March 21, 1996
Harvard
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New Cause of Glaucoma Found

Discovery may lead to novel treatments for the blinding disease

By William J. Cromie

Gazette Staff

For a very long time, eye specialists thought that glaucoma, a disease responsible for blinding an estimated 10 million people worldwide, was caused by too much pressure in the eye.

For a long time, Evan Dreyer believed there was more to it than that. He was not alone. Several of his colleagues at the Medical School and its affiliated hospitals agreed with him.

One day in 1989, Dreyer, who heads the glaucoma service at Massachusetts Eye and Ear Infirmary, was having lunch with one of those colleagues, Stuart Lipton, an associate professor of neurology at Children's Hospital. The conversation got around to research done in 1957, which showed that monosodium glutamate (MSG) injected into the skin and eyes of rats damaged their retinas. That's the screen at the back of the eye where what you see is imaged and then sent to the brain.

"The damage looks much the same as destructive changes in human retinas caused by glaucoma," Dreyer observed. Lipton concurred.

That conversation triggered a long investigation wherein they studied everything published about glutamate damage in the eyes and brain. Glutamate is produced naturally in these organs, and when a molecule of sodium is added to it, it becomes MSG, a seasoning often used in Chinese food.

The researchers then spent six years gathering and testing samples from the eyes of 47 people who underwent cataract surgery, 26 of whom had glaucoma. Careful analysis of tissue between the lens and retina revealed that the eyes of the 26 glaucoma patients showed excess amounts of glutamate.

This month, Dreyer and his colleagues announced proof of the connection that everyone else had missed for 39 years.

"We've shown for the first time that something besides pressure is responsible for the vision loss caused by glaucoma," Dreyer said. "And the finding promises to lead to new drug treatments for glaucoma, hopefully in the near future."

He quickly adds that the MSG, which gives some lovers of Chinese cuisine howling headaches, will not blind you. "Absolutely no evidence exists that MSG taken by mouth has anything to do with eye or brain damage in adults," Dreyer assures us.

Treatments in Sight

One of the most serious eye disorders in people older than 60 years, glaucoma is responsible for 15 percent of adult blindness in the United States. An estimated 4 million to 10 million people in this country suffer from the disease.

"The estimate is so broad because many cases go undiagnosed," explains Dreyer, who is also an assistant professor of ophthalmology at the Medical School. "It's a silent disease that often goes undetected until it reaches an advanced stage. That's a good reason to have regular checkups."

If eyedrops, pills, and other medications don't relieve the pressure caused by buildup of fluids, physicians resort to surgery. "But even with excellent pressure control, many people still go blind," Dreyer says. "That's why we felt so strongly that something else is involved."

With the help of David Zurakowski of Children's Hospital, Dreyer and Lipton did a statistical study that pinpointed glutamate and eliminated other factors such as age, sex, race, and other medical conditions.

If this chemical was a poison from outside the body, researchers would have a relatively easy task finding out where it comes from and how to get rid of it. But glutamate, produced by nerve cells in the eyes and brains, is necessary for both sight and life.

"Without it, you not only go blind, you die," Dreyer says emphatically. "It's overproduction that makes it toxic. Our data suggest that the worse the glaucoma, the higher the glutamate. A doubling of normal amounts eventually kills the retina."

This situation leaves scientists with two problems, discovering the cause of glutamate's overabundance and finding a drug that will stop its excesses but not block its vital functions. "The latter is a 'Holy Grail' being pursued in dozens of university and drug-company laboratories," Dreyer notes.

This frenzy is fed by the fact that drugs to control glutamate may also help people who suffer from Alzheimer's disease, stroke, AIDS dementia, and amyotrophic lateral sclerosis (ALS).

The Food and Drug Administration (FDA) recently approved riluzole, a glutamate regulator, for ALS, a muscle-wasting malady also known as Lou Gehrig's disease. But Dreyer believes riluzole has too many side effects to use for glaucoma treatment. He and his colleagues are taking a hard look at memantine, a glutamate blocker not yet approved by the FDA. Another possibility is dextromethorphan, a weakened form of which is a main ingredient in cough syrups.

"These and other drugs are being tested on patients with a variety of diseases," Dreyer notes.

Glutamate also seems to be involved in the death of brain cells in Alzheimer's victims. And high levels of it can result from a blocked brain artery, which often triggers stroke.

"All the evidence convinces me that glutamate is a part of the final pathway that leads to the death of nerve cells in the brain and eyes," Dreyer maintains. "Pursuing this idea to reach a successful treatment for glaucoma might take anywhere from three to 30 years, depending on how long we need to find the right drug and drug delivery system. I hope to see that happen before I retire."

Dreyer is 39.

 


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