Geographic atrophy

Short description: Advanced form of age-related macular degeneration

Geographic atrophy

Fundus of geographic atrophy

Geographic atrophy (GA), also known as atrophic age-related macular degeneration (AMD) or advanced dry AMD, is an advanced form of age-related macular degeneration that can result in the progressive and irreversible loss of retinal tissue (photoreceptors, retinal pigment epithelium, choriocapillaris) which can lead to a loss of central vision over time.[1][2][3][4] It is estimated that GA affects over 5 million people worldwide and approximately 1 million patients in the US,[5][6] which is similar to the prevalence of neovascular (wet) AMD, the other advanced form of the disease.

The incidence of advanced AMD, both geographic atrophy and neovascular AMD, increases exponentially with age. Most current clinical trials aim to reduce the progression of GA lesion enlargement.[7]

The name derives from the resemblance of the regions of atrophied cells to a geographical map.

## Contents

* 1 Presentation
* 2 Risk factors
* 3 Pathogenesis
* 4 Diagnosis
* 4.1 Quantification of GA progression
* 5 Treatment
* 6 Research
* 7 References

## Presentation

Geographic atrophy is a chronic disease, which leads to visual function loss centrally. This often results in difficulties performing daily tasks such as reading, recognizing faces, and driving, and ultimately has severe consequences on independence.[8][9][10]

Initially, patients often have good visual acuity if the GA lesions are not involved in the central macular, or fovea, region of the retina.[7][11] As such, a standard vision test may underrepresent the visual deficit experienced by patients who report challenges reading, driving or seeing in low light conditions.[12] Reading speed is often initially unaffected due to foveal sparing, but worsens progressively as the area of atrophy enlarges.[13][14][15] As the disease progresses, vision-related quality-of-life declines markedly.[16]

While fluorescein angiography and optical coherence tomography are today well established for diagnosing and tracking progression in geographic atrophy more complex diagnostic assessments may be required in the context of clinical trials.[17] In February 2023, the FDA approved Pegcetacoplan for the treatment of people with geographic atrophy secondary to age-related macular degeneration.[18]

## Risk factors

A plethora of in vivo risk factors for GA progression have been published and validated.[19]

Recent studies indicate that geographic atrophy may be due to deficiencies in blood flow within the choriocapillaris.[20][21][22] These studies used swept-source optical coherence tomography angiography to examine the choriocapillaris. Using imaging algorithms, they then determined which regions of the choriocapillaris had deficient blood flow, thus creating a heat map of the blood supply to the retinal pigment epithelium. They went on to use fundus autofluorescence to image the retinal pigment epithelium over a year, this allowed them to map out the direction and magnitude with the geographic atrophy spread. They then found that regions of the choriocapillaris that had less blood flow were more likely to degenerate and become geographic atrophy. Since the choriocapillaris is the main blood supply of the retinal pigment epithelium in the macula, which has no retinal blood supply, it is leading some to believe that geographic atrophy is primarily an ischemic disease (disease due to decreased blood flow).[citation needed]

It was also shown that non-exudative neovascular membranes, which can recapitulate the choriocapillaris, are associated with a markedly slower GA progression.[23] This further supports the vascular insufficiency hypothesis.[citation needed]

## Pathogenesis

The pathogenesis of GA is not fully understood yet. It is likely multifactorial and triggered by intrinsic and extrinsic stressors of the poorly regenerative retinal pigment epithelium (RPE), particularly oxidative stress caused by the high metabolic demand of photoreceptors, photo-oxidation, and environmental stressors such as cigarette smoke. Variations in several genes, particularly in the complement system, increase the risk of developing GA. This is an active area of research but the current hypothesis is that with aging, damage caused by these stressors accumulates, which coupled with a genetic predisposition, results in the appearance of drusen and lipofuscin deposits (early and intermediate AMD). These and other products of oxidative stress can trigger inflammation via multiple pathways, particularly the complement cascade, ultimately leading to loss of photoreceptors, RPE, and choriocapillaris, culminating in atrophic lesions that grow over time.[24][25]

Age-related macular degeneration (AMD) is characterized by retinal iron accumulation and lipid peroxidation. Ferroptosis is initiated by lipid peroxidation and is characterized by iron-dependent accumulation. Studies on iron accumulation and elevated lipid peroxidation in the aging retina, and their intimate role in ferroptosis, have implicated ferroptosis in AMD pathogenesis.[26]

## Diagnosis

Diagnosis of geographic atrophy is made by an ophthalmologist or optometrist in the clinic. Fundus autofluorescence and optical coherence tomography angiography are imaging modalities that can be used in the diagnosis. While fundus autofluorescence is the standard modality for viewing geographic atrophy, optical coherence tomography can offer unique benefits. Optical coherence tomography angiography can help the physician see if there is any subretinal fluid in the eye.[27] This is useful because it could indicate that the patient may be developing wet AMD. Since patients with geographic atrophy are at higher risk for developing advanced wet AMD (neovascular AMD), this could be especially useful in the monitoring of patients with geographic atrophy. If signs of neovascular AMD are found, the physician can initiate treatment of wet age-related macular degeneration.[28]

### Quantification of GA progression

Traditionally, GA progression is quantified in terms of the area of retinal pigment epithelium atrophy.[29] Multiple imaging methods can be applied to quantify this area of retinal pigment epithelium atrophy including short-wavelength (blue) fundus autofluorescence imaging,[30] green fundus autofluorescence imaging,[31] and en face optical coherence tomography imaging.[32]

However, more recent data suggest that photoreceptor degeneration is not limited to the area of retinal pigment epithelium atrophy, but extends beyond this area. These more subtle changes can be quantified by volumetric analyses of optical coherence tomography data.[33][34]

## Treatment

In February 2023, Apellis Pharmaceuticals received the first FDA approval of pegcetacoplan for the treatment of this condition.[35]

Avacincaptad pegol (Izervay) was approved in the United States in August 2023 for the treatment of geographic atrophy secondary to age-related macular degeneration.[36][37]

## Research

It was recently discovered that the aging pigment lipofuscin can be broken down with the help of melanin and drugs through a newly discovered mechanism (chemical excitation).[38] The pigment lipofuscin plays a central role in the development of dry AMD and geographic atrophy. This breakdown can be supported by medication. This discovery can be translated into the development of a therapy to treat dry AMD.

## References

1. ↑ Lindblad, AS; Lloyd, PC; Clemons, TE; Gensler, GR; Ferris FL, 3rd; Klein, ML; Armstrong, JR; Age-Related Eye Disease Study Research, Group. (September 2009). "Change in area of geographic atrophy in the Age-Related Eye Disease Study: AREDS report number 26.". Archives of Ophthalmology 127 (9): 1168–74. doi:10.1001/archophthalmol.2009.198. PMID 19752426. PMC 6500457. https://escholarship.org/content/qt7dx2n6hg/qt7dx2n6hg.pdf?t=oq3lf4.
2. ↑ Sunness, JS (3 November 1999). "The natural history of geographic atrophy, the advanced atrophic form of age-related macular degeneration.". Molecular Vision 5: 25. PMID 10562649.
3. ↑ Bonilha, Vera L (2008). "Age and disease-related structural changes in the retinal pigment epithelium". Clinical Ophthalmology 2 (2): 413–424. doi:10.2147/opth.s2151. ISSN 1177-5467. PMID 19668732.
4. ↑ Lindner, Moritz; Fleckenstein, Monika; Schmitz-Valckenberg, Steffen; Holz, Frank G. (2018) (in en), Atrophy, Geographic, Springer Berlin Heidelberg, pp. 207–209, doi:10.1007/978-3-540-69000-9_1125, ISBN 9783540682929
5. ↑ Wong, Wan Ling; Su, Xinyi; Li, Xiang; Cheung, Chui Ming G; Klein, Ronald; Cheng, Ching-Yu; Wong, Tien Yin (February 2014). "Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis". The Lancet Global Health 2 (2): e106–e116. doi:10.1016/S2214-109X(13)70145-1. PMID 25104651.
6. ↑ Rudnicka, Alicja R.; Kapetanakis, Venediktos V.; Jarrar, Zakariya; Wathern, Andrea K.; Wormald, Richard; Fletcher, Astrid E.; Cook, Derek G.; Owen, Christopher G. (July 2015). "Incidence of Late-Stage Age-Related Macular Degeneration in American Whites: Systematic Review and Meta-analysis". American Journal of Ophthalmology 160 (1): 85–93.e3. doi:10.1016/j.ajo.2015.04.003. PMID 25857680.
7. ↑ 7.0 7.1 Sadda, SriniVas R.; Chakravarthy, Usha; Birch, David G.; Staurenghi, Giovanni; Henry, Erin C.; Brittain, Christopher (October 2016). "Clinical Endpoints for the Study of Geographic Atrophy Secondary to Age-Related Macular Degeneration". Retina 36 (10): 1806–1822. doi:10.1097/IAE.0000000000001283. PMID 27652913.
8. ↑ Brown, Jamie C.; Goldstein, Judith E.; Chan, Tiffany L.; Massof, Robert; Ramulu, Pradeep (August 2014). "Characterizing Functional Complaints in Patients Seeking Outpatient Low-Vision Services in the United States". Ophthalmology 121 (8): 1655–1662.e1. doi:10.1016/j.ophtha.2014.02.030. PMID 24768243.
9. ↑ Tschosik, Elizabeth; Leidy, Nancy Kline; Kimel, Miriam; Dolan, Chantal; Souied, Eric; Varma, Rohit; Bressler, Neil M. (11 June 2015). "Quantifying functional reading independence in geographic atrophy: the FRI Index". Investigative Ophthalmology & Visual Science 56 (7): 4789. ISSN 1552-5783. http://iovs.arvojournals.org/article.aspx?articleid=2334770.
10. ↑ DeCarlo, DK; Scilley, K; Wells, J; Owsley, C (March 2003). "Driving habits and health-related quality of life in patients with age-related maculopathy.". Optometry and Vision Science 80 (3): 207–13. doi:10.1097/00006324-200303000-00010. PMID 12637832.
11. ↑ Lindner, Moritz; Böker, Alexander; Mauschitz, Matthias M.; Göbel, Arno P.; Fimmers, Rolf; Brinkmann, Christian K.; Schmitz-Valckenberg, Steffen; Schmid, Matthias et al. (July 2015). "Directional Kinetics of Geographic Atrophy Progression in Age-Related Macular Degeneration with Foveal Sparing". Ophthalmology 122 (7): 1356–1365. doi:10.1016/j.ophtha.2015.03.027. ISSN 0161-6420. PMID 25972258.
12. ↑ Sunness, JS; Applegate, CA; Haselwood, D; Rubin, GS (September 1996). "Fixation patterns and reading rates in eyes with central scotomas from advanced atrophic age-related macular degeneration and Stargardt disease.". Ophthalmology 103 (9): 1458–66. doi:10.1016/S0161-6420(96)30483-1. PMID 8841306.
13. ↑ "Foveal-Sparing Scotomas in Advanced Dry Age-Related Macular Degeneration". J Vis Impair Blind 102 (10): 600–610. October 2008. doi:10.1177/0145482X0810201004. PMID 20224750.
14. ↑ "Determinants of Reading Performance in Eyes with Foveal-Sparing Geographic Atrophy". Ophthalmol Retina 3 (3): 201–210. March 2019. doi:10.1016/j.oret.2018.11.005. PMID 31014695. https://ora.ox.ac.uk/objects/uuid:fea17910-5b2e-4b83-95cb-b6c722a16d54.
15. ↑ "Association of Reading Performance in Geographic Atrophy Secondary to Age-Related Macular Degeneration With Visual Function and Structural Biomarkers". JAMA Ophthalmol 139 (11): 1191–1199. September 2021. doi:10.1001/jamaophthalmol.2021.3826. PMID 34591067.
16. ↑ "Determinants of Quality of Life in Geographic Atrophy Secondary to Age-Related Macular Degeneration". Invest Ophthalmol Vis Sci 61 (5): 63. May 2020. doi:10.1167/iovs.61.5.63. PMID 32462198.
17. ↑ Holz, Frank G.; Sadda, SriniVas R.; Staurenghi, Giovanni; Lindner, Moritz; Bird, Alan C.; Blodi, Barbara A.; Bottoni, Ferdinando; Chakravarthy, Usha et al. (April 2017). "Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings". Ophthalmology 124 (4): 464–478. doi:10.1016/j.ophtha.2016.12.002. ISSN 1549-4713. PMID 28109563.
18. ↑ "FDA Approves Syfovre (pegcetacoplan injection) as the First and Only Treatment for Geographic Atrophy (GA), a Leading Cause of Blindness" (Press release). Apellis Pharmaceuticals. 17 February 2023. Archived from the original on 17 February 2023. Retrieved 18 February 2023 - via GlobeNewswire.
19. ↑ "The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration". Ophthalmology 125 (3): 369–390. March 2018. doi:10.1016/j.ophtha.2017.08.038. PMID 29110945.
20. ↑ Thulliez, M (June 2019). "Correlations between Choriocapillaris Flow Deficits around Geographic Atrophy and Enlargement Rates Based on Swept-Source OCT Imaging.". Ophthalmol Retina 3 (6): 478–488. doi:10.1016/j.oret.2019.01.024. PMID 31174669.
21. ↑ Nassisi, M (21 August 2018). "Choriocapillaris impairment around the atrophic lesions in patients with geographic atrophy: a swept-source optical coherence tomography angiography study.". Br J Ophthalmol 103 (7): 911–917. doi:10.1136/bjophthalmol-2018-312643. PMID 30131381.
22. ↑ "Choroidal Flow Signal in Late-Onset Stargardt Disease and Age-Related Macular Degeneration: An OCT-Angiography Study". Invest Ophthalmol Vis Sci 59 (4): AMD122–AMD131. March 2018. doi:10.1167/iovs.18-23819. PMID 30140905.
23. ↑ "Type 1 Choroidal Neovascularization Is Associated with Reduced Localized Progression of Atrophy in Age-Related Macular Degeneration". Ophthalmol Retina 4 (3): 238–248. March 2020. doi:10.1016/j.oret.2019.09.016. PMID 31753808. https://ora.ox.ac.uk/objects/uuid:bf6099d6-b58f-4fde-a693-b02ee5fe2076.
24. ↑ Holz, Frank G.; Strauss, Erich C.; Schmitz-Valckenberg, Steffen; van Lookeren Campagne, Menno (May 2014). "Geographic atrophy: clinical features and potential therapeutic approaches.". Ophthalmology 121 (5): 1079–1091. doi:10.1016/j.ophtha.2013.11.023. PMID 24433969.
25. ↑ Saleh Abdelfattah, Nizar; Zhang, Hongyang; Boyer, David S.; Sadda, SriniVas R. (2016). "Progression of Macular Atrophy in Patients with Neovascular Age-Related Macular Degeneration Undergoing Antivascular Endothelial Growth Factor Therapy". Retina 36 (10): 1843–1850. doi:10.1097/iae.0000000000001059. PMID 27135213.
26. ↑ DOI: 10.14336/AD.2020.0912
27. ↑ Garcia-Layana, Alfredo. "Optical Coherence Tomography in Age-related Macular Degeneration". http://www.amdbook.org/content/optical-coherence-tomography-age-related-macular-degeneration.
28. ↑ Malciolu Radu Alexandru (January–March 2016). "Wet age-related macular degeneration management and follow-up". Rom J Ophthalmol 60 (1): 9–13. PMID 27220225.
29. ↑ Fleckenstein, M; Mitchell, P; Freund, KB; Sadda, S; Holz, FG; Brittain, C; Henry, EC; Ferrara, D (March 2018). "The Progression of Geographic Atrophy Secondary to Age-Related Macular Degeneration". Ophthalmology 125 (3): 369–390. doi:10.1016/j.ophtha.2017.08.038. PMID 29110945.
30. ↑ "Semiautomated image processing method for identification and quantification of geographic atrophy in age-related macular degeneration". Invest Ophthalmol Vis Sci 52 (10): 7640–6. September 2011. doi:10.1167/iovs.11-7457. PMID 21873669.
31. ↑ "Green-Light Autofluorescence Versus Combined Blue-Light Autofluorescence and Near-Infrared Reflectance Imaging in Geographic Atrophy Secondary to Age-Related Macular Degeneration". Invest Ophthalmol Vis Sci 58 (6): BIO121–BIO130. May 2017. doi:10.1167/iovs.17-21764. PMID 28632841.
32. ↑ "Correlations Between Choriocapillaris and Choroidal Measurements and the Growth of Geographic Atrophy Using Swept Source OCT Imaging". Am J Ophthalmol 224: 321–331. April 2021. doi:10.1016/j.ajo.2020.12.015. PMID 33359715.
33. ↑ "Progression of Photoreceptor Degeneration in Geographic Atrophy Secondary to Age-related Macular Degeneration". JAMA Ophthalmol 138 (10): 1026–1034. October 2020. doi:10.1001/jamaophthalmol.2020.2914. PMID 32789526.
34. ↑ "Subretinal Drusenoid Deposits and Photoreceptor Loss Detecting Global and Local Progression of Geographic Atrophy by SD-OCT Imaging". Invest Ophthalmol Vis Sci 61 (6): 11. June 2020. doi:10.1167/iovs.61.6.11. PMID 32503052.
35. ↑ MA, Laura Joszt (October 19, 2025). "FDA Approves First Treatment for Geographic Atrophy | AJMC". https://www.ajmc.com/view/fda-approves-first-treatment-for-geographic-atrophy.
36. ↑ "Novel Drug Approvals for 2023". 18 August 2023. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023.
37. ↑ "Iveric Bio Receives U.S. FDA Approval for Izervay (avacincaptad pegol intravitreal solution), a New Treatment for Geographic Atrophy" (Press release). Astellas Pharma Inc. 4 August 2023. Retrieved 25 August 2023 - via PR Newswire.
38. ↑ Lyu Y, Tschulakow AV, Wang K, Brash DE, Schraermeyer U. Chemiexcitation and melanin in photoreceptor disc turnover and prevention of macular degeneration. Proc Natl Acad Sci U S A. 2023;120(20):e2216935120.

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