AGE-RELATED MACULAR DEGENERATION UPDATE: A REVIEW OF PATHOGENESIS, CLINICAL FINDINGS, AND TREATMENT

BY MARCO ZARBIN, MD, PhD, FACS

Supported in part by Research to Prevent Blindness, Inc. and the New Jersey Lions Eye Research Foundation.

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Risk factor reduction

1) Ultraviolet and visible light. It probably makes sense to wear broad-brimmed hats and sunglasses to avoid excessive sun exposure in order to reduce the risk of skin cancer and eye diseases such as pterygium, conjunctival carcinoma, and cortical cataract. The evidence that the risk for AMD can be reduced, however, is weak. Ultraviolet and high energy visible light are damaging to the retina, but most ambient ultraviolet light is absorbed by the cornea and the crystalline lens. Patients who lack a crystalline lens (e.g., surgical aphakia) probably should wear lenses that filter all ultraviolet light as well as high energy visible (violet and blue) light.

2) Vitamins and minerals. Animal studies have shown that vitamin A or E deficiency induces retinal degeneration and that vitamin C supplementation protects against experimental light toxicity. The significance of these data with respect to AMD pathogenesis and prophylaxis is still unknown. Clinical studies provide conflicting data, but there does seem to be a general trend demonstrating a correlation between high serum levels of antioxidants (e.g., vitamins C and E, carotenoids) and a reduced risk of AMD. A study carried out by Dr. Johanna Seddon and her colleagues is noteworthy because it demonstrated that patients in the highest quintile of carotenoid intake had a 43% lower risk of advanced AMD compared to participants in the lowest quintile. Among specific carotenoids, lutein and zeaxanthin were most strongly correlated with reduced risk.

Carotenoids are obtained mainly from dark leafy green vegetables such as spinach, collard greens, kale, turnip greens, and mustard greens. (Carrots are enriched in carotenoids with vitamin A activity and in beta carotene, but are low in lutein and zeaxanthin.) Unlike many other studies that simply correlate serum antioxidant levels with disease severity, Dr. Seddon's demonstrated that different diets (vs. serum levels of antioxidants) were associated with different outcomes.

The Age-related Eye Disease Study (a National Eye Institute-sponsored, multicenter prospective study) will provide important data regarding the value of vitamin and mineral supplementation in preventing AMD, once it is completed. In the meantime, it seems reasonable to recommend that patients eat a balanced diet enriched in green leafy vegetables. The use of a multivitamin a day is fine, but patients should be warned of the dangers of excessive vitamin intake (e.g., pseudotumor cerebri with hypervitaminosis A, copper deficiency anemia and worsening cardiovascular disease with zinc toxicity), and the fact that no well designed study has demonstrated a benefit of vitamin supplementation (of any kind) in the prevention of AMD should be stressed. It may be appropriate to point out that the use of vitamin supplements is helpful in reducing the risk of some nonocular diseases (e.g., vitamin E and cardiovascular disease).

3) The cardiovascular risk profile. Hypertension, hypercholesterolemia, and cigarette smoking are associated with an increased risk of developing exudative AMD. No controlled study has shown that lowering blood pressure or cholesterol or stopping cigarette use reduces this risk. Still, for reasons of

cone density, and possibly other factors. It may be that the subfoveolar RPE is the longest-lived source of neovascular signal(s) in this metabolically distressed region, thus accounting for the tendency of CNVs to grow towards the foveola both initially and after laser photocoagulation.

What are the clinical manifestations of AMD? In AMD, abnormal deposits called drusen accumulate under the RPE. Clinically, drusen look like yellow flecks or spots under the retina, and they are the earliest clinical manifestation of AMD. Several classifications and careful clinical descriptions of drusen have been reported. Currently, we favor a classification based on features of drusen morphology that are evident clinically: hard and soft drusen. All types of drusen can undergo calcification, thus giving the drusen a glistening appearance. Calcification of soft drusen usually presages drusen regression and the development of RPE atrophy.

Typical hard drusen are usually round, yellow, small (< 64 µm diameter), well-demarcated, and are localized accumulations of hyaline material over which the RPE may be thinned. Small hard drusen can occur at a young age and continue to be formed during life. Focal densifications of Bruch's membrane, termed microdrusen, may precede the formation of overlying small hard drusen. Sarks pointed out that excessive numbers of hard drusen may predispose to atrophy of the RPE at a relatively young age.

Small hard drusen have a tendency to cluster and fuse. Hard drusen tend to have a rim of amorphous material with dispersed more electron lucent material comprising the portion of the drusen closest to Bruch's membrane. Clustered hard drusen remain well demarcated as long as this rim is intact. Fused hard drusen clusters tend to occur in middle age and have a good prognosis unless a cluster is under or threatens the foveola. Fused hard drusen clusters tend to regress over time, leaving foci of thinned or atrophic RPE. Soft cluster-derived drusen arise from the breakdown of the amorphous rim of a drusen cluster into globules. The globules can break down further to finely granular material. Soft cluster-derived drusen tend to be more common near the fovea.

Soft drusen are usually pale yellow and large (> 63 µm diameter) with poorly demarcated boundaries. (Sixty-three microns is approximately half the width of a major retinal vein at the optic nervehead.) Green and Enger and Bressler and coworkers pointed out that soft drusen can represent focal accentuations of basal linear deposit in the presence or absence of diffuse basal linear deposit-associated thickening of the inner aspects of Bruch's membrane. Soft drusen can also represent a localized accumulation of basal laminar deposit in an eye with diffuse basal laminar

deposit. Although soft cluster-derived drusen and soft membranous drusen can be distinguished histologically, it is not clear that they can be reliably distinguished clinically. Large confluent soft drusen can form clinically evident pigment epithelial detachments without underlying choroidal neovascularization. Soft drusen can form in the absence of small hard drusen although both types are often present in patients with AMD.

Hard drusen are common in young persons and probably are not prognostic of the development of AMD. In persons over the age of 55 years, soft drusen, particularly those larger than 63 µm, are associated with the presence of diffuse thickening of the inner aspect of Bruch's membrane and are a sign of AMD. In contrast, basal laminar (or cuticular) drusen comprise diffuse accumulations of material internal to the RPE basement membrane having internal nodularity. Basal laminar drusen are not associated with AMD.

If drusen are under the fovea, mild visual loss can occur, but the vision is often normal. Eventually, the RPE and photoreceptors overlying drusen may die, and the patient is said to have the atrophic or "dry" form of AMD. If these areas of degeneration are present in the fovea, then vision is permanently reduced. In some patients with AMD, CNVs grow from the choriocapillaris and leak fluid and blood under the RPE and macula. This leakage causes degeneration of the RPE and overlying photoreceptors and is associated with visual loss. A subretinal scar ("disciform scar") develops in many patients with CNVs. This is the exudative or "wet" form of AMD. The stimulus for CNV growth in AMD is unknown (see Histological changes in AMD above).

In AMD, the majority (80-90%) of cases of severe visual loss are due to the growth of CNVs with attendant exudative retinal detachment, hemorrhage, and subretinal scarring. A small proportion (10%) of cases of visual loss arise from the atrophy of RPE and retinal photoreceptors in the fovea without CNVs. Occasionally, CNVs bleed extensively causing massive subretinal hemorrhage with loss of peripheral as well as central vision.

What is the risk of developing CNVs? Among patients with bilateral drusen, the risk of developing CNVs is approximately 3%/year. Among patients with CNVs in one eye and drusen in the other eye, the risk of developing CNVs in the fellow eye ranges from ~10% to ~90% over five years. Patients with 5 or more drusen, large drusen, focal hyperpigmentation, and systemic hypertension constitute the highest risk group (87% risk of CNV/5 years) while those with none of these features constitute the lowest risk group (7% risk/5 years).

Can AMD be prevented? At the moment, there is no proven way to prevent AMD, but several studies have tried to identify risk factors for the disease.