View complete transcript
He led recently published initiatives to make a new [00:01:00] classification of myoclonus. John, thank you so much for joining me today.
Prof. John Caviness: Oh, thank you, Marina.
Prof. Marina de Koning-Tijssen: I would like to start by asking you, there was a new classification made. Can you say something why you thought that was necessary and what's new about the classification?
Prof. John Caviness: Yes, the forward classification that was authored by Marsden, Hallett and Fahn. I think Marina, it has served us well for like over 40 years, for a long time. However, at the same time it aged and became, somewhat outdated and really needed to be revamped if you will. A lot of the terms in the old former classification were not only outdated, but at times they're even erroneous, for example, essential myoclonus vast majority of essential myoclonus. They're not, idiopathic, they're genetic, and they're not even essential. They're [00:02:00] not just isolated cases of myoclonus. So if you were somebody trying to learn myoclonus and you went into the, Marsden Hallett Fahn classification and tried to learn about essential myoclonus, you'd probably get the very wrong idea about it. And so that I think was concerning to a lot of us. Also, there's been so much genetic information that is new about myoclonus and so much neurophysiological information that's new about myoclonus really wasn't incorporated almost at all into the former or older classification.
So there really was an opportunity here to take a different approach. And if I may, go on, we had some work done for us, if you will, by the classifications that were done by the Movement Disorder Society for Tremor and Dystonia. And they adopted an axis approach with axis one being clinical characteristics and axis two being etiology.
And so we thought that was a good [00:03:00] template to build on for the sake of myoclonus. We also did a few things different and I could go into that if you wish but that was why we thought the former classification needed to undergo some substantial revisions.
Prof. Marina de Koning-Tijssen: Yes. I'd like to go into that a little bit more, John, because I think what's interesting. Like you said, we have the clinical axis and the etiology axis, but with myoclonus we added in 1B, which is the clinical neurophysiology axis. That was not included in the dystonia and tremor classification.
Can you say something about that, why you think that is important in myoclonus?
Prof. John Caviness: Yeah I think that was a critical move on the panel's part. Neurophysiology is very part of myoclonus, and we use neurophysiology to not just classify myoclonus, but we use neurophysiology to [00:04:00] decide what might be the best treatment approach. So it's not just important, Marina, I think academically, I think it's important for clinicians as well.
What we did is we made it as, as you say, part of axis 1B. So you could take clinical characteristics and neurophysiological characteristics of myoclonus and then let the clinician formulate the syndrome that it might form into and so I thought it was, very important.
Physiology is important for other movement disorders as well, of course. But, I might, humbly make the argument that it's probably. Even more important for myoclonus in the way clinicians need to think about it.
Prof. Marina de Koning-Tijssen: Yes. And then what I like in the classification is then you then move onto the clinical syndromes, right? There have been syndromes defined in tremor and in dystonia as well. But it was interesting to see that the classification ends up with certain syndromes, and I think that's a nice way [00:05:00] of making it a bit more simple for the clinicians.
Can you say something about those syndromes?
Prof. John Caviness: Yeah. No, I think you hit the nail on the head. The syndromes is what the clinician sees in the clinic, and so it really is what presents to the clinician and not in an academic way, I would argue, but in a very clinical way. And then, once the clinician is able to define or characterize the syndrome, let's move on to etiology.
But I think it's very important that the syndrome lets them define what the patient has is going through and lets them lead to trying to figure out what the etiology of that syndrome may be, and it's important to know that anyone, myoclonus syndrome can of course have numerous etiologies, not just one.
Prof. Marina de Koning-Tijssen: Yes. I really like that about the new case classification and talking a bit about the electrophysiology bit more because in the physiology [00:06:00] part, you actually define based on your findings, where in the nervous system you think the myoclonus originates from.
So from cortical or cortical subcortical or subcortical spinal. Can you say, based on your experience and also on the literature what is the most common one? Of all these types of myoclonus, because I think some of them are very rare and some are quite common.
Prof. John Caviness: Yes and I would say that cortical myoclonus is by far the most common. We see it in a variety of etiologies and cortical myoclonus is in my experience at least, also most commonly multifocal in distribution. And it characterizes itself, that way it may have seizures associated with it.
It may not. But I think cortical is by far and away the most common etiology. And that's important to realize. I think because I think that [00:07:00] also can help you, typify the syndrome. 'cause with cortical myoclonus, there may be other cortical clinical problems there as well, such as, cognitive dysfunction, I mentioned seizures.
And then also, when we get the treatment, acknowledging the cortical source of the myoclonus is very important to acknowledge.
Prof. Marina de Koning-Tijssen: And I fully agree with you that cortical is by far the most often seen myoclonus. And if you see that type of myoclonus in your outpatient clinic what is then the main causes that you think of, because we all know about the genetic disorders, but at the end they're usually quite rare.
What are the causes that you would consider as a clinician?
Prof. John Caviness: Yeah, I think Maria, the causes they... And see if you agree, but they may differ according to what kind of clinic you have. Whether you have a referral center or whether you have just a more, [00:08:00] of a clinic that kind of sees all kinds of neurology, common causes of myoclonus.
It's a little bit hard to talk about because there's no one cause of myoclonus that causes the majority of cases of myoclonus. And so you're talking about, causes that you may be post hypoxic myoclonus myoclonus due to, as you say, genetic progressive myoclonic syndromes drugs metabolic causes are also very common metabolic causes particularly common in the hospital setting.
But I would say those are the most common, causes of myoclonus that a referral center perhaps would see.
Prof. Marina de Koning-Tijssen: Yes, And just one step back about the electrophysiology, because I know you are very good at electrophysiology and you have all the setup for that, but not everyone has an electrophysiology possibility in this clinic. Do you think then that it's necessary to [00:09:00] refer all the patients to a referral center, or do you think that most of the patients can be based on clinical grounds, also be classified by the type of myoclonus?
Prof. John Caviness: Yeah. First of all, Marina, you're very kind. But I would say that whenever possible referring it to a neurophysiology lab would be ideal. But of course, all over the world that is just not always possible. So if we're thinking about typifying the syndrome, or if we're thinking about getting to treatment, because cortical myoclonus is so common, if you suspect an etiology that is likely to give rise to cortical myoclonus, you see a multifocal distribution or you have some other clinical association that might make a cortical myoclonus. I think it's okay to do that. The only thing I would say is that fairly widespread is the ability just to do EMG. And if you can do EMG, you can [00:10:00] also do surface EMG and just characterizing the surface EMG myoclonus discharges can be useful as well. And cortical myoclonus is a paper that your group, recently has put out the discharges are considerably shorter than they are in subcortical, myoclonus, and perhaps shorter than other causes of myoclonus as well. So if you can at least use that surface EMG to back up a presumed cortical cause I think that helps.
Prof. Marina de Koning-Tijssen: Thank you. And you've spoken already a few times, you mentioned the treatment. Can you guide us through how you treat the patient with cortical myoclonus, where you start and how you approach them.
Prof. John Caviness: Yeah cortical myoclonus being, being cortical myoclonus. And the analogy, if you will with epilepsy. We use anti-seizure medications. Mostly in cortical myoclonus. [00:11:00] Bad deal being is that, a seizure, is hyperexcitability, paresis of hyperexcitability in the cortex.
Cortical myoclonus is also, a hyperexcitability of that cortical physiology. And so we often start out with the agent Keppra or Levetiracetam. There's areas of the world that clinicians can use Paracetam as well. That usually is used as a first line.
The unfortunate thing is though, is that, often the treatment is incomplete. It doesn't work a hundred percent, and the clinician is often, I don't want to use the word force, but I'm often compelled to add on other agents as well. Alternate first line agents for myoclonus would be valproic acid, as well as clonazepam.
And some people would argue, perampanel as well. But you have to be cautious in adding on agents to the first line agents because you're [00:12:00] gonna get more side effects and you've gotta really make sure that when you add a second agent for cortical myoclonus, and certainly a third, that you're getting more efficacious treatment and trade off for any side effects that you will begin to see.
But those are I think the first line agents, the alternate first line agents and the way that the treatment is approached. But, to be honest, Marina, it's difficult. Myoclonus treatment is, is well short of where we want it to be, and we have a lot of progress to be made there. And also, good clinical trials are uncommon as well in myoclonus treatment unfortunately.
Prof. Marina de Koning-Tijssen: Yeah. And, because I share your experience that you usually end up with multiple medication. Say I start with levetiracetam, if you add the other ones, do you try to reduce the levetiracetam then a bit that you have a bit lower dose of each of the three? Or how do you titrate that?
Prof. John Caviness: [00:13:00] Yeah I do exactly that, Marina. And the main reason is to reduce the side effects. These agents can be synergistic with each other and so I don't wanna keep patients with myoclonus on a maximal dose of one agent when it's really not in their best interest to do so. because you can't assume that an agent like Keppra is playing the same role in the treatment as it is when it's combined with another agent.
And so you gotta work for the minimally maximal effective dose of each of your combination.
Prof. Marina de Koning-Tijssen: And then a final question about treatment. Like we talked about the classification of myoclonus in line with the classification of tremor and dystonia. And in tremor and dystonia, you have medication as well, but if it all doesn't work we try deep brain stimulation, right? DBS. Do you have any thoughts, because there have been a few cases [00:14:00] published on DBS with myoclonus. Do you have any experience with that and do you have any thoughts of that?
Prof. John Caviness: I think it should be considered there's, certain etiologies that are probably better studied than others. For instance, if you have a patient with a genetic myoclonus, dystonia deep brain stimulation, I think can offer them something that's valuable. If we're discussing a case of cortical myoclonus due to post hypoxic injury. I think the jury is still out on that. I think we still need to understand better, it's efficacious there and even as which target might be better because different targets have been used. So I still think there's much to be, sorted out there. But I think, you bring up a very good point because as clinicians, when we have a myoclonus patient where everything has not worked. They're gonna ask about brain surgery, and so you have to [00:15:00] consider it, but it should, only be considered, very carefully because of the amount of data we have and don't have. But I would say probably the best case for it is in genetic myoclonus dystonia.
Prof. Marina de Koning-Tijssen: Yeah. And that's not the cortical myoclonus, right? So we have to work harder to find out perhaps if it is also feasible and helpful in cortical myoclonus. But there is, as you said, very little known at this moment. There have not been much cases published. So something for the future.
Prof. John Caviness: As you know, Marina when somebody has a patient or a couple of patients that have a good result, they publish those results. But then, you and I both hear about cases where the outcome was not, not as good for the patient as we would've liked to.
Prof. Marina de Koning-Tijssen: Yes, I agree. Well, John, thank you so much with this. Perhaps aim for the future to see for new treatments for myoclonus patients. And thank you for all your insights in the new [00:16:00] classification. I think we are coming to the end of this first episode on the Myoclonus special series. And thank you so much.
Prof. John Caviness: Thank you. It was my pleasure.