Pauline Anderson

January 06, 2011

January 6, 2011 (San Antonio, Texas) — The American Epilepsy Society (AES) awarded the society's top honors to Douglas A. Coulter, PhD, and Tracy A. Glauser, MD, for their contributions to basic and clinical epilepsy research, respectively, during their recent annual meeting.

Dr. Douglas A. Coulter

Dr. Coulter, a neuroscientist at The Children's Hospital of Philadelphia and associate professor in the Department of Pediatrics, Division of Neurology, University of Pennsylvania, helped identify a transcription factor expressed shortly after a brain injury that changes the excitability of neurons and could set the stage for recurrent seizures.

"We think this might be very promising as a target for therapy," said Dr. Coulter, who won the AES Epilepsy Research Recognition Award for Basic Science.

Dr. Tracy A. Glauser. Courtesy Cincinnati Children's Hospital Medical Center.

Dr. Glauser, director of the Comprehensive Epilepsy Center and codirector of the Genetic Pharmacology Service at Cincinnati Children's Hospital Medical Center in Ohio, received the society's Epilepsy Research Recognition Award for Clinical Science.

He was honored for his leadership and innovation in the design of clinical trials and epilepsy drug research.

High-Speed Imaging Techniques

Some children with a head injury eventually develop epilepsy, but there is currently no way to avoid these seizures, Dr. Coulter says. In the future, if his theory pans out, such patients could be given a drug that targets the affected transcription factor and prevents epilepsy.

"That's what we're shooting for; we're not there yet, but we have ideas, some leads," he said, although he is understandably somewhat secretive about the details of this new research as he is in the process of getting it published.

For his pioneering basic science work, Dr. Coulter has used a variety of physiological, anatomical, and molecular approaches to study epilepsy in animal models and human brains. One approach is the adaptation of high-speed imaging techniques to view the complex neuronal activity that generates seizure activity. He uses fluorescent dyes that allow him, among other things, to track ions that regulate excitability.

He likens this work to inverting pyramids to study their underlying mechanics. “What we're trying to do is turn the pyramid over and look at what the base is doing and try to figure out what are the important cells in the context of the circuit,” Dr. Coulter told Medscape Medical News.

Another aspect of Dr. Coulter's research involves trying to understand the role of astrocytes in epilepsy. Once viewed as the "glue" that holds neurons together, these brain cells are now known to play a much more active role in brain function. Not only do astrocytes transport nutrients from the bloodstream to support the metabolic activity of neurons, they also remove neurotransmitters that are released during synaptic transmission. This last function is tremendously important. "If neurotransmitters stay around too long, neurons die," Dr. Coulter explained.

In epilepsy, these astrocytes, which are normally small cell bodies, drastically change their form in a process called reactivity, said Dr. Coulter. "They change their anatomy; they get big and angry and spidery, and they change a lot of the proteins they express."

Astrocyte Reactivity

Dr. Coulter's research group devised a strategy to isolate astrocyte reactivity, allowing a closer inspection of this process. They determined that these reactive cells play an integral role in generating hyperexcitability.

"The inhibitory systems aren't responding well anymore in the presence of reactive astrocytes," said Dr. Coulter. "Inhibition normally holds seizures in check and keeps the brain working and finely tuned; when you lose this check, it's like losing the brakes on your car."

Determining how these reactive astrocytes change the function of neurons holds immense promise for epilepsy treatments. "If we can find out what's critical about how astrocytes are changing the neurons, we can maybe have a metabolic therapy and restore something that astrocytes aren't providing anymore," Dr. Coulter speculates.

But it is not exactly clear sailing. "One of the complicating things is that when astrocytes become reactive, there are all these other changes in neurons that accompany it, so we can't figure out which is the chicken and which is the egg."

After obtaining his PhD in biology, Dr. Coulter worked in the field of learning and memory in the mammalian hippocampus. But he grew frustrated at being unable to determine how pathways mediate the flow of information into the hippocampus. "I wanted to go from soup to nuts and really have the whole thing characterized, and it didn't look like it was going to be possible. So I looked around for something where I could make those connections."

He switched his focus to the study of neurons in epilepsy and found this much more satisfying. "The behavior of the neurons you're seeing in vitro is really what's generating the seizures, so it's a very direct link to behavior. Once I made that choice and started understanding that, I was hooked."

Every year, the winner of this basic science award is chosen by peers, based on cumulative lifetime accomplishments. This year, Dr. Coulter was the unanimous choice.

His novel research could lead to exciting breakthroughs, commented Jacqueline A. French, MD, a neurologist at the NYU Comprehensive Epilepsy Center in New York City. His work is multifaceted and encompasses a number of different approaches.

"At the molecular level, he has studied expression level messenger RNAs encoding ion channels and receptors coupled with recordings of channel function; at the cellular level, he has studied the intrinsic and synaptic properties of diverse cellular populations; and at the systems level, he has used multiple state-of-the-art circuit imaging approaches to record neuronal network behavior," Dr. French told Medscape Medical News.

Drug Response Variability

The other winner, Dr. Glauser, has focused part of his research on identifying the factors that determine why some children respond to epilepsy drugs, whereas others do not.

"The goal is to try to improve care of kids with epilepsy by identifying both genetic and nongenetic factors that try to explain why there's so much variability in their response to medicine," he told Medscape Medical News.

Another goal is to determine the best drug for a particular patient. Unlike in specialties such as cardiology and pulmonary medicine, there is not a lot of hard evidence to identify the best treatment choices in neurology, especially pediatric neurology, said Dr. Glauser.

"When you look at treatment in epilepsy, most of it is done by identifying the patient's seizure type or epilepsy syndrome and then selecting among a group of medicines," said Dr. Glauser, adding that there are in the neighborhood of 15 epilepsy drugs now available. "The evidence upon which that selection is made is lacking; there's not a huge amount of rigorous scientific evidence to make our selections."

Difficult Task

Physicians are left to make clinical decisions by integrating information from regulatory trials that do not always inform clinical practice with information from their own practice experience and from case reports, case series, and open-label trials. "That's a very difficult task and doesn't really get at the heart of the issue of what is the best medicine for this particular patient," said Dr. Glauser.

However, he is making good headway in turning that situation around. He leads the landmark national multicenter Childhood Absence Epilepsy Study, the short-term results of which were published earlier this year in the New England Journal of Medicine (2010;362:790-799).

The results, reported by Medscape at that time, suggested that although ethosuximide (Zarontin) and valproic acid (Depakote) were both more effective than lamotrigine (Lamictal) in achieving freedom from treatment failure, ethosuximide had an additional advantage over valproic acid of a better profile related to adverse attention effects.

"The study is the largest pediatric epilepsy trial ever done," said Dr. Glauser. "It's an attempt to better define what is the optimal initial monotherapy for this very common pediatric epilepsy; in fact, absence epilepsy is the most common pediatric epilepsy syndrome."

Dr. Glauser has also participated in the development of 6 evidence-based guidelines in the treatment of epilepsy. He is an author of more than 130 articles and book chapters in medicine and has given more than 150 lectures throughout the world.

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