Age-related Macular Degeneration: Clinical Features and Therapeutic Options

Age-related macular degeneration is the leading cause of irreversible legal blindness in the elderly. Although nothing can reverse the associated vision loss, treatments are available that can slow the rate of progression of this condition. These options include supplemental high-dose vitamin therapy, diet and lifestyle changes, laser photocoagulation, photodynamic therapy, and intravitreal injection of anti-angiogenic medications. Early diagnosis and initiation of appropriate treatment are critical.

Susanna S. Park, MD, PhDAssociate Professor of Ophthalmology

Department of Ophthalmology & Vision Science

Sacramento, Calif

PRACTICE POINTS

• A person older than 50 years with discoloration of the macula may have dry AMD.
• A diet rich in green, leafy vegetables contains antioxidants that are protective against AMD.
• First-degree relatives of patients with AMD should have a regular annual dilated eye exam after age 50 years.

Age-related macular degeneration (AMD) is the leading cause of irreversible legal blindness in the elderly population in the United States. More than 7 million individuals are at risk for the condition,¹ and the number of patients is expected to increase with the aging of the baby boomer generation. Currently, 1.75 million Americans have vision loss from advanced AMD in at least 1 eye.¹ This number is expected to increase to 2.95 million in 2020.¹ Primary care physicians must increase their awareness of this common eye condition so that patients can be identified and referred to an ophthalmologist before vision loss occurs. Although the etiology of AMD is still unknown, several risk factors for disease progression have been identified. Managing those risk factors may reduce the risk of progression to AMD.

Clinical Features

AMD is seen in people older than 50 years. Incidence and severity increase with advancing age.¹ In 60-year-old persons, the incidence is 10% to 15%; in those who are 75-years-old, it is 30%.² AMD is a bilateral, progressive disease, but severity and rate of progression are highly variable among individuals, and AMD can be asymmetric in the eyes of the same individual. As its name suggests, AMD damages the macula?the portion of the retina that provides the fine detailed central vision. As the condition progresses, patients gradually lose the ability to drive, read, and recognize faces (Figure 1). In advanced cases involving both eyes, legal blindness will result. Because peripheral vision usually remains intact, AMD rarely causes total blindness, even in patients with advanced disease.

Dry AMD

AMD is divided into 2 types?"dry" and "wet." All patients begin with dry AMD, the more common and milder form that accounts for 85% to 90% of all cases.² Individuals may experience a gradual worsening of vision as the photoreceptor cells in the macula slowly degenerate. The earliest sign of dry AMD is macular drusen (Figure 2a). These yellow, round lesions correspond histologically to abnormal thickening of the inner aspects of Bruch's membrane. They can be transient and vary in size and number. Large drusen (>125 mm in diameter) are more likely to be associated with progressive disease than are a few small drusen (<64 mm in diameter).³ As the condition progresses, atrophy of the retinal pigment epithelium (RPE) gives the macula a mottled, depigmented appearance. When the affected areas become contiguous, a well-defined area of RPE degeneration may be seen clinically, referred to as geographic atrophy (Figure 2b). In these affected areas, the overlying photoreceptors are usually damaged or absent. Thus vision may be affected, especially if the central macula or fovea is involved. Vision loss is usually gradual but progressive.

Wet AMD

In approximately 15% of patients, neovascular tissue can develop under the retina or RPE.² These buds of capillaries that grow from the choriocapillaris can bleed and result in severe, sudden, irreversible vision loss. This condition is referred to as "wet" or exudative AMD. The fibrovascular tissue eventually disrupts and destroys the overlying photoreceptors/Bruch's membrane/RPE complex, resulting in a disciform scar, a sign of end-stage AMD. Such a process accounts for 90% of all cases of severe, irreversible vision loss in patients with AMD.⁴

Any eye with disturbance of Bruch's membrane associated with AMD can develop wet AMD, but it is more common in patients with advanced signs of AMD, such as large drusen or RPE atrophy, and in those with wet AMD in the other eye.³ Such high-risk patients need to be monitored closely for progression to wet AMD.

If a patient with AMD develops new visual distortion and/or vision loss, that patient should be examined promptly for signs of progression to wet AMD. Funduscopic examination may reveal a new retinal hemorrhage or exudate (Figure 3a) associated with edema and elevation of the macula. If any of these signs or symptoms is present, a fluorescein angiogram should be performed promptly to identify and localize the neovascular tissue for possible laser treatment (Figure 3b).

Risk Factors

Since the etiology of AMD is unknown, many large epidemiologic studies have attempted to identify risk factors associated with disease progression. Hypertension, atherosclerosis, obesity, elevated plasma fibrinogen level, and cigarette smoking have been shown to increase risk for more severe forms of AMD.^5,6 Therefore, patients should be strongly encouraged to stop smoking and adopt a healthier lifestyle.

A diet high in saturated or polyunsaturated fat has been associated with advanced AMD.⁷

Although there are no convincing data showing that the use of hats and sunglasses is protective, indirect evidence suggests that exposure to sunlight may play a role in disease progression.^8,9 Red-or blond-haired and blue-eyed individuals were found to be more likely to develop early AMD than those with darker hair or eyes in some studies.^8,9 In addition, the amount of outdoor leisure time before age 40 years appears to increase risk of early AMD.⁹ Based on these observations, ultraviolet- light protective eyewear is recommended for patients with AMD who spend a lot of time outdoors.

Genetics

It is well acknowledged that a genetic component is involved in the pathogenesis of AMD, but the magnitude of its role is controversial. Several studies have reported a familial aggregation of AMD, estimating that risk increases several-fold in first-degree relatives of patients.^10,11 In addition, AMD can develop at a younger age among family members.¹¹ Yet genetics do not appear to solely dictate the severity of disease, since rate of progression can vary considerably among members of the same family. Therefore, a regular dilated eye examination performed by an ophthalmologist is strongly recommended for all first-degree relatives of AMD patients after the age of 50 years.

Role of Diet and Supplementation

Epidemiologic studies have shown that a diet rich in fruits and vegetables?especially green, leafy vegetables such as spinach?contains antioxidants that are protective against AMD.¹² A diet rich in omega-3 fatty acids has also been shown to have protective effects.⁷ Thus, individuals who already have or are at risk for AMD should be encouraged to adopt a diet rich in fruits, vegetables, and fish.

Based on this observation that a diet rich in antioxidants appears to protect against AMD, the possible benefits of nutritional supplementation was investigated in a prospective, randomized, multicenter clinical trial, the Age-Related Eye Disease Study (AREDS), sponsored by the National Eye Institute.¹³ The AREDS formula consisted of vitamins and minerals known to be potent antioxidants, including vitamin A(as beta-carotene), vitamin C, vitamin E, and zinc (Table).

The AREDS study showed that supplementation with this combination of vitamins and minerals decreased the rate of AMD progression by 25% among patients with moderate AMD (ie, medium-to large-sized drusen) or with advanced AMD in one eye.¹³ It had no beneficial effects in patients with early AMD or with advanced AMD in both eyes. Although the daily dose of the vitamins was 4 to 13 times higher than the current recommended daily intake, this combination of vitamins and minerals was well-tolerated over the 6-year study period.

The long-term safety of this high-dose vitamin supplementation formula is still unknown, however, and is not recommended for patients with early AMD or those without AMD. Nor is it recommended for current or recent smokers, since high-dose vitamin A therapy has been linked to an increased risk of lung cancer among smokers in separate clinical trials.¹⁴

The beneficial effect of other nutritional supplements, in particular lutein and zeaxanthin, has yet to be proven in a prospective, randomized clinical study. Nevertheless, many commercially available AREDS-formula supplements for AMD contain lutein and zeaxanthin.

Screening for Neovascular AMD

Neovascular complications of wet AMD can result in severe, sudden, irreversible vision loss in the affected eye. Primary care physicians can encourage patients with AMD to monitor their eyesight daily using an Amsler grid (Figure 4). The patient looks at the grid with 1 eye at a time, fixating on the central spot, to determine if there is new distortion of the lines.

Any patient with AMD who presents with new visual distortion or a new macular hemorrhage or exudate on funduscopic examination should have a fluorescein angiogram as soon as possible to determine whether a choroidal neovascular membrane is present.

Treatment for Neovascular AMD

Macular laser photocoagulation

Macular laser photocoagulation is the treatment of choice for patients with wet AMD when the choroidal neovascular membrane does not involve the fovea. The goal is to coagulate the neovascular membrane and prevent it from bleeding or growing into the fovea and causing severe, usually irreversible vision loss. Patients should be seen 2 weeks after the procedure for a repeat fluorescein angiogram.

The Macular Photocoagulation Study (MPS) showed that focal laser treatment decreased the risk of severe vision loss compared with untreated eyes.¹⁵ However, approximately 50% of patients experienced severe vision loss 5 years after treatment from recurrent neovascular AMD.¹⁵ In addition, laser photocoagulation usually results in a permanent scotoma corresponding to the treated area, because the laser destroys the retina overlying the neovascular membrane. Therefore, this treatment is not recommended for patients with a subfoveal choroidal neovascular membrane who have a visual acuity of 20/200 or better.

Photodynamic therapy

Photodynamic therapy (PDT) was approved by the Food and Drug Administration (FDA) in April 2000 for patients with subfoveal neovascular AMD who have a visual acuity of at least 20/200. Patients are injected with a photosensitizing drug, such as verteporfin (Visudyne), which is activated by an application of a particular wavelength of light to the affected area. This incites a localized photochemical reaction that leads to capillary endothelial damage and vessel thrombosis. The randomized, prospective, multicenter clinical trial, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP), demonstrated a reduced risk of severe vision loss compared with no treatment.¹⁶ The disadvantage is that the treatment may need to be repeated every 3 months. Since the photosensitizing drug is not cleared by the body for up to 5 days after injection, the entire body remains sensitive to sunlight during this time. As a result, patients must remain indoors for a few days after treatment.

Intravitreal corticosteroid injection

Triamcinolone acetonide (eg, Kenalog, Tac, Triamonide) is injected directly into the vitreous cavity to minimize inflammation in the eye. When used alone, it does not appear to have any beneficial effect in neovascular AMD.¹⁷ However, several recent pilot studies have reported that it can enhance the efficacy of PDT, and this combination treatment is now used off-label by many clinicians. The combined therapy resulted in a lower retreatment rate and higher rate of visual improvement than was found with PDT alone in the TAP study.¹⁸ The exact mechanism of action is unknown, but decreased inflammation may reduce the production of angiogenic factors.

The disadvantage of this therapy is that approximately 20% to 30% of patients develop glaucoma. Cataract formation is also possible. The most serious side effect is endophthalmitis, an acute microbial infection within the eye, which occurs in up to 1% of patients.¹⁹ Patients need to be followed closely for several weeks to months after treatment.

Intravitreal pegaptanib sodium

Pegaptanib sodium (Macugen) is a selective vascular endothelial growth factor (VEGF) antagonist that was approved by the FDA in December 2004 for the treatment of subfoveal neovascular AMD in patients with a visual acuity of 20/200 or better. VEGF, which induces angiogenesis, vascular permeability, and inflammation, has been thought to play a key role in ocular neovascularization.²⁰ In a recent randomized, prospective, multicenter clinical study, intravitreal injection of pegaptanib decreased the rate of vision loss from neovascular AMD.²¹ It is administered every 6 weeks for 1 to 2 years. Unlike triamcinolone, there is no risk of glaucoma. However, endophthalmitis and cataract formation from the trauma of repeat injections are potential limitations of this therapy.

Vitreous surgery

Two surgical approaches to the treatment of AMD have been explored in the past 12 years, but they have become less popular in recent years, with the advent of PDT and anti-VEGF therapy. Surgical removal of the subfoveal choroidal neovascular tissue is technically possible and can result in significant visual improvement in some patients.²² However, most patients experience progressive visual decline despite surgery, and a recent randomized, prospective trial found no visual benefits for the long-term.²³

Surgical translocation of the macula to a new area with a healthier underlying RPE has also been tried.²⁴ Significant improvement in vision has been reported in some patients. The limitation of this procedure is the risk of retinal detachment and diplopia postsurgery and long-term outcomes are not known.

Conclusion

AMD is already a leading cause of irreversible blindness and visual impairment in the elderly population, and it will become even more common with the aging of the baby boomer generation. Once vision loss occurs, it is usually permanent. Thus, early diagnosis is critical. The primary care physician can help patients at risk for AMD by educating them on proper nutrition and the use of the Amsler grid for self-testing vision. All patients suspected of being at risk for AMD should be referred to an ophthalmologist so they can be monitored closely.

Disclosure statement

Dr Park receives grant/research support from Genentech and Alcon.

SELF-ASSESSMENT TEST

1. Which of these statements about AMD is NOT true?

• The dry form always precedes the wet form
• Associated vision loss is irreversible

2. All the following conditions are signs or symptoms of dry AMD, except:

• Mottled macula
• Depigmented macula

3. Which of the following conditions is NOT a risk factor for severe AMD?

• Obesity
• Alcohol abuse

4. For which of these patients would the AREDS vitamin/mineral supplement be appropriate?

• Man with advanced AMD in both eyes
• Man with AMD who quit smoking 3 months earlier

5. Which of these statements about the treatment of AMD is NOT true?

• Photodynamic therapy is appropriate for patients with subfoveal neovascular AMD with a visual acuity of 20/200 or better
• Intravitreal corticosteroid injection enhances the efficacy of photodynamic therapy

(Answers at end of reference list)

Arch Ophthalmol.

1. Friedman DS, O'Colmain BJ, Munoz B, et al, for the Eye Diseases Prevalence Research Group. Prevalence of age-related macular degeneration in the United States. 2004;122:564-572.

Retina.

2. Seddon JM. Epidemiology of age-related macular degeneration. In: Ryan SJ, ed. Vol 2. 3rd ed. St. Louis, Mo: Mosby; 2001:1039-1050.

Arch Ophthalmol.

3. Macular Photocoagulation Study Group. Risk factors for choroidal neovascularization in the second eye of patients with juxtafoveal or subfoveal choroidal neovascularization secondary to age-related macular degeneration. 1997;115:741-747.

Arch Ophthalmol

4. Ferris FL III, Fine SL, Hyman L. Age-related macular degeneration and blindness due to neovascular maculopathy. . 1984;102:1640-1642.

Arch Ophthalmol

5. Hyman L, Schachat AP, He Q, et al, for the Age-Related Macular Degeneration Risk Factors Study Group. Hypertension, cardiovascular disease, and age-related macular degeneration. . 2000;118:351-358.

Arch Ophthalmol

6. Smith W, Mitchell P, Leeder SR, et al. Plasma fibrinogen levels, other cardiovascular risk factors, and age-related maculopathy: the Blue Mountains Eye Study. . 1998;116:583-587.

Arch Ophthalmol.

7. Seddon JM, Cote J, Rosner B. Progression of age-related macular degeneration: association with dietary fat, transunsaturated fat, nuts, and fish intake. 2003;121:1728-1737.

Ophthalmology

8. Mitchell P, Smith W, Wang JJ. Iris color, skin sun sensitivity, and age-related maculopathy. The Blue Mountains Eye Study. . 1998;105:1359-1363.

Arch Ophthalmol

9. Cruickshanks KJ, Klein R, Klein BEK, et al. Sunlight and the 5-year incidence of early age-related maculopathy: the Beaver Dam Eye Study. . 2001;119:246-250.

Am J Ophthalmol

10. Seddon JM, Ajani UA, Mitchell BD. Familial aggregation of agerelated maculopathy. . 1997;123:199-206.

Arch Ophthalmol.

11. Klaver CCW, Wolfs RCW, Assink JJM, et al. Genetic risk of age-related maculopathy. Population-based familial aggregation study. 1998;116:1646-1651.

JAMA.

12. Seddon JM, Ajani UA, Sperduto RD, et al, for the Eye Disease Case-Control Study Group. Dietary carotenoids, vitamin A, C, and E, and advanced age-related macular degeneration. 1994;272:1413-1420.

Arch Ophthlamol

13. 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. . 2001;119:1417-1436.

J Natl Cancer Inst

14. Omenn GS, Goodman GE, Thornquist MD, et al. Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. . 1996;88:1550-1559.

Arch Ophthalmol

15. Macular Photocoagulation Study Group. Laser photocoagulation for juxtafoveal choroidal neovascularization. Five-year results from randomized clinical trials. . 1994;112:500-509.

Arch Ophthalmol.

16. Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials?TAP report 2. 2001;119:198-207.

Arch Ophthalmol.

17. Gillies MC, Simpson JM, Luo W, et al. Arandomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results. 2003;121:667-673.

Ophthalmology.

18. Spaide RF, Sorenson J, Maranan L. Combined photodynamic therapy with verteporfin and intravitreal triamcinolone acetonide for choroidal neovascularization. 2003;110:1517-1525.

Am J Ophthalmol

19. Moshfeghi DM, Kaiser PK, Scott IU, et al. Acute endophthalmitis following intravitreal triamcinolone acetonide injection. . 2003;136:791-796.

Arch Ophthalmol

20. Krzystolik MG, Afshari MA, Adamis AP, et al. Prevention of experimental choroidal neovascularization with intravitreal anti-vascular endothelial growth factor antibody fragment. . 2002;120:338-346.

N Engl J Med.

21. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al, for the VEGF Inhibition Study in Ocular Neovascularization Clinical Trial Group. Pegaptanib for neovascular age-related macular degeneration. 2004;351:2805-2816.

Ophthalmology

22. Thomas MA, Grand MG, Williams DF, et al. Surgical management of subfoveal choroidal neovascularization. . 1992;99:952-968.

Ophthalmology

23. Hawkins BS, Bressler NM, Miskala PH, et al, for the Submacular Surgery Trials (SST) Research Group. Surgery for subfoveal choroidal neovascularization in age-related macular degeneration: ophthalmic findings: SST report no. 11. . 2004;111:1967-1980.

Ophthalmology

24. American Academy of Ophthalmology. Macular translocation. . 2000;107:1015-1018.

Answers:

1. C; 2. A; 3. D; 4. A; 5. C