Geographic atrophy

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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.

Contents

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

Presentation

Geographic atrophy is a chronic disease, which leads to visual function loss. 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]

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. [19] [20]

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. [21]

Risk factors for GA progression

A plethora of in vivo risk factors for GA progression have been published and validated. [22]

Recent studies indicate that geographic atrophy may be due to deficiencies in blood flow within the choriocapillaris. [23] [24] [25] 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 the course of 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 which 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).

It was also shown that non-exudative neovascular membranes, which can recapitulate the choriocapillaris, are associated with a markedly slower GA progression. [26] This further supports the vascular insufficiency hypothesis.

Diagnosis

Diagnosis of geographic atrophy is made by an ophthalmologist 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 geography atrophy. If signs of neovascular AMD 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 and new findings

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]

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.

Related Research Articles

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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" (PDF). Archives of Ophthalmology. 127 (9): 1168–74. doi:10.1001/archophthalmol.2009.198. PMC   6500457 . PMID   19752426.{{cite journal}}: CS1 maint: numeric names: authors list (link)
  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. PMC   2693982 . PMID   19668732.
  4. ↑ Lindner, Moritz; Fleckenstein, Monika; Schmitz-Valckenberg, Steffen; Holz, Frank G. (2018), "Atrophy, Geographic", Encyclopedia of Ophthalmology, 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. 1 2 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. PMC   5384792 . 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. PMC   6746569 . 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.
  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. S2CID   11146594.
  11. ↑ Lindner, Moritz; Böker, Alexander; Mauschitz, Matthias M.; Göbel, Arno P.; Fimmers, Rolf; Brinkmann, Christian K.; Schmitz-Valckenberg, Steffen; Schmid, Matthias; Holz, Frank G. (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.
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  15. ↑ Künzel SH, Lindner M, Sassen J, Möller PT, Goerdt L, Schmid M, Schmitz-Valckenberg S, Holz FG, Fleckenstein M, Pfau M (September 2021). "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. doi:10.1001/jamaophthalmol.2021.3826. PMC   8485212 . PMID   34591067.
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  17. ↑ Holz, Frank G.; Sadda, SriniVas R.; Staurenghi, Giovanni; Lindner, Moritz; Bird, Alan C.; Blodi, Barbara A.; Bottoni, Ferdinando; Chakravarthy, Usha; Chew, Emily Y. (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. ↑ 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.
  20. ↑ 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. S2CID   28757961.
  21. ↑ DOI: 10.14336/AD.2020.0912
  22. ↑ 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.
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  24. ↑ 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 . hdl: 2434/721615 . PMID   30131381.
  25. ↑ Müller PL, Pfau M, Möller PT, Nadal J, Schmid M, Lindner M, de Sisternes L, Stöhr H, Weber BH, Neuhaus C, Herrmann P, Schmitz-Valckenberg S, Holz FG, Fleckenstein M (March 2018). "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. doi: 10.1167/iovs.18-23819 . PMID   30140905. S2CID   52077435.
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  27. ↑ Garcia-Layana, Alfredo. "Optical Coherence Tomography in Age-related Macular Degeneration". AMD book. Retrieved 8 December 2019.
  28. ↑ Malciolu Radu Alexandru (January–March 2016). "Wet age-related macular degeneration management and follow-up". Rom J Ophthalmol. 60 (1): 9–13. PMC   5712923 . 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. ↑ Schmitz-Valckenberg S, Brinkmann CK, Alten F, Herrmann P, Stratmann NK, Göbel AP, Fleckenstein M, Diller M, Jaffe GJ, Holz FG (September 2011). "Semiautomated image processing method for identification and quantification of geographic atrophy in age-related macular degeneration". Invest Ophthalmol Vis Sci. 52 (10): 7640–6. doi:10.1167/iovs.11-7457. PMID   21873669.
  31. ↑ Pfau M, Goerdt L, Schmitz-Valckenberg S, Mauschitz MM, Mishra DK, Holz FG, Lindner M, Fleckenstein M (May 2017). "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. doi: 10.1167/iovs.17-21764 . PMID   28632841. S2CID   10855695.
  32. ↑ Shi Y, Zhang Q, Zhou H, Wang L, Chu Z, Jiang X, Shen M, Thulliez M, Lyu C, Feuer W, de Sisternes L, Durbin MK, Gregori G, Wang RK, Rosenfeld PJ (April 2021). "Correlations Between Choriocapillaris and Choroidal Measurements and the Growth of Geographic Atrophy Using Swept Source OCT Imaging". Am J Ophthalmol. 224: 321–331. doi:10.1016/j.ajo.2020.12.015. PMC   8058170 . PMID   33359715.
  33. ↑ Pfau M, von der Emde L, de Sisternes L, Hallak JA, Leng T, Schmitz-Valckenberg S, Holz FG, Fleckenstein M, Rubin DL (October 2020). "Progression of Photoreceptor Degeneration in Geographic Atrophy Secondary to Age-related Macular Degeneration". JAMA Ophthalmol. 138 (10): 1026–1034. doi:10.1001/jamaophthalmol.2020.2914. PMC   7426886 . PMID   32789526.
  34. ↑ Reiter GS, Told R, Schranz M, Baumann L, Mylonas G, Sacu S, Pollreisz A, Schmidt-Erfurth U (June 2020). "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. doi:10.1167/iovs.61.6.11. PMC   7415285 . PMID   32503052.
  35. ↑ FDA Approves First Treatment for Geographic Atrophy
  36. ↑ "Novel Drug Approvals for 2023". U.S. Food and Drug Administration (FDA). 18 August 2023. Retrieved 25 August 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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