Retinal Care Update
Here's the latest information on treating diabetic retinopathy and age-related macular degeneration.
By Charles L. Schepens, M.D., and J. Wallace McMeel, M.D.

The treatment of eye disease has undergone a profound evolution during the past 50 years. Today, cataract surgery produces excellent results and patients return home the same day. Retinal detachment operations are now successful in 95% of cases and only require a short hospital stay. Glaucoma patients can often be treated successfully with drops instead of surgery.

Unfortunately, the treatment of diabetic retinopathy and age-related macular degeneration (ARMD) have progressed more slowly. Here, we'd like to present an overview of our current state of knowledge regarding the causes, progression and treatment of these two conditions.

Diabetic retinopathy

Most recent advances in the treatment of diabetic retinopathy have been designed to minimize the growth of abnormal blood vessels, which cause most of the profound visual loss in diabetic retinopathy. New approaches include:

Using angiostatic agents to counter the stimulation of new vessels in the hypoxic eye. Because an increased level of vascular endothelial growth factor (VEGF) is present in hypoxic eyes with proliferative diabetic retinopathy, re-searchers are testing compounds that inhibit VEGF. The goal is to inhibit VEGF through actions such as the inhibition of protein kinase C, which is important to cell division.

Treating the entire body. Several health conditions may impact the progression of diabetic retinopathy:

• Most ophthalmologists recognize that systemic hypertension may accelerate the progression of diabetic retinopathy, especially if the retina is in the pre-proliferative stage. (Renal disease is often present in these instances.)
• Several studies have shown that an angiotensin converting enzyme (ACE) inhibitor not only slows the progression of kidney disease, but also retards the development of diabetic retinopathy.
• The damage inflicted on the vascular endothelium by chronic local infections (such as in the feet, gums or tonsils) and subclinical stealth diseases such as Lyme disease, syphilis, tuberculosis, Rickettsia and Chlamydia may also promote progression of retinopathy. Clement Trempe, M.D., has documented numerous remarkable improvements in retinopathy when treating these conditions.

Using enzymes to create liquefaction of the vitreous gel. This shows promise as a way to clear vitreous hemorrhages and weaken the junction between the gel and the retina, reducing the risk of new vessel growth into the vitreous cavity.

Age-related macular degeneration (ARMD)

Today, this condition is the most frequent cause of blindness in people over age 60 in the United States. Although a cure hasn't been found, several treatments are known to help prevent or contain it. These fall into several categories:

Lifestyle changes. Helpful factors include:

• avoiding excessive sunlight
• maintaining physical fitness
• avoiding tobacco consumption
• eating a diet rich in vegetables, fresh fruit and fish, and low in fats and red meat. A recent study sponsored by the National Eye Institute at the National Institutes of Health found that eating vegetable, monounsaturated, and polyunsaturated fats and linoleic acid was directly associated with the risk of developing advanced ARMD. (Highly processed, store-bought snack foods and fast foods like potato chips and french fries contain a lot of these fats.) Diets high in cholesterol are also contraindicated. In contrast, intake of omega-3 fatty acids and fish seemed to have a protective effect, although only in individuals with low linoleic acid levels.
• vitamin C and E supplements. (A recent study conducted by the National Eye Institute confirmed this.)
• selenium supplements. (Selenium's potential side-effects make this a less desirable option.)

Several carotenoids appear effective as ARMD preventives, particularly lutein and zeaxanthin, which are mostly concentrated in dark green leafy vegetables such as spinach, kale and collard greens. Beta carotene is also said to be effective, even though it doesn't penetrate into the retina.

Lasering faulty blood vessels. Damage resulting from the wet form of ARMD is largely caused by the growth of (and leakage from) new subretinal blood vessels in the underlying choroid or over Bruch's membrane. As a result, many recent treatments have used lasers to prevent new vessel growth, or to stop or prevent leaks. These include:

• Using an argon laser to seal the leaky blood vessels. (The leaky vessels can be detected using fluorescein or indocyanine dyes.) Unfortunately, when the offending vessels lie beneath the fovea, laser treatment can decrease the patient's vision. Surgeons are now using a scanning laser ophthalmoscope to determine the precise extent of the central scotoma so the laser avoids areas of the posterior retina that still function.
• A variation on this approach is photodynamic therapy (PDT), in which injected verteporfin, a light-activated drug, is absorbed by damaged, abnormal vessels in the retina and choroid. By using a laser that selectively affects the new vessels dyed by the verteporfin, it's possible to stop leakage without damaging the rest of the retina and choroid. PDT has maintained or improved vision in about 60% of treated patients, but the treatment may have to be repeated several times to achieve this result. (Researchers hope to find other injectable dyes that may minimize the disadvantages of verteporfin, such as the need for the patient to shield his body from exposure to strong light sources for several days).
• Transpupillary thermotherapy treatment (TTT) uses infrared light to focus moderate heat on the retinal lesion caused by ARMD. This type of treatment has been championed by Dr. Trempe for several years. Dr. Trempe repeatedly applies a low-intensity 100-mw green laser to the entire lesion for periods of 10 to 15 seconds, for a total treating time of 100 to 200 seconds. This allows a more even distribution of heat in the treated area, causing less damage in the macular area than the high-intensity, very short duration treatment still used routinely by most surgeons.
• Using a weak laser to treat early dry ARMD is still under study. One approach uses a weak argon laser to cause barely visible spots of reaction around the macula; this has produced controversial results because many such laser marks enlarge considerably over the years. Another prophylactic treatment of one form of dry ARMD -- soft drusen -- uses weak infrared laser burns. This method of treatment is still under study.

Surgical intervention. Current approaches under investigation include:

• Subretinal excision of the scar produced by ARMD. This rarely gives favorable results, although it's often helpful for younger patients affected with macular histoplasmosis.
• A Translocation of the macular area is a very extensive operation that, so far, has been marginally effective. (It also causes diplopia and torsional problems and can leave the patient with marked astigmatism.)
• Recent research has focused on using retinal cell transplants to create function in the fovea. Studies conducted during the past decade have shown that retinal cell transplants remain viable in animals for up to 6 months. In human studies, researchers have tried removing the new, abnormal, subretinal vessels and transplanting early fetal retinal pigment epithelium beneath the foveal neurosensory layers. They've also tried implanting autografts of iris pigment epithelium. Unfortunately, these surgical attempts have not yet produced durable postoperative visual improvement.
• Researchers in the United States, Japan, and Europe are currently experimenting with retinal prostheses -- implanting chips to replace non-functioning retinal rods and cones in patients who are totally blind but still have the necessary neural "wiring" for vision, such as many patients affected by profound ARMD or retinitis pigmentosa. The miniaturized chip may be placed either on the macula or under it; some researchers are experimenting with placing the chip directly on the brain. For now, the procedure (if successful) is only expected to give the patient gross visual perception.

So far, researchers haven't conducted extensive human trials. The main problem has been uncertainty about the long-term tolerance of the retina or brain for the chip because silicon-based materials can be toxic and react unfavorably with fluids in the eye. Scientists at the Space Vacuum Epitaxy Center in Houston are now experimenting with thin, photosensitive ceramic films that don't have this disadvantage.

Other treatments. These include:

• Treating with angiostatic agents. This approach has had variable success. One group of compounds under investigation, metalloproteinase inhibitors, decreases the ability of protease enzymes to lyse matrices into which neovascular buds can protrude. (In our experience the most useful medication of this type has been minocycline, an inexpensive generic drug.)
• P. Campochiaro et al. are working on a method for delivering the gene that encodes the pigment-epithelium-derived factor to the retina, as a means of decreasing or preventing the growth of abnormal subretinal vessels.
• Treatments involving microcurrent stimulation, shark cartilage and rheotherapy blood filtration are still in use, despite a lack of evidence that they cause improvement. Treat-ments involving thalidomide, interferon, X-ray radiation and the proton beam have been largely abandoned due to a lack of demonstrable improvement or too much collateral damage.

Hope for the future

In the long fight to conquer blindness caused by diabetic retinopathy and ARMD, we're beginning to see light at the end of the tunnel. No one can say for sure how soon these conditions will be effectively prevented and cured, but today, final victory looks more reachable than ever. OM

Charles L. Schepens, M.D., is Clinical Professor Emeritus at Harvard Medical School; he was the director and founder of the world's first retina service; and he founded Schepens Retina Associates and the Schepens Eye Research Institute. He's published hundreds of scientific papers and four books, and has received numerous awards. J. Wallace McMeel, M.D., is president of Schepens Retina Associates and is a clinical senior scientist at the Schepens Eye Research Institute. He's also an associate clinical professor of ophthalmology at Harvard Medical School and has published more than 100 scientific papers.