Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a degenerative disease of the retina. The macula—the central most part of the retina that is responsible for fine visual details—is the primary site of involvement.
Previous classification of AMD identified two manifestations: “wet” and “dry.” Newer terminology favors the use of “early” and “late” stages.
Early AMD is characterized by the presence of small drusen—yellow, focal deposits within the retina that can be visualized during dilated ophthalmologic examination. Small deposits are often found in people aged 50 years and over. Therefore, the presence of such lesions is neither essential for diagnosis nor pathognomonic. However, in conjunction with increased or decreased pigmentation of the epithelial layer of the retina, drusen are a sign of early AMD. Development of early AMD may be asymptomatic or may cause blurred vision or impaired vision in low light.
As AMD progresses to late stage, central vision gradually worsens until patients are no longer able to perform tasks requiring fine visual acuity. AMD is the most common cause of legal blindness (defined as 20/200 or worse in both eyes) in the geriatric population in the United States. Peripheral vision is often spared and may allow limited performance of certain daily activities.
The late stage of AMD is further subdivided into two categories based on the changes observed within the subretinal space: neovascular and non-neovascular. Neovascular AMD was previously known as “wet” AMD, due to an abnormal growth of vessels. While neovascular AMD is less common than non-neovascular AMD (10%-15% of all cases), it carries a worse prognosis and can account for extensive visual loss. Neovascularization can progress quickly. Therefore, any acute alteration in vision should prompt immediate consultation with an ophthalmologist.
Non-neovascular AMD can transform to neovascular AMD, and vice versa. Both processes may be diagnosed in the same eye or each eye may show unique changes. It is not clear whether neovascular and non-neovascular AMD are different manifestations of the same disease or two different entities.
AMD is thought to be caused in part by exposure to ultraviolet radiation, mainly from sunlight. Just as skin can be damaged by excessive sun exposure, the pigmented layer of the retina that protects photoreceptors can also become damaged with excessive ultraviolet rays. Blue light has also been found to induce similar damage.
Race and Ethnicity. Non-Hispanic whites in the US have a 2.5% prevalence. In contrast, the US Black and Hispanic populations each have a prevalence of about 0.9%.
Age. AMD rarely occurs in persons under age 55. The prevalence is 0.8% in those aged 70 and older, increasing to 16% in those over 90.
Smoking. Individuals who smoke have a relative risk of 2.0 and greater, compared with those who have never smoked. Risk may remain elevated for 15 or more years after smoking cessation.
Family history. Genetic factors are linked to increased AMD risk, particularly when combined with smoking.
Alcohol. Heavy use has been linked to early disease.
Sunlight. AMD is believed to be more prevalent near the equator.
The minimum age for diagnosis of AMD is 50 years. The classification of disease severity is based not on visual acuity, but on the characteristic findings on dilated retinal examination. These include alterations in the retinal pigmented epithelium, periretinal hemorrhages, retinal atrophy, and/or retinal scarring. As noted above, drusen are not pathognomonic.
- Ocular coherence tomography (OCT) is the gold standard in diagnosing and managing patients with neovascular AMD.
- Slit-lamp photography of the macula is sometimes performed to document progression.
- Fluorescein angiography detects the presence and location of any subretinal neovascularization, but the introduction of OCT has replaced it as a tool.
Late stages of both neovascular and non-neovascular AMD can resemble other ophthalmologic diseases, which must always be ruled out first.
For prevention steps, see Nutritional Considerations, below.
Early AMD is managed by lifestyle modifications. These may include but are not limited to avoidance of tobacco and alcohol. Patients should be referred to an ophthalmologist for close observation.
Vitamins C and E, beta-carotene, and zinc: Foods naturally high in these antioxidants have been shown to reduce progression from early to late disease (see Nutritional Considerations).
For intermediate to advanced disease, antioxidant supplements are indicated (See Nutrition Considerations, below). However, according to the Age-Related Macular Degeneration Preferred Practice Pattern 2015 guidelines, evidence does not support the use of these supplements for patients with less than intermediate AMD.
There is no specific medical or surgical treatment for non-neovascular AMD. Patients should be regularly monitored by an ophthalmologist and should report any abrupt changes in vision as this may indicate neovascularization.
If OCT or fluorescein angiography reveals the classic features of neovascularization, the first choice for treatment is the use of intraocular injections of biologic agents, such as VEGF inhibitors. Aflibercept, ranibizumab, and bevacizumab (off-label use) are among the vascular endothelial growth factor inhibitors utilized. Thermal laser photocoagulation or photodynamic (laser) therapy are older options but may still be used in some cases. Recurrences with these therapies are common.
- Photodynamic therapy is performed after intravenous injection of verteporfin, a photosensitizing agent. The role of this drug is to close newly formed vessels which are leaky and contribute to vision loss. Therefore, verteporfin does not restore vision, but rather can prevent further vision loss. Due to low efficacy, this treatment option is less commonly administered.
- Intravitreal steroid injections have achieved mixed results.
Submacular surgery is generally not recommended. Within a year, patients continue to experience vision loss.
Macular translocation surgery has many complications but could be a viable alternative for those who are not candidates for laser therapy. It remains unclear which patients are best served by this invasive approach. Long-term studies are being conducted.
Dietary factors appear to play an important role in AMD. In epidemiologic studies, the following factors are associated with reduced risk of onset or progression of the disease:
Maintenance of ideal weight. Studies have found a higher risk for AMD in patients with metabolic syndrome. Measures of adiposity, including body mass index and waist/hip ratio, can assist in determining undiagnosed metabolic syndrome in those without any other indicators.,,
Low fat intake. Studies have found an association between a high intake of saturated fat and cholesterol and AMD., Vegetable fat and total fat intake have also been implicated as culprits in the development of early AMD.,, People who regularly consume processed baked goods doubled their risk of AMD, compared with those who rarely consume these products. The effect may relate to adverse effects on blood lipids or to an inflammatory response.
In general, following a healthful dietary pattern—defined in a 2020 review as prudent, Mediterranean, or Healthy Eating Index—is associated with a protective effect against AMD while Western dietary patterns are associated with an increased progression of the disease. Some have suggested that routine intake of fish is associated with reduced AMD prevalence, at least in certain populations. This is presumably due to the omega-3 content, found as DHA and EPA (eicosapentaenoic acid and docosahexaenoic acid respectively).,,, However, the Age-Related Eye Disease Study 2 (AREDS2), a randomized, double-blind, placebo-controlled study found no protective benefit of DHA or EPA at five-year follow-up. A 2015 systematic review supported these findings. Genetics may influence the effect of fatty acids on AMD; more research is warranted.,,
High consumption of fruits and vegetables. Lutein and zeaxanthin are the principal carotenoids in the macular region of the retina. They are abundant in dark green, leafy vegetables and may play an important role in the prevention of macular degeneration., Several studies have found that people with high intake of fruits and vegetables had a significantly lower risk for AMD compared with those with lower intake.,, The Health Professionals Follow-Up Study and Nurses’ Health Study found an inverse association between fruit intake and risk for neovascular age-related maculopathy.
Antioxidant supplements. In the Age-Related Eye Disease Study, individuals with moderate or advanced AMD who received 500 mg of vitamin C, 400 IU of vitamin E, 15 mg of beta carotene, and 80 mg of zinc oxide (along with 2 mg of cupric oxide to prevent copper deficiency) had significantly reduced progression of their disease, compared with subjects receiving a placebo. Caution is advised, however, for several reasons: This evidence derives from a single study. Also, some evidence suggests that beta-carotene supplementation may increase lung cancer risk among smokers. Finally, daily doses of vitamin E exceeding 400 IU may increase cardiovascular and all-cause mortality.
In the lutein antioxidant supplementation trial (LAST), a 10-mg supplement of lutein taken daily, alone or with an antioxidant vitamin combination, increased macular pigment density and improved visual function when compared with a placebo. Lutein supplementation also improved visual performance (visual acuity and glare sensitivity) in other controlled trials. Due to a saturation of transport mechanisms for these carotenoids, some individuals do not achieve increases in macular pigment density, in spite of increases in blood levels of lutein and zeaxanthin, following supplementation. Other individuals may not benefit if they are overweight, because lutein and zeaxanthin will be taken up by adipose tissue, rather than by the macula. An ophthalmologist should make patient-specific recommendations, because the age of the patient, disease severity, duration of treatment, and potential inhibitory effect of lutein supplementation on other carotenoids must be taken into account.
See Basic Diet Orders chapter.
Emphasize fresh fruits and vegetables, particularly leafy greens, such as collards or turnip greens, kale, and spinach. Orange peppers, corn and squash are also good sources of lutein and zeaxanthin.
Consider the following supplements in consultation with an ophthalmologist: Vitamin C 500 mg, vitamin E 400 IU, beta-carotene 15 mg, zinc oxide 80 mg, and cupric oxide 2 mg daily.
Lutein should be dosed per ophthalmologist recommendations.
What to Tell the Family
Appropriate medical care and self-care can slow the loss of vision due to AMD. It important to encourage smoking cessation, along with a diet that is low in fat and cholesterol and high in fruits and vegetables. That means including at least 1 serving daily of a dark leafy green vegetable, such as spinach, kale, collards, or turnip greens, along with 3 servings of fresh fruit per day. This diet is also beneficial to family members, who may have a higher risk of AMD. Supplemental lutein and certain vitamins and minerals (C, E, beta-carotene, and zinc/copper oxide) may be beneficial, but their use should be supervised by an ophthalmologist. Low-vision aids (such as specialized lighting and magnifiers) are available through eye clinics.
- Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358(24):2606-17. [PMID:18550876]
- Caban-Martinez AJ, Davila EP, Lam BL, et al. Age-related macular degeneration and smoking cessation advice by eye care providers: a pilot study. Prev Chronic Dis. 2011;8(6):A147. [PMID:22005640]
- de Jong PT. Age-related macular degeneration. N Engl J Med. 2006;355(14):1474-85. [PMID:17021323]
- Glickman RD. Ultraviolet phototoxicity to the retina. Eye Contact Lens. 2011;37(4):196-205. [PMID:21646980]
- Sui GY, Liu GC, Liu GY, et al. Is sunlight exposure a risk factor for age-related macular degeneration? A systematic review and meta-analysis. Br J Ophthalmol. 2013;97(4):389-94. [PMID:23143904]
- National Eye Institute. Age-Related Macular Degeneration (AMD) Tables. National Eye Institute. https://www.nei.nih.gov/learn-about-eye-health/resources-for-health-educat.... Accessed October 13, 2020.
- Weih LM, VanNewkirk MR, McCarty CA, et al. Age-specific causes of bilateral visual impairment. Arch Ophthalmol. 2000;118(2):264-9. [PMID:10676793]
- Myers CE, Klein BE, Gangnon R, et al. Cigarette smoking and the natural history of age-related macular degeneration: the Beaver Dam Eye Study. Ophthalmology. 2014;121(10):1949-55. [PMID:24953792]
- Chong EW, Kreis AJ, Wong TY, et al. Alcohol consumption and the risk of age-related macular degeneration: a systematic review and meta-analysis. Am J Ophthalmol. 2008;145(4):707-715. [PMID:18242575]
- Fraser-Bell S, Wu J, Klein R, et al. Cardiovascular risk factors and age-related macular degeneration: the Los Angeles Latino Eye Study. Am J Ophthalmol. 2008;145(2):308-16. [PMID:18222193]
- Chong EW, Simpson JA, Robman LD, et al. Red meat and chicken consumption and its association with age-related macular degeneration. Am J Epidemiol. 2009;169(7):867-76. [PMID:19234096]
- Ersoy L, Ristau T, Lechanteur YT, et al. Nutritional risk factors for age-related macular degeneration. Biomed Res Int. 2014;2014:413150. [PMID:25101280]
- Vassilev ZP, Ruigómez A, Soriano-Gabarró M, et al. Diabetes, cardiovascular morbidity, and risk of age-related macular degeneration in a primary care population. Invest Ophthalmol Vis Sci. 2015;56(3):1585-92. [PMID:25670489]
- Bird AC, Bressler NM, Bressler SB, et al. An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group. Surv Ophthalmol. 1995;39(5):367-74. [PMID:7604360]
- Abdelsalam A, Del Priore L, Zarbin MA. Drusen in age-related macular degeneration: pathogenesis, natural course, and laser photocoagulation-induced regression. Surv Ophthalmol. 1999;44(1):1-29. [PMID:10466585]
- Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. Arch Ophthalmol. 2003;121(12):1728-37. [PMID:14662593]
- Knudtson MD, Klein R, Klein BE. Physical activity and the 15-year cumulative incidence of age-related macular degeneration: the Beaver Dam Eye Study. Br J Ophthalmol. 2006;90(12):1461-3. [PMID:17077116]
- Loprinzi PD, Swenor BK, Ramulu PY. Age-Related Macular Degeneration Is Associated with Less Physical Activity among US Adults: Cross-Sectional Study. PLoS ONE. 2015;10(5):e0125394. [PMID:25933421]
- Age-Related Eye Disease Study Research Group. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10):1417-36. [PMID:11594942]
- American Academy of Ophthalmology Preferred Practice Pattern Retina/Vitreous Committee. Age-Related Macular Degeneration PPP - Updated 2019. American Academy of Ophthalmology. https://www.aao.org/preferred-practice-pattern/age-related-macular-degener.... Accessed October 13, 2020.
- Lebuisson DA, Leroy L, Rigal G. [Treatment of senile macular degeneration with Ginkgo biloba extract. A preliminary double-blind drug vs. placebo study]. Presse Med. 1986;15(31):1556-8. [PMID:2947098]
- Fies P, Dienel A. [Ginkgo extract in impaired vision--treatment with special extract EGb 761 of impaired vision due to dry senile macular degeneration]. Wien Med Wochenschr. 2002;152(15-16):423-6. [PMID:12244891]
- Evans JR. Ginkgo biloba extract for age-related macular degeneration. Cochrane Database Syst Rev. 2013. [PMID:23440785]
- Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: one-year results of 2 randomized clinical trials--TAP report. Treatment of age-related macular degeneration with photodynamic therapy (TAP) Study Group. Arch Ophthalmol. 1999;117(10):1329-45. [PMID:10532441]
- Gillies MC, Simpson JM, Luo W, et al. A randomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. Arch Ophthalmol. 2003;121(5):667-73. [PMID:12742844]
- Giansanti F, Eandi CM, Virgili G. Submacular surgery for choroidal neovascularisation secondary to age-related macular degeneration. Cochrane Database Syst Rev. 2009. [PMID:19370663]
- Ghaem Maralani H, Tai BC, Wong TY, et al. Metabolic syndrome and risk of age-related macular degeneration. Retina (Philadelphia, Pa). 2015;35(3):459-66. [PMID:25207946]
- Seddon JM, Cote J, Davis N, et al. Progression of age-related macular degeneration: association with body mass index, waist circumference, and waist-hip ratio. Arch Ophthalmol. 2003;121(6):785-92. [PMID:12796248]
- Zhang QY, Tie LJ, Wu SS, et al. Overweight, Obesity, and Risk of Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2016;57(3):1276-83. [PMID:26990164]
- Smith W, Mitchell P, Leeder SR, et al. Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. Arch Ophthalmol. 1998;116(5):583-7. [PMID:9596493]
- Smith W, Mitchell P, Leeder SR. Dietary fat and fish intake and age-related maculopathy. Arch Ophthalmol. 2000;118(3):401-4. [PMID:10721964]
- Mares-Perlman JA, Brady WE, Klein R, et al. Dietary fat and age-related maculopathy. Arch Ophthalmol. 1995;113(6):743-8. [PMID:7786215]
- Cho E, Hung S, Willett WC, et al. Prospective study of dietary fat and the risk of age-related macular degeneration. Am J Clin Nutr. 2001;73(2):209-18. [PMID:11157315]
- Seddon JM, Rosner B, Sperduto RD, et al. Dietary fat and risk for advanced age-related macular degeneration. Arch Ophthalmol. 2001;119(8):1191-9. [PMID:11483088]
- Francisco SG, Smith KM, Aragonès G, et al. Dietary Patterns, Carbohydrates, and Age-Related Eye Diseases. Nutrients. 2020;12(9). [PMID:32962100]
- Augood C, Chakravarthy U, Young I, et al. Oily fish consumption, dietary docosahexaenoic acid and eicosapentaenoic acid intakes, and associations with neovascular age-related macular degeneration. Am J Clin Nutr. 2008;88(2):398-406. [PMID:18689376]
- Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013;309(19):2005-15. [PMID:23644932]
- Lawrenson JG, Evans JR. Omega 3 fatty acids for preventing or slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2015;4:CD010015. [PMID:25856365]
- Merle BM, Silver RE, Rosner B, et al. Adherence to a Mediterranean diet, genetic susceptibility, and progression to advanced macular degeneration: a prospective cohort study. Am J Clin Nutr. 2015;102(5):1196-206. [PMID:26490493]
- Souied EH, Aslam T, Garcia-Layana A, et al. Omega-3 Fatty Acids and Age-Related Macular Degeneration. Ophthalmic Res. 2015;55(2):62-9. [PMID:26610051]
- Reynolds R, Rosner B, Seddon JM. Dietary omega-3 fatty acids, other fat intake, genetic susceptibility, and progression to incident geographic atrophy. Ophthalmology. 2013;120(5):1020-8. [PMID:23481534]
- Scripsema N, Hu D, Rosen R. Lutein, zeaxanthin, and meso-zeaxanthin in the clinical management of eye disease. J Ophthalmol . 2015;2015:1-13.
- Bernstein PS, Li B, Vachali PP, et al. Lutein, zeaxanthin, and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease. Prog Retin Eye Res. 2016;50:34-66. [PMID:26541886]
- Wu J, Cho E, Willett WC, et al. Intakes of Lutein, Zeaxanthin, and Other Carotenoids and Age-Related Macular Degeneration During 2 Decades of Prospective Follow-up. JAMA Ophthalmol. 2015;133(12):1415-24. [PMID:26447482]
- Zeimer M, Hense HW, Heimes B, et al. [The macular pigment: short- and intermediate-term changes of macular pigment optical density following supplementation with lutein and zeaxanthin and co-antioxidants. The LUNA Study]. Ophthalmologe. 2009;106(1):29-36. [PMID:18551295]
- Tan JS, Wang JJ, Flood V, et al. Dietary antioxidants and the long-term incidence of age-related macular degeneration: the Blue Mountains Eye Study. Ophthalmology. 2008;115(2):334-41. [PMID:17664009]
- Cho E, Seddon JM, Rosner B, et al. Prospective study of intake of fruits, vegetables, vitamins, and carotenoids and risk of age-related maculopathy. Arch Ophthalmol. 2004;122(6):883-92. [PMID:15197064]
- Miller ER, Pastor-Barriuso R, Dalal D, et al. Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med. 2005;142(1):37-46. [PMID:15537682]
- Richer S, Stiles W, Statkute L, et al. Double-masked, placebo-controlled, randomized trial of lutein and antioxidant supplementation in the intervention of atrophic age-related macular degeneration: the Veterans LAST study (Lutein Antioxidant Supplementation Trial). Optometry. 2004;75(4):216-30. [PMID:15117055]
- Olmedilla B, Granado F, Blanco I, et al. Lutein, but not alpha-tocopherol, supplementation improves visual function in patients with age-related cataracts: a 2-y double-blind, placebo-controlled pilot study. Nutrition. 2003;19(1):21-4. [PMID:12507634]
- Trieschmann M, Beatty S, Nolan JM, et al. Changes in macular pigment optical density and serum concentrations of its constituent carotenoids following supplemental lutein and zeaxanthin: the LUNA study. Exp Eye Res. 2007;84(4):718-28. [PMID:17306793]
- Hammond BR, Ciulla TA, Snodderly DM. Macular pigment density is reduced in obese subjects. Invest Ophthalmol Vis Sci. 2002;43(1):47-50. [PMID:11773011]