Pathophysiology

Age-related macular degeneration (AMD) is a progressively deteriorating eye condition affecting the central portion of the retina which is responsible for high-acuity vision. AMD is a leading cause of vision loss for adults; patients with AMD have central blindness, but their peripheral vision is spared, and there are 2 forms of the condition:1-3

  • “Dry” (atrophic) AMD accounts for approximately 80% to 90% of reported cases and is characterized by a slow degeneration of the retinal pigment epithelium and retinal photoreceptors. Dry AMD can either progress to geographic AMD (late-stage dry AMD) or wet AMD, both of which are considered end-stage disease.
  • “Wet” (neovascular) AMD accounts for approximately 10% to 20% of cases but has a more aggressive course, with rapid deterioration of vision. Wet AMD is responsible for up to 90% of cases of legal blindness caused by AMD.

The retina undergoes many changes as part of the natural aging process. AMD is a complex disease characterized by pathologic changes in the retinal pigment epithelium and the Bruch membrane, the extracellular matrix that lies between the retinal pigment epithelium (RPE) and the choroidal vasculature. The RPE supports the function of the retinal photoreceptor cells by removing metabolic wastes and transporting them through the Bruch membrane to the choroidal vasculature. As the RPE cells age, they accumulate lipofuscin, end products of incomplete metabolism of external segments of the photoreceptors, leading to an accumulation of material that deposits between the RPE and Bruch membrane, forming drusen, the focal yellow deposits of acellular debris that can be seen through an ophthalmoscope. The pathogenesis of AMD, especially geographic AMD, is not completely understood; however, evidence indicates that the key contributors to the development of AMD include lipofuscin/drusen accumulation, chronic inflammation, oxidative damage, and mutations in the complement system.1,4

AMD is characterized by 3 main levels of severity:1,5-8 (See Figure below)

  • Early AMD is characterized by small drusen, few medium drusen, and minimal or no retinal pigment epithelial changes.
  • Intermediate AMD is characterized by extensive medium drusen or 1 or more large drusen in one or both eyes or geographic atrophy (GA) that does not extend to the center of the macula. At this point, patients are considered to be at risk for progression to advanced AMD.
  • Advanced AMD is defined as either progression to choroidal neovascularization or GA involving the center of the macula. Examination will reveal focal atrophy of the retinal pigment epithelium over the macula in patients with geographic AMD. These patients also have cell death in the adjacent areas of the retinal pigment epithelium. In patients with wet AMD, new vessels from the choroidal or retinal circulation will be visible in the subretinal space (choroidal neovascularization, CNV), often with a collection of blood and/or fluid beneath the retina.

A subclinical level of severity has also been noted where patients may demonstrate abnormal dark adaptation, but still exhibit no evidence of drusen formation or RPE defects via fundus evaluation.9

AMD, age-related macular degeneration; GA, geographic atrophy; RPE, retinal pigment epithelium.
Figure: Classification of AMD severity10

Drusen play a role in inhibiting the transport of metabolites to the choroid vessels and their molecular components also initiate inflammation through the complement cascade.1,11 This inflammation damages the RPE, photoreceptor cells, and choroidal vessels and may lead to geographic atrophy. Continued damage to the RPE leads to further dysfunction of the Bruch membrane, which in some patients, is accompanied by a rise in vascular epithelial growth factor (VEGF), resulting in the growth of new vessels under the retinal pigment epithelium and the retina. These new, fragile vessels will leak causing fluid to build up under the retina which can result in the detachment of retinal cones and pigment cells (RPE detachment) and sudden vision loss. Eventually, a disciform scar forms in the macula characterizing the end stage of wet AMD.1

Oxidative stress also appears to contribute to the development of AMD. Retinal tissues are among the most demanding in terms of oxygen consumption, and The macula is in a constant state of stress from light exposure and high oxygen consumption.1,12 For antioxidative processes to function correctly, patients need substantial amounts of vitamins (including vitamins C and E); minerals, such as zinc, selenium, copper, and manganese; antioxidants such as glutathione; and carotenoids such as lutein and mezoxantine. Although studies about the protective effects of nutritional supplementation on the eyes have been ambiguous, researchers agree that patients with AMD are in a metabolically altered state of oxidation reduction and antioxidant supplementation is convenient and promotes health.1,4 The main genetic abnormalities associated with AMD occur in the genes that regulate inflammation, such as the complement factor H gene.1,2 Many studies have investigated the role of genetic variants, such as the complement factor H gene and the age-related maculopathy susceptibility gene 2 (ARMS2), on the development and progression of AMD.1,13

The neovascular component of wet AMD has been the focus of rigorous research that has helped with understanding a small part of the complex process of angiogenesis in a wide range of diseases.5,14 Those studies have led to the identification of various molecules that serve as proangiogenic factors, including VEGF, basic fibroblast growth factor, placental-like growth factor (PLGF), transforming growth factor-b, platelet-derived growth factor (PDGF), interleukin-8, nitric oxide synthetase, angiopoietin, and pleiotrophin among others.5,14-18

References

  1. Cunningham J. Recognizing age-related macular degeneration in primary care. JAAPA. 2017;30(3):18-22.
  2. Cheung CM, Wong TY. Is age-related macular degeneration a manifestation of systemic disease? New prospects for early intervention and treatment. J Intern Med. 2014;276(2):140-153.
  3. American Academy of Ophthalmology. Age-Related Macular Degeneration PPP—2019. https://www.aao.org/preferred-practice-pattern/age-related-macular-degeneration-ppp. Accessed April 3, 2020.
  4. Michalska-Malecka K, Kabiesz A, Nowak M, Spiewak D. Age related macular degeneration—challenge for future: pathogenesis and new perspectives for the treatment. Eur Geriatr Med. 2015;6(1):69-75.
  5. Velez-Montoya R, Oliver SC, Olson JL, et al. Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention. Retina. 2014;34(3):423–441.
  6. Swaroop A, Chew EY, Rickman CB, Abecasis GR. Unraveling a multifactorial late-onset disease: from genetic susceptibility to disease mechanisms for age-related macular degeneration. Annu Rev Genomics Hum Genet. 2009;10:19-43.
  7. Davis MD, Gangnon RE, Lee LY, et al. The Age-Related Eye Disease Study severity scale for age-related macular degeneration: AREDS Report No. 17. Arch Ophthalmol. 2005;123:1484-1498.
  8. Ferris FL, Davis MD, Clemons TE, et al. A simplified severity scale for age-related macular degeneration: AREDS Report No. 18. Arch Ophthalmol. 2005;123:1570-1574.
  9. Gerson J; Clinical Advisory Committee. Practical guidelines for the treatment of AMD. Rev Optometry (Suppl). 2017. https://www.reviewofoptometry.com/publications/ro1017-practical-guidelines-for-the-treatment-of-amd. Accessed April 3, 2020.
  10. Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:1313–1330.
  11. Bradley DT, Zipfel PF, Hughes AE. Complement in age-related macular degeneration: a focus on function. Eye. 2011;25(6):683-693.
  12. Jarrett SG, Boulton ME. Consequences of oxidative stress in age-related macular degeneration. Mol Aspects Med. 2012; 33(4):399-417.
  13. Schmidl D, Garhöfer G, Schmetterer L. Nutritional supplements in age-related macular degeneration. Acta Ophthalmol. 2015; 93(2):105-121.
  14. Mousa SA, Mousa SS. Current status of vascular endothelial growth factor inhibition in age-related macular degeneration. BioDrugs. 2010;24:183–194.
  15. Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res. 1997;57: 963–969.
  16. Ferrara N, Alitalo K. Clinical applications of angiogenic growth factors and their inhibitors. Nat Med. 1999;5:1359–1364.
  17. Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis. Nature. 2011;473:298–307.
  18. Velez-Montoya R, Clapp C, Rivera JC, et al. Intraocular and systemic levels of vascular endothelial growth factor in advanced cases of retinopathy of prematurity. Clin Ophthalmol. 2010;4:947–953.

Clinician Scientific & Educational Resources

The RELIEF Clinical Toolkit is an online tool that aims to provide clinicians with up-to-date information on the presentation, prognosis, pathophysiology, and treatment strategies for age-related macular degeneration (AMD). Click on one of the options below to learn more about AMD.

This activity is provided by Med Learning Group. This activity is co-provided by Ultimate Medical Academy/Complete Conference Management (CCM). This activity is supported by an independent medical education grant from Regeneron Pharmaceuticals, Inc.

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Scientific Council

Neil M. Bressler, MD

James P. Gills Professor of Ophthalmology
Professor of Ophthalmology, Johns Hopkins University School of Medicine
Wilmer Eye Institute, Johns Hopkins Medicine
Baltimore, MD

A. Paul Chous, MA, OD, FAAO

Specializing in Diabetes Eye Care & Education, Chous Eye Care Associates
Adjunct Professor of Optometry, Western University of Health Sciences
AOA Representative, National Diabetes Education Program
Tacoma, WA

Steven Ferrucci, OD, FAAO

Chief of Optometry, Sepulveda VA Medical Center
Professor, Southern California College of Optometry at Marshall B. Ketchum University
Sepulveda, CA

Julia A. Haller, MD

Ophthalmologist-in-Chief
Wills Eye Hospital
Philadelphia, PA

Allen C. Ho, MD, FACS

Director, Retina Research
Wills Eye Hospital
Professor and Chair of the Department of Ophthalmology
Thomas Jefferson University Hospitals
Philadelphia, PA

Charles C. Wykoff, MD, PhD

Director of Research, Retina Consultants of Houston
Associate Professor of Clinical Ophthalmology
Blanton Eye Institute & Houston Methodist Hospital
Houston, TX