The Eighth Annual Neuroscience Conference at Wake Forest Baptist Health addresses current concepts, as well as in-depth analysis and clinical updates in the treatment and management of neurological disorders.
At the conclusion of these presentations, participants should be better able to:
• Discuss the current medical and surgical management of epilepsy. • Describe the latest interventions for emergency treatments of stroke. • Cite the most successful treatments for spinal disorders. • Identify new developments in functional neurosurgery. • Discuss an update on the comprehensive care of stroke patients. MATTHEW WONG, M.D.: As we're prone to do, I have no disclosures. I don't have any stock in any of these companies we're going to talk about or their medications thereof. So just to kind of get us all on one track, and for most of you this is obvious to you, but I wanted to start with a definition of what epilepsy is. The simplest way to define epilepsy is that it's a condition in which a person has two or more unprovoked seizures. And what we mean by provocation, it's actually not as clear as what one might think; but there are clear things that are provokers that if you have multiple seizures from them, you don't have epilepsy. For example, alcohol withdrawal. If you have someone who comes in withdrawing from alcohol multiple times and had multiple seizures, generally we don't consider that they have epilepsy. The thing with epilepsy is that it is a symptom of an underlying brain abnormality. There are literally hundreds of causes of epilepsy. Some of the common ones we hear about, particularly with young men and women coming back from the wars in Afghanistan and Iraq, are traumatic brain injury. About 50% of people with penetrating head wounds will get epilepsy. Ischemic stroke, brain tumors. In children, genetic defects in their sodium channels, and we'll talk a little bit about that, or other genetic defects, and abnormalities of brain development. Whether that be the neurons didn't migrate correctly in the brain, or, as I said, there are a multitude of other reasons. As I said, epilepsy is caused by a lot of things, literally hundreds of different things. But one of the kind of unifying thoughts we have about epilepsy is it results in abnormal discharges in the cortex the brain. And these discharges are excitatory, which means that there's too much neural activity. And they're sporadic. They come when they want. Most people with epilepsy do not have a provoking factor, and what I mean by at is have these provocation in two different ways; but you hear about things like flashing lights, sleep deprivation. Those things are actually relatively rare with epileptic seizures, so that's something to keep in mind. So they have these sporadic discharges that cause dysfunction. What we know when we talk about medical treatments, and first we'll talk about medicines, is that the whole goal of medical treatment is to decrease this increased excitation of these neurons. And so we'll go into that a little bit. This slide is really just meant to kind of enforce that when neurons fire, what controls them-- they can be excited as they are on the left side. And then on the right side, they could be inhibited. And there are certain biochemical mechanisms which allow that. For example, when neurons fire, it's normal that there is a passage of sodium into the cell. As well as calcium into the cell. When they are inhibited, or they're quiet, there's potassium passing out of the cell and chloride is going into the cell. This all has to do with the voltage across the neural membrane. The point being is that medications for epilepsy either work on decreasing excitation or increasing inhibition. So you can either shut down the mechanisms that make the cells excitable firing by doing things on the left, or you can increase inhibition, I know it's kind of a double negative, by doing things on the right. And I'm being deliberately vague their when I'm saying doing things. I'm certainly not a master at this. I'm going to inflict this slide upon you. The point of this slide is to show some of the mechanisms of increased activity and decreased activity in the neurons. At the top, excitation. In the bottom, inhibition. And you can't see it here because, unfortunately, my slide's been cut off, I think the size of the monitor, but I was talking about how when sodium goes into the cell, you get increased excitation of neurons. Well, many of the anti-convulsant, anti-seizure drugs we use, and you can't see the older ones there, carbamazepine and phenytoin, which you've probably heard of, work by modulating sodium going into the cell. So they decrease excitation by blocking sodium. On the inhibitory side, as I said, you can also increase inhibition. And one of the most common ways of doing that is old drugs such as benzodiazepines and barbiturates, phenobarbital, which work on GABA receptors, which increase inhibition of the cell membrane and thus prevent seizures that way. Now the one thing we do want to notice is that many medications work in multiple ways. Topamax, which you probably have heard of, works both on sodium channels and also works down here on GABA. And there are a multitude of medications that do work in different ways, both on the excitation and inhibition side. The one thing to keep in mind is you'll see that there's lots of different drugs here, some you may have heard of, some you may have not, that work in different ways and we're not going to go through and explain those. But you would think that given our understanding of excitation and inhibition in nerve cells, that we'd design drugs based on that. So for example, we know that sodium channels are involved, so it would make sense that when we design a medication, we would design it to block sodium channels. In fact, most of the medications, at least historically, were not discovered or designed that way. There are a few, but most of them were found serendipitously. They just happened to work on mouse and rat models of epilepsy. I'll give you a good example. Valproic acid was discovered because it was being used as a solvent with another experimental epilepsy drug. So they were dissolving another experimental epilepsy drug in valproic acid and they were using this on mouse models. And they noticed that the placebo and the active arm that was getting the experimental drug were doing the same, and they all had decrease seizures. So they realized that the solvent, valproic acid, was actually in anti-convulsant and that's how it was discovered. They knew nothing about how it worked at that time. And it's really the discovery of these medications as being effective that sometimes lets us figure out how they work afterwards. And that's, in general, what's happened. Another medication called Keppra, or levetiracetam, works by inhibiting this vesicle release of a neurotransmitter called SV2A. We knew nothing about that. Keppra was discovered, it actually sat on the shelves for years and then kind of rediscovered. And it was only because we found out Keppra was effective that we discovered this target for the drug. So I guess what I'm trying to say is that when we discover epilepsy drugs, a lot of it is serendipitous. There are a lot more epilepsy drugs coming on the market, and my goal here is to talk briefly about some of these new ones. I'm sure many of you, if you've dealt with epilepsy patients, have heard of the ones that were marketed before 1993. Between 1993 and 2005, we have a whole host of other medications. Some of the more widely used ones are topiramate, zonisamide, oxcarbazepine, Trileptal you'll notice, levetiracetam, Keppra, and Lamictal. But even over the last three years, there's been a host of other medications that are either just coming on the market or have been on the market for two to three years. And my job here today is to try to show you one, the characteristics of those medications, and when you might want to use them. Actually, I'm going to talk about perampanel, which is one of the first medications. They're not really chosen in any particular order. I did want to talk just slightly about how medications are approved for epilepsy, because it's a very controversial subject actually. So, when an epilepsy medication goes through the FDA, it has to go through a certain number of drug trials. The first trial is a phase 1 trial that looks at the pharmacokinetics of the medications. This is done in healthy volunteers, generally in hospital. They get given the medication and they measure all sorts of lab values to detect how fast does it clear, what is its half life, and basically just to look at what the body does to the medication. They may look at interactions with other medications, so they may give Dilantin to someone and then give them the new medication and see if there's an interaction between the two. Phase 2 is in the actual target population. So they take people with epilepsy and they give them the medication, but it's for safety and tolerability. It's not to demonstrate that the medication works, or efficacy. And then phase 3 is when we actually do a trial of medications. But the trial is actually kind of strange. The trial subjects are people with refractory, and I'll define that, partial onset epilepsy. So partial onset meaning that their seizures come from one spot in the brain. Refractory means that they're typically on two to three other medications. And their seizure frequency is typically more than four a month, two to four a month. So here you have a very special population. These are not common patients. If you think, just to take a perspective, 70% of all epilepsy patients can be controlled with medication, probably after two medications. These are that 30% or 20% who can't be controlled. So the FDA mandates that medications are used in those patients. So what happens is the experimental medication, there's a double blind study and the experimental medication is added to their other medications, and then the seizure frequency is documented over typically three months and they see if there's an effect. The reason I say this is that when a medication comes on the market, its actual indication is for refractory partial onset seizures. That's what it's indicated for; however, as you all know, that's probably not what it's used for. What I mean by that is as an epileptologist, I might have a difficult patient who doesn't have partial onset seizures and use a medication that the FDA has approved for that and use it in that other type of patient. So the point is that the population is not representative of the typical epilepsy patient. So that's something to keep in mind. As a drug matures, new studies come out. So as you are all aware, studies come out a lot of times related to non-epilepsy things. Gabapentin is a great example for neuropathic pain, and it comes out for different indications for epilepsy. So Topamax has an FDA indication for monotherapy, just being used as one drug, but its original indication was only as an add on. So it it's kind of a very strange process and something that a lot of people are fighting against, because we don't think that it always demonstrates-- that you might be throwing out good drugs because you're trying them in patients with the worst type of epilepsy essentially. I'll point out which ones here were studied that way. So perampanel is soon-- the FDA has licensed it. It's soon to be released. Epileptologists always get excited when there's a new mechanism of action. And you remember that last slide that was very busy and it had all the drugs interacting at different spots. Well, sodium channels, for example, there are lots of drugs that target sodium channels, that block sodium channels, that do things to sodium channels. But this medication is new in that it binds to the AMPA glutamate receptor. So glutamate is a neurotransmitter in the brain that is excitatory. Too much glutamate, you have seizures. So if you block the receptor, the main receptor is AMPA, then the idea is that you might have less seizures, and that's borne out. And this is the first real AMPA antagonist we have, so we're very excite. In patients who have tried other types of medications, maybe this will give them another option. It has a nice feature of a very long half life, 70 to 110 hours, so it can be dosed once a day. You could even dose it less frequently if you wanted to, but it's once a day dosing. It's metabolized highly through the liver, which is not a great thing, just because it does have some other drug interactions. It doesn't seem to affect other drugs, but other drugs will affect it. So for example, phenytoin and carbamazepine, which induce liver enzymes, will decrease the level of perampanel. And it's highly likely that other medications outside of anticonvulsants that induce the liver enzymes will also decrease perampanel. When I talk about side effects in anti-seizure medications, they're usually all the same. They are like dizziness, ataxia, make you sleepy, sometimes give you a rash, so you'll see these type of lists pop up quite frequently. So I won't bore you with this. There are three phase 3 trials. The dosing from 2 milligrams to 12 milligrams, and two of the studies demonstrated at 4, 8, and 12 milligrams there was seizure reduction. And again, this is in these extremely intractable patients. One study had a very high responder rate to placebo and was not able to demonstrate efficacy. And the reason I bring this up is this is very interesting. The placebo rate in epilepsy studies has been going up over the last 10 years. So it used to be that about 10% of people when getting placebo would decrease their seizure frequency. I mean, it's not uniform. But now, it's routine to see up over 20% percent. In two large studies, medication studies failed partially because of that. They probably would've-- and we don't know why. Some people claim that it's because these studies are being done in other countries, at smaller centers, but all subgroup analysis has not shown why the placebo rate is going up. If your placebo is working better, then it's making medications harder to get approved. And there's a medication I don't really talk about, brivaracetam, which is a relative of levetiracetam, Keppra, which is going through repeat studies at a cost of about $1 billion because of this problem essentially. I mean, it's not as simple as that. So in any case, one of the studies didn't show efficacy. Again, another medication I get excited about, and I know it doesn't take much, but retigabine or ezogabine. It, again, works in a different way. It works on potassium channels, and this is the first drug that has ever done this. And you're probably getting a sense when I told you that these drugs are just discovered serendipitously, more and more are they trying to target particular channels and particular physiology and pharmacology. So this is dedicated towards potassium channels. It has a 6 to 10 hour half life, so it's a three times a day administration, which isn't great. For me, anything more than twice a day is incredibly difficult to get patients to take. I'm sure everybody has had to take three times a day antibiotics or stuff, and I always forget. I'm the worst patient. It doesn't seem to have any significant drug interactions, and it's a little different. It can be cause a confusional state, and interestingly, urinary retention. And the reason why is potassium channels or avidly expressed on smooth muscle, so it does all sorts of things to the muscle sphincters that we really, I don't think, have a true appreciation of right now. So people with benign prostatic hypertrophy, other urinary problems, probably shouldn't be on this medication, or they should be watched carefully. So that's kind of unique to this medication. Oops. I think I went-- just, as I said, all these medications have been approved so they all were in phase two or three studies, but 800 milligram to 1,200 milligrams administered, or divided t.i.d., was kind of the dosing. The one thing to keep in mind is while the FDA approves dose ranges, at least as a seizure doctor, I tend to ignore them all the time. So Keppra is approved, levetiracetam is approved, up to 3,000 milligrams a day, so 1,500 milligrams b.i.d., it's a b.i.d. drug; but I came from this place where we felt Keppra was like water, we could just pour it into people. One of my mentors used to say, back up the dump truck and pour it in. And we would routinely-- he would go up to 10,000 milligrams a day of Keppra. My thing is 6,000 milligrams. But the reason I bring this up is if you send someone to us, one, you'll see that we frequently ignore these type of issues, like the dosing; and every one of us will have a different practice. So I know some of my colleagues will say, you're crazy, Wong, for doing 6,000 milligrams a day. And then some, as I said, my colleague, I'm sure he would have gone higher than 10,000. I'm sure it was probably his patient didn't like eating all those pills. So anyway, there are different philosophies around that. I'm sorry I don't give the-- well, many of these trials, and I didn't bring it up, are all done in adults. So many of these drugs are not approved in children. I'll point out the ones that are, but I don't give the dosing for children because they're not approved in children, although will be frequently used in children. And sometimes they get approval later on. So this one is one that you've probably heard of, or might have heard of, lacosamide, otherwise known as Vimpat. It works in kind of a unique way, but it does work on sodium channels, but in a specific way on sodium channels. It's a twice a day drug, doesn't really interact with any other medications. It's become very popular. And one of the reasons it's popular is because it comes in an intravenous formulation. So there's not many epilepsy drugs that come intravenously, which is a big problem if you have someone who comes in for surgery in hospital and you want to give them IV. Or they come in status epilepticus, they're having frequent seizures and you want to give them their medication IV. In terms of Dilantin comes IV, phenobarbital comes IV, valproic acid comes IV, Keppra, and lacosamide, and I'm forgetting one other, I think. So all the other drugs are just oral. And that's something to think about in terms of if you care for inpatients. One of the issues with lacosamide is it does cause dizziness probably a little bit more than most medications. Probably about 20% of people get dizzy on it. And it's worse if you're on a medication that causes dizziness already. So people on Dilantin or carbamazepine, in particular, if you add lacosamide to it, it's frequent they will call and say, oh, I'm feeling like I'm drunk. It does go away sometimes, but not all the time. So that's one thing to keep in mind that is a little bit more noted in lacosamide than anything else, I think. As I said, multiple studies, phase 2 and phase 3. They showed responder rates in the individual studies at 400 milligrams a day and 600 milligrams a day. And this is an interesting medication because it's really easy to use because it has a very low dosing range. Keppra, as I said, you can start at 500 twice a day and I can spend three years going up to 6,000 milligrams a day. Lacosamide, it's starting dose is 100 twice a day, and then you quickly go to 400 milligrams a day, and then you might be able to go to 600 if they can tolerate it because of the dizziness. So you quickly find out whether it works or not. You don't have to keep pushing it up, pushing it up, pushing it up. The one thing I did want to point out is with many of these new drugs, it is very unusual we would check a drug level. With the older medications, they have very narrow therapeutic index of efficacy, and also outside of that, they develop toxicity quickly. But if you've ever seen the ranges on some things like Keppra, they're incredibly wide and almost meaningless. So I rarely check drug levels, except for specific purposes. Whether I'm worried a patient is not taking medication, so I might check a drug level then. Or if I'm pushing the medication so high, and some people are fast metabolizers. So if I have my Keppra at 6,000 milligrams and I get a drug level and it's-- I can't even remember what the normals are-- and it's low, then I might use that. But in general, I just dose them. I would probably check a drug level on these type of medications once every couple weeks, and I might have seen 30 epilepsy patients. Just to keep that in mind. I did mention 600 milligrams a day does have an additional effect, but it has a lot greater side effects. I'll be quick with eslicarbazepine. It was just approved seven days ago. It's a relative of carbamazepine. It's thought that it has less side effects, although that has not been shown, but it's once a day dosing. That's what the advantage is. But it works in a similar mechanism to carbamazepine and Trileptal, which is oxcarbazepine. So that's coming on the market. Now, I talked to you about medications for people with intractable partial onset epilepsy, and we talked about how that stuff's approved, and that most medications are approved for that. There are some medications that are targeted at specific type of epilepsies. In particular, what we call the epileptic encephalopathies. I don't know if anybody's heard if Lennox-Gastaut syndrome, or infantile spasms. These are severe childhood epilepsies that have many different types of seizure types. In Lennox-Gastaut syndrome, one of the most debilitating seizure types is drop attacks, so either tonic or atonic seizures. And if you see someone who is wearing a helmet, it's usually because they have atonic or tonic seizures. And many of those patients, not all of them, have Lennox-Gastaut syndrome. So there are several medications that have been approved for that. Rufanimide is one of them. And their approval process is very different. I'm not going to dwell on it, but the point being is that they're targeted towards these very specific things. And it's a good thing for us as seizure doctors just because it gives us something else, because atonic seizures are very difficult to control. If you have a child or teenager who's having 15 atonic seizures a day and falling just smack onto the floor each time, it's horrible. And we can offer things surgically, corpus callosotomy, where they divide the brain, can be helpful for that. And my colleague, Dr. Munger Clary, may talk about that. But anything we can do for these type of patients is really important. It's interesting, just quickly, it's been shown to be effective in partial onset seizures, but it was approved for, as I said, Lennox-Gastaut syndrome from a very small study. But I think the FDA with the severe epilepsies, their bar is lower for getting these medications through. Clobazam you may have heard of. Its called Frisium, or Onfi. Onfi is the American marketed name. It's been available for years in Canada and the United Kingdom. It's a benzodiazepine, and it's approved for Lennox-Gastaut syndrome, again for tonic and atonic seizures. It's thought to be less sedating and you develop less of a tolerance to this medication, so it's another one of these targeted at a particular patient group. I won't dwell, it had a completely different trial design. Look at the time. Finally, vigabatrin. You may have heard of this medication. It's also called Sabril. It's used in severe partial epilepsy, as well as infantile spasms. I wouldn't expect, unless you're an epilepsy doctor, to be using this. We don't even use it that often. It causes visual field defects in about 30% of people, so they can get a complete constriction of their visual field. It's very difficult to monitor because many of the patients who have these type of epilepsies can't report it, so it's only used for the most severe of epilepsies, but is highly efficacious. There's only one pharmacy-- you have to go through a special pharmacy in the United States to prescribe it. It's been available for years as well, and kind of because we needed these medications for people and we would actually bring these in through special pharmacies from Canada, in years past the FDA would approve that, and it's finally being marketed here. I just wanted to talk quickly about an old thing, the ketogenic diet. The ketogenic diet, I don't know if you've ever heard of anybody on this for their epilepsy, but it's extremely old, so this is not a new medical treatment. But it was noted in 1911 that people who were starving had less frequent seizures, and the theory was because of ketone bodies that they could, I guess, measure in the urine. And they developed a thing called the ketogenic diet back in the 1920s, where they did a 4:1 ratio of fats to proteins and carbohydrates. There's related diets. The medium chain triglyceride diet, the modified median chain triglyceride diet. In this one, they used medium chain triglycerides in an oil, so you have to take this oil, but it's more ketogenic, produces more ketone bodies. The whole point of these different diets is to make the ketogenic diet more palatable, and that's where I really wanted to focus on. This is kind of small. But if you look here, the classic ketogenic diet, you're eating 90% fat, which can't be good for you and we don't really know the long term effects of doing that, 6% protein, 4% carbohydrates. And then there's different divisions as we go down. Now, what's interesting is the modified Atkins diet. With the ketogenic diet, you actually need to bring people into hospital to start it, and you have to weigh your food, and it's very difficult to stay on. Most patients who get a benefit from it or can stay on it are children, usually with severe disabilities where their parents can monitor exactly what they're eating, even though they probably don't like it. That's the big one. There's been a measure to try to modify the ketogenic diet to make it more palatable. So just so you know, the ketogenic diet has been used for years. There wasn't a randomized trial till 2008 that showed that it worked pretty well, as well as an anti-seizure drug in children with intractable epilepsies. Oh, I've gone to-- did I hit it twice? UNKNOWN FEMALE: I don't know. MATTHEW WONG, M.D.: OK. Sorry. One of the problems was, as you can imagine, abdominal side effects and people feel horrible on it. Lack of energy, hunger, constipation. But what they've noted, there's an expert at Johns Hopkins who has done a lot of work in this area-- is that in general, people stay on it if it works. In some people, it really works miraculously, and whether that's because the parents are like, finally, my child is not having 10 seizures a day. But the compliance to it is very low. So if it works, you stay on it; otherwise, no one will ever stay on it just because it's so difficult to maintain. There are no clinical trials and adults in the ketogenic diet. The modified Atkins diet, the nice part about this is you don't need to weight your food. You still need to eat, I think, about 65% fat. And there has been a recent trial done in India in children that did show that it was effective. And I know of anecdotal evidence of this working. It's still a very hard diet to do. I don't know if anybody here has done the Atkins diet. I think this one's a little bit more rigorous. But the point being is that this could work in adults because they'd be more prone to be able to tolerate it. People with normal cognition can't tolerate the ketogenic diet. That that's not always true, I mean, but in a lot of patients that is true. So that is an option and it's kind of fascinating that it's probably is effective as a medication. We don't really know why these diets work. We talk about ketosis and ketone bodies, but there's not a strong relationship between ketone bodies and whether you get seizure control. So there's lots of theories about how they work, but we don't really have a full understanding. So I've spent a lot of time here talking about all these medications and the one thing I want to take a step back and say, are we doing any better with them. So the one thing to keep in mind is-- and I hate to be kind of a sour puss, but I am-- is that none of these medications, at least the ones that are targeted towards partial onset seizures, are likely any better than older medications. What I mean is that we don't have any data that says with any of these newer medications that they treat seizures better. And in fact, we have very little data about seizure medications like that in general. People don't compare seizure medications. Once a seizure medication is licensed, there's really not a lot of benefit in comparing them. There have been large-scale comparisons of certain medications. For example, in childhood absence epilepsy, there's a big trial done that compared ethosuximide to Lamictal to Depakote. And ethosuximide, which I guess is the oldest medication, was the most effective. So my point being is that these new medications are great in terms that they give us other options. And as a seizure doctor I'm eternally hopeful and I will try people on 15 to 20 medications if they'll let me and they're not a surgical candidate, which Dr. Munger Clary will talk about, but one thing with the newer medications is they're usually better tolerated than the older medications, they're more easily administered so they're more likely to have once a day dosing, and they have better drug-drug interactions. And that's a big deal, particularly in times when people are on so many other medications and the biggest growing group of people with epilepsy is older adults and senior citizens. You want something that doesn't interact with other drugs. And then finally, I just wanted to end on I've talked about these anti-seizure medications, but really, the real progress will come with anti-epilepsy medications. And I'm using that term provocatively because we tend to use these terms interchangeably. We call them anti-epilepsy drugs, all those ones I just talked about, but they really don't treat epilepsy. They treat the symptom of seizure. And what lots of research is going into now is how do you prevent epilepsy in people who are at the highest risk of it? So, we have no way in someone with traumatic brain injury in which to give them-- because they're at high risk of developing epilepsy-- to do anything to prevent it from coming on. It's the same with post stroke epilepsy, herpes encephalitis, which frequently causes epilepsy. There's genetic abnormalities. So the real march forward will be understanding the causes of epilepsy. Why do people with certain conditions have these abnormal networks, these abnormal firing of neurons? And a lot of work is going into looking at inflammation as being a cause. People have tried things like giving people steroids and that, but a more detailed look at inflammatory processes and those inflammatory processes might be the cause of why we generate epileptic circuits. So, I'm hoping in two to three years, although I think it'll be a lot longer, unfortunately, that we do have medications that actually target epilepsy and not just treat seizures, particularly for those patients who have such a high percentage of developing epilepsy, and that the biggest one is traumatic brain injury. So, I'm done. Are there any questions at all? [APPLAUSE]