Risk Factors And Prevention Of Age Related Macular Degeneration

Fred H. Lambrou, Jr., M.D. and Amr Dessouki, M.D.
Fred H. Lambrou, Jr., M.D. and Amr Dessouki, M.D.
are Retina Specialists with Retina Associates, P.A.

Age related macular degeneration (AMD) is the leading cause of legal blindness amongst the elderly in the United States, and is responsible for 200,000 new cases of blindness per year. The Beaver Dam Eye Study1 demonstrated that macular degeneration was present in over eighteen percent of patients in the age group of 65 to 74 years of age. In patients over 75 years of age, the incidence increased to almost 30%.

Age related macular degeneration is typically divided into two categories: Atrophic or "dry" AMD and Exudative or "wet" AMD. In dry AMD, one observes whitish-yellow, discrete subretinal lesions known as "drusen" and alteration of the retinal pigment epithelium (Figure 1). Over time, drusen may coalesce and eventually lead to geographic atrophy. This is characterized by extensive atrophy of the retinal pigment epithelium (RPE) and the overlying photoreceptor cells. This may lead to substantial loss of central vision. Furthermore, the presence of bilateral drusen markedly increases the risk for the development of choroidal neovascularization.

This choroidal neovascularization (CNV), which extends into the subRPE and the subretinal space, is the hallmark of wet AMD (Figure 2). The new blood vessels are extremely fragile and can spontaneously hemorrhage, leading to the development of a fibrovascular or disciform scar, and severe, irreversible visual loss (Figure 3). Although the wet form of AMD is only seen in ten to twenty percent of patients, it is responsible for eighty to ninety percent of patients with severe visual loss. When one eye has developed CNV, it is important to monitor the remaining eye for CNV since it is highly likely that there has been substantial visual loss in the first eye. The Macular Photocoagulation Study (MPS) Group reported 35% overall incidence of CNV in the fellow eyes of patients with CNV in their first eyes over a
five year period. Application of life table estimation methods to this data yielded cumulative rates of 10%, 28%, and 42% at one, three, and five years respectively.2

Figure 1. Yellow-white drusen in the left eye of a patient with age-related macular degeneration.
 Figure 2. A choroidal neovascular membrane in the right eye of a patient with wet AMD. A small subretinal hemorrhage is present as well as a small amount of subretinal fluid from the CNV. Figure 3. A disciform scar in the left eye of a patient with AMD.

The purpose of this paper is to discuss the various risk factors for AMD and how behavioral modification may help in the prevention of visual loss from AMD.

Genetic Risk In AMD

It has long been thought that there is a genetic risk for the development of AMD. The first medical description occurred in 1875, when three patients were described as having "familial drusen".3 Since then, multiple twin studies, as well as studies of siblings, have supported the idea of a familial nature of AMD. Kline and associates4 described concordance in eight of nine monozygotic twins. Myers and associates5 reported one-hundred percent concordance in twenty-three pairs of monozygotic twins compared with only twelve percent of dizygotic twin pairs. Piguet and co-workers6 studied the characteristics of drusen in spouses and siblings of affected AMD patients. Their work demonstrated that there was marked concordance between siblings, but not between spouses. This suggested that genetic factors were more important than environmental factors.

Large population based segregation studies, such as The Beaver Dam Eye Study,7 as well as family aggregation studies, such as The Rotterdam Eye Study,8 and Seddon's study in Boston9 also suggest a strong genetic risk factor for AMD. The Beaver Dam Eye Study examined 564 families. The results indicated a strong sibling correlation for ophthalmoscopic findings. The Rotterdam Study looked at 101 cases with end-stage AMD, compared with 154 randomly selected patients without evidence of AMD. The results indicated that siblings had a 4.8 times greater risk for the development of early AMD, and 19.8 times greater risk for the development of end stage AMD compared to matched controls. The children of AMD patients also had a 6.6 times greater risk for the development of early AMD. Finally, they concluded that twenty-three percent of all end stage AMD could be due to a genetic basis. The study by Seddon9 in Boston compared first degree relatives of 119 AMD patients with 72 control individuals without AMD. Patients with first degree relatives with AMD had a 2.4 times greater risk for the development of AMD compared to those without a positive family history. Furthermore, the odds of developing a choroidal neovascular membrane were 3.1 times higher in patients with a first degree relative with AMD. However, in this same study, the risk of developing geographic atrophy was 1.5 times greater which was not statistically significant. The study pointed to the heterogeneity of AMD and suggested that there may be different relative contributions of genetic and environmental factors corresponding to the different types of AMD present.

It has been speculated that AMD is caused by environmental factors, which trigger the disease in genetically susceptible subjects. Identifying the genes involved would be important to try to identify those individuals at risk. Researchers have looked at hereditary retinal dystrophies that have an appearance similar to AMD. Stargardt's Disease is the most common autosomal recessive macular dystrophy and leads to macular retinal pigment epithelium atrophy and decreased vision. It has been found that the condition is caused by mutation in the ABCR gene, which is part of the ATP binding cassette transporter super family. Subsequent studies attempting to correlate a defect in this gene with AMD patients have been equivocal. It is not known whether or not the ABCR gene plays a significant role in determining genetic susceptibility to AMD.10

Doyne's Honeycomb Retinal Dystrophy is an autosomal dominant dystrophy characterized by the early appearance of drusen in young adults. The gene for this disorder was recently identified. However, in a study of 494 patients with AMD, no patient was found to have a mutation of this gene. Similar negative associations have been found between AMD and Best's disease and Sorsby Fundus Dystrophy.10

Thus, while it appears that there is a genetic risk factor to AMD, identifying the locus of this genetic defect is a difficult task. Further studies are needed to identify those individuals who are at risk genetically for the development of AMD. In the interim, it seems prudent to warn siblings and children of patients with AMD that they may be at risk and recommend periodic retinal evaluation.

Nutrition

The role of poor nutrition as a risk factor for macular degeneration and nutritional supplementation as a preventive measure for age related macular degeneration has been suggested. Theoretically, diet may impact the development of AMD by altering oxidative damage in the retina. Expo
sure to light can generate free radicals that can cause oxidative damage. The retina is prone to this type of oxidative damage because of its high concentration of polyunsaturated fatty acids in the photoreceptor outer segments. This oxidative damage is constantly occurring and theoretically, vitamins and minerals that have anti-oxidative properties could be beneficial. Vitamins E, C, the carotenoids, selenium, zinc and a number of enzymes have been suggested.

Epidemiological studies evaluating the impact of anti-oxidants are both limited and inconsistent. The Baltimore Longitudinal Study on Aging11 examined the relationship between plasma levels of vitamins E, C, and beta-carotene and AMD. Only levels of vitamin E showed a statistically significant difference between AMD patients and controls. The Eye Disease Case Control Study12 evaluated the serum levels of anti-oxidants, as well as a history of dietary consumption, in patients with neovascular AMD. Patients with high serum levels of carotenoids, or high dietary consumption of carotenoid containing food sources were less likely to have neovascular AMD. High vitamin C consumption was also associated with a slight reduction of neovascular AMD. However, serum levels of vitamins E, and dietary consumption of vitamin E could not be correlated with the presence or absence of AMD. The Beaver Dam Study looked at the relationship between vitamin supplementation and AMD.13, 14 It evaluated plasma levels of carotenoids and tocopherols. It showed that the serum level of the carotenoids that compose macular pigment, lutein and zexanthin, were unrelated to AMD. In addition, there was no statistical difference with vitamin E and AMD when serum cholesterol was controlled. However, the Beaver Dam Study also showed that zinc intake was mildly protective against the development of early forms of AMD, but not neovascular AMD.

Studies examining the role of vitamin supplementation have also been inconsistent. In 1988, Newsome and associates published a study evaluating oral zinc supplementation as a means for prevention of AMD.15 In this study, 80 patients were treated with zinc and 71 patients received a placebo. The patients in the placebo group had a greater decline in visual acuity than the zinc patient group. Furthermore, the zinc treated group remained stable and had less visible drusen, compared to the placebo group. In a contradictory study, however, the Eye Disease Case Control Study found higher serum zinc levels in patients with neovascular AMD, compared with the control group. This trend remained, even when patients taking oral supplementation were excluded.12

Another study evaluated the effects of oral zinc supplementation on the development of AMD in the fellow eye of patients with neovascular AMD.16 One hundred twelve patients were included in this study. Patients were randomized into receiving 200 mg of oral zinc sulfate daily or placebo daily for twenty-four months. Although serum levels of zinc increased significantly in the treated group, there was no difference in the course of AMD between the two groups.

Another study evaluated the use of lutein supplementation for 140 days.17 Two patients received dietary supplements of 30 mg of lutein daily for 140 days. Serum lutein concentration and macular pigment optical density were measured. In both patients, there was an increase in macular pigment optical density. This was felt to correspond to a thirty to forty percent reduction in the amount of blue light that would reach the photoreceptors. Theoretically, this reduction in blue light could aid in reducing the oxidative damage that may be occurring in AMD.

With the studies being so inconsistent, it is unlikely that the risk of developing AMD can be markedly reduced through supplemental antioxidant vitamins and minerals. The Age Related Eye Disease Study, a ten year multi-centered, randomized trial conducted by the National Eye Institute, is currently ongoing. This study should give us more reliable information about the benefit of oral supplementation with regards to AMD. Until more definitive studies such as this are available, we do not recommend routine supplementation for patients, but recommend a healthy diet with plenty of green leafy vegetables.

Alcohol Consumption

It has been thought that alcohol use may also be a risk factor for AMD. However, most epidemiological studies have not shown a significant correlation. The Blue Mountain Eye Study,18 the Framingham Eye Study,19 and the Physician Health Study20 showed no appreciable increased risk for AMD with alcohol consumption. The Beaver Dam Eye Study showed a slight correlation between consumption of beer and neovascular AMD, as well as beer drinking and the appearance of retinal drusen.21 This same study showed no association with wine consumption but the First National Health Nutrition and Examination Survey showed that moderate consumption of wine could decrease the odds of developing AMD.22

Smoking, Hypertension And Cardiovascular Disease

Smoking can increase the risk of AMD by two methods. It has been shown to promote ischemia and micro-infarction, which can increase the risk of the macular degenerative changes. In addition, smoking may increase the oxidative stress in patients and thus increase the risk of AMD.

Numerous epidemiological studies have demonstrated the risk of smoking with regard to AMD.23 Hayman and associates showed a 2.6 relative risk for male smokers, but no significant risk for female smokers.24 The Eye Disease
Case Control Study showed smoking to be a marked risk factor for the development of neovascular AMD.25 The Rotterdam Study showed that smoking increased the risk of AMD in all patients.26,27 In this study, current smokers in the age group of 55 to 84 years of age had a relative risk of 3.6, compared with non-smokers, and smokers over the age of 85 had a relative risk of 5.2. The Beaver Dam Study showed that smoking status and current exposure to passive smoking were not associated with early AMD. However, there was a strong association with neovascular AMD.28 This association of smoking with late AMD was also confirmed in the POLA (Pathologies Oculaires Liees a l'Age) Study.29

Prospective studies have also shown a relationship between smoking and AMD. Seddon and associates enrolled 31,843 female nurses between the ages 50 to 59 in a twelve year prospective study.30 In this study, patients who smoked 25 or more cigarettes per day had a relative risk of 2.4, compared to non-smokers. Former smokers also had an increase in relative risk of 2.0 compared to non-smokers. In another study, Christen and Associates followed 21,157 American male physicians over seven years.31 In this group, smokers of 20 or more cigarettes a day, had a relative risk of 2.46, compared to non-smokers. It is obvious from the consistency of these studies that smoking is an avoidable risk factor for the development and the progression of AMD. All patients with AMD or at risk of developing AMD should be advised to stop smoking.

Studies on hypertension and cardiovascular disease and its relationship to AMD have been inconsistent. A recent case control study suggested that neovascular AMD was associated with moderate to severe hypertension. However, non-neovascular AMD was unrelated to hypertension in the same study.32 The Framingham Study19 also indicated an association of AMD with systemic hypertension. However, the Beaver Dam Eye Study33 and a Finnish study34 showed no correlation between hypertension, cardiovascular disease, and AMD.

Conclusion

Macular degeneration is a significant public health concern. It is the leading cause of blindness in the elderly population and current treatments are limited, at best. The current data indicate that genetics may play a role in the development of AMD. An AMD patient's siblings and children should be counseled to have routine retinal examinations, as they are at risk for the development of AMD in their later years. Patients should refrain from smoking, as this has clearly been demonstrated to increase the risk for the development of AMD. Control of hypertension, and cardiovascular risk factors, also may play a role. Finally, the use of nutritional supplementation is controversial. There is no definitive evidence that nutritional supplementation is of benefit in the prevention of AMD. Despite the paucity of data supportive of a benefit, pharmaceutical companies have subjected elderly patients to extensive marketing on the benefits of vitamin supplementation. These supplements can be expensive. Instead of vitamin supplements, we counsel our patients to make sure they have a good nutritional diet high in the carotenoids found in green leafy vegetables. This, along with the cessation of smoking and control of hypertension may reduce their risk of developing AMD. Patients with neovascular AMD should be advised of the importance of self-monitoring their vision, one eye at a time. Upon detecting new symptoms they should seek care of an ophthalmologist experienced in the detection and management of AMD.

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September, 2000/ Jacksonville Medicine

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