munoz B, Philips D, West SW. Prevalence of age-related macular degeneration in a population based study: SEE project. Invest Ophthalmol Vis Sci 1998; 39:S463.

29. Hirvela H, Luukinen H, Laara E, Sc L, Laatikainen L. Risk factors of age-related maculopathy in a population 70 years of age or older. Ophthalmology 1996; 103:871-7.

30. Quillen D, Blankenship G, Gardner T. Aged eyes: ocular findings in individuals 90 years of age and older. Invest Ophthalmol Vis Sci 1996; 47:S111.

31. Klein R, Wang Q, Klein BE, Moss SE, Meuer SM. The relationship of age-related maculopathy, cataract, and glaucoma to visual acuity. Invest Ophthalmol Vis Sci 1995; 36:182-91.

32. Sunness JS, Applegate CA, Haselwood D, Rubin GS. Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease. Ophthalmology 1996; 103:1458-66.

33. Sunness JS, Gonzalez-Baron J, Bressler NM, Hawkins B, Applegate CA. The development of choroidal neovascularization in eyes with the geographic atrophy form of age-related macular degeneration. Ophthalmology 1999; 106:910-9.

34. Macular Photocoagulation Study Group. Five-Year Follow-up of fellow eyes of patients with age-related macular degeneration and unilateral extrafoveal choroidal neovascularization. Arch Ophthalmol 1993; 111:1189-99.

35. Macular Photocoagulation Study Group. Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. Arch Ophthalmol 1997; 115:741-7.

36. Sunness JS, Bressler NM, Maguire MG. Scanning laser ophthalmoscopic analysis of the pattern of visual loss in age-related geographic atrophy of the macula. Am J Ophthalmol 1995; 119:143-51.

37. Nasrallah F, Jalkh AE, Trempe CL, McMeel JW, Schepens CL. Subretinal hemorrhage in atrophic age-related macular degeneration. Am J Ophthalmol 1989; 107:38-41.

38. Brown B, Kitchin JL. Dark adaptation and the acuity/luminance response in senile macular degeneration (SMD). Am J Optom Physiol Opt 1983; 60:645-50.

39. Brown B, Tobin C, Roche N, Wolanowski A. Cone adaptation in age-related maculopathy. Am J Optom Physiol Opt 1986; 63:450-4.

40. Sunness JS, Massof RW, Johnson MA, Finkelstein D, Fine SL. Peripheral retinal function in age-related macular degeneration. Arch Ophthalmol 1985; 103:811-6.

41. Sunness JS, Johnson MA, Massof RW, Marcus S. Retinal sensitivity over drusen and nondrusen areas. A study using fundus perimetry. Arch Ophthalmol 1988; 106:1081-4.

42. Sloan LL. Variation of acuity with luminance in ocular diseases and anomalies. Doc Ophthalmol 1969; 26:384-93.

43. Brown B, Lovie-Kitchin J. Contrast sensitivity in central and paracentral retina in age-related maculopathy. Clinical & Experimental Optometry 1987; 70:145-8.

44. Sjostrand J, Frisen L. Contast sensitivity in macular disease. A preliminary report. Acta Ophthalmol (Copenh) 1977; 55:507-14.

45. Sjostrand J. Contrast sensitivity in macular disease using a small-field and a large-field TV-system. Acta Ophthalmol (Copenh) 1979; 57:832-46.

46. Midena E, Degli Angeli C, Blarzino MC, Valenti M, Segato T. Macular function impairment in eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 1997; 38:469-77.

47. Steinmetz RL, Walter D, Fitzke FW, Bird AC. Prolonged dark adaptation in patients with age related macular degeneration. Invest Ophthalmol Vis Sci 1991; 32:711.

48. Steinmetz RL, Haimovici R, Jubb C, Fitzke FW, Bird AC. Symptomatic abnormalities of dark adaptation in patients with age-related Bruch's membrane change. Br J Ophthalmol 1993; 77:549-54.

49. Sunness JS, Massof RW, Johnson MA, Bressler NM, Bressler SB, Fine SL. Diminished foveal sensitivity may predict the development of advanced age-related macular degeneration. Ophthalmology 1989; 96:375-81.

50. Klein ML, Mauldin WM, Stoumbos VD. Heredity and age-related macular degeneration. Observations in monozygotic twins. Arch Ophthalmol 1994; 112:932-7.

51. Gorin MB, Sarneso C, Paul TO, Ngo J, Weeks DE. The genetics of age-related maculopathy. In: Hollyfield JG, Anderson RE, LaVail MM, editors. Retinal Degeneration: clinical and laboratory applications. New York: Plenum Press; 1993. p. 35-47.

52. Piguet B, Heon E, Munier FL, Grounauer PA, Niemeyer G, Butler N, Schorderet DF, Sheffield VC, Stone EM. Full characterization of the maculopathy associated with an Arg-172-Trp mutation in the RDS/peripherin gene. Ophthalmic Genet 1996; 17:175-86.

53. Allikmets R, Shroyer NF, Singh N, Seddon JM, Lewis RA, Bernstein PS, Peiffer A, Zabriskie NA, Li Y, Hutchinson A, Dean M, Lupski JR, Leppert M. Mutation of the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997; 277:1805-7.

54. Pennisi E. Gene found for the fading eyesight of old age. Science 1997; 277:1765-6.

55. Sunness JS. Geographic Atrophy. In: Berger JW, Fine SL, Maguire MG, editors. Age-related macular degeneration. St. Louis (MO): Mosby; 1999. p. 155-166.

56. Marmor MF, McNamara JA. Pattern dystrophy of the retinal pigment epithelium and geographic atrophy. Am J Ophthalmol 1996; 122:382-92.

57. Gass JDM. Stereoscopic atlas of macular diseases: diagnosis and treatment/Macular diseases. 4th ed. St. Louis (MO): Mosby; 1997.

58. Gouras P, Algvere P. Retinal cell transplantation in the macula: new techniques. Vision Res 1996; 36:4121-5.

59. Weisz JM, deJuan E, Humayun MS, Sunness JS, Dagnelie G, Soylu M, Rizzo L, Nussenblatt RB. Allogenic fetal retinal pigment epithelial cell transplant in a patient with geographic atrophy. Retina. In press 1999.

60. Lewis H, Straatsma BR, Foos RY, Lightfoot DO. Reticular degeneration of the pigment epithelium. Ophthalmology 1985; 92:1485-95.

Sunness, Mol Vis 1999; 5:25 <>
©1999 Molecular Vision <>
ISSN 1090-0535