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 m diameter), welldemarcated, 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 m 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 m, 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.

general health, hypertension and hypercholesterolemia should be managed actively, and cigarette smoking should be discouraged. What treatments are available for patients with AMD? There is no proven treatment for the atrophic form of AMD. The only proven treatment for patients who have developed CNVs is laser photocoagulation. Laser treatment cauterizes the CNVs, and the vascular thrombosis stops subretinal bleeding. Laser treatment also destroys the overlying retina. As a result, each area of laser treatment is incapable of seeing, and treatment leaves the patient with a blind spot ("scotoma") in or near the center of vision. Still, without laser treatment, the blind spot induced by the CNVs would be even bigger. Among most patients with extrafoveal CNVs, laser photocoagulation effectively delays the onset of severe, central visual loss by about 18 months, on average. Unfortunately, only a minority (10-20%) of patients with CNVs are eligible for laser photocoagulation. The size of the lesion and the degree to which its boundaries can be identified precisely with fluorescein angiography are the factors most commonly rendering patients ineligible for laser photocoagulation. The most common cause of treatment failure following laser photocoagulation is recurrent CNV growth, which occurs in half the patients. Low vision aids can be very useful for patients with central visual impairment. Patients with intermediate visual loss (e.g., visual acuity 20/40-20/80) benefit the most from a low vision evaluation, which includes a careful refraction, demonstration of various hand held magnifying devices, high intensity lamps (e.g., halogen lamps), computerized text enlargers, and, in selected centers, special video glasses that project images onto functioning paracentral retina. What is the risk of blindness once a CNV develops? The risk of visual loss depends on the size, location, and angiographic features of the CNV. In general, the closer the CNV is to the fovea, the larger the CNV, and the more well defined the CNV, the worse the prognosis. If a patient has a well defined subfoveal CNV (i.e., the borders of the CNV are well demarcated angiographically), the risk of severe visual loss (i.e., e" 6 line loss of vision on the visual acuity chart) is 45%, and the mean visual acuity is 20/500 at four years follow-up without treatment, vs. 23% and 20/320 among treated eyes, respectively. (Patients with visual acuity equal to or worse than 20/200 are legally blind.) Patients with poorly defined CNVs have a somewhat better prognosis. What are the future directions for research? Most efforts are directed at developing treatments for the neovascular complications of AMD. Experimental protocols involve treatment with antiangiogenic drugs (e.g., thalidomide), photodynamic therapy (i.e., ablation of CNVs using subthermal laser energy and photosensitizing agents with the goal of minimizing retinal destruction), low dose radiation therapy (teletherapy, which can reduce growth of and leakage from vascular tumors, e.g., choroidal hemangiomas), surgical excision of CNVs (to eliminate the source of exudative retinal detachment and subretinal scarring), and retinal cell transplantation therapy (to replace cells removed iatrogenically, e.g., RPE, or lost through atrophy).

Transplantation of retinal cells in conjunction with surgical excision of abnormal blood vessels may offer hope to many patients (even those with "dry" AMD may benefit from RPE transplantation). Retinal cell transplantation is a great challenge, and it will not be easy to accomplish. Drusen can disappear spontaneously, probably as a result of RPE atrophy. Sarks, Sarks, and Killingsworth pointed out that geographic atrophy in AMD is associated with loss of accumulated basal linear deposit. They also noted that the growth of CNVs from within Bruch's membrane into the subRPE space occurs in areas of basal linear deposit, possibly because: 1) there is true cleavage plane between the RPE and Bruch's membrane in these loci, and 2) in these areas the outer retina and RPE are under greatest metabolic distress and stimulate CNV growth. Thus, elimination of soft drusen might eliminate basal linear deposit and reduce the risk of exudative maculopathy in AMD. Disappearance of drusen in areas adjacent to sites of laser photocoagulation was first noted by Gass in 1973. Several reports have confirmed these findings. Laser photocoagulation-induced drusen regression might prevent CNV development. While this approach to CNV prophylaxis may hold promise, one study has shown an increased risk of developing CNVs among some eyes undergoing light laser photocoagulation to induce drusen regression. A multicenter study to assess the ability of low energy laser photocoagulation to induce drusen regression and prevent CNV development is now being organized. REFERENCES Allikmets R, Shroyer NF, Singh N et al. Mutation on the Stargardt disease gene (ABCR) in age-related macular degeneration. Science 1997; 277:1805-7. Bird AC. Pathogenesis of retinal pigment epithelial detachment in the elderly; the relevance of Bruch's membrane change. Eye 1991; 5:1-12. Bird AC. What is the future of research in age-related macular degeneration. Arch Ophthalmol 1997; 115:1311-3. Bressler NM, Silva JC, Bressler SB, Fine SL, Green WR. Clinicopathologic correlation of drusen and retinal pigment epithelial abnormalities in age-related macular degeneration. Retina 1994; 14:130-42. Burns RP, Feeney-Burns L. Clinicomorphologic correlations of drusen and Bruch's membrane. Trans Am Ophthalmol Soc 1980; 78:206-23.