Student discovers an epilepsy therapy

A diet that simply cuts back on calories may hold an answer to controlling epilepsy, according to research done by a Boston College undergraduate and published in the medical journal Epilepsia. The study is the work of Amanda Greene '00, and was begun while she was a junior.

Epilepsy is a chronic disorder marked by disturbances in the brain's normal electrical functions. These sudden and intense bursts of electricity, or seizures, affect a person's awareness, movement, or sensation. About 40 million people worldwide have epilepsy. Their seizures can be controlled, but there is no cure. The most common treatment is medication that suppresses the brain's tendency to produce excess electrical discharges. When that doesn't work, the involved part of the brain may be surgically removed. Another option, popular to varying degrees in this country since the 1920s, is the ketogenic diet, which consists mainly of fats with very little protein or carbohydrates. The diet is moderately successful in children, but has unpleasant digestive side effects.

In 1998, Dr. Mariana Todorova, who is director of biological labs at BC, was researching the effectiveness of the ketogenic diet in a breed of seizure-prone mice, developed for epilepsy studies. She was working with biology professor Thomas Seyfried, who also was looking at diet therapies in mice on another project--exploring the potential impact of diet on brain cancer. His focus was on the effects of calorie reduction.

When junior Amanda Greene appeared at the lab in Higgins Hall asking for the chance to do some research, Todorova and Seyfried decided to see whether caloric restriction would do anything for the seizures that define epilepsy.

"It was a shot in the dark--we didn't have a clear idea what would happen," Seyfried says. "But, we figured, what did we have to lose?"

For a semester, Greene shadowed Todorova, learning to handle the mice--how to pick them up by their tails to induce the stress that helps activate seizures--and to document data. To hone her understanding of the statistical methods required for her project, she turned to Richard McGowan, SJ, at the Carroll School of Management. In her senior year, as a scholar of the College, Greene pursued the epilepsy experiment as her independent project.

For the experiment, Greene fed juvenile mice the same nutritious mouse chow that she fed to a comparable control group, only 15 percent less. She also fed two adult groups 15 percent and 30 percent less than their counterparts in an adult control group. After processing the numbers, Greene found that the reduced-calorie diets had cut the incidence of seizures in the juvenile and the adult mice.

In the young animals, the reduced diet delayed the onset of epilepsy. Moreover, Greene's dieting juveniles had fewer seizures than did young mice elsewhere in the lab who were on the ketogenic diet.

The adult mice benefited less, seeming to require larger calorie cuts to achieve smaller gains. But, since adult mice obtain no benefit from the ketogenic diet, even a modest improvement was significant.

"The data is really striking," Seyfried says, and he plans to find another student to test the idea further. "We think we've defined a new therapy with no adverse effects."

Equally significant, Greene found out why the diet works, and why the ketogenic diet also helps prevent seizures.

The ketogenic diet is named for ketones, substances formed by the body when it breaks down fat. Scientists have long known that large amounts of ketones in the blood--typically present when a person is starving and has literally to live off fat--are associated with a decrease in seizures. The idea behind the ketogenic diet is that eating large quantities of fat produces more ketones and will reduce seizure activity.

Greene noted in her mice that a lower-calorie diet produced an increase in ketones, but also resulted in a decrease in the amount of glucose in the blood, which, she theorized, explains why the body turned to metabolizing fat, or ketone bodies, in the first place. The brain usually metabolizes glucose for energy, but when the supply of glucose is low, it resorts to metabolizing ketone bodies. The energy gained is sufficient to meet normal needs, Greene hypothesized, but not powerful enough to support seizures.

"What Mandy found was that ketones were a red herring, taking attention away from the really important issue, which was glucose," Seyfried says. "The ketones are the effect of reducing glucose, but glucose is the major metabolite regulating the seizures. It's a conceptually important study."

Greene's paper, which credits Todorova, McGowan, and Seyfried as coauthors, appeared in Epilepsia last November. According to the journal's editor, Timothy A. Pedley, publication by an undergraduate is a rarity.

Gregory Holmes, a professor of neurology at Harvard Medical School, describes Greene's study as "provocative." Says Holmes, "It's a very clever idea and a nice model. It indicates that some of the torturing things we do to kids [to treat seizures] may not be necessary." Holmes cautions that further research will be needed to make sure that calorie cuts won't impair learning, but he sees an encouraging sign in Greene's findings that lab mice on the lower-calorie diet appear more alert and active than those getting full feed.

Greene, now 24, is doing neurology research at Boston's Children's Hospital as part of a team studying periventricular leukomalacia, a condition underlying cerebral palsy in premature infants. She's applying to medical school and wants to be a pediatric neurologist.

Johanna Seltz

Johanna Seltz is a writer based in Hingham, Massachusetts

Photo: Greene in the BC lab where she made her finding

Lee Pellegrini


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