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 retina (photoreceptors, retinal pigment epithelium, choriocappillaris) which can lead to a loss of visual function over time.[1][2][3][4] It is estimated that GA affects >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 and while there are therapies for wet AMD, GA currently has no approved treatment options. 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 foveal, 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] 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.[13]

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.[14][15]

Recent studies indicate that geographic atrophy may be due to deficiencies in blood flow within the choriocapillaris[16]. These studies used swept source optical coherence tomography angiography to examine the blood flow within the choriocapillaris. They also used fundus autoflorescence to image the retinal pigment epithelium over the course of a year. They found that prior to atrophy of the retinal pigment epithelium, there is a deficiency in choriocapillaris blood flow. Since the choriocapillaris is the main blood supply of the retinal pigment epithelium, it is leading some to believe that geographic atrophy is primarily an ischemic disease (disease due to decreased blood flow).

Diagnosis

Diagnosis of geographic atrophy is made by an ophthalmologist in clinic. Fundus autoflorescence and optical coherence tomorgraphy angiography are imaging modalities that can be used in the diagnosis. While fundus autoflorescene 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[17]. This is useful because it could indicated that the patient may be developing wet age related macular degeneration. Since patients with geographic atrophy are at higher risk for developing wet age related macular degeneration, this could be especially useful in the monitoring of patients with geography atrophy. If signs of wet age related macular degeneration are found, the physician can initiate treatment of wet age related macular degeneration[18].

Treatment

There are currently no approved treatments to reverse or halt the progression of geographic atrophy.

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 (Chicago, Ill. : 1960). 127 (9): 1168–74. doi:10.1001/archophthalmol.2009.198. PMC 6500457. PMID 19752426.
  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 (Auckland, N.Z.). 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. 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.
  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.
  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. PMC 2730505. PMID 8841306.
  13. 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.
  14. 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.
  15. Boyer DS, et al. Retina 2016; epub Nov 29, 2016
  16. 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.
  17. Garcia-Layana, Alfredo. "Optical Coherence Tomography in Age-related Macular Degeneration". AMD book. Retrieved 8 December 2019.
  18. Malciolu Radu Alexandru (January–March 2016). "Wet age related macular degeneration management and follow-up". Rom J Ophthalmol. 60(1): 9–13. (1): 9–13. PMC 5712923. PMID 27220225.
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