For release: Thursday, October 29, 2009
A seizure in a newborn is frightening for parents, and made more so by the fact that commonly used anti-seizure medications do not work as effectively in newborns as they do in adults and children. A new study funded by the National Institute of Neurological Disorders and Stroke (NINDS) helps explain why the newborn brain responds differently to these medications. It also suggests that effective treatment for newborn seizures could be a matter of repurposing an available drug and using it to supplement conventional anti-seizure therapies.
Although there are many new anti-seizure medications, phenobarbital has a long history of use for treating newborn seizures. The problem is that when a newborn has a convulsive seizure, phenobarbital can eliminate the convulsions, but usually does not eliminate seizure activity in the cortex, the outer layer of the brain and the home of its higher level control centers.
The result is “electroclinical uncoupling,” which refers to electrical activity in the brain that has all the hallmarks of a seizure but is clinically silent. These silent seizures can be detected by electroencephalography (EEG), a procedure that involves placing electrodes on the scalp to measure activity in the cortex.
The new study, published in Neuron,* explains the likely basis for electroclinical uncoupling, and takes a step toward a combination drug therapy that could suppress seizures in the newborn cortex.
The public health impact of silent cortical seizures in newborns is unknown, but potentially vast. Seizure activity is capable of causing long term damage to the developing brain. Unfortunately, many newborns probably have cortical seizures that are not only silent but also undetected.
“Do we know how much public health burden can be attributed to these cortical seizures? No, but if we had an effective treatment, we probably would make a good dent in conditions such as cerebral palsy, epilepsy and cognitive disabilities,” says Kevin Staley, M.D., chief of Neurology at the Massachusetts General Hospital for Children (MGHfC) in Boston, and the senior author of the new study. The first authors on the study were Joseph Glykys, M.D., Ph.D., a clinical fellow at MGHfC, and Volodymyr Dzhala, Ph.D., an instructor at the MGH Institute for Neurodegenerative Disease (MIND).
A seizure occurs when neurons in the brain become abnormally active. Convulsions will occur only if the seizure involves subcortical structures deep within the brain, in turn spreading to the spinal cord and activating muscles in the body.
Phenobarbital and related drugs work by mimicking the action of a brain chemical called GABA. GABA inhibits mature neurons, which explains why phenobarbital is effective for treating seizures in the adult brain. Immature neurons have different electrical properties and different proteins (one in particular called NKCC1) that make them respond to GABA in the opposite way. Instead of turning off immature neurons, GABA turns them on. Dr. Staley and his team suspected that this difference might explain electroclinical uncoupling in the newborn brain.
Specifically, the researchers theorized that neurons in the cortex mature later than neurons in subcortical parts of the brain, and they therefore develop inhibitory responses to GABA and phenobarbital later. In the new study, the researchers tested that idea in experiments on the newborn rodent brain. They showed that GABA-like compounds inhibited activity in the subcortical structures, but increased activity in the cortex. They also showed that during the newborn period, cortical neurons have higher resting chloride levels than subcortical neurons. Neurons with higher levels of chloride are more likely to be excited by GABA.
Finally, the researchers tested the effect of combining phenobarbital with bumetanide, a diuretic (or drug that increases urination) commonly used to treat heart disease and kidney problems in infants. This drug blocks the NKCC1 protein, which pumps chloride into neurons and thus primes them for excitation by GABA. The combined drug treatment effectively suppressed both subcortical and cortical seizures in the newborn rat brain.
Dr. Staley is now working with other investigators to conduct a clinical trial of phenobarbital and bumetanide for newborn seizures (www.clinicaltrials.gov/, ID number NCT00830531). The trial is funded by Citizens United for Research in Epilepsy (CURE) and the lead investigator is Janet Soul, M.D., an assistant professor of neurology at Children’s Hospital Boston.
-By Daniel Stimson, Ph.D.
*Glykys J et al. “Differences in Cortical versus Subcortical GABAergic Signaling: A Candidate Mechanism of Electroclinical Dissociation of Neonatal Seizures.” Neuron, September 10, 2009, Vol. 63, pp. 1-16.
Neurons in this brain section from a newborn mouse appear as different colors depending on whether they have low (blue) or high (red) levels of chloride. Compared to neurons in subcortical structures, neurons in the newborn cortex tend to have higher levels of chloride, a sign that they are still maturing. From Neuron, Sept. 2009, Vol. 63, pp. 1-13.
Last Modified October 30, 2009