Table 17.2  Age-related macular degeneration (AMD) categories in the Age-Related Eye Disease Study (AREDS)

RPE depigmentation, and noncentral geographic atrophy (GA). For assessing the individual risk of each patient for developing advanced AMD, either nonneovascular or neovascular, it is important to examine the macula carefully at every visit, paying attention to the signs mentioned above. As the classification of AMD according to AREDS is based upon the evaluation of photographs in a central reading center and using a special grid, it is not easily applicable for daily clinical use. A simplified severity scale was therefore developed and tested on the AREDS study population.28 It does not include drusen area, which in a clinical setting is quite difficult to measure, since a strong association between maximum drusen size and drusen area had been found.29 Patients without signs of advanced AMD were classified in the simplified severity scale by maximal drusen size and presence or absence of any pigmentary changes in one or both eyes. Bilateral intermediate-size drusen was counted as one risk factor. Small drusen did not count as any risk. The presence of at least one large druse and pigmentary abnormalities in both eyes would sum up to a risk factor of four. The 5-year risk of advanced AMD increases from 0.5% for a patient with 0 risk factors to 3% (one risk factor), 12% (two risk factors), 25% (three risk factors) and 50% (four risk factors). It is not clear to what extent other risk factors such as smoking, genetic predisposition, diet, or supplement use might influence these risks.

The symptoms experienced in nonneovascular AMD vary greatly according to the location and size of changes present. They also depend very much on the involvement of either one or both eyes. Even the presence of large drusen may not cause any visual disturbance as long as the fovea is not directly involved or the other eye is not affected. Confluent centrally located drusen might however cause metamorphosia without the presence of any neovascular changes such as choroidal neovascularization as well as blurred vision. First symptoms in GA are often reading difficulties, increasing when GA involves large areas of the center. In addition, patients will have greater difficulties in dim light as well as marked photophobia. In advanced nonneovascular AMD there can be severe vision loss, including loss of reading ability.

TREATMENT OPTIONS

Currently the treatment options in nonneovascular AMD are limited to trying to prevent disease progression. As mentioned above, oxidative stress in the macular region – no matter what the cause – is considered to be one of the components in the pathogenesis of AMD. The observation that vitamins and minerals with antioxidative properties reduce the risk of AMD progression supports this concept. The potential of antioxidants to scavenger or quench free radicals of different origin may protect photoreceptors and RPE cells. Different antioxidants and minerals have been investigated in nonneovascular AMD.

VITAMIN C

Vitamin C (l-ascorbic acid) is a water-soluble antioxidant and one of the widely used vitamin supplements and is known to act as an antioxidant for several decades. Supplementation of vitamin C reduces light-induced retinal damage30,31 in animal experiments. The data of human studies are, however, inconclusive. Whereas several reports revealed a correlation between low vitamin C plasma concentration and AMD, others failed to find a protective effect of vitamin C.32,33

CAROTENOIDS

Three members of the carotenoid famlily have been proposed to be beneficial for dry AMD. As a first approach, beta-carotene, which is one of the major precursors of vitamin A, has been proven to be an effective antioxidant.34 The Eye Disease Case-Control Study found that a higher dietary intake of carotenoids was associated with a lower risk for AMD.33 However, it has been shown that high-dose beta-carotene may increase the risk of cancer, especially in smokers and former smokers.35 Today, in many preparations targeting dry AMD, beta-carotene has been replaced by lutein and/or zeaxanthin. Lutein and zeaxanthin also belong to the family of carotenoids and are the major components of the macula pigment. Although the exact role of macular pigment remains to be fully elucidated, it has been shown that the macula pigments play a major role in the reduction of light scatter and chromatic aberration in the macula and may protect against the adverse effects of high-energy short-wavelength light. Consequently, it has been hypothesized that dietary supplementation with lutein and/or zeaxanthin might delay the progression of AMD. Preliminary studies using exogenous supplementation of lutein and zeaxanthin have been promising. Lutein and zeaxanthin are part of the protocol evaluated in the recently initiated AREDS 2. Furthermore, all participants will be offered additional treatment with the study formulation used in AREDS 1. Patients, who agree to take this additional supplement will be further randomized to original AREDS 1 medication or modified AREDS 1 medication without beta-carotene or lower levels of zinc.

VITAMIN E

Because vitamin E is mostly given as a combination with other vitamins, the data about vitamin E supplementation alone are sparse. Dietary deficiency of vitamin E has been shown to lead to lipofuscin accumulation in the RPE. Whether this relates to changes seen in AMD has yet to be clarified. The AREDS report indicates that vitamin E, when given in combination with other vitamins and zinc, delays the progression of AMD.15

MINERALS

Given that certain minerals such as zinc, copper, iron and others act as cofactors in the human enzymatic antioxidant system, deficiency of these nutritional cofactors negatively affects the antioxidant capacity.

Pharmacotherapy to Amenable Diseases Retinal • 3 section

Degeneration Macular related-Age neovascular • 17 chapterNon

Thus, it has been hypothesized that supplementation of these minerals may be beneficial for patients with AMD. However, direct evidence for a protective role in AMD is sparse and is mainly derived from AREDS, which demonstrates a beneficial role for zinc, especially in combination with other antioxidants.15

TREATMENT OUTCOMES AND

PROGNOSIS

Epidemiological studies report that people with high vitamin intake are at a reduced risk of developing AMD. However, they do not prove that exogenous supplementation of vitamins and/or minerals is beneficial for patients with dry AMD. To prove the effect of antioxidants on the progression of AMD, large prospective, longitudinal interventional studies are necessary. Until now, evidence for the effectiveness of vitamin and mineral supplementation is mainly based on the AREDS. The study was designed to identify the effect of high-dose vitamin and mineral supplementation on the development of cataract and AMD. This multicenter, prospective, randomized study included 3640 patients aged 55–80 years with AMD from 1992 to 1998.15 The average follow-up was 6.3 years. The patients were randomized into four groups and received daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta-carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo. Primary outcomes of the study were progression to advanced AMD and at least moderate visual acuity loss from baseline (15 letters). Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (regimen 3) (OR, 0.72; 99% confidence interval, 0.52–0.98).15 Supplementation with antioxidants or zinc alone did not demonstrate a significant odds reduction. It was found however that participants with extensive small drusen, nonextensive intermediate drusen, or pigment abnormalities (category 2) had only a 1.3% 5-year probability to progress to advanced AMD. By excluding category 2 patients, significant odds reduction was also seen for antioxidants or zinc alone. A significant odds reduction for at least moderate vision loss was only seen in patients assigned to antioxidant and zinc (regimen 3) (OR, 0.73; 99% confidence interval, 0.54–0.99).15 The combination of vitamins and minerals shown in Table 17.3 is currently recommended for nonsmoking patients with nonneovascular AMD of at least AREDS category 2. High-dose supplementation of antioxidants and cofactors is currently not recommended for the general population.

AREDS has several limitations. Given that a combination of antioxidants was used, it is not clear which component is responsible for the beneficial effect. Furthermore, vitamin C, vitamin E, and zinc were included at much higher doses than the recommended daily allowance (www.nal.usda.gov). Thus, it is not entirely clear if a long-term supplementation of such high doses of vitamins could be harmful. In particular, there is evidence that high doses of beta-carotene increase the risk of cancer in smokers and former smokers.36 To investigate these questions further, the AREDS 2 study started enrolling in the fall of 2006. Its primary objective is to determine whether oral supplementation

Table 17.3  Formulation of high-dose vitamin and mineral supplementation used in the Age-Related Eye Disease Study (AREDS)

Table 17.4

Randomization

with lutein/zeaxanthin and/or omega-3 fatty acids in combination with other vitamins may be beneficial for patients with AMD.

SUMMARY AND KEY POINTS

Although significant improvement has been made in understanding the pathogenesis of nonneovascular AMD, many questions remain to be answered. Until now, unfortunately, the available pharmacological approaches, in particular the supplementation of antioxidants and minerals, can only reduce the risk of disease progression but are unable to prevent the disease. Evidence for the effectiveness of high-dose antioxidant vitamin and mineral supplementation in reducing the risk of developing advanced AMD is mainly derived from one single interventional study (AREDS), performed in the USA. The AREDS formulation­ (Table 17.3) is currently recommended for nonsmoking nonneovascular AMD patients with at least AREDS category 2 findings, based on best evidence available. Whether these results can be applied to other populations with a different nutritional status has yet to be investigated. AREDS 2 has been initiated to evaluate lutein and zeaxanthin as well as omega-3 fatty acids (Table 17.4).

The new insight into the role of polymorphisms in CFH and HTRA1 provides a promising approach to new preventive treatments for nonneovascular AMD, especially when used in combination with genetic risk evaluation. However, this new approach has just entered first clinical trials. Furthermore, infectious and/or inflammatory diseases potentially triggering the disease may play an additional role in the pathogenesis of AMD.

Within the past several years, nonneovascularAMD has truly become a most progressive field for pharmacotherapy. Hopefully, promising treatment and prevention options will soon be introduced into clinical practice.

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Pharmacotherapy to Amenable Diseases Retinal • 3 section