For release: Friday, March 14, 2008
For the first time, researchers have shown that treating epilepsy-prone animals with an anticonvulsant drug prior to the development of chronic epilepsy can significantly reduce the number of seizures the animals experience, even after the treatment stops. The study provides hope that researchers may eventually be able to prevent epilepsy in people who are at risk of the disorder because of genetic mutations or other factors.
“This is a proof of principle study. It shows that, in at least one model of epilepsy, we can prevent the development of seizures with early treatment,” says Hal Blumenfeld, M.D., Ph.D., of Yale School of Medicine in New Haven, Connecticut, who led the new study. The work was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS) and appears in Epilepsia.
"Whether early treatment stops the progression of the disease state is a crucial question in epilepsy research," says Margaret Jacobs, the NINDS program director for this work. "Using this genetic model not only provides insight into underlying mechanisms of epileptogenesis, but also in testing potential therapies." Epileptogenesis is the process by which epilepsy develops in the brain.
The researchers studied a strain of rats that is prone to developing absence epilepsy, a genetic form of epilepsy which causes brief episodes of staring and unresponsiveness. Absence seizures are a type of generalized seizures, or seizures that affect both sides of the brain.
In the new study, Dr. Blumenfeld and his colleagues gave the rats an anticonvulsant drug, ethosuximide, continuously in their drinking water from 3 weeks of age (before the point when seizures usually develop) to 5 months of age (when the rats have reached adulthood and display full-blown epilepsy). Another group of rats received the treatment until 8 months. Rats were studied for three months after treatment stopped.
The researchers found that ethosuximide treatment blocked almost all seizures during the time the rats received the drug. After the drug was stopped, the treated rats had about a third as many seizures as untreated rats. This suggests that there is a critical period for development of epilepsy and that treatment during that time may permanently prevent seizures.
Additional studies showed that ethosuximide treatment prevented changes in sodium and potassium ion channels that were seen in untreated rats. Ion channels are pore-like structures that control the flow of ions in and out of cells and regulate neuron signaling. Researchers believe that changes in these channels often contribute to the development of epilepsy. Many studies have shown that seizures trigger changes in the brain that increase the likelihood of future seizures. The new findings show that early treatment can interrupt this seizure-perpetuating cycle in a genetic form of epilepsy.
Epilepsy may result from the brain's attempts to learn and adapt to seizures and other stimuli, Dr. Blumenfeld suggests. "The brain has evolved to learn. There are critical developmental windows for language acquisition and other skills. However, the brain can also learn bad things," he says.
The study raises hope that researchers might find ways to prevent epilepsy in people who are at risk of the disorder due to genetic factors. Doctors can currently predict only a few rare genetic forms of epilepsy. However, efforts to identify the gene variations underlying more common forms of epilepsy are now underway. Doctors may eventually be able to screen people for those genetic variations and prescribe treatments that will stop epilepsy from developing.
The ability to prevent epilepsy in this animal model will also allow researchers to test factors that might contribute to development of epilepsy. Such studies could lead to a much improved understanding of epilepsy and new ways of stopping it from progressing.
While the results of this study are promising, much more research is needed before such epilepsy prevention strategies can be tested in people, Dr. Blumenfeld says. In addition to identifying genetic risk factors, researchers need to develop treatments that can be safely administered to children who have a high risk of epilepsy. They also need ways to determine whether treatments affect the disease process or just the symptoms of the disease, he says.
Dr. Blumenfeld and his colleagues are now planning research that will use the rat model from this study to better define the critical period for treatment to prevent seizures. They also plan to study other animal models to learn whether different types of epilepsy can be prevented through early treatment.
The NINDS is a component of the National Institutes of Health (NIH) within the Department of Health and Human Services. The NIH — The Nation's Medical Research Agency — includes 27 Institutes and Centers and is the primary Federal agency for conducting and supporting basic, clinical, and translational medical research. It investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.
-By Natalie Frazin
Blumenfeld H, Klein JP, Schridde U, Vestal M, Rice T, Khera DS, Bashyal C, Giblin K, Paul-Laughinghouse C, Wang K, Phadke A, Mission J, Agarwal RK, Englot DJ, Motelow J, Nersesyan H, Waxman SG, Levin AR. “Early treatment suppresses the development of spike-wave epilepsy in a rat model.” Epilepsia, March 2008, Vol. 49, No. 3, pp. 400-409.
Last Modified March 14, 2008