Potential novel treatment targets for the most common form of childhood epilepsy

Jul 6 2005

New research suggests novel treatment targets for the most common form of childhood epilepsy - with the potential to have fewer side effects than traditional therapy. The findings from Wake Forest University School of Medicine are reported in the July issue of the Journal of Neurophysiology.

Through studies in animals, the researchers learned more about the possible brain pathways involved in absence, or petit mal, seizures and tested a drug that revealed a potential new target for blocking seizures before they spread.

"Many current therapies act on the entire nervous system and can have such side effects as sleep disruptions, dizziness and increased risk of developmental side effects," said Georgia Alexander, who with Dwayne Godwin, Ph.D., co-authored the new study. "Because this treatment blocks the pathway that may cause the spread of seizures, it could be more effective and have fewer side effects."

Absence seizures, which are most common in children between 6 and 12, get their name because during the seizure the child seems to be temporarily unconscious of his or her surroundings. Although they last only a few seconds, the seizures can occur hundreds of times a day and can dramatically impact learning and development.

Doctors don't know exactly what causes the seizures, but a prevalent theory is that an abnormal electrical discharge originates in the cerebral cortex, the part of the brain that controls thinking and feeling, and travels to the thalamus, a part of the brain that controls consciousness and certain brain rhythms. The abnormal rhythmic discharges that result may then spread to other parts of the brain. Other types of seizures may also spread this way, including Lennox-Gastaut seizures, a severe form of childhood epilepsy that is often resistant to treatment.

"We know that the cortex communicates with the thalamus continuously, and current theories suggest that when the 'conversation' gets too loud, seizures can occur," said Alexander. "We wanted to see if there was a way to calm the dialog."

In studying this possible pathway of seizures, Alexander made an important finding about its organization. It was already known that cells in the thalamus communicate with cells in the cortex by releasing the neurotransmitter glutamate. The glutamate travels across the gap -- creating a pathway for cell-to-cell communication.

Alexander and Godwin were the first to show that in addition to releasing glutamate, thalamus cells also have a special type of glutamate receptor that acts almost as a braking system - slowing the release of glutamate when there is high-intensity brain activity associated with a seizure.

"It's like the gas and brake pedals of your car, "said Godwin, associate professor of neurobiology and anatomy and the senior researcher on the project. "Glutamate is important for normal communication in the brain, but sometimes it's necessary to put on the brakes in order to preserve normal function. This receptor appears to slow down the rate at which glutamate is released across the synaptic gap, and may protect the cells from becoming overexcited."

Alexander hypothesizes that in epilepsy patients, the protective receptors may not function well or that glutamate production may be abnormal. A treatment that targets these protective glutamate receptors has the potential to block the pathway involved in seizures, with the added benefit of allowing normal communication to continue.

"If this research leads to drugs that can target these newly discovered receptors, it would be an important advance in therapy," said William L. Bell, M.D., a specialist in epilepsy at Wake Forest University Baptist Medical Center.

Godwin explained that design of improved drugs to target the receptors wouldn't be a cure, but would short-circuit the type of abnormal activity that results in seizures.

In this research, the scientists studied the pathway by simulating seizure-related activity within brain circuits. They will continue the research by studying animals that are genetically predisposed to epilepsy.