BETHESDA, M.D.—Age-related macular degeneration is one of the many diseases associated with aging eyes. In some cases the disease progresses so slowly that changes in vision are barely perceptible. In others, it moves so swiftly that a patient might lose sight in both eyes over the course of a few years.

The most common form of AMD—dry AMD—is the slower-moving and less serious version. Dry AMD occurs when the light-sensitive cells in the macula slowly break down, gradually blurring central vision in the affected eye. As less of the macula functions, central vision is gradually lost. Those suffering from dry AMD have slightly blurred vision. They might have trouble recognizing faces and need more light for reading and other tasks. The most common early sign of dry AMD is drusen—yellow deposits under the retina often found in people over 60.

However, while dry AMD makes up the majority of intermediate AMD and a third of advanced AMD—two-thirds of patients with advanced AMD have wet AMD. Wet AMD occurs when abnormal blood vessels behind the retina start to grow under the macula—a process known as neovascularization. These new blood vessels tend to be very fragile and often leak blood and other fluid. The fluid raises the macula from its normal place at the back of the eye. After that begins, damage to the macula occurs quickly and loss of central vision progresses rapidly.

Treatment for both forms is limited, and there are many gaps in researchers’ knowledge of how the conditions progress and what exactly causes them in the fi rst place.

Pathology of AMD

Last month scientists at the National Eye Institute presented the state of the science on AMD, outlining the disease pathology, epidemiology and future directions for research and treatment.

“AMD is more than what would occur in normal aging. It’s more exaggerated compared to what happens in normal aging,” explained Farzin Forooghian, M.D., clinical researcher at NEI. “

“During normal processes, a few small drusen and RPE (retinal pigmentary epithelial) degeneration, thickening of Bruch’s membrane, and the internal limiting membrane [are expected]. Also, anomalies in the distal cone axons are common,” Dr. Forooghian said. “AMD pathology is characterized by degenerative changes and atrophy involving the outer layer of the retina, RPE, Bruch’s membrane, multiple drusen [and more].”

Drusen, the hallmark of AMD, come in two varieties—hard and soft drusen. Hard drusen are small, nodular and discrete. Nestled between the RPE and Bruch’s membrane, they are formed of a hyaline-like material. The other type, soft drusen, is the more important of the two in terms of clinical diagnosis.

“Soft druse tend to be larger and have poorly demarcated boundaries,” Dr. Forooghian said. “They are the important type because they’re the ones that predispose to [both kinds of AMD].”

How exactly excess and soft drusen help cause AMD is not entirely understood, though there are some strong connections.

“Macrophages are one arm of the immune system that’s been implicated in AMD,” Dr. Forooghian explained. “They can come in and gobble up the drusen, which are essentially accumulations of waste product. But when they can’t do that, when they’re overwhelmed, they release a lot of inflammatory mediators that can cause a lot of damage. And that’s one of the ways they are thought to help cause AMD.”

Also, Complement factor H—a gene involved in regulating inflammatory pathways—has been strongly linked to AMD. CFH is present in abundance in drusen, and a mutation in the CFH gene would increase inflammation and its consequences.

“That suggests it’s playing a role, but the exact role it’s playing is still being worked out,” Dr. Forooghian said.

Predicting the Disease

“The epidemiology of this disease really points to where we may be going and how we can better treat this disease,” explained Frederick Ferris, M.D., clinical director at NEI.

“Up until the age of 70, the presence of this [advanced version of the] disease is really quite low. It explodes in the later years. Not only do we have a problem related to AMD, but with an aging population, that problem is going to dramatically increase.”

Also, he added, AMD is unlikely a single disease process.

“What we call age-related macular degeneration is likely to be a conglomeration of multiple diseases,” Dr. Ferris said. “How does geographic atrophy (dry AMD) develop, though? That’s the underpinning of AMD.”

The NIH Age-Related Eye Disease Study (AREDS) completed in 2003 looked at clinical information on 95 patients who would go on to develop dry AMD. They found that 94 percent of those patients had large confluent drusen an average of 6 years before developing the disease. Four years before clinicians saw hyperpigmentation and at two years they saw hypopigmentation.

“This is a long, slow process,” Dr. Ferris said.

“The wild card in this is that at any moment neovascularization can develop in these eyes that have large confluent drusen,” Dr. Ferris declared.

Researchers working on AREDS developed a scale to calculate a patient’s risk of getting the disease.

“We identified very simple clinical features that predicted quite well who was going to progress to get the disease and who wasn’t,” Dr. Ferris said. “We looked at the right eye and the left eye and we asked whether they have large drusen and whether they have pigment changes.”

A “yes” answer for either eye equaled one point, creating a risk ratio between 0 and 4.

“Your risk ranges from half a percent of risk if you have nothing to 50 percent if you had both drusen and pigment changes in both eyes,” Dr. Ferris said.

Risk, Prevention and Treatment

With some understanding of what pre-clinical AMD looks like, clinicians might be able to help patients prevent the disease from progressing to the point of vision loss.

“There are a number of risk factors for AMD,” Dr. Ferris said. Those factors include genetic predisposition, smoking, CV disease, poor nutrition, smoking, and fundus features (interior surface of the eye).

“Body mass index is also an interesting [risk factor]. It’s not a huge risk factor, but it is associated with increased risk. It’s also associated with CV disease, which is not so much associated with the development of large drusen as it is associated with neovascularization,” Dr. Ferris said.

“Smoking, of all of the risk factors, is probably the biggest where you can do something about it,” he added.

Smoking doubles or triples a patient’s risk of developing AMD.

“There’s even a progression,” he said. “The more you smoke, the higher your risk.”

However, none of these risk factors come close to the impact of age on progression of a disease. And the presence of large drusen or pigmentary changes indicate a hundred-fold increase in the likelihood of developing the disease.

“That totally swamps the other risk factors,” Dr. Ferris said.

Information on nutrition has provided at least one weapon for physicians in helping prevent AMD. AREDS found that those patients who ate lots of greens and fish that are high in omega 3 had a 30- to 50% drop in developing neovascular AMD compared to patients that ate little.

Also, the study looked at zinc and antioxidants and found that patients taking a daily dose of those vitamins were less likely to develop AMD, though patients who already had AMD in the early stages did not benefit from beginning a vitamin regimen.

“There was a 28% risk (placebo) compared to 20% (using both zinc and antioxidants),” Dr. Ferris said. “That’s a pretty small decrease, but it’s just taking vitamins. However, if we look at the development of large drusen, the supplements did nothing.”

As for treatment, the first success in years of trial and error was the Lucentis (ranibizumab) trials, Dr. Ferris explained. Lucentis, developed by Genentech, is an anti-VEGF (vascular endothelial growth factor) antibody that inhibits VEGF activity. The drug is injected intravenously over the course of one to two years in patients with wet AMD. Approximately 95% of patients maintain their baseline vision during the course of the treatment, while up to 40% actually gain vision back.

“It’s the first treatment ever to have the promise of improving visual acuity,” Dr. Ferris noted. “The downside is that you get injected introvisually with ranibizumab every month [until] you’re stable and then you still might be getting injections over the pursuing years. I don’t think any of us who are giving monthly injections want to keep doing that forever.”

The bottom line, Dr. Ferris said, is that until more treatments are developed, prevention is the best bet in lowering the impact of AMD on the population. Using the risk-reduction program developed by AREDS—targeting nutrition and other risk factors—25% of those that might develop advanced AMD will not.

“It’s a relatively small impact that translates into a big public health impact of 329,000 people,” Dr. Ferris said.