by Valerie R. Gregg

he miracle of vision is tiny and fragile, centered in a collection of cells in the retina, barely the size of this "o." Called the macula, it allows to us read the words of a novel, watch a vivid sunrise, and see the smiling faces of our children and grandchildren.

When something goes wrong here, the results are devastating. Macular degeneration, an age-related atrophy or scarring of the central retina, is the leading cause of blindness in people over 55 and affects more than 3 million Americans every year.

Just 15 years ago, when elderly patients with macular degeneration came to the Emory Eye Center for treatment, little could be done for them. Even halting the progression of this disease seemed hardly possible.

Today that outlook is changing. Macular degeneration remains an imposing public health problem. About 20% of all 75-year-olds suffer from it, few patients are good candidates for treatment, and there is no cure. But this disease is the focus of much more attention than in the past, and a good deal of this effort is being led by people at Emory.

"We've been involved in virtually every major clinical trial for macular degeneration," says Tom Aaberg Sr., director of the Eye Center. "We've been the leading force on many of the panels organizing these studies. No other center in the Southeast has all of our capabilities together in one place. We were in on the ground floor."

The macula, where images and light are
focused, is 100 times more sensitive to
detail than the peripheral retina. People
with macular degeneration may see
lines of print as wavy or curved, and
colors are dimmed.

Sometimes as people age, these retinal cells die as the blood vessels behind them atrophy. This is called "dry" macular degeneration. In the "wet" version, a tangle of excess blood vessels grows under the macular retina. They hemorrhage and leak, scarring the light-sensitive tissue. Once the damage is done, the retina cannot be repaired. The result is blurring and dim colors in central vision. Straight lines appear curved or wavy. Sometimes, there is simply a dark or empty area in the center of vision.

For patients, the worst thing about this disease is losing their quality of life. For physicians, the worst thing is being unable to fix it.

Paul Sternberg, head of the Eye Center's retina section, says macular degeneration is probably the center's biggest research challenge. "First of all, it's so prevalent, and it will become more so as people continue to live longer," he says.

Most patients will eventually become legally blind, unable to read or drive.

"Second, it's so devastating, particularly when so many patients are otherwise healthy. Many of these people have worked so hard to survive cardiovascular and cancer risks, and they're now 70 or 80 years old, and they physically feel good. They're independent and living by themselves. If they lose their vision, they become dependent. They must often leave the house where they raised their children. They can't read the Bible, play cards, knit, or sew."

The disease sometimes strikes patients during their 50s, says Aaberg Sr. "People in this age group are still very productive in their jobs. It's also a time when they're hoping to enjoy traveling and reading. If they lose their vision, that's all eliminated. They can still travel, but they can't see clearly when they get to the places they want to go."

Tom Aaberg Jr. is testing transpupillary
thermal treatment, long used against
malignant tumors, for effectiveness
against macular degeneration.

For years, the only way to stop this leakage was with surgery using a heat laser, called photocoagulation therapy. Laser photocoagulation is an option for only 10% of patients with wet macular degeneration, and it has drawbacks. "This procedure always causes a blind spot -- a region of blackness in vision," says Sternberg. "The impact of the blind spot depends on its size and location with regard to central vision."

A new alternative called photodynamic therapy (PDT) substantially reduces the risk of blind spot by using a cold laser. The patient is given a photosensitizing drug called Visudyne that concentrates in the abnormal vessels behind the retina. When the laser is shone on the macula, the drug is activated and those vessels are destroyed. Recently approved by the FDA, the treatment requires no hospitalization, and patients can return to normal activities almost immediately. Patients sometimes experience temporary vision loss, which subsides within a few weeks. Research results show that PDT preserves or improves vision in 38% of patients and slows vision loss in another 31%.

The only drawback is a high recurrence rate, says Sternberg. But that is offset by the relative ease and low risk of the procedure. "It's outpatient - 10 minutes in the office - and there is no recovery time," he says. "With wet macular degeneration, recurrence is a problem no matter what treatment you use. Once you get to the wet stage, it becomes very difficult to stop. It is very persistent."

Transpupillary thermal treatment (TTT), another therapy using a laser and a drug, offers some hope for longer intervals between recurrences. Emory physician Tom Aaberg Jr. has used the technique for many years to treat malignant tumors, such as melanoma and retinoblastoma, and is currently leading a study to test its application in macular degeneration.

"It was natural for me to see another use for this technique," he says. "Certain tumors don't absorb laser well, so by coupling laser with a certain dye, I get a better laser uptake. The same principle may apply in the excess growth that causes wet macular degeneration. This study will help us find out."

The TTT clinical trial for macular degeneration began late last year and has enrolled 60 patients so far.

Another promising strategy involves inhibiting the molecular growth factors that encourage growth of blood vessels in the eye. Emory ophthalmologist Daniel Martin supervises phase I of a clinical trial of a new drug aimed to inhibit vessel growth.

"We're testing the safety of a drug that has been shown to block neovascularization in animals without toxicity," he says. "This is an extremely promising concept."

Thus far, the drug has proved safe enough to move on to clinical trials to determine its effectiveness.

Paul Sternberg, head of the retina service.

Paradoxically, the primary risk of treatment is blindness.

Surgically rotating the retina - called translocation - is one of the more high-risk, investigational approaches. It is also the only treatment offering hope for improved vision.

The retina is moved either partially or completely. Rotating the entire retina requires an incision around the entire circumference of the eye, detaching the retina, and moving it to a new area where there are no abnormal vessels. Because of the large incision, there is a greater chance of complications.

"The best candidates are those with small, recent-onset new blood vessel membranes," Sternberg says. "Up to 25% of patients suffer a complication from the surgery that can significantly decrease their vision. These include retinal detachment, double vision, cataract, and bleeding."

On the up side, 25% to 30% of patients experience improved visual acuity. Because of the risks, however, Sternberg says the recent FDA approval of PDT may decrease the need for translocation surgery.

Another ongoing surgical clinical trial at Emory, submacular surgery, is sponsored by the NIH. This procedure allows the surgeon to work inside the eye and remove the abnormal blood vessel growth from under the retina.

This surgery is best for patients with larger, new blood vessel growth that is hemorrhaging substantially. The risks of bleeding, cataract, and retinal detachment are less common than with translocation surgery. But halting vision loss is the objective rather than improving sight.

Submacular surgery may also prove helpful in retinal transplantation, now being studied in animals. Transplantation could eventually halt the progress of dry macular degeneration. Emory immunologist Judith Kapp, who has joint appointments in ophthalmology and pathology, is studying how mice reject cells that have been transplanted just under the macular retina.

"Our goal is to learn enough about rejection so we can tailor therapies to prevent it as well as develop the surgical technique for transplantation," says Kapp.

Transplantation is especially promising in the eye because the eye is immunologically privileged. Transplanted tissues like the cornea are rarely rejected, even without immunosuppression. "The subretinal space is privileged too but not as much as the cornea," says Kapp. "So transplantation is a promising strategy for macular degeneration. But as I always say, we've cured a lot of mouse diseases. We have a lot more work to do in this area, on mice and in nonhuman primates, before it's a real option for people."

David Martin supervises phase 1 of a
trial of a new drug aimed at inhibiting
molecular growth factors that encourage
blood vessels to grow in the eye.

At least that's the theory. A long-term study sponsored by the NIH is aimed at finding out for sure. Emory has participated in the Age-Related Eye Disease Study for the past 10 years. Study participants take varying doses of beta-carotene, vitamins C and E, and minerals zinc and selenium versus placebo. They are being followed to see if and when they develop macular degeneration and how it progresses.

Any study of the aging process is bound to take years. Along with biochemist Dean Jones, Sternberg is trying to speed up the process. Using retinal cells in tissue culture, they are observing cell responses to different antioxidants. They subject cultures to light oxidation and see what chemicals appear protective. They're also investigating ways to help antioxidants work more effectively.

"Taking vitamin supplements orally doesn't necessarily mean you'll increase the level of those vitamins in the retina," says Sternberg. "We need more sophisticated ways to augment antioxidants within retinal cells."

Epidemiologic studies have found that diets high in certain fruits and vegetables may help prevent macular degeneration. It may be that certain substances in these foods, including glutathione, help deliver antioxidant vitamins to the eye.

Sternberg hopes this basic science work will help move antioxidant therapy from the bench to the bedside sooner rather than later.

Although macular degeneration is a disease of aging, about 30% of those affected have a strong family history. Environmental factors and genetic predisposition both play a part. Antioxidant treatment for the genetically predisposed might help prevent or delay the onset of both wet and dry macular degeneration.

"Studies indicate that we start to deplete our antioxidant reserves in our fifth decade, which suggests that in cases of disease caused by oxidative insult, we should start treating patients in their 40s," says Sternberg.

"Macular degeneration will never be cured because it's part of an aging process that some people are more susceptible to, and you can't stop aging," says Aaberg Sr. "But we have a good chance to delay its onset and eliminate it from the younger age groups."

"We can also offer patients hope," says Sternberg. "By the time their children are older, we should be able to prevent this disease from disabling them."

Valerie Gregg is assistant director of publications in Emory's Woodruff Health Sciences Center.