A New Prescription for Treatment: Is Lowering the Dose the Answer?
Katherine Holland, MD, PhD, is out to challenge everything she ever learned about the medications she gives children with epilepsy. Director of the epilepsy research program in the Comprehensive Epilepsy Center, she is studying how patients respond to epilepsy medications and the role of genetic factors in that response.
Holland conducts much of her work in the New Onset Seizure Clinic, where most of the children seen are between 2 and 18 years of age. She defines them as “relatively healthy kids who ultimately will go on to be healthy adults.” Their seizures can be caused by any number of factors — developmental or chromosomal glitches, hypoxic injury at birth — but most often there is no clear-cut explanation for why they happen.
What is known is that most of the children will need medication to get them to a seizure-free state, and those medications can be problematic. Holland is on a mission to change that.
“There are about 20 percent of patients that medications just aren’t working for,” she says. When she tackled the task of figuring out why, what she discovered surprised her.
Less May Be More
“For most of the patients whose seizures were controlled with medicines, the medications worked at relatively low doses. In fact, most of them worked at doses below what I would have put them on,” she says. “And I suspect we might find out that for most people, even lower doses would work.”
Holland says the traditional approach for children with partial onset seizures has been to start them on carbamazepine at doses around 15-20 milligrams per kilogram (2.2 pounds) of body weight. This is the target dose that Holland was taught to aim for routinely.
She now believes it might be more than many children need. Holland arrived at this conclusion by review of 100 charts of children seen in the New Onset Seizure Clinic. “I went through the charts and asked, ‘What dose of medicine are children taking who are not having seizures?’”
The results, published in the journal Neurology, were that kids who become seizure-free tend to do so at dosing levels between 5 and 15 milligrams per kilogram. At the upper range of 20 milligrams per kilogram where she often used to start treatment, Holland says, nearly all the children stop having seizures, but half will stop taking their medication because of side effects. She expects that starting lower will work for at least half the children, with side effects in as few as 10 percent.
Even when there are no noticeable side effects, Holland advises caution in giving unnecessarily high doses of medicine.
“Medicines that act in the brain probably produce changes in abilities to do things that may not be noticed,” Holland says. “So if I’m treating somebody with more medicine than they need to have, they may be more tired and moving a lot more slowly, but they don’t notice. That doesn’t mean the medicines aren’t potentially causing a problem.”
Why Medications Work — or Don’t
The next phase of understanding proper medication dosing, says Holland, is learning why medications work for some children and not for others.
She is studying how patients respond to carbamazepine, the most commonly prescribed drug for new onset seizures. The drug acts on the sodium channels, which regulate how cells send messages to the brain.
“We looked at the sodium channels in people who didn’t respond to medications, and compared them to the channels of those who did respond,” Holland says.
She found a common variation in the sodium channel genes that seem to occur more frequently in those people who didn’t respond to the medicine. Because carbamazepine alters the way the channels function, Holland suspects that the genetic variant might be the reason the medication doesn’t work for some people.
Building on this preliminary data, Holland became the principal investigator on an NIH-funded grant studying the clinical and functional significance of sodium channel gene variation in children with epilepsy. The long-term aim of this research is to develop more effective treatments for children with epilepsy by identifying those unlikely to respond to typical first-line therapies and by developing methodologies that can identify potential new medications for patients based on their genetics.
Although the findings are early, she hopes to explore this further, with the goal of putting children on more effective medications from the start. “Ideally, we would be able to see if people have a variant in the channel, maybe carbamazepine doesn’t work as well as the first choice. So we could choose another drug.”
