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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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.

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