Yale Medicine-Ophthalmology

Explaining glaucoma

New studies in gene expression, neural signaling add to a solid core of basic research.

When Marvin Sears, M.D., came to Yale in 1961 to head the eye service, ophthalmology occupied 130 square feet in the Department of Surgery and had one full-time faculty member: a young recruit from Hopkins named Marvin Sears.

Under his leadership during the next three decades, ophthalmology developed into a full-fledged department with top-flight research and clinical care, culminating in the opening of the Yale Eye Center in 1986. Under Dr. Sears, Yale turned out specialists in eye care and visual science who went on to lead their own departments around the United States, Europe and Japan.

Much of that excellence revolved around glaucoma, a disease that affects 3 million Americans and has blinded more than 120,000 people in the United States alone. Dr. Sears started the glaucoma service at Yale and has devoted his research to explaining how glaucoma increases pressure within the eye with such devastating results. His work in adrenergic pharmacology made Yale an international center for glaucoma treatment and led to the development, and FDA approval in 1978, of timolol, the first useful topical medication for glaucoma since 1908. He also developed two innovative surgical procedures for clot removal and tumor removal from the eye, used worldwide.

Although Yale is now branching out into other areas of ophthalmology—retinal treatment and research in particular—new department chair Bruce Shields is a dyed-in-the-wool glaucoma specialist, and pupil of Sears. “When I was studying to become an ophthalmologist, his writings and teachings were already part of the foundation of our understanding,” says Dr. Shields, who headed the glaucoma service at Duke before coming to Yale in 1996. Dr. Shields was named the first Sears Professor of Ophthalmology and Visual Science in 1997.

Glaucoma damages vision in most cases by increasing pressure inside the eye through the buildup of fluid known as the aqueous humor. In the most common form, open-angle glaucoma, fluid between the iris and cornea is unable to drain freely and ultimately exerts pressure on the optic nerve at the rear of the eye. If this pressure is not relieved over time, peripheral vision begins to fade and can progress to blindness.

Dr. Shields says that despite new areas of focus, “we are very committed to maintaining excellence in glaucoma and continuing to build there.” Physicians and scientists in the department are exploring several promising lines of research. For example, Yale researchers have found that mutations in a gene called myocilin (also known as TIGR) affect the drainage of aqueous humor from the eye in many patients with glaucoma. Yale scientists also have found expression of the gene in the ciliary body, which produces the aqueous humor.

The myocilin gene encodes a protein critical to structures in the eye that regulate pressure. Its discovery may be useful in identifying people at risk for glaucoma before they begin to lose their sight. Because symptoms of glaucoma often do not appear until the disease has progressed, early diagnosis is important. “In the future there may be great value in detecting whether or not a person carries these gene mutations,” says Miguel Coca-Prados, Ph.D., professor of ophthalmology and visual science, in whose laboratory the myocilin gene research is being conducted.

Pressure within the eye follows a circadian rhythm, rising during the day and falling at night. Research scientist Douglas Gregory, Ph.D., and colleagues have found that catecholamines, substances that function as neurotransmitters, are important in controlling aqueous humor flow in both humans and rabbits. This information is being used to study the interaction between catecholamines and the cells that produce aqueous humor.

Glaucoma results specifically from the loss of nerve cells in the retina known as ganglion cells. And while glaucoma is most often characterized by increased pressure within the eye, a significant number of patients with this disease have normal intraocular pressure, says Colin Barnstable, D.Phil., professor of neuroscience and director of research in the department. If one could discover what causes these ganglion cells to die, he suggests, it might be possible to help patients with normal pressure glaucoma.

Dr. Barnstable, who has been studying the formation of retinal ganglion cells for many years, is testing the theory that a high concentration of the neurotransmitter glutamate may be the cause of ganglion cell death. Because glutamate in high concentrations is thought to be the cause of brain damage in strokes, cell death in glaucoma could be similar to other brain injuries and diseases.

This hypothesis is being tested by isolating ganglion cells, growing them in culture and studying the effects of glutamate on the cells. A system has been designed to study the effects of drugs that may block the damage caused by glutamate. Dr. Barnstable is also examining whether increasing any of the factors important in the growth of retinal ganglion cells allows the cells to withstand high concentrations of glutamate. According to Dr. Barnstable, growth factors can be supplied that allow the cells to survive for extended periods in culture.

Yale is one of 11 centers participating in the Advanced Glaucoma Intervention Study, a clinical trial to determine the optimum surgical intervention when medical therapy is no longer adequate. Eydie Miller, M.D., associate professor of ophthalmology, is the principal investigator at the Yale site. Although argon laser surgery decreases resistance to aqueous outflow, the results last only about five years, and repeating the procedure is less effective, says Marc Weitzman, M.D., assistant professor of ophthalmology. “The AGIS study should give us answers to questions about when to use argon laser surgery in advanced glaucoma and what types of patients are the best candidates for it.”

Among the newest instruments in glaucoma treatment are the semiconductor diode lasers, which have recently been obtained at Yale and are being evaluated in the hope of finding better therapies to prevent blindness in patients with advanced forms of glaucoma. Over the past 10 years, Dr. Shields has studied the effectiveness of laser surgical techniques to reduce the pressure in eyes by destroying portions of the ciliary body. “This has been a major advance,” says Dr. Weitzman, “because there is much less pain and inflammation, and there are fewer complications than with similar, earlier procedures.”

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