CHDD researcher investigates neurological underpinnings and consequences of childhood epilepsy

In recent years, the topic of pediatric epilepsy has received more attention as clinicians and researchers recognize that epilepsy in children is often much different from epilepsy in adults, says CHDD research affiliate Dr. Philip Schwartzkroin. "For many years clinicians tried to apply the same principles used in treating adult epilepsy to infants, but the drugs and treatments that had been successful in adults didn't always work in children," he notes. "Now pediatric epilepsy has emerged as an independent field, and new drugs and treatments especially for children are being developed."

However, there is still a long way to go toward understanding the basic mechanisms of seizure activity in the immature nervous system and how those mechanisms are linked to development. Investigating the relationship between pediatric epilepsy and other developmental problems is a research question that has important implications for clinical management, explains Schwartzkroin, professor of neurological surgery and of physiology and biophysics.

"We know that some pediatric epilepsies are associated with developmental abnormalities of the brain. These epilepsies are often accompanied by motor and cognitive deficits," explains Schwartzkroin. "So we are asking, do developmental problems give rise to abnormal brain structures which in turn cause epilepsy, or is it the other way around?"

The answer is significant for clinical problems, such as whether it is necessary to stop all seizures that occur in children. Currently available drugs can have significant side effects. Some forms of pediatric epilepsy appear to be "benign" and are outgrown. So there is often a real question about how important it is to stop the seizures, explains Schwartzkroin. If seizures lead to cognitive dysfunction, the risk/benefit balance rests on the side of stopping seizures. On the other hand, if the seizures are harmless and soon stop on their own, there may be no need to treat them, especially if the treatment involves drugs that have adverse side effects.

Schwartzkroin's research aims at understanding the basic cellular mechanisms underlying epilepsy. Using electrophysiological recording, Schwartzkroin and his lab group measure and characterize the patterns of electrical activity of cells in brain tissue from animal models, as well as human epileptic brain tissue removed during neurosurgical operations. They also do anatomical studies to relate their findings about electrical activity with structural changes in brain cells.

The goal of this research is to gain an understanding of seizures by uncovering the cellular circuitry and properties of nerve cells in the hippocampus, a part of the brain that plays a major role in many forms of epilepsy. Schwartzkroin's studies of hippocampal neurons have shed much light on the ability of cells in that region to reorganize and to interact with each other differently after being damaged by trauma-a characteristic known as "plasticity." The work on plasticity has led to studies to determine why some cells in the hippocampus are particularly vulnerable to injury and how cellular organization changes with damage. Determining how brain cells can forge new pathways of interaction has significant implications for understanding complex behaviors such as learning and memory, and unraveling the details of epilepsy in the immature brain.

A major emphasis of Schwartzkroin's research is investigating the properties of the cells of the immature brain that might be responsible for the special forms of seizures seen in young children. These properties might also explain why the immature brain is so seizure-prone. Schwartzkroin and his colleagues are developing animal models to study differences between the young nervous system and the adult nervous system. They are currently investigating the relationship between traumatic incidents around birth--such as periods of low oxygen levels--and seizure activities in babies. They are asking if trauma-induced seizures in a baby can predispose the adult to epilepsy. To learn further about the developmental consequences of some types of childhood epilepsy, they are looking at possible relationships between abnormal brain development, the resulting anatomical anomalies and the occurrence of seizures.

Schwartzkroin and his colleagues have also begun working with molecular biologists in collaborations aimed at understanding the genetic contribution to seizure susceptibility. "It may not be one gene that causes an epilepsy, but many predisposing genes which, when interacting with a trauma, increase the likelihood of an individual having seizures," Schwartzkroin points out. "It's an exciting time with so many techniques available to study genes and development. As we begin to study some forms of pediatric epilepsy arising from developmental abnormalities, we are likely to uncover information relevant to other developmental disabilities."

Book on pediatric epilepsy integrates perspectives of clinicians and researchers

Focusing on seizures and epilepsy in the immature brain, a national conference held in 1992 attempted to bridge the gap. The conference was unique in bringing together clinicians, neuroscientists who specialize in pediatric epilepsy and neurobiologists who study normal development, explains Schwartzkroin. Basic neurobiology has had a great deal of success in the past 15 years or so gaining insights into mechanisms of normal brain development, he says. And, knowing what is normal is important if you are going to answer questions about what has gone wrong. Such background is especially important for learning how to approach the epilepsies of the developing brain.

Schwartzkroin, one of the conference organizers, is also co-editor of a book that grew from interactions among conference participants. The volume, entitled Brain Development and Epilepsy published by Oxford University Press, is geared toward both clinicians and researchers. By providing overviews of experimental research integrated with clinical issues, the editors aim to foster communication about childhood seizure disorders in the context of development. Chapters in the book address key questions in pediatric epilepsy research and suggest directions for future investigation.

Finding the causes of pediatric epilepsies and developing appropriate treatment approaches will take a combined effort encompassing a variety of disciplines, emphasizes Schwartzkroin. "Pediatric epilepsy is so complex, and there are so many ways of thinking about it, that no one scientist can do it all," he says. "Collaboration and interaction among a variety of disciplines are crucial."

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