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Faculty Focus

Gregory Holmes, M.D.: Myth buster

together." Epilepsy can be caused by illness, tumors, brain damage due to head injury or stroke, or abnormal brain development; in some cases, there may be genetic factors involved. It's usually diagnosed using information obtained fromthe person'smedical history, a physical examination, and an electroencephalogram (EEG), in which electrodes placed on the scalp measure the brain's electrical activity and help pinpoint where the seizure is originating—a spot known as the seizure focus.

Even though there have been improvements in medications since the 1960s, the new drugs still don't help about 30 percent of people with epilepsy, Holmes explains. Surgery, such as a procedure to remove the seizure focus, may help some of those people. The surgery has "gotten better and better," thanks to improved technology to locate the focus, such as MRI scanning and better EEG recording methods, he says.

In fact, the University of Virginia, where Holmes earned his M.D. and also did a residency in pediatric neurology, was one of the first medical centers in the nation to continuously monitor EEGs, while videotaping patients, to see how their brain activity corresponded with their seizures. In 1997, the Food and Drug Administration approved a device called a vagus nerve stimulator—a pacemaker-like apparatus implanted in the chest that reduces seizures by delivering periodic small shocks to the brain via the vagus nerve.

Holmes actually began working in health care even before he entered medical school. One summer while he was in college, he participated in a program that recruited undergraduates to work in mental institutions; he was posted at Fairfield Hills State Hospital in Newtown, Conn. "They would assign us several patients," he says. "You'd work with the psychologist or the psychiatrist. He'd give you a game plan on what to do, how to interact with the patients, and the treatment goals." And at night, Holmes volunteered at Connecticut's Southbury Training School, for thementally retarded. Years later, during his residency in pediatrics at Yale, he returned to the training school to treat patients with epilepsy. The work with epilepsy led him into neurology and sparked his interest in developmental neurobiology. He soon began doing research on how seizures affect the developing brain. And he continued to see patients.

Today, he cares for patients with epilepsy at DHMC and, for one week every summer, at Camp Wee Kan Tu in Duxbury, Mass. The camp, run by the Epilepsy Foundation ofMassachusetts and Rhode Island, is both educational and fun. "Many of [the campers] have never known anyone else to have epilepsy," explains Holmes, nor seen a seizure before. "If wemake it so it's not such a big

Grew up: Toledo, Ohio
Education: Washington and Lee University '70 (B.S.); University of Virginia School of Medicine '74 (M.D.)
Training: Yale (pediatrics); University of Virginia (pediatric neurology); Institut National de la Sante et de la Recherche Medicale, Paris (visiting research scientist)
Previous position: Professor of Neurology at Harvard and Director of the Center for Research in Pediatric Epilepsy at Children's Hospital, Boston (and before that, posts at the Medical College of Georgia, from 1986 to 1988, and the University of Connecticut, from 1979 to 1986)
Favorite neckties: Any that picture Mickey Mouse
Favorite sports: "I love the Red Sox and Patriots, but my favorite is college football. I am a big University of Virginia fan, although they are usually terrible."

"The problem is you can't do much [about a seizure], which makes it very frightening," says Holmes, who is a past president of the American Epilepsy Society.

deal, they don't see it as a big deal for themselves." He confesses that he'd love to start an epilepsy camp in New Hampshire some day.

What he doesn't love, however, is the fact that 10 percent of children with epilepsy suffer eventual cognitive decline. "We see a lot of children that just dwindle in front of our eyes," he says sadly. "The first time they come in to see you—they've had a couple of seizures, and they look pretty good." Then as their epilepsy progresses and they continue to have seizures, "they go frombeing the best in their class, to just getting through, to where they don't go on to the next grade, [to] requiring special education. It's pretty tragic."

But, he continues, it is difficult for doctors to determine whether it is the seizures themselves, or the medications used to treat them, that are affecting the brain. There are somany variables, including the age of onset of the seizures, as well as their length, duration, and cause, that it's hard to sort out what's causing what.

That's where his research comes in. In the lab, at least, the variables can be controlled or eliminated. "We think that seizures in the developing brain may have much different consequences than in the adult brain, in which the circuits are pretty well formed," explains Holmes. In a child's brain, if "there's too much aberrant electrical activity, it can really screw up the circuitry. They may never recover."

In one study, Holmes's research team is working with rats in an effort to

understand the association between recurrent seizures and spatial memory. Spatial memory is tested using a Morris water maze, a shallow pool containing a platform hidden just beneath the water's surface. After repeated trials, the rats learn to use external cues to find the platform every time, no matter where they have been dropped in the pool. The rats also wear tiny electrode-studded caps that measure signals from their spatial-memory neurons.

"We have found that rats, even with very brief seizures, have impairments of spatial memory," says Holmes. "We were surprised at how profound the defects were." In addition, the signals from their spatial-memory neurons are less stable than normal and show less precise firing patterns and lower firing rates.

The findings suggest that in humans, "even brief seizures can dramatically alter the brain's function, and we're not sure how permanent this is," Holmes adds. "Nevertheless, if you're having seizures you're probably not thinking correctly. Your memory is going to be screwed up." For instance, he explains, children who've had a brief seizure may not be quite right for a day or so afterwards and can demonstrate impaired learning.

Of course Holmes has served on the requisite editorial boards; churned out hundreds of journal articles, abstracts, and book chapters; and held leadership positions on national committees and societies.He has traveled the world giving lectures on epilepsy. At DHMC, he hopes to turn the Section of Neurology into a department. He sees patients on a regular basis. And he's running several clinical trials to test new therapies for epilepsy. DHMC is one of the major centers in New England testing a responsive neurostimulator system, a device that is implanted on the surface of the brain and that can detect oncoming seizures and deliver shocks to stop them before they happen.

Still, Holmes is frustrated that he doesn't have time to do hands-on research any more. He used to enjoy day-to-day laboratory work, and he continues to follow his lab's progress exploring epilepsy's long-term consequences on the developing brain; discovering novel ways to alter brain excitability; determining which parts of the brain are impaired following seizures; and investigating how seizures affect learning, memory, and decision-making processes. Now, however, the actual experiments are done by others.

But he doesmake time to ensure that people with epilepsy are treated with respect. And to dispel all thosemyths. As he wrote in his letter to SI: "While [grand mal seizures] are frightening and everyone feels the need to 'do something,' the first goal should be not to do anything harmful."

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Laura Carter is the associate editor of Dartmouth Medicine magazine.

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