Epilepsy
Learning to predict the best medicine for each patient
| Darcy is seizure-free, and "she's a pleasant child again." |
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Sherry and Jay Whitehead remember exactly when they knew something was wrong with Darcy. It was when they lost her at the mall.
The family was shopping. One moment Darcy, then 8, was walking alongside them. A moment later, she wasn't there. She had suddenly stopped walking and was left behind in the crowd.
Why did she do that? And why was she falling behind in school? Her teacher said she wasn't paying attention in class and thought she might have an attention deficit disorder.
Sherry and Jay knew they had to find out what was going on with Darcy.
When their doctor ordered an EEG, a test that maps brain waves, the mystery was solved. Darcy had epilepsy. That's when she came to Cincinnati Children's Hospital Medical Center to see neurologist Tracy Glauser, MD, one of the nation's leading experts in pediatric epilepsy.
Darcy was diagnosed with childhood absence epilepsy (sometimes called petit mal epilepsy). The seizures caused by absence epilepsy usually last less than 30 seconds and may occur many times a day. Darcy would stop what she was doing for 10-15 seconds, then continue on, with no memory of what had happened. It was easy to miss the signs of a seizure or to misinterpret them as daydreaming. "I really don't know how often or for how long she'd been having them," Sherry says.
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Incorporating genetics in dosing is the new frontier.
Tracy Glauser, MD |
Treatment for Epilepsy
The goal in treating epilepsy is to choose a medication that maximizes seizure control and minimizes side effects. Achieving the balance can be difficult, since every medication causes some side effects, and individuals react very differently to the drugs. Often only trial and error will tell what medicine will provide the best results for the patient. "There's not as much evidence as we'd like to help physicians make decisions," says Dr. Glauser.
Dr. Glauser started Darcy on valproic acid, one of the drugs most commonly used for epilepsy. Like other epilepsy medicines, this drug controls seizures in some patients but doesn't work in others. It seemed to work for Darcy. She began with a low dose. Every two weeks the dose was increased a bit until she was receiving enough to control her seizures. In July 2003, five months after she was diagnosed, an EEG showed that she was seizure free.
That was the good news. The bad news was that the medication caused significant mood swings. She had temper tantrums. She slammed doors in her parents' faces, stomped on the dog and "was a bear in school," her mother recalls. "She was a nasty child."
Sometimes side effects subside as the body adjusts to the medicine, but that didn't happen with Darcy. By February it was clear that it was time to try a new medication. Her personality, her progress in school and the family's quality of life were suffering too much. But the old medicine couldn't be stopped suddenly. Dr. Glauser started her on another drug, and over a period of months gradually reduced the dose of valproic acid.
By the end of May, Darcy had transitioned entirely to the new drug. She's now seizure-free and "she's a pleasant child again," Sherry says. But she'll need to repeat third grade.
If Only We Could Predict
Imagine how much better it would have been for Darcy and her family if Dr. Glauser could have known in advance which drug would be best for her. His research may soon make that possible.
Dr. Glauser is a leader in the emerging science of predictive medicine. The goal, he explains, is to be able to personalize medicine by predicting the best treatment for each patient.
In September 2003, he received a $17 million grant from the National Institute of Neurologic Disorders and Stroke. It is the largest grant ever awarded for research in pediatric epilepsy. The grant supports wide-ranging research that will change the way medicine is prescribed for children with epilepsy.
Comparing Medications
A major focus of the NIH-funded research will be a clinical trial comparing the three most commonly used drugs for absence seizures, with the goal of determining the best initial medicine. This five-year study will enroll 439 children at 20 sites across the country.
Meanwhile, in another effort to help doctors prescribe the best medicine for each patient, Dr. Glauser was a senior member on a panel appointed by the American Academy of Neurology to review evidence from existing studies of the safety and effectiveness of seven epilepsy drugs. The panel reviewed scientific articles published between 1987 and 2003. In May 2004, the Academy published the findings as guidelines for physicians, offering doctors the first detailed look at which drugs work for the various subtypes of epilepsy.
The New Frontier: Learning How Medications Interact With Genes
Another type of research Dr. Glauser is doing takes advantage of new knowledge from the study of the human genome to understand the interaction between drugs and genes. Being able to know from a blood test which patients will respond to a medication and which will not would be a great advance.
"Incorporating genetics in dosing is the new frontier," Dr. Glauser says. A recognized expert on clinical trials of new medications, Dr. Glauser has retrained as a pharmacogeneticist in order "to look at more fundamental issues that will make a bigger impact."
One approach he is taking is looking at the drug's actions. Does the drug turn genes on and off? Does it leave a distinctive "signature" that can help us understand why some people respond well and others don't?
Dr. Glauser recently published the results of a study of patients taking valproic acid. His research found that in patients who did well on the drug, a pattern emerged where some genes were turned on while others were turned off. He is beginning a larger study that will look at two drugs and will follow the patient's response over a period of four months. "Eventually we'll learn why drugs work or not, and why some are more toxic," he says.
Introducing the Genetic Pharmacology Service
While research continues, Dr. Glauser and colleagues in the Pediatric Pharmacology Research Unit and the Molecular Genetics Laboratory have launched the Genetic Pharmacology Service (GPS) at Cincinnati Children's. This cutting-edge service applies knowledge from the Human Genome Project to help doctors prescribe medications in a way that assures each patient has the optimal response. Cincinnati Children's is the only pediatric hospital in the United States to offer such a service.
The GPS lab analyzes blood samples to help physicians prescribe any of 37 commonly prescribed medications that are significantly influenced by variations in four well-understood genes. The test might show that the patient will not respond to a particular medication or will need a larger or smaller dose.
"Helping physicians incorporate their patient's genetic information to improve drug dosing and reduce side effects represents a rare opportunity to make a fundamental change in how medicine is practiced," says Dr. Glauser.
