New Approaches for Treating EpilepsyMar 21, 2014
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Julie: For nearly one-third of epilepsy patients, currently available medications simply do not work to control their condition. Dr. Karen Wilcox is investigating the biological basis of epilepsy, with a goal of finding new therapies. Dr. Wilcox, how common is epilepsy?
Dr. Wilcox: Well, Julie, epilepsy afflicts between 1 to 3% of the population. It's known that nearly 16 million people worldwide have epilepsy and that probably roughly one-third of those patients have very difficult-to-control seizures, even with existing drug therapies.
Julie: What are some of the major challenges that people with epilepsy still face?
Dr. Wilcox: Patients with epilepsy have a lot of issues still today with stigma. It can impact their ability to hold down jobs, and they aren't allowed to drive often if they're still having seizure activity, and certainly it can impact learning and memory in the developing brain for young patients. Some of the other things that people are unaware of are the high rate of sudden, unexplained death in epilepsy, or SUDEP. It turns out that epilepsy is responsible for more deaths a year than breast cancer.
Julie: So since some patients respond to drugs and others don't, does that mean there are different types of epilepsy?
Dr. Wilcox: Oh, that's a fabulous question, Julie. We know that probably about two-thirds of all epilepsies are the result of genetic mutations in a variety of genes. Over 120 genes to date have been identified that have mutations that can sometimes lead to epilepsy. So there's a genetic predisposition in some people. We also know that in about a third of other epilepsies, they result from traumatic brain injury of some sort, or an insult to the central nervous system, be it infection, traumatic brain injury, status epilepticus, which is a state of constant seizures. So there are a lot of reasons that people develop epilepsy, and these complex reasons and the complex genetics underlying it can really make it difficult to understand why some patients respond quite well to anticonvulsant drugs while others do not.
Julie: This has been a subject of research in your lab for a little while. What have you discovered so far?
Dr. Wilcox: One of the things that my laboratory is particularly interested in trying to understand is what is it about the one-third of those patients who still have their seizures despite taking many medications. And we're trying to understand the biology of these pharmaco-resistant seizures, trying to understand the pathophysiology of these pharmaco-resistant seizures, and trying to identify new therapeutic approaches. One of the areas that my laboratory particularly focuses on, which is a little bit unique, is the role of astrocytes in neuronal function. So astrocytes are a very specific type of cell in the brain. In fact, they outnumber neurons in the brain . . .
Julie: Oh, really?
Dr. Wilcox: . . . quite considerably, and these astrocytes have always been thought of as sort of the housekeeping genes, or housekeeping cells, of the brain. They do a lot of important maintenance of activities in the brain. They take up neurotransmitters, they balance the ions that are in the brain, and they can help dampen excitability. But we now know that following an insult to the brain, there are dramatic changes in astrocytes that really have not been thought about all that much in the literature. And so our laboratory is very much focused on trying to understand structure and function of astrocytes that might change as a consequence of brain injury.
Julie: Now I'm guessing that most people haven't heard of astrocytes. Why is that?
Dr. Wilcox: Well, neuroscience has focused on neurons.
Julie: There you go. It's not astrocyte science, I guess.
Dr. Wilcox: Or glial science.
Julie: Yeah, um-hum.
Dr. Wilcox: We like to call ourselves a glial science lab. The astrocytes are a form of glial cells, and glia is actually a Latin term for glue, so people thought that astrocytes were the glue that held the brain together, and, in fact, they do impart structural integrity to the nervous system. However, it's recently become well understood that they're not passive at all, and, in fact, astrocytes are now known to release a number of signaling molecules that directly interact with neurons to change the neurons behavior. And so that happens normally during normal neural function, and now we're beginning to understanding that those functions change dramatically following an insult to the brain.
Julie: What happens to neurons during epilepsy, and how might astrocytes feed into that?
Dr. Wilcox: Oh, that's a very good question also. So neurons absolutely are required for epilepsy. Neurons are firing action potentials all at the same time during a seizure, so a seizure is really defined as a hypersynchronous activity of a population of neurons in the brain. But what astrocytes may or may not be doing correctly during that seizure activity is the focus of my laboratory. And so we're trying to understand if perhaps there are different proteins on astrocytes that could actually serve as therapeutic targets for novel drugs, and whether or not we can interfere with astrocyte behavior so that we're not interfering as much with the actual neuronal behavior that's so important for other functions that the brain is responsible for, emotions and cognition, and things of that nature.
Julie: Do you know, are astrocytes triggering the neurons to have this epilepsy response, or are they just sort of passing the message along to other neurons?
Dr. Wilcox: Well, those are great questions that we really haven't had the tools to understand until very recently. So now we're beginning to develop the appropriate tools to look scientifically, to be able to look at the function of astrocytes before a seizure, during a seizure, and after a seizure. And this results from collaborations that my laboratory has with others here at the university, with Dr. John White in bioengineering, and Drs. Peter Taverdek [SP] and Mario Capecchi in human genetics. In work that we've been doing with them, we've been developing new, novel mouse models that will enable us to directly visualize, using very sophisticated microscopy, the activity patterns of astrocytes, because they're going to now express a protein that will fluoresce when the astrocytes become activated.
Julie: But basically your idea is that astrocytes play an important role in some types of epilepsy but not other types of epilepsy, or . . .
Dr. Wilcox: Well, that remains to be seen.
Dr. Wilcox: One of the interesting things that we've noticed in a couple of our animal models is that, even in some of the genetic models of epilepsy, you can engineer mice to have the same mutations as humans do that then results in epilepsy. And what we found there is even in the lack of obvious neuronal damage or cell death, we do see changes in these astrocytes, so they do become inflamed, or what we refer to as activated. They go into their activated state. Just by virtue of having a seizure, even if you don't have epilepsy, it can cause an inflammatory response in the brain, and this is something that's really just beginning to become understood, because for many decades it was not recognized that the immune system was actually involved in brain function. And so we're all starting to recognize that this pathology, which wasn't really appreciated before, might actually contribute to all sorts of seizure activity.
Julie: And so with new information, it possibly could give you new targets for controlling epilepsy.
Dr. Wilcox: That's our thoughts exactly.
Dr. Wilcox: And that's our hypothesis, is that if we can enhance the things that they do well, so, for example, it can help to dampen excitability in the brain. So perhaps we could find therapies by exploiting the good or diminishing the bad activities that occur as a consequence of activation of these astrocytes.
Julie: Now something that's been in the news lately is the use of cannabinoids, which comes from marijuana, as a way to control epilepsy in some patients. Is this something that might also work for those patients that don't respond to currently available drugs?
Dr. Wilcox: As recently shown on T.V. specials by Sanjay Gupta at CNN, we know there are some patients, in particular, for example, Charlotte Figi, who has a type of epilepsy called Dravet syndrome, a very severe type of epilepsy that results as a consequence of genetic mutations in a variety of different genes that encode for ion channels, and she has reportedly responded very well to a very specific type of extract from marijuana called Charlotte's Web, named after Charlotte. This has offered a lot of hope to families. Here in Utah recently, a new bill is being passed to deschedule extracts from low THC-containing marijuana plants so that these families can maybe try these compounds. I think the epilepsy community is very cautious whenever a new therapy is identified, or a new approach is identified, and what we'd like to see is research to be done. And the research has been hampered over the years because of marijuana's scheduling as a schedule one compound, which makes it very difficult for researchers to get it, makes it very difficult for the science to be done. And so what we'd like to see is more rigorous clinical trials, that are double-blind, placebo-controlled trials, in the right patient populations. It may work in some patients. It may not work in all patients, like just about every anticonvulsant agent out there. And so what we'd like to see is, moving forward, the ability to do the science to really confirm that treating with extracts from marijuana plants or medical marijuana do no harm and actually are efficacious.
Woman: Interesting, informative, and all in the name of better health. This is The Scope Health Sciences radio.