Rachel (00:00:00):
Hi, and welcome everybody. My name's Rachel Byrne. I'm the executive director of the Cerebral Palsy Foundation, and I am so excited to welcome you all to this month's new Horizon's Virtual Town Hall. I have two very distinguished guests with me today, Dr. Heather Riordan and Dr. Michael Kruer. Dr. Heather Riorden is the medical director of the Phelps Center for Cerebral Palsy and Neurodevelopmental Medicine at Kennedy Krieger Institute, and she's also the assistant professor of the pediatric neurology at Johns Hopkins Hospital. Dr. Riorden's clinical interests include the diagnosis of neurogenetic disorders and treatment of spasticity and complex movement disorders including dystonia and chorea. Dr. Michael Kruer is a leading pediatric movement disorders neurologist, developmental pediatrician, and molecular geneticist. He is the associate professor of child health genetics, neurology and cellular and molecular medicine at the University of Arizona College of Medicine in Phoenix. Oh my gosh, there's so many different things that both of you're extraordinary at. And then Dr. Kruer also serves as the director of the Cerebral Palsy and Pediatric Movement Disorders Program at Phoenix Children's Hostel. Welcome to both of you.
Michael (00:01:14):
Great to be here.
Heather (00:01:16):
Thank you so much for having us.
Rachel (00:01:18):
Of course. So today's town hall is really learning more about dyskinesia and we are going to sort of be diving into lots of different elements about what that means and sort of what group of movement types and movement disorders are underneath that umbrella. But we also really want to highlight today some of the recent research, noting actually how common dyskinesia is more common than it is previously thought. And then key points that families and adults with cerebral palsy and dyskinetic movements really should know. And we've been fortunate enough actually, that a lot of our audience has sent in questions prior to today. But please, as we're going through, if you've got any other questions, make sure you put them in the chat. We'll also be diving a little bit into potential treatments, new research and related considerations, but definitely want to highlight that we will not be giving individual medical advice during this town hall. I'd also like to acknowledge that this town hall is made possible with the support of Neurocrine Biosciences, but let's get into the topics of today and really would like to first start off with both of you asking the question on what made you decide to specialize in the care of patients with cerebral palsy? Heather, I'll let you go first.
Heather (00:02:39):
Oh, yeah, that's a wonderful question. I think that I really, as I was going through my training, first became interested in movement disorders, and what I found is that our patients with complex movement disorders oftentimes present initially to a cerebral palsy clinic, whether they have cerebral or another condition. That's what initially got me in those clinics. But after I spent some time there, I quickly fell in love with the cerebral palsy population as a whole. They've just been a lovely population to work with. I will also mention that I have a brother-in-Law with cerebral palsy.
Rachel (00:03:20):
Yeah, I think it is one of those areas from an interest area. Once you get into it, it's amazing, but it really is the community that keeps you there. There's no doubt about it.
Heather (00:03:29):
Absolutely.
Rachel (00:03:31):
Michael, what about yourself?
Michael (00:03:34):
Yes. So during my training, I knew that I wanted to work with people with neurodevelopmental disorders. And so my fellowship training was actually in neurodevelopmental disabilities at Oregon Health and Science University, and I was working with individuals with intellectual and cognitive disabilities mostly to start with. But I think that along the way I had the opportunity to work with kids and families that had physical disabilities and the opportunity to use some of the tools that existed in terms of medications and procedures and even surgeries, really just caught my interest. And I felt like that although we had these amazing tools, we needed to understand how to use them better, and we needed completely new tools to try to help the very people that we were trying to help. And so that's just fascinated and perplexed me for years, but it's what's led me to this particular branch of developmental medicine.
Rachel (00:04:45):
And I will say it's interesting when we are talking about the topic of today, right? Like dyskinesia, it's a term that maybe some of our audience and actually our listeners and who was watching today don't really know a lot about
Heather (00:04:57):
Cerebral palsy is an umbrella term that includes a group of disorders that have a similar presentation. The definition includes a disorder that starts in the developing brain, so usually somewhere before the age of two that is non-progressive, meaning we don't expect new brain lesions to showing up or things like that. And that affects movement and posture. When we think about cerebral palsy, we divide it based on what kind of movement is affected. The most commonly discussed form of cerebral palsy is spasticity, but there are also forms of cerebral palsy that affect coordination that we call ataxic cerebral palsy, as well as a type of cerebral palsy called Dyskinetic cerebral Palsy, where there are additional or extras that are caused by the brain.
Rachel (00:05:58):
All right. So if we're thinking about dyskinetic types of cerebral palsy or dyskinesia, I suppose both of those terms seem to be interchangeably used. Michael, I'll ask you this question here. Should they be interchangeably used? Is it the same thing? And what categories are underneath that?
Michael (00:06:18):
Yeah, so I think it depends on our goals. I think that using the term dyskinesia is a great way to start the conversation, but I think that dyskinesia for most of us in the field really refers to an umbrella term. And we already know that cerebral palsy represents an umbrella condition that actually has many different subtypes. So there are different faces of cerebral palsy. There are also different faces or aspects of dyskinesia. Dyskinesia represents an important subtype of cerebral palsy. But within that subtype, there's actually two important groups, and these are specific movement disorders that actually can affect the function of a person with cerebral palsy in important ways. The first is the dyskinetic subtype that we refer to as dystonia and dystonia often will involve twisting or posturing movements. Dystonia tends to be particularly elicited by changes in emotion or changes in movement or state. Then I think today we want to especially focus on the subtype of dyskinetic CP that involves other movement disorders, and those are specifically called chorea, athetosis, and ballism.
Rachel (00:07:44):
So for our audience who might be hearing these words for the first time, can you sort of talk about how common this might be? So for example, I think it's actually in the literature just recently, we're actually realizing that potentially dyskinetic CP is far more common than we thought, and that people can have a lot more mixed presentations. So for example, they may have spasticity but also have dyskinetic cp. Can you just expand, and Heather, I'll ask you this one a little bit more about that and why it's taken us so long to even understand it.
Heather (00:08:17):
Yeah, wonderful question. So traditionally the literature has said that the vast majority of people have pure spastic cerebral palsy, and only around five to 10% of people had primary dyskinetic cerebral palsy. But there's been some nice research recently that has come out that has shown that for those people who have spasticity, many of them, well over 50, 60% also have co-occurring dystonia or other dyskinetic symptoms as part of their presentation. So while we will define people being primarily spastic or primarily kinetic, it's really not this nice dichotomy. We traditionally like to think about it, and this has important implications when we're thinking about helping people understand what's going on with their body, but also how we think about potential treatments and medications that might be useful for them. I think part of the reason that it's taken us so long to really have this elicited in a meaningful way is that oftentimes we're using terms differently. And so you can have many people in the same room who might be thinking of dystonia a little bit differently or be defining the differentiation between dystonia and spasticity a little bit differently. And more recently, over the last decade, I think we've become a little bit more clear on how we're differentiating these things. We've come out with some tools that help to clinically differentiate between spasticity and dystonia, and that's been really useful.
Rachel (00:09:48):
Yeah, I think it's great for the community to be aware, right? There's the bit that we say, all right, well, what does it matter? Does it really matter if you know what type or what is going on? And the answer is yes, because it really does impact potentially what treatments or what interventions could actually be appropriate or really lead to changing somebody's ability to do something. And I think that's sort of where these conversations are exciting that they're finally happening. So rather than saying, okay, yes, it's all the spasticity. So if we're thinking about differentiating between the dyskinesias and between the different dyskinetic types of cerebral palsy, how do we do that? How do we look at understanding the difference between say, dystonia and then chorea or apoptosis? Michael, do you want to have a go at answering that one?
Michael (00:10:42):
Yeah, and I think this goes, the answer goes back a little bit to what Heather was saying just a moment ago, is that in the past, these things have sometimes been somewhat differentially viewed by different physicians. I think there's been a little bit of a history in medical practice. This is dystonia because I'm an expert and I say it's dystonia. And I think that what's been very exciting is that there's been a recognition that we really do need to have a common language as a very first step, but we also need to have common tools and more sophisticated tools to try to reliably recognize these differences when they do exist. So I think we are at the point where the experts, as they were, do agree what these differences are. By and large, I think that the tools have been developed for the most part to distinguish these different entities.
And I think it's also, it bears repeating that Heather was saying that this is important because sometimes this means that what we thought we were treating might actually be a different animal and it might need a different treatment, and it might not respond how we thought if it wasn't exactly what we thought we were dealing with. So in general, dystonia is something that will often lead to hypertonia, what a lot of families and people with CP will refer to as muscle tightness. And this muscle tightness is involuntary, and there are some, sometimes subtle but important differences between the muscle tightness that you get with say, spasticity. In contrast, movements like chorea or ballistic movements, they tend to be much more jumpy or jerky or sometimes flailing. They tend to be a lot more intermittent. They can also dystonia be provoked by state, by changes in emotion, by changes in a person's position or their level of comfort. But these movements in general are a lot more transitory, although they can significantly impact comfort and function. There are some important distinctions.
Rachel (00:12:59):
Yeah, I think that's really important because how you've used a lot of descriptive terms to distinguish between the two of them. Is that now part of the assessments to actually look at and see, okay, what are we actually seeing from a descriptive perspective? How are those movements different? Heather, I know you've described to me sort of the difference between some of them is some are more slow than others and things like that. Can you give some more, I suppose, common terms that might be used that people use to describe the different types of dyskinetic cp? Like if we start with dystonia, then we'll go into say your apoptosis and then into your career.
Heather (00:13:38):
Absolutely. So when we think about dystonia, like Dr. Kruer was saying, oftentimes it has more to do with a posture or tightening. Oftentimes what we'll see is some you may have actually even loose in between or have a resting state, but then when there's stimulation either from an emotional standpoint touch or trying to move another part of your body, you may get a tightening or twisting of a movement in your body. Oftentimes when we see things like waning movements where the fingers kind of come up and over, when we see really rigid extension that comes and goes in the knees with twisting of the toes going in arms, getting stuck in a backwards posture, particularly when going through the door, those are common presentations of more dramatic dystonia that we see. Chorea tends to have a more fluid quality to it. So chorea tends to be by itself, tends to be a little bit more jumpy, twitchy, sometimes crossing over joints like your hand or your muscles are jumping
Closely related to chorea. We have athetosis. Athetosis tends to be a more snake-like or riving movement with kind of a slow transition of the movement or wave-like movement between different joints of the body ball. Ballismus on the other hand, or ballistic movements tend to be very big broad flailing movements where the arm or the leg is moving very rapidly across very large distances and tends to be very problematic when you're trying to, in terms of its ability to be able to sit and keep your posture for positioning safety if you're trying to keep yourself from hurting yourself by hitting things like that.
Rachel (00:15:45):
And quite a question for you, because some of the descriptions that you just used there as sort of were descriptions of say, somebody's limbs moving or things like that. Can it impact every part of the body? We've actually had a question come in from one of our community members around can you see dyskinetic CP in your face, for example, in your tongue in those different pieces? What's the answer there?
Heather (00:16:11):
So that's an excellent question. Just like cerebral palsy can look different from person to person in terms of what types of movements. Cerebral palsy can look different in terms of what parts of the body are affected. So for one person, they may affect one part of the body, and for another person it may look different in terms of where it's presenting. Some people have a dyskinetic movement only in one limb or one small isolated part of the body. Other people have it all over, but certainly can affect any type of part of the body. Some people have disc kinetic movements in just their arms or the legs. Other people can have facial movements, eye movements, hunger, mouth movements that can affect swallowing or chewing safely or speech or truncal movements that can then affect comfort, positioning, and posture.
Rachel (00:16:59):
So we've spoken about what it looks like and where it can impact you. Now I want to look at the how. So Michael, if we're asking these questions, how does Dyskinetic CP impact somebody's body? Does their muscles, their bones, their mobility, does it have an impact beyond, I suppose just the different movements that you see?
Michael (00:17:26):
Yes, the general answer is yes. And again, piggybacking on what Heather was just saying, how it impacts a given person can really differ from individual to individual. At the least, dyskinetic movements tend to be disruptive. So sometimes we'll talk as physicians about intrusions that chorea, for example, has a way of invading what a person is intending to be a normal movement and subverting it. And so we see this most commonly when someone's using their hands and their chorea will make their arm jerk or when they're trying to walk, and the chorea will actually affect their stability or their stepping. And so yes, it can certainly have functional impacts. Going back to that facial chorea that Heather was just mentioning, that can also have impacts on speech, on swallowing, sometimes even on breathing, depending upon how severe it is. And so it's important to kind of understand for any person that's dealing with symptoms like this, how it's impacting them.
(00:18:39):
For other people, they may have these things, but it might not be as functionally impairing as say another aspect of their cp. And so it's very important to kind of tease out, well, so what part of it? How does this actually impact your day? How does this impact your quality of life? There's also a comfort aspect. So for people with dystonia, it's very common to have this abnormal muscle activation that can be either relatively constant or quite intense. People with dystonia will sometimes talk about how it feels for all the world, like a muscle spasm or a Charlie horse. And even for people without cp, they can relate to how that feels. It's not pleasant. And so this can contribute to chronic discomfort and chronic pain. But outside of dystonia, for people that have chorea or that have ballistic movements, those can also be uncomfortable. And in particular, they can lead to a lot of distress if a person doesn't feel like they have control over their own body. Furthermore, the chorea or the ballistic movements can be painful in some cases, particularly because a lot of times if a person is engaging in an involuntary movement, the thing that stops it isn't always that person. Sometimes it's another person, their face, their head, the wall. And so these things can get to be quite debilitating depending upon how much they affect that person.
Rachel (00:20:12):
We've got a great question that's just coming from Catherine actually, and it sort of will lead a bit more upon this sort of involuntary movement. So she's asking what does it really mean that movements that are difficult to control? Heather, can you talk about the movement, I suppose that's involuntary versus the movement that you're trying to actually achieve and how that actually ends up happening?
Heather (00:20:34):
Yeah, absolutely. So when we think about movements, if I'm wanting to reach for something, I'm telling my body to do it. My brain talks through lots of channels, talks to my hand, my hand moves forward. For somebody with spasticity, they may have challenges just doing that just because their arm is tight. It has difficulty relaxing enough to be able to make the movement for somebody who has problems with what we call ataxia. They may have problems where they can get it there, but they have a hard time getting it exactly where they want because can't coordinate exactly where the hand's going. For people with dyskinesia, it's a little bit different. So when they're reaching, what might happen is suddenly another movement comes in that they didn't tell their brain to do that they didn't want to have happen. So that could look like a sudden twisting posture where their hand gets stuck and they can't relax it to be able to do the movement they want, or it could look like a jerking or even a flailing movement where suddenly their hands going to a different direction that they didn't want to have happen or they didn't consciously make happen.
Rachel (00:21:39):
That's goes to the question, obviously, if you're trying to learn a new movement or do something, can you learn to control these movements or is this really something that is involuntary and it's more mechanisms on how to get around it?
Michael (00:22:00):
It's a really challenging question, and I think that we've talked so far a lot about the positive symptoms of dyskinesia, the so-called unwanted involuntary movements. And so just to talk about that at first, that can be very difficult to control. People almost feel like they're having to fight with their own bodies in order to get the action or the effect that they want to happen to actually occur. They may have to fight against their dystonia, they may have to compensate for their chorea, which is pulling them out of the right trajectory while they're trying to do something. So that can be very disconcerting. It can be very functionally impairing for people. And although people can in some cases briefly suppress some of these movements overall, these really should be considered involuntary unwanted movements. The other thing I wanted to mention is that something we don't always talk so much about is that there's also negative aspects of some of these movements.
And so for dystonia, a lot of people that live with dystonia will tell me it's not just the dystonia causing the unwanted muscle activation or the spasm. It's that when I want to get the right muscles to turn on at the right time, it's like my body doesn't listen to me. And people with chorea can have very similar symptoms, difficulty with what we sometimes call selective motor control, turning on the right muscles at the right time in the right way. And with chorea, it can be particularly difficult because there can be an aspect called impersistence. So if I have chorea and I'm just trying to hold out my hands like this, I might have the strength to be able to do that. But if I as their doctor say, okay, I want you to do that for 10 seconds, a person with chorea might only be able to do that for a few seconds before they're not able to sustain it any longer. And so that kind of negative aspect, that difficulty getting your body to do what you want it to do can be a really tough symptom to work through.
Rachel (00:24:08):
So I suppose that sort of leads into the conversation around, well, what can you do about it? There's lots of things that we talk about. Strength training will help improve muscles and muscle coordination and all those different things, particularly in children with spasticity. But can you do therapy? So more traditional things like physical therapy or occupational therapy to help improve these things, or as you said before, there's a lot of it that's involuntary that is so far out of your control. It doesn't matter how much therapy that you would do, some of it can't be controlled, and if so, what treatments are available? So Heather, I'll hand this one to you.
Speaker 3 - Heather (00:24:48):
Yeah, no, great question. So I think in terms there's kind of a few different levels that we think about to help address dyskinetic symptoms. One of the things that a lot of individuals who have dyskinesia learn, whether consciously or subconsciously, is ways to avoid triggers. So for example, if anxiety is a big trigger, working on going through that, if they know that going through a door is a trigger, then trying to find ways to do that in a way, take a time to maintain or close their eyes or something that makes that not as big a trigger. If they find that when a certain posture or place that they're touched when they're trying to do cares is a trigger avoiding those types of things. So that's number one.
The data on different types of therapies like physical therapy, stem bracing and things for disconnect symptoms is a little bit mixed. It's a little bit hit or miss. There are some things that are very intriguing that are going on in that category, but I think we need more data to be able to fully understand what's going to be most helpful. Certainly there can be different devices along that way that can be helpful, whether it be accommodated pencils or pens or things like that that can make tasks easier with the dystonia or the other dyskinetic symptoms. And then after that, we move into the category of medications or medical interventions. So while we need much better data about what types of medications and therapies are helpful for dyskinetic symptoms, there are a number of medications that we will use. The data behind each individual medication isn't great, not because they don't work, but because we don't have the quality of studies, there are also some surgical options that people may choose to explore. For some people, intrathecal baclofen can be helpful for certain types of dyskinetic symptoms, and for some people, a treatment called the deep brain stimulator can be helpful to decrease the amount of symptoms that they have.
Michael (00:27:14):
Can I just add?
Rachel (00:27:15):
Yeah, go for it.
Michael (00:27:17):
Yeah, so I completely agree with everything that Heather said. I guess I would just add that over time I've come to appreciate that it is important to avoid triggers, but just living life is a trigger. If stress is a trigger for your movements, I don't think any of us are very good at avoiding that every day. So I think that one thing that I've also found helpful with my patients is that I've come across some therapists doing some great work with trying to help our patients and their families with awareness training and with state regulation, because if you become upset, that can trigger your movements, but maybe you can't avoid that completely. But once you are upset, figuring out how to deal with that and how to not necessarily lead that into a spiral where your frustration and your anxiety perpetuates your movements, which then causes more frustration and anxiety can be very helpful. So trying to avoid that and then also sometimes even though you person can't completely prevent a movement from happening, they can learn to some degree how to adapt that movement into a more purposeful movement, into a larger, more adaptive movement. And so that can also be helpful.
Rachel (00:28:43):
Riley, as part of our audience actually just asked a question around medications. Heather, you mentioned it briefly around the medication piece. Are there different types of, is the different types of dyskinesia treated differently or are the medications really used across the board? So for example, if you have dystonia, chorea, athetosis, are they similar medications or is that also part of the reason why you really want to identify the different types?
Heather (00:29:10):
Yeah, absolutely. In general, we do treat dystonia, spasticity and chorea or other types of similar movements with different types of medications. There are some medications that may be helpful for both. So for example, Baclofen, which is commonly used for spasticity may also be helpful with dystonia. But in general, the medicines that we use for chorea, BEUs and apoptosis are things that may downregulate our dopamine systems as opposed to dystonia where in addition to muscle relaxants medications that we use are either anticholinergics or things that upregulate our dopaminergic systems. So it's almost the opposite effect that we typically look for. I will say that becomes a challenge when you have people who have mixed movement disorders with both dystonia and chorea and many people do. And in those cases, what we typically try to do is kind of what Dr. Crew and you were saying earlier, find the movement that's causing the most problems that's affecting function and comfort in the most significant way and address that first. And sometimes even though the medicine may not be the one we would've thought for the other movement disorder, downregulating, the most prominent problematic movement disorder actually has positive effects on the other movement disorders for some of the reasons that Dr. Kruger was saying in terms of regulation and of state and things like that. And also because there's probably a lot of things we don't know about what's going on in the brain and how these medications are working in people with cerebral palsy. We desperately need more and better quality studies.
Rachel (00:31:01):
I want to dive a little bit deeper into that. You mentioned dopamine, and for the audience that are listening who doesn't necessarily know what dopamine is or what it does or why you would actually want to down-regulate it in Korea or athetosis, can you explain a little bit more about the function of dopamine in the brain and its impact on movement?
Michael (00:32:36):
It's the movement molecule, and so with what we're talking about, dystonia can be a challenging condition because in some ways there is, as we've already discussed, there are these abnormal involuntary movements. There are these muscle spasms or muscle activation that a person doesn't want, but dystonia brings it to the table. Other aspects of dystonia make it difficult for a person to turn on the right muscles. So even though we know that dopamine is the movement molecule, sometimes there's a complex relationship between do dopamine and dystonia. And just like Heather was saying with chorea, sometimes we can see somewhat of the opposite effect, but again, each patient is different, and so I think that it's really important to consider the whole person consider what their main concerns are, what their goals are, and agree on those goals together so that you can put together the most effective treatment plan.
Rachel (00:33:44):
Yeah, absolutely. I think being able to understand even mechanistically what's going on obviously does inform then the treatments that you're going to use, but to both of your points, it is so important to not necessarily always treat the mechanism but actually treat the functional impairment if what is ever the high priority for the individual or the person, and also functionally what is going on first and foremost, what you're actually trying to impact and change. So yeah, I think that's great advice. I suppose I'll just dive in a little bit more because sort of intrigued by this a little bit. So talking about chorea and athetosis, how do medications work to reduce extra movements? How do they switch them off? Heather want to,
Heather (00:34:30):
So if we think about dopamine as the movement molecule, the kind of dogma that we use is that with chorea we have too much of these extra movements. So the idea is that if you decrease the amount of dopamine transmission that's happening in brain, then you can kind of slow down some of these extra jerking or writing movements that somebody is having. And there's a couple ways that we can do that. Some of the medicines that we use for Korean athetosis work by making it so that the dopamine isn't released as readily from different cells, and then others make it so that it's harder for the dopamine to communicate with the nerves and either of those can work with dystonia. Typically, there are medications that can either directly give dopamine to the brain or increase the brain sensitivity to dopamine or work in other ways with other neurotransmitters that may be involved.
Rachel (00:35:33):
I was going to say we've spoken about dopamine. Are there other sorts of things that you would look to target as well in relation to chorea or athetosis or dystonia?
Heather (00:35:43):
Yeah, so some of the medications that we use sometimes for dystonia and chorea are medicines that work on a neurotransmitter called GABA. GABA is another neurotransmitter that basically tells the brain to calm down in what it's doing. So there are a lot of medicines for seizures, for example, that act gaba. A lot of our muscle relaxants like Baclofen work on GABA, and then our benzodiazepines or clonazepam or gaba, and sometimes those can be helpful. And then there's another group of medicines called anticholinergics that can sometimes be used for dystonia, but not as much for the chorea. I don't know, Michael, if you had other things you wanted to add. I'm going down the list in my head.
Michael (00:36:33):
No, I think that was a great summary and this is why many of us spend years training because I think that these mechanisms start with fundamental principles and that's core to what we do, but we also find lots of exceptions and lots of ways that what's going on in these movement disorders is more complex even than the neurotransmitter systems that we often think about. So it really does require an individualized approach. For example, sometimes a patient with dystonia will try levodopa, and for many patients that's very effective for other patients, they won't respond, and so sometimes we'll turn around and we'll block dopamine and it helps. So when I teach my trainees that they kind of go, okay, there's a lot we need to learn. And I say, yes, absolutely.
Heather (00:37:26):
To follow up on that, one of the important things and the frustrating things to know about treatment of these disorders is there has to be a little bit of trial and error because every person with dyskinesia is so different in terms of how they're going to respond to different medications. So it requires us as doctors to be a little bit humble and unfortunately requires both individuals with cerebral palsy and doctors to be a little bit patient and a little creative in the way that we approach things.
Michael (00:37:57):
A lot of times I'll tell my patients and their families, well, the good news is we've got lots of options and the bad news is we've got lots of options.
Rachel
Another question, well, thinking about trials, are there new clinical trials out there when we're thinking about dyskinesia? Have we been able to move the pipeline along when it comes to the trials that are currently going on?
Heather (00:42:13):
There are a couple of clinical trials that are actively going on that are looking at two very similar medications for particularly chorea, and athetosis in cerebral palsy. Both of these medications are in a class we call VMA inhibitors. Basically, they are the category of medications that decrease the release of dopamine in the brain. They're already approved in other conditions that cause chorea, but what we're hoping to do is see, get some good quality data to see if they work in patients with dyskinesia related to cerebral palsy.
Michael (00:43:55):
It's really exciting that we are seeing this renewed interest in dyskinetic cerebral palsy and in dyskinetic symptoms for all people with cerebral palsy. I think that recognizing that these symptoms, these movements may affect people in important ways, and really the dedication of the community to try to recognize this and discuss it and make people aware of it is important, but I think it's also exciting that we're starting to see interest from commercial partners that they want to help the community and they want to help drive the science and offer more options for our patients, which is great.
Rachel (00:44:45):
Yeah, it sort of brings up that point about what can we learn from others. Heather, you mentioned obviously the two trials that are currently happening looking at medications that have been shown to be effective in other diseases, and so we see other movement types and it comes up in our community a lot like Huntington's disease, Parkinson's Disease, Tourette Syndrome. How much of that can we take from the learnings that they have done and actually bring across to cp, similar to what you just spoke about with these two medications that are currently on trial or how much of it is different? We get asked a lot, oh, okay, if it works in Parkinson's, will it work in CP type thing? And I get probably mechanistically things are differently happening, but how much can we learn from each other here so that we are not having to reinvent the wheel?
Heather (00:45:37):
Absolutely. I think before answering that question, I think there are two important things to keep in mind. Number one is that most of the medications that we're using in cerebral palsy do not have a specific FDA approval for cerebral palsy, whether it be spasticity or dyskinesia, and our use of them in cerebral palsy is already an extrapolation based on what we know about their effects in other conditions. So I think we have to be honest and upfront about that from the beginning. So that's the state of the evidence that we have right now that we're using to guide our clinical practice. I think the second thing we have to keep in mind, and Michael has done some really important work in this area, is that because cerebral palsy is an umbrella term to describe as a group of disorders that have a similar presentation, we're already lumping together people who have genetic conditions and brain malformations and birth injuries and all these different things together in the same category.
So in that way it kind of fits that we would look at other conditions as well that have similar phenotypes because we're kind of already doing that. I think it is a good place to start to extrapolate from other conditions. I think we can learn a lot, and I think partnering with physicians, scientists, patient advocates in those other conditions will make us stronger in terms of having unit five front in drug development and treatment development for similar movement types that mimic what we're seeing our patients with cerebral palsy. I also think that we need to be humble that just because something looks similar in Parkinson's disease or hunting disease or a progressive genetic disorder, that it's necessarily going to work in cerebral palsy. We still need data and trials to prove that it's working in people with cerebral palsy to prove that there's not a different side effect profile in patients with cerebral palsy, and more specifically to understand which endophenotypes or endogroups of cerebral palsy or subgroups respond to which medications because there may even within cerebral palsy be that differential effect.
Rachel (00:47:56):
So you mentioned a word there that was pretty important, progressive, and at the beginning of this town hall we spoke about that cerebral palsy is not progressive, but actually got a question that came in again from the community. So asking my doctor says that dystonia is not progressive, but my wheelchair rep says that it is. Can dystonia be progressive? Michael, can you sort of talk a little bit to this because we definitely, there is moments where people talk about this non-progressive versus progressive elements.
Michael (00:48:32):
This is another really hot topic of discussion in the field among professionals and among people and families with cerebral palsy as well. I think that the definition of cerebral palsy discusses this, but it does so in a way that has left some, I think some questions in many people's minds, and this has been shown recently through some publications, some very nice publications. The question of progression, cerebral palsy, I guess the way that I like to think about it is that cerebral palsy is not a degenerative disorder. It's not something where the brain is injured or impacted by CP in a way that necessarily gets worse and worse and worse. Some other conditions unfortunately do. However, we do know that even over the course of a child's lifetime from the time that they're two until the time that they're 21, if we look at the motor function of a group of patients that have cp, we can see that there's a detectable decline for many of them even during the time of adolescence.
And I think we're hearing from more and more adults with CP that they're dealing with things like chronic pain and they're dealing with changes in their function. I think these are very real phenomenon, and this is a major call to action in the field, why this is happening. I think that there's a lot of potential. We do know that musculoskeletal deformities tend to accumulate, even if the movement disorder may not be changing very much, the wear and tear injury that cerebral palsy can cause on a body can certainly accumulate. There's been a lot of good research about potential premature aging that can happen for people with cp, and I think that this is another really important topic. And so understanding where this is coming from is a huge currently unmet need, although I think that there are a lot of efforts that you might want to speak to Rachel that are trying to address this.
Rachel (00:50:53):
Yeah, absolutely. On that particular piece, we've got a large international effort that we are leading in relation to the preventative healthcare guidelines for adults with cp, really looking at those components across all body systems, but across the lifespan. So what can we do to think about delaying the onset of aging or identifying other areas of the body, not just muscles and bones that are getting impacted? And I think there is fortunately a group of individuals now internationally working on those issues, but it's still, I would say a huge hole as far as understanding of what we have of what the natural progression looks like. But then most importantly, well, what can we do about that? I think this all comes down to it. And Heather, we've got a question that's come in. So what types of clinicians would be most likely to diagnose and treat dyskinesia, and how does someone go about finding them? Yeah, there's a parent in going, I think my child has it. Who do I go to?
Heather (00:51:51):
Yeah. So I think that question's going to depend a little bit on where you live in the world or if you're in the us, where you live in the US because the resources are going to look different and even who the primary caretakers for cerebral palsy are from a medical home standpoint can be different depending on what center you're in. I think that certainly pediatric movement disorder physicians like myself and Dr. Kruer tend to be very comfortable thinking about dystonia and chorea because it's something that we live and eat and breathe. This is kind of our focus of the way we approach patient care and the lens with which we come to cerebral palsy. There are many physiatrists who are very comfortable with dystonia and some that are very comfortable with chorea. So having an honest discussion with who your primary, what I like to call primary tome provider, your primary CCP provider with them about what their comfort level is, I think is really important.
Rachel (00:53:03):
So Michael, on that, what's some of the best advice then? So say for example, if somebody doesn't have access to experts like both of yourselves, what are some of the best advice or best questions that a family could go with to their physician to start the conversation if they're unsure whether dyskinesia is something that's impacting them or, yeah, it is mainly around starting that conversation. What are some tips to,
Michael (00:53:35):
I think you hit the nail on the head there, Rachel. It is about having a dialogue and starting a conversation. I think whether your primary CP provider is a rehab doc, a neurologist, a developmental pediatrician or someone else, the bottom line is that if you have a good working relationship with that professional, you should be able ask questions and to puzzle through things together. And so I think that the best conversations will often start with observations and questions. Hey, I've noticed that my hand does this and that's bothering me because why do you think that is? Things like that can be really helpful to jumpstart a conversation that's focused around a person with CP or their family's concerns and how those symptoms are impacting day-to-day life, but it starts it from a kind of collaborative problem solving type of mentality. We need to work on this together to try to figure it out.
Rachel (00:54:39):
There are two other really important questions that have sort of come through from the audience. One of them is around pain, and one of them is around sleep. So I want to make sure we get to both of those because very functional problems that someone may be having. So Renee's asked this question, sometimes it is painful and causes other parts of my body to cramp up. How do I stop it? Heather, what are some sort of things when we are thinking about pain management and is dyskinesia painful for a lot of people? Is that even a symptom and a sign of dyskinesia? And then if it is, is there a known treatment regime around it or is it something again that's so individualized that you would go through different elements?
Heather (00:55:25):
So unfortunately, pain is not an uncommon symptom in cerebral palsy in general, and particularly as people get into older adolescents and adulthood. Fortunately, there has become an increased interest in understanding pain in individuals with cerebral palsy, and I'm hopeful that'll give us even better treatments than we have now in terms of how it relates to dyskinesia. Dyskinesia can cause pain in a number of different ways. Like Michael was saying, certainly dystonia in and of itself can be painful from a muscular standpoint, just like a Charlie horse or a spasm, especially if it's prolonged, if somebody has a dislocated hip or at other orthopedic complication, that increased strain from the dystonia can sometimes aggravate that orthopedic pain. The third way that dystonia and chorea can cause pain is due to injuries caused by the movements themselves. So for example, if your dystonia causes you to hit something or to pull against a strap and cause a pressure source, something like that, that can be really problematic as well.
And each of those have kind of a different approach to it. I think the easy thing that we can say the low hanging fruit is to say, if we can control the movement, that's going to be helpful. So certainly working to try that can be helpful, making sure we're addressing other sources of pain that are contributing. So for example, if the it is causing orthopedic pain, is there something that we can do to minimize that that's helpful? Outside of that, it really is an individualized approach. Certainly there are some patients who do benefit from medications that are directed towards pain itself. We have come into, as we've learned more about the potential risks of opioid medications, I think we're really pushing to try and have other types of medications that are used first line, whether it be a topical NSAIDs, and then leading it last line to have something like an opioid medication. If it's absolutely necessary, nothing else is working.
Rachel (00:57:57):
Yeah, I think that's really good advice. Actually, before we get to sleep, because Vanessa's just asked another question. So she's pretty sure that her six month old has a form of dyskinesia and she's just waiting on an official diagnosis. Are there early interventions that you think of in really young children, and how early can these diagnoses be made? Obviously, her child's six months old, but for others that may be listening, can dyskinesia present very early on? And then if it is, are there early interventions that say would be different to how an adolescent or an adult would be treated? Michael? Yeah,
Michael (00:58:42):
So fortunately through work that the foundation has really spearheaded as well as others internationally, there's been an increased recognition and awareness that cerebral palsy can be diagnosed earlier than we used to think, and it can be diagnosed early and accurately as early as six months and in some cases even earlier. So I think seeking a diagnosis is often an important first step. It's only the first step, but in getting a diagnosis and getting the correct diagnosis, it helps us to know where we're starting from and the best way to get where we want to go is to have a good sense of where we're starting from. So I think that that's particularly important. The manifestations of some of these movements can emerge over time. They can change over time. And I think that part of that is because all of this is happening superimposed on the context of normal brain development.
And so there's a tremendous amount of brain development that's happening in a typically developing child, but also in a child with cerebral palsy. And so yes, I would say that that's a long-winded answer to the question. But yes, early diagnosis is incredibly important. Early intervention is important. And in terms of what intervention, I think again, you're going to hear the same thing, that it does have to be individualized based on a child's needs. However, I will say that oftentimes a combined approach is really the most effective, where you have a team of professionals that are working for your family and your child. And by that I mean that as we've already discussed, we have some wonderful medical interventions. We have medicines, we have procedures, we even have surgical interventions that can be helpful for cerebral palsy, including forms of dyskinesia. And yes, we need more studies on those.
We need to learn how to better use them, and we need more effective treatments and new options. But what I often say to families is that even our best treatments for us as medical providers, we're just trying to take away the bad stuff. We're trying to take away the abnormal unwanted movements. We're trying to take away the pain. We are just simply trying to open doors. And it really, a cornerstone of progress in cerebral palsy is really made through therapy and through all the painstaking efforts that patients and their families make every day because simply taking away the bad stuff is only part of the solution, and the children need the right supports in order to make developmental gains when we can help to relieve some of those symptoms.
Heather (01:01:25):
I want to follow up on two pieces to that because what Michael's saying is so important. I think that the first is that when we are talking about early diagnosis, early diagnosis is important. CP is part of the diagnosis. The second part of the diagnosis is why does a child have cerebral palsy? And that's important because the reason may have implications on what types of treatments are available. And this is particularly true with patients with dyskinesia as many of the genetic forms of cerebral palsy are associated with dyskinesia, and some of those have very specific treatments that are available. The second thing I would say is that while we don't have enough data to say that the early intervention, the forms of our early intervention therapies like pt, ot, speech therapy necessarily change the course of dyskinesia, there are reasons to think that getting those therapies early on may change the trajectory of that patient in some ways, and that has to do with what Michael was talking about with that these early changes in cerebral palsy are superimposed on normal development. So if we can find ways to create more normal, more healthy motor patterns in that early developing brain that may be protective in some way down the road. So cannot emphasize enough how important that early diagnosis and intervention is.
Rachel (01:03:01):
And I think what we're learning around the early interventions is this whole individualized approach across and the specificity that needs to get done right. There's generic early intervention, and then there's a specificity that's around cerebral palsy and for each of those individual children. And I think the other piece, as we sort of look at more early interventions and what they can look like, I think you're going to have a lot of progress happening in that area beyond motor. And I think this is the piece too. Obviously the motor symptoms may be what you're seeing early on and maybe what sort of is exposed because of different movement or delay, but actually there's really good evidence around other elements, whether it be cognition, sleep, for example, which I do have to ask that one question coming from the audience. But there are other elements in relation to development where we do have really good evidence to look at diet and nutrition and all these things to think about that aren't just motor related. But I suppose the motor part may be what brings you to some of these issues to begin with. But yeah, I do have this last question from our audience, and it's in relation to sleep. And we are going now from early back to adults that we've had actually a couple of adults express that dyskinesia seems to get worse when they're trying to sleep. Why is that? And I don't know, I'll hand it over to either of you to answer this question.
Heather (01:04:25):
I think a lot of, was that saying you wanted or was that saying fast? Okay. I think there's two things on that. I would say that that has been my experience of what my patients have expressed to me is that that change of state when somebody's going from awake to sleep is a time that for some people, not everybody, but for some people, it's a time when their dyskinetic symptoms really kick up, particularly chorea. And that can be really problematic because if you have these extra movements that can affect your ability to fall asleep, which can then create this vicious cycle, because if you're sleep deprived, that also makes your movements worse. I think traditionally we will say that when somebody's actually in a sleep state, so not that falling asleep state, but when they are, that their movement disorder gets better, I will say that whether it's because these times we all have these moments where we're half awake or whether it's because we don't fully understand these movement disorders, they certainly have people who say that they notice their children, for example, having movements in sleep, although they tend to be much better than when they're awake.
The reason for that probably has to do with these changes in what's going on during drowsiness and initiation of sleep. There's a lot that's going on in the brain and changes during that time. And sleep itself is something that we as neurologists do not fully understand. So I don't have a good answer for why, but I will say that it's typical. Identifying that symptom is important because if you do have somebody where the dyskinetic symptoms are preventing them from falling asleep, sometimes we can slate our medication regimens in a way that helps to target that. And that may be adding a medicine just specifically at night that helps calm down the chorea or the dystonia before they go to sleep, knowing that some of those medications can be sedating, that that's not necessarily a bad thing when somebody's trying to go to sleep. Or sometimes what we'll do is we'll change our medication regimen where there's maybe a smaller dose in the morning and a larger dose at night to be able to help target that.
It's also important to note, sorry for some children, people with severe dyskinesia to be aware that sometimes we choose to, for some people with severe dyskinesia, that time when they're going to sleep can be a time when they develop injuries because they're either falling out of their bed or their limbs are flailing and hitting a wall or railing or things like that. And if that is the case for you or for your child, it's important to talk to your provider about that because there are certain bed types that are safer in those situations to help prevent those injuries.
Rachel:
Yeah, I think sleep is such an important topic, even when you're thinking about state regulation and all those different things, right? The perpetual nature of a lack of sleep and what that can do for both. Obviously encouraging more sleep, but then also what do you feel like then during the day, and particularly when you're thinking about these movements, and if you've got an individual who is waking up multiple times a night, that is definitely worth the discussion because I think there are things, when we think about the term sleep hygiene, what are the things when around sleep hygiene, it's around positioning. It's around, okay, what is your state regulation? It's around all those different things that really could have a huge impact on somebody's life, not just to give them better sleep, but then also to think how they're functioning in the day.
Michael:
I think that's a great point, and I think kudos to Heather for answering a tough question very well. I completely agree that there's a lot we still don't understand about dyskinesia in general and about the intersection with sleep. But I did want to reinforce what you were saying there, Rachel, and that for whatever reason that is a common complaint and from families and from people with particularly really challenging dystonia in particular, that they will have difficulty with their sleep. And a lot of times, sure, getting to sleep can be a challenge, but staying asleep can be a real challenge with multiple nighttime awakenings and sometimes real stretches of pain and discomfort at night, which can be very disruptive. So it's very important to have those conversations and try to troubleshoot a solution.
Rachel:
And I think a lot of what we've just discussed today is that you don't have to necessarily tolerate the status quo, right? If these are things from a functional perspective, whether it's sleep, whether it be different movements that are impacting you during the day, that actually you do have the right to have those conversations with your doctor to say, these are impacting me in a way that's either different to before or something that I wasn't aware of that we could talk about. And I think that's the piece, if I can give any advice for anyone listening today, is to feel empowered from this conversation to be able to say, give yourself permission to have these conversations with your doctors or with your treating team, or whoever it might be, so that if there are things that are really impacting you from a functional perspective, that those are getting treated, because I don't think you have to have the status quo. We've got another question that came in. It's like, I've been in pain for years. I didn't think to ask about it. Or if you're having bad sleep, things can be done. We don't always have all the answers, as many of you as both of you have talked about during this town hall, but I think if you can try to find that physician who will have those conversations with you, it's really important to co-develop what the treatment plant might be.
Michael:
Absolutely. And we've talked a lot and emphasized a lot about how there is no one size fits all and how we are starting to think about all of the differences in different types of cerebral palsy, but I just wanted to also mention that it doesn't always have to be that difficult. Sometimes we do have some basic tricks of the trade that we use them a lot because they work a lot and they really can help. So definitely completely agree. Please have those conversations with your docs because they want to help, but they need to know what you're experiencing.
Rachel:
Heather, do you have any sort of final comments for our listeners today?
Heather:
Yeah, no, I really would just like to echo what you said, Rachel. My hope is that people, that what we've offered here is something that will help people become more aware of how dyskinesia may be affecting them and give them permission to talk about it, bring it up, and to work on it with their medical team if it's something that they feel is affecting
Rachel:
Affect. Yeah, no, I think it's so important and to have those conversations. And if you're not comfortable, I think you have the right to also look elsewhere if you're finding that your medical team isn't being able to engage with you in those conversations. But I would just like to thank both of you for your time today and obviously all your incredible insights. I think this is definitely a very evolving space. It's exciting to see how much work is happening within dyskinesia and really is understanding it, but then also ultimately finding better treatments and how we can then impact more. And I'd also like to thank everyone who tuned in today and for all your incredible questions. I know we didn't get through all of them, but we can go through and try to answer and put you in the right direction for some of those different things in the chat. And I'd also like to thank Neurocrine Biosciences who made this town hall possible, so thank you both.
Heather:
Thank you for having us.
Rachel:
Thank you.