Most people know how hard it can be to stick to a diet. But for children with epilepsy, maintaining a restrictive high-fat, low-carbohydrate regimen known as the ketogenic diet is far more difficult than any weight-loss plan. Someday, however, they may be able to control seizures with a simple supplement instead, if a new finding in mice holds up in humans.
Almost a third of epilepsy patients, many of them children, don't respond to antiseizure drugs. For reasons that are not well understood, the ketogenic diet can prevent seizures for some of these children. But it's by no means an easy fix. Patients need to eat 80% to 90% of their daily calories as fat, usually in the form of vegetable oil or butter. Only some versions of the diet allow any carbohydrates at all, and sugary desserts are off-limits. "Eating a cookie can break the effect of the diet, resulting in a seizure," explains Karin Borges, a neurobiologist at the University of Queensland, Brisbane, in Australia.
Hoping to design a more palatable alternative to the ketogenic diet, Borges and her colleagues began experimenting with a synthetic oil often found in antiwrinkle creams and other cosmetics. The compound, called triheptanoin, is already used to treat certain metabolic disorders; researchers believe it works because it replenishes specific molecules needed to produce the energy-carrying molecule adenosine triphosphate (ATP). Borges reasoned that these metabolites, which are also the building blocks for certain chemical messengers in the brain, might be depleted by the flurry of brain activity that occurs during a seizure. Lower ATP levels in the brain can destabilize neurons, triggering more seizures. Borges hoped that a diet supplemented with triheptanoin would replenish the brain's supply of metabolites and boost ATP production, helping to control epileptic bursts.
She and her colleagues tested this hypothesis in mice. Some of the rodents ate a normal laboratory diet, but others were fed a diet in which 35% of the calories came from triheptanoin. After 3 weeks, the researchers induced seizures in the mice using either a drug injection or electrical stimulation of the brain. It was more difficult to produce seizures in mice on the 35% triheptanoin diet, the team reports in this month's issue of Neurobiology of Disease. The supplement had effects similar to those of some antiseizure drugs currently on the market, says Borges.
The team also found that triheptanoin restores some of the brain's missing metabolites. But Borges cautions that there is a lot more research to do before her team knows for sure why the supplement acts as an anticonvulsant. The next step will be preparation for a clinical trial, she says, to see if what works for mice will be safe for people.
For humans, a diet composed of one-third triheptanoin adds up to almost 800 calories. Borges is hoping epilepsy patients won't need quite such a high dose, however. If the compound works for them, she says, they should be able to resume a normal diet; they would just need to add the flavorless compound to their food, possibly by mixing it into sauces and salad dressings.
Targeting metabolites specifically, says Susan Masino, a neurobiologist at Trinity College in Hartford, Connecticut, "is a new concept in epilepsy therapy." She believes that a dietary supplement like triheptanoin could make metabolic therapy more realistic for more people.
Adam Hartman, a pediatric neurologist at the Johns Hopkins University School of Medicine in Baltimore, Maryland, agrees. Borges's research, he says, establishes that putting metabolites back into the brain is a viable technique for treating epilepsy. And, because triheptanoin has been used to treat humans in the past, the outlook for conducting a clinical trial is good.