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PARTICIPANTS Carl W. Bazil, MD, PhD New York Presbyterian Hospital Columbia College of Physicians and Surgeons Susan T. Herman, MD University Hospital of Brooklyn Epilepsy Center

Now, prior to 1993, there hadn't been a new drug for epilepsy for 15 years. Since 1999, there have been three new alone, and since '93, eight new drugs. So lots of progress has been made. We're going to get into all of the treatments.

Joining me now to discuss that, on my left, is Dr. Carl Bazil. He's an assistant professor of neurology at Columbia University in New York City. Next to Dr. Bazil is Dr. Sue Herman. She's an assistant professor of neurology at SUNY Downstate Medical Center across the river in Brooklyn. Welcome to you both. Dr. Carl, can I call you Dr. Carl?

CARL W. BAZIL, MD, PhD: Sure.

DAVID FOLK THOMAS: Why all the new drugs all of a sudden? What's going on in all this research for epilepsy?

CARL W. BAZIL, MD, PhD: This was really an unfulfilled need, and it was kind of shameful that it went that way. But there were a lot of people who had either unacceptable side effects or continued seizures on the medications that were available. There weren't very many at that time. The NIH actually had an initiative to develop new drugs for epilepsy that began a couple of decades ago, and is really only in the last 10 years coming to fruition with all these new drugs.

DAVID FOLK THOMAS: Sue, why, say, the last year? What's happened to get three since 1999?

SUSAN T. HERMAN, MD: I think it's an extension of what Dr. Bazil was talking about. It takes a long time to do the preliminary research for the medications to be available. And so it just so happened that the medications that have been in progress for quite a long time have come out in the past year. It's all stemming from this drug development program that started a couple of decades ago.

DAVID FOLK THOMAS: A lot more money been pumped in, private and federal or —?

CARL W. BAZIL, MD, PhD: The pharmaceutical industry has finally realized that there is a need for these drugs, and they've developed a number of them, as you can see.

DAVID FOLK THOMAS: Let's start out, Sue. What are these three new drugs that are out now?

SUSAN T. HERMAN, MD: The three new drugs that have become available in the past year are Levatiracetam, or Keppra.

DAVID FOLK THOMAS: Now, Keppra is the —

SUSAN T. HERMAN, MD: Is the trade name.

DAVID FOLK THOMAS: Cola to Coca-Cola.

SUSAN T. HERMAN, MD: Right. When you go to the drugstore to buy the medication, it'll be called Keppra.

DAVID FOLK THOMAS: And then when you look at the fine print, it's got the longer name.

SUSAN T. HERMAN, MD: Right.

DAVID FOLK THOMAS: Okay, I got you.

SUSAN T. HERMAN, MD: There's also a medication called oxcarbazepine. That's the generic name. And the trade name is Trileptal. And the final medication is zonisamide, and the trade name is Zonegran. These are the three new drugs that have come out most recently.

DAVID FOLK THOMAS: Carl, what's the, why three drugs? What's the difference?

CARL W. BAZIL, MD, PhD: Well, that's a complicated question. I can talk a little bit about each of them. Levatiracetam was approved in December of 1999. It, like most of the newer approved drugs, is only approved for partial seizures, a specific type, in adults with epilepsy as add-on therapy. But, in fact, we know that these drugs probably -- well, we know that they work alone in monotherapy, and we know that they work in children as well.

Levatiracetam seems to have a very good side effect profile, compared with the older drugs. In other words, less sedation, less cognitive effects, and less interaction with other medications. That drug is relatively early in development worldwide. We don't have a lot of experience with it. But it looks to be very promising.

The next one approved is a drug called oxcarbazepine or Trileptal. It's similar to an older drug called carbamazepine or Tegretol, except that it seems to have fewer side effects. That is only effective in partial seizures, and there's no reason to believe it would be effective in other types.

The third of those three is zonisamide or Zonegran. That was actually developed in Japan. It has been on the market in Japan since the late 1980s. In fact, by the year 2000, it was the number two drug in Japan. It's probably effective for all types of seizures. It's easier to take, and has probably a better side effect profile also than some of the older drugs.

DAVID FOLK THOMAS: So it was available in Japan for years and years before it's been available here?

CARL W. BAZIL, MD, PhD: What happened was, the development here was slowed down by a report of kidney stones. And, as it turned out, when all that was analyzed, kidney stones happened anyway, and it seems that actually it was no higher than the people who were getting placebo. So it's not, there is some concern about that, but it's not overriding, and that was one of the things that held it up. There's always a lot of administrative things that slow these drugs down in this country as well.

DAVID FOLK THOMAS: Now, Sue, are these new drugs, are they replacing the old drugs or are they supplementing?

SUSAN T. HERMAN, MD: The way that most of the new drugs are approved in the United States is, they're approved as add-on therapy. There are a few exceptions to that. But because it's not really a good thing to put somebody who has seizures, which can be a life-threatening event, on a placebo, most of the studies were done adding the new medications to whatever the patients were taking to control their seizures before. So the first way that a medication gets approved is as an add-on therapy, to the other medications that they were on.

Trileptal, or oxcarbazepine is an exception to that, in that it's approved for first line use. There were a lot of trials that were done in people with new-onset seizures, to determine whether it was effective in those patients as well. So the way that most people use them now is to add on. If somebody has failed a medication, they continue to have seizures or they have severe side effects on their first medication, then we would try one of the newer medications.

CARL W. BAZIL, MD, PhD: There are cases, though, where we might use one of the newer drugs first. Most of the time, as Sue is mentioning, we go to the older drugs. Dilantin or Tegretol, as first line, or the drug we use first. But, for instance, say you have a woman who wants to take an oral contraceptive. That will be ineffective or have a high rate of failure with either of the older drugs. So you might choose to use one of the newer ones that you're more comfortable with, either Zonegran or Keppra, in that woman.

DAVID FOLK THOMAS: Now, as far as side effects, without going into big detail, do these newer drugs, the new ones, have less side effects than the older ones, or different side effects?

SUSAN T. HERMAN, MD: They tend to have fewer effects on memory and concentration than the older medications. And so patients tolerate them better on a day-to-day basis. The side effects that are very serious, allergic reactions and things like that, are rare. And what people really have to deal with are the side effects that they have on a daily basis. If you can't concentrate at work or you're falling asleep in school, then that's a big problem. And so many of the new medications have a much better cognitive side effect profile. It makes people less sleepy during the day.

CARL W. BAZIL, MD, PhD: And that's really the most important thing about them, because there haven't been a lot of direct comparisons with the older drugs, in terms of which drug is more effective. We can't say that any of these is clearly more effective for epilepsy overall than one of the older ones. But what we can say is that they seem to be better tolerated. And that's a really important thing for a lot of patients.

DAVID FOLK THOMAS: And, Sue, we've mentioned that, since '93, I guess, there have been five others, if my math has been good, before 1999. But if you could do a quick, a very quick run through.

SUSAN T. HERMAN, MD: The first medication that came out in 1993 is a medication called felbamate, or Felbatol is the trade name. And that's not in very much use any more. It was the first new drug in many, many years, and it was prescribed fairly widely. And after it had been out on the market for about a year, there were a lot of reports of severe hepatitis and problems with anemia and blood problems. And so the drug was withdrawn, or very restricted, and is used only for patients who have seizures that don't respond to any of the other medications, or have very specific, difficult to control seizures.

The next medication that came out is a medication called Neurontin or gabapentin. And that was a very good medication for several reasons. It has a very good side effect profile. It doesn't cause sleepiness in most people, it doesn't cause memory problems. Some people get a little bit dizzy or have some double vision. The bad side is that it needs to be taken many times a day. It has a very short half-life, so it doesn't stay in the blood for very long, and people need to take the medications at least three times a day, which can be a problem for people who lead active lives. Do you want to go on to the next?

CARL W. BAZIL, MD, PhD: I can continue from that point. The next one approved is a drug called lamotrigine or Lamictal. It is similar to Neurontin. Very well tolerated. In fact, people really perk up on it sometimes, especially if they've been on a sedating drug like phenobarbital. It's effective for many different seizure types. But it has to be started slowly because a certain number of people will develop a rash.

The next one approved is a drug called topiramate, or Topamax is the trade name. Again, usually well tolerated. This one has a higher incidence of cognitive effects. Some people sort of have mental slowing on it.

And the next one approved is one called Gabitril or tiagabine. It also has to be started very slowly. Many of these, actually those last three have to be started slowly over several weeks, which can be a downside. That one is effective only for partial seizures, but the main side effect, it can have cognitive side effects, but also has some incidence of GI upset, of stomach problems.

DAVID FOLK THOMAS: I've also heard of some sort of pacemaker. What's that all about?

SUSAN T. HERMAN, MD: Right. It's called the vagus nerve stimulator, and it's actually a small device that's implanted under the skin of the chest wall, just like a pacemaker for the heart would be. But instead of the wire going to the heart, the wire actually goes to a nerve in the neck called the vagus nerve.

The device is implanted under general anesthesia. We're not exactly sure how it works, but the vagus nerve goes back to the brain and has widespread effects on many areas of the brain. And so somehow it suppresses seizures. The pacemaker or the stimulator is only on for about 30 seconds every five minutes, and so the side effects are limited to the time where the pacemaker is on. Which is mostly hoarseness, small change in the voice when the stimulator is actually on, and sometimes a little tickle in the throat or a cough. But those can be adjusted by minimizing the stimulus.

And the device is giving some promising effects in people with difficult to control epilepsy. It's usually not thought of as a choice for people with newly diagnosed seizures, but for people who have already failed several medications, it can be a very good option.

CARL W. BAZIL, MD, PhD: And it doesn't really stop them completely, or very rarely. What it can do, if people are having a lot of seizures, it can cut them down substantially, which is certainly a benefit.

DAVID FOLK THOMAS: We're almost out of time. Carl, let me give you the last word here. We've had so many new drugs, I guess, in the last 8-10 years. What's in the future? More to come, or is this going to be it for a while?

CARL W. BAZIL, MD, PhD: There are several very promising drugs in development right now. There probably won't be any more released, I would guess, before the end of 2001. But we're always working on more treatments, both in terms of pharmaceuticals and in terms of other devices like the vagal nerve stimulator. That doesn't work really well in a lot of cases, but there may be a variant of that that will work well. And people are looking into that.

DAVID FOLK THOMAS: I want to thank my guests, Dr. Carl Bazil, and Dr. Sue Herman. We've been talking about the new drugs for treatment of epilepsy, and it appears there's good news out there for those people who suffer from this disease. And, as I mentioned before, if you live till 80, you have a 10% chance of having a seizure yourself. So, good news on the medical front for epilepsy. That's all the time we have. I'm David Folk Thomas. We'll see you next time.