Aaron Miller, MD, Hideki Garren, MD, and Kate Dawson, MD, discuss the top findings for teriflunomide, ocrelizumab, and tecfidera plus tysabri from the The 69th American Academy of Neurology Annual Meeting for patients with multiple sclerosis.

Miller, professor of Neurology and medical director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai Hospital in New York, discusses the safety profile of teriflunomide for patients with multiple sclerosis.

Garren, group medical director, Genentech & Roche Pharmaceutical, discusses ocrelizumab (Ocrevus) for relapsing, primary progressive multiple sclerosis.

Dawson, VP, US Medical Biogen, discusses early treatment with tecfidera and tysabri for patients with multiple sclerosis.

Multiple Sclerosis AAN Video Highlights

Chris O’Brien, MD, discusses the frequency of tardive dyskinesia in the United States and the availability of the first treatment for the disorder: valbenazine (Ingrezza). O'Brien discussed this information at the 69th American Academy of Neurology Annual Meeting.

O’Brien, chief medical officer, Neurocrine Sciences, Inc., discusses the frequency of tardive dyskinesia, which affects more than 500,000 individuals in the United States.

Prior to the recent US Food and Drug Administration’s approval of valbenazine (Ingrezza), there was no approved therapy for tardive dyskinesia; the patients were only looked at, not treated, O’Brien said. 

Tardive Dyskinesia AAN Video Highlights

At AAN 2017, Larry Altstiel, MD, PhD, EVP, Chief Medical Officer, vTv Therapeutics, spoke with MD Magazine about his team’s two phase 3 studies in Alzheimer’s disease that studied a “well-established” target called the receptor for advanced glycation endproducts (RAGE).  

Novel Alzheimer's disease Therapy to Slow Cognitive Decline?

At AAN 2017, Merit Cudkowicz, MD, MSc., Chief of Neurology, Massachusetts General Hospital explained that ALS has changed dramatically in the last decade. Researchers previously only considered ALS as one illness, but new knowledge has changed that mentality and has shown experts they need to personalize treatment approaches.

The Unmet Needs in ALS Research: Diagnose, Treat Patients Earlier

AT AAN 2017, Andres Kanner, MD, Professor of Clinical Neurology, Chief of Epilepsy Division from the University of Miami Miller School of Medicine spoke with MD Magazine about the latest advancements in epilepsy research. “There are a very vast amount of advances in all areas like genetics; variety of treatment modalities including epilepsy surgery and pharmacologic treatment; and in our understanding of the pathogenic mechanisms associated with epilepsy,” said Kanner.

What Are New Developments in Epilepsy Research?

Larry Altstiel, MD, PhD, EVP, Chief Medical Officer, vTv Therapeutics also discussed their team’s programs in type 2 diabetes surrounding an activator of an enzyme called glucokinase and a glucagon-like receptor agonist. “GLP-1s right now are all injectables, and they all have side effects of nausea and vomiting. In our particular case, ours is an oral molecule, and it also doesn’t seem to have the gastrointestinal side effects.”

Advancing Innovative Technology into Safe and Effective Medicines

Andres Kanner, MD, Professor of Clinical Neurology, Chief of Epilepsy Division from the University of Miami Miller School of Medicine addressed that there were several medications in the pipeline being tested for different aspects of epilepsy treatment. 

Transforming The Approach to Epilepsy Treatment

At AAN 2017, Robert Zivadinov, MD, PhD, Professor of neurology, University at Buffalo, discussed the primary findings in the phase 3 randomized, placebo controlled TOPIC study, which focused really on the differences between the two doses (7 and 14mg) of Aubagio and placebo. 

The Effect of Disease Modifying Treatment In Multiple Sclerosis Patients

At AAN 2017, Peter Goadsby, M.B., B.S., Director of the NIHR- Wellcome Trust King’s Clinical Research, London, Professor of Neurology, University of California at San Francisco, discussed the recent FDA approval of the gammaCore non-invasive vagal nerve stimulator. Goadsby believed this would have a significant impact on patients with cluster headache. It’s an acute treatment; so it’s a way of treating the attacks that come. 

Treating Cluster Headaches with Non-Invasive Vagal Nerve Stimulator

Robert Zivadinov, MD, PhD, Professor of Neurology, University at Buffalo, highlighted that now that they learned Aubagio had this important effect on cortical atrophy, their team needs to understand how the effect is achieved. â€œOur goal is to go more into mechanism affects of Aubagio especially with respect to B-cell mechanism because Aubagio works through the T-cell and B-cell.â€

Multiple Sclerosis: The Impact on Cortical Atrophy

So there's been quite a few development in the field of epilepsy over the last several years, and I think I can break it down into a couple of different aspects. I think first and foremost for other physicians who are not in the field of epilepsy it's important to understand that the definitions have actually changed or have evolved over the years.

So within the last couple of years for example, the definition of epilepsy itself has evolved. 20 years ago in order to be diagnosed with epilepsy you had to have two or more unprovoked seizures, okay so if you had one you don't have epilepsy. But within the last couple of years there have been several guidelines that have come out that really emphasize the fact that you don't need to have two seizures in order to have epilepsy and they've given several examples of how that could be so.

So the concept is, is that even if after one seizure if it's become pretty obvious that your brain is predisposed to having more seizures then by definition you have epilepsy, so that's sort of a little bit of a shift in terms of definition.

The other aspect is in terms of cure. So most people think of epilepsy as if you become seizure-free then your quote ‘cured’. But within the last couple of years we've codified it so that you have to be seizure-free for 10 years and to be off of medications for 5 years in order to really be considered quote ‘a cure’. So

I think that that's one of the changes in that regard.

There are also a number of other specific avenues that the field of epilepsy has gone to. For example, neural inflammation that's one of the big areas. Inflammation occurs whenever the body has some sort of injury and it's actually fairly well known that after seizures the brain produces markers for inflammation.

One of those markers is for example a marker called interleukin-1 beta. Interleukin-1 beta has been shown in animal models and mice and rats that when you inject this compound, this molecule into the rats brains you actually can provoke seizures or induce the rats to have seizures. The flipside is that when you inject markers into the rat’s brain, that is an antagonist or counteracts the influence of that interleukin-1 beta seizures tend to stop, so suggesting that an inflammatory process may help drive seizures the reason why that may be important in terms of humans and seizures in humans is that if we have certain medications that can be developed to decrease inflammation and if they work then that could potentially be a game-changer.

So just to give you an example something that we take all the time for example, nonsteroidals, like ibuprofen or any of those things so there actually was a study in a type of animal called zebrafish in which these animals as a model they produce seizures and when they were given this anti-inflammatory agent the frequency of their seizures went way down so if that's something that can be translated to humans, that would you know potentially be very significant.

We have a number of anti-inflammatory agents. For example one as an example would be, as I said Ibuprofen. It's cheap, its ubiquitous and if ibuprofen can be shown to really help manage or control seizures then that could be a fairly inexpensive way of helping patients who have epilepsy.

Another very common anti-inflammatory agent is cortical steroids, so prednisone, decadron things like that. And again if those are shown to be effective then that would be a powerful tool to treat seizures.

Jerry J Shih: Improved Epilepsy Understanding

Brivaracetam is one of the newest anti-seizure drugs that was approved

by the Food and Drug Administration, and as such, there's a tremendous amount of interest regarding Brivaracetam.

Brivaracetam is actually a unique compound. It's one of those compounds that actually targets a type of protein or type of vesicle called the SV2 which is on the presynaptic terminus.

It's a cousin if you will, or it's structurally related to a drug that we use fairly commonly now called levetiracetam, or the brand name is Keppra.

It's been out for you know over 15 years, and been a very effective anti-seizure drug. But one of the main problems with the use of this drug levetiracetam or Keppra is that in about one in five - one in six people have mood issues. They're irritable, they're grouchy and you know that's complicated in the sense that if your seizures are well controlled, but you're then — it's something that you know is a problem and alters quality of life so it happens to one in five - one in six people. So it's not uncommon for that to happen to levetiracetam.

Brivaracetam this newer drug is felt to potentially have less mood side effects. So that the potential for Brivaracetam is that maybe it has the effectiveness of the levetiracetam that's already approved, but it may not have some of the side effect profile, so that's the hope and the goal it's been out for you know a little over a year, year and a half, so we don't have as much experience with it.

I think time will tell where Brivaracetam fits in terms of our armamentarium of anti-seizure drugs that we use. As you may know there are over 18, 19 drugs that are available by prescription here in the United States to treat seizures, so it's going to take a little bit of time us to sort of figure out where Brivaracetam fits on that spectrum but I think it's very promising.

Jerry J Shih: Brivaracetam and Levetiracetam for Seizures

the layman's term is medical marijuana, is

that are pretty devastating and catastrophic — they

about maybe five, ten years ago, there was

think, the historical context of the laws

term Charlotte's Web, but Charlotte's Web

legal environment, a lot of physicians where kind of reluctant to really try to use medical marijuana because it would put them in legal jeopardy. It was illegal to try to prescribe marijuana. So there are a group of people, researchers, epilepsy researchers who actually really sat down and I think did a great job of saying ‘let's try to design some studies to see if a medical marijuana is safe’ and B, ‘if medical marijuana is effective.’ And I think over

the last couple of years we've actually had some new data that shows essentially both are true. And just in context, I think it's important to mention that in the year 2014 when the public was saying, ‘oh let's do medical marijuana for seizures,’ and stuff, the American Association of Neurology put out a statement that said we cannot condone the use of medical marijuana because we don't know if it's safe or effective. We're not saying it's not but we really need to have more studies to demonstrate that this is a safe and effective compound. That was 2014 I think.

One of the earliest studies, good studies that came out demonstrating that medical marijuana or cannabidiol is safe was a Lancet article published in December of 2015, and Lancet neurology is a very high-powered journal so they obviously did a great job in that respect. But this article showed that CBD was indeed safe in a large group of patients who were given that compound. And that led to further studies including one that was just recently published in May of 2017, so last month in the 

 that demonstrated in a population of patients with Dravet syndrome the very type of problem that Charlotte of Charlotte's Web had in patients with Dravet syndrome, that medical marijuana or CBD was effective in decreasing the amount of total seizures in that population.

So it's sort of, in a sense a landmark article, because it's the first to demonstrate that medical marijuana is indeed effective in reducing seizures in patients with epilepsy — at least that specific kind of epilepsy Dravet syndrome. And so the corollary to that is obviously, you know, there are people who have seizures due to a number of other causes and whether CBD would be effective for those other causes of epilepsy remains to be determined.

Jerry J Shih: Medical Marijuana for the Treatment of Seizures

And it's not common but when it happens it's obviously very tragic and catastrophic. So in children the incidence of SUDEP is about one in 4,500 patients per year. So every year, you know, if you have a practice that sees 4,500 children in your practice you can expect that you'll have one SUDEP every year in children. In adults it's actually a little bit higher. It's about 1 in 1,000 adults per year who have epilepsy have SUDEP, so it really is a significant problem.

The guidelines really basically came out because there are a lot of controversy regarding SUDEP. Why do we have SUDEP? What are the causes? What are the risk factors? And over the years a number of articles came out, some of which conflicted with each other. One said this, one said that, some agreed, some didn't agree so I think the American Academy of Neurology and the American Epilepsy Society really felt that it was important to release a statement that solidified what we know about SUDEP, what are the causes and what are the things that we can do to try to either prevent it, or at least minimize the chances of it happening.

So I think one, we know that SUDEP is clearly a big problem. Number two is the fact that SUDEP tends to occur after a generalized tonic-clonic seizure. So a major risk factor that was identified is that patients with generalized tonic-clonic seizures or grand mal compulsions, if you will, are at the greatest risk for having SUDEP. If a patient has other types of seizures like petit mall or absence seizures that didn't go into a convulsion the risks are much lower, so grand mal seizures really put patients at higher risk.

Number two is that maybe seizures that occur mostly at night or patients who have seizures often at night are at higher risk possibly, and then also possibly patients who are developmentally disabled, patients who are on multiple seizure medications or who've tried multiple seizure medications were thought to potentially be risk factors. But the one main risk factor is patients with generalized tonic-clonic seizures or grand mal seizures.

The important message to treating physicians is don't stop trying to stop grand mal seizures. Sometimes physicians get a little complacent in the sense that if we start to see a patient, or if we see a patient initially in our practice and we got them down from five seizures a month to one seizure a month we're like, ‘Hey wow, we did a great job! We cut their seizures by over 80%!’

But if these patients are still having one grand mal seizure a month they are at risk for SUDEP and I think, you know, this type of information really lets physicians know, look, people are still at risk if they have grand mal seizures and let's be aggressive in continuing to try to make them seizure free.

The other part of the guideline is again in regards to the nocturnal aspect, the nighttime seizures. And the recommendation is that, if appropriate, the families of patients with seizures should really think about either some type of nocturnal supervision for the patient, or some type of nocturnal monitoring, because SUDEP occurs after a seizure, and it's thought that maybe if, you know, if family was aware that a patient had a grand mal they can intervene in certain ways interact that would minimize the chances of that.

So those are sort of the major aspects of the guideline in terms of what are the risks, what are the things that can be done.

The third aspect that the guideline put out is to really encourage physicians to talk about SUDEP with their patients. And I can tell you personally that when I first started in my career as an epilepsy physician that sometimes it's hard to talk to families about SUDEP. You know, how do you tell a mother of a patient that you're seeing that her son or daughter can die? He can die suddenly? It's a tough conversation to have, especially when, at that time, we didn't have a great idea of what the causes were and what we could do to potentially mitigate the risk or intervene. So you know, many physicians didn't have that type of conversation.

The other aspect is, as physicians sometimes we don't want our patients to become, you know, traumatized by certain types of news. And the thought originally was that, you know, patients may not want to hear something like this. Well I think it's become fairly obvious with research over the years that families do want to know about SUDEP, and that physicians really should inform their patient population, the families of their patients that this is a, you know, a rare the real risk and really should be addressed.

Jerry J Shih: What We Know About SUDEP

The field of epilepsy is such that there are multiple things that are going on right now. There are multiple unmet needs and there are multiple new avenues of research and information coming out. I'm just going to list a couple.

So I think one of the more just interesting developments over the last several years is the shift towards what we call minimally invasive surgery to treat epilepsy. So we've known for the last 50 years that in patients with certain types of seizures, surgical treatment, or surgical removal of the seizure focus is the best way to make that patient seizure-free. But surgical removal meant brain surgery, means that the surgeon has to shave the hair, has to do what we call a craniotomy, and basically temporarily remove a portion of the skull, go in and remove the seizure focus, then put the skull back on, healing et cetera.

So it was a major ordeal, and patients oftentimes, you know, needed 4 to 6 weeks to recover from that type of surgery, which ultimately was helpful because it made them seizure-free. But it was, you know, a pretty tough experience to go through.

Over the last several years there have been techniques developed for what we call minimally invasive surgery. One specific one is what we call laser ablation therapy, and that's where, when we know where the seizure focus is, instead of doing this large craniotomy, or you know, half the skull being removed, there's a little, little hole that's drilled —  3 millimeters, 3 millimeters hole that's drilled on the skull, and then a catheter is inserted through that skull, or through that hole, and into the area where the seizures are, where the seizure focus is. And then using heat energy – laser heat energy – we basically thermal coagulate that seizure focus. Knock it out.

The catheter is withdrawn. That little hole, you know, the surgeon puts a stitch or two, and the recovery time is much shorter. In fact, for laser ablation therapy to treat epileptic seizures, patients usually go home after one day. The length of stay is one day after laser ablation therapy, compared to anywhere from 3 to 5 days for traditional open craniotomy procedures.

And the other thing is, as opposed to sort of taking 4 to 6 weeks to heal, most people are up and about in several days. In fact, I had one patient, a young man who had this laser ablation treatment, and a week later his dad calls me up and, you know, every time I get a call from a dad a week after surgery I'm always thinking “Oh heck, hopefully nothing bad has happened.”

Well he called them and he said, “I just had a question. We were just outside playing basketball for a couple of hours, and I didn't even realize it, and I'm just calling to say, is there something I should do?”

“Oh yeah, yeah he's fine. He once got and play again, but I just realized that we just had surgery last week!”

And I said, “Do not play basketball. I'm glad to hear he's doing great and feeling well enough that he wants to play basketball, but do not play basketball, okay? At least not for another couple of weeks.”

My point is, is that, you know, people just heal up very quickly, and they recover quickly, and their quality of life comes back quite a bit faster than if you had an open craniotomy. So laser ablation therapy is one of those newer therapies that are out there.

I think there are also a couple of fascinating research avenues now that are being used in patients with epilepsy. The area of what we call brain computer interface, or brain-machine interface. Now this type of research doesn't specifically help seizure patients, but with the assistance of these patients we’re actually able to get great information on how the brain works.

So just to give you an example, right now patients can type words on a computer screen without speaking or moving their arm. So we can actually decode brainwaves to the point where patients can spell words on a computer screen without ever talking or writing. And it gets us into the realm of almost science fiction. But it's not. This is reality now.

And with epilepsy patients and some of the studies we do, we're also able now to try to decode how the brain processes certain types of information. Also, how speech processes work. So there's a project in my lab that really looks at the potential for decoding speech and getting to a point in which you can talk through a computer without ever speaking, so that's another avenue of research.

Jerry J Shih: Advancements in Epilepsy Surgeries and Treatments

seizure-free, and absolutely that's our primary goal.

undergone all of the appropriate studies —

for developing mood problems, and then to

AAN Conference Perspectives