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What causes macular degeneration in the eyes? Have there been any advances in curing this condition?

Edwin M. Stone, M.D., Ph.D., Director of the Center for Macular Degeneration and the Molecular Ophthalmology Laboratory at the University of Iowa, provided this medical outline:

The term macular degeneration refers to a group of disorders that affect the central portion of the retina and, as a result, the center of the field of vision. The most common forms of this disease usually affect patients over the age of 65 and are collectively the most frequent cause of legal blindness in developed countries.

These late-onset forms are often called "age-related macular degeneration." Age-related macular degeneration is extremely prevalent, with as many as one in 10 patients over the age of 65 affected to some degree. Fortunately, severe visual loss is much less common, affecting perhaps one in 100 people over the age of 65.

What Is Macular Degeneration?

The inside of the eye is lined by three layers of tissue, each critical for normal vision. The innermost layer (the one first struck by the light that enters the eye) is known as the retina and consists of a complex network of nervous tissue. Some of the cells in this layer (the photoreceptors) convert light into an electrical signal that is then amplified and processed by other cells before being sent to the brain via the optic nerve.

cross section of human eye
Image: Edwin M. Stone
CROSS SECTION of a human eye. Light enters through the cornea, passes through the pupil and the lens and strikes the retina. The center part of the retina--called the macula--has been artificially colored to show its position with respect to the remainder of the retina.

The central part of the retina--the macula--has a number of special structural features that allow images focused on it to be seen with very high resolution. The middle layer is a one-cell-thick sheet known as the retinal pigment epithelium, or RPE. The RPE provides metabolic support for the photoreceptor cells and also removes old bits of cellular debris from the tips of the photoreceptor cells as they renew themselves. The layer farthest from the incoming light is a rich network of blood vessels known as the choroid. These vessels supply oxygen and nutrients to the retinal pigment epithelium and photoreceptor cells and carry away waste products.

In macular degeneration, clumps of yellowish cellular debris--possibly of retinal origin--gradually accumulate within and beneath the retinal pigment epithelium. These deposits are visible to the clinician looking inside the eye as small yellow dots known as drusen (singular: druse). With the passage of time, patches of retinal pigment epithelial cells may die, resulting in bare spots known as geographic atrophy.

When the support functions of the RPE are lost, the photoreceptor cells overlying the areas of geographic atrophy cannot function and the vision from this patch of retina is lost. If these patches become large and involve the very center of the macula (the fovea), the individual's visual acuity can fall to the point that he or she is considered legally blind. This atrophic phase of macular degeneration is sometimes referred to as "dry" macular degeneration.

In approximately 10 percent of patients with macular degeneration, the injury to the retinal pigment epithelium stimulates the choroidal blood vessels to grow up into the RPE and retina--seemingly in an attempt to heal the defects in these layers. This reparative response is very similar to those that occur elsewhere in the body in response to injury--such as scar formation after a cut on the skin. Unfortunately, the retina is such a complex and highly ordered tissue that the in-growth of these new blood vessels causes more visual loss than the original degenerative process. In fact, although only 10 percent of patients develop new blood vessels, this complication is responsible for most of the legal blindness associated with macular degeneration. The vascular phase of macular degeneration is sometimes called "wet" macular degeneration.

Because the new blood vessels (also known as choroidal neovascular membranes) can be so damaging, a wide variety of treatments have been tried to arrest their growth. By far the most successful to date has been the use of laser light to cauterize the blood vessels. Unfortunately, laser treatment has a number of significant drawbacks including a high recurrence rate, laser injury to the retina, and an inability to treat the majority of patients affected with neovascular membranes (because the lesions are too large or ill-defined when discovered).

Causes of Macular Degeneration

Physicians have wondered about the causes of macular degeneration for over a century. In the late 1800s, when doctors first began looking into eyes with ophthalmoscopes, they believed that the drusen they observed represented some type of infection, or at least inflammation, of the choroid. Even today, there is some evidence to suggest that the body's immune system plays a role in the development of some forms of macular degeneration, especially the development of neovascularization.

Environmental factors make up another group of possible causes. Epidemiologists have searched for evidence of such factors for decades. Those that have been studied in this way include various nutritional factors (e.g., zinc, B-vitamins, antioxidant substances), light exposure, drugs (e.g., caffeine, nicotine, oral contraceptives, etc.) and toxins. Although some of these factors appear to have a demonstrable effect on prevalence or course of macular degeneration (green leafy vegetables are good, cigarettes are bad), none has emerged as a likely major cause of it.

Another important group of possible causes of age-related macular degeneration is mildly abnormal genes. It has been recognized for over a century that some forms of macular degeneration run in families. During the past 25 years, increasing evidence has been gathered to suggest that a significant fraction of macular degeneration has a hereditary basis.

This has important implications for understanding macular degeneration at the molecular level, as well as for designing improved treatments for the disease. When a disease like macular degeneration is caused by a dominant gene, a number of family members may be similarly affected. Such families can be studied by modern molecular genetic methods in ways that allow the causative gene to be identified.

In the past 10 years, the chromosomal locations of at least 10 genes that cause macular-degenerationlike conditions have been identified, and three of the genes have actually been identified. Unfortunately, none of these three genes causes a measurable fraction of typical late-onset macular degeneration, but the disease mechanisms are similar enough to the latter condition that scientists can already begin developing animal models of macular degeneration based on these genes to use in new treatment research.

The genetic approach is particularly appealing because if a genetic predisposition to macular degeneration can be identified, it raises the possibility that individuals can be tested for the predisposition early in life, and given some sort of treatment that will delay or prevent the onset of the macular disease. Such treatment has the potential to be safer, simpler, cheaper (and hence more widely available) than some of the other experimental treatments currently under development.

Areas of Promising Research

Since the majority of severe visual loss is caused by abnormal blood vessels growing beneath the retina, a massive effort is underway to identify methods of arresting this process. Any breakthrough in this area could be of immediate benefit to thousands of patients with macular degeneration. Strategies under investigation at this time include the use of drugs, growth factors, anti-growth factors, surgery, and radiation. All these strategies are designed to retard new blood vessel growth without significantly damaging the overlying retina (as occurs with conventional laser treatment).

Ninety percent of patients with age-related macular degeneration never develop new blood vessels and lose vision instead because of atrophy of the retinal pigment epithelium. For this reason, investigators are actively looking for ways to lessen this cell death (e.g., with growth factors) as well as ways to replace the cells that are lost (e.g., with RPE cell transplantation). There are even efforts underway to transplant cultured photoreceptor cells into the retina to replace those lost from advanced disease.

Although exciting and promising, none of these experimental treatments has yet been demonstrated to be of significant benefit to patients with typical late-onset macular degeneration. It is not clear at this time which strategy will be refined to the point of widespread human application first. Thus, although it is common for patients to be willing to "do anything" to try to save their vision, it is important for the scientific community to judge any new treatment carefully--and show it to be of more benefit than harm--before offering such treatments to patients outside the context of a controlled clinical trial.

In 1997, the mainstays of therapy for patients with macular degeneration include daily monitoring of the integrity of their central vision (usually by viewing a simple printed grid) as well as periodic visits to their eye doctor. Both of these strategies are designed to identify treatable new blood vessel membranes as early as possible. When such a growth is suspected, it is confirmed by an angiographic procedure. If the membrane has characteristics that have been shown to be favorable for treatment, laser photocoagulation is applied by an ophthalmologist who has had special training in the technique.

Patients who lose vision despite treatment, or who lose vision from atrophic disease, can often be significantly helped by a thorough low-vision-rehabilitation program. Such a program is administered by an optometrist or ophthalmologist with special training in low vision and consists of a number of integrated parts ranging from counseling to the prescription of special glasses, magnifiers and even electronic devices.

It is important for all patients (and family members of patients) with macular degeneration to know that although the disease can injure the central vision of both eyes severely enough to render one "legally blind," it is extremely uncommon to cause complete blindness in even a single eye. Thus, although it can be devastating to lose one's ability to drive or to read without some type of low vision aid, with appropriate rehabilitation, most patients can remain very active and self sufficient even if they have advanced disease.

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