Okay, hello everyone. This is Christina Gnan from AAPMR. I'm glad to join you guys today on your lecture series. I don't have my camera on. There we go. No longer just a voice coming from somewhere. I'm just here to introduce Dr. Shruti Thomas. She's a pediatric physiatrist and physician scientist at Texas Children's Hospital, which is affiliated with Baylor College of Medicine in Houston, Texas. She completed her medical and graduate training at the University of Colorado with a PhD in neuroscience and stayed on as a resident in their combined pediatrics and PM&R residency program. As a clinician, Dr. Thomas's main areas of focus are cerebral palsy and inpatient rehabilitation. She's also the medical director of Texas Children's Enthroclifin Pump Program. My apologies, I'm mispronouncing that. Dr. Thomas studies both spasticity and dystonia management with a special emphasis on neurosurgical interventions. She's a board member of the American Academy of Cerebral Palsy and Developmental Medicine, an editorial board member of AJPMR and editor of the annual CP Special Edition of JPMR. We can go right ahead and we can get started, Dr. Thomas. All right, thank you, everyone. Please let me know if you see any technical difficulties I'm presenting from one computer and talking on another thanks to some Poll Everywhere issues. So let me know if you have any difficulties. But thank you so much, Christina, for that introduction and thank you for taking time out of your day to join me to hear about dystonia. This is a topic I can wax philosophical about for many hours. Typically, I prefer to do it with a glass of wine, but I think we're all on a working day, so that's not possible. So you'll just have to imagine for now. But when we had surveyed the membership about what topics were high yield topics that we wanted to make sure that we touched on, dystonia was one of those topics, and I was honored to be selected to present on this topic. So I hope that you find this to be useful both for people who are more junior as well as for people who are senior. All right, so while I'm starting to go through these introduction slides, I would greatly appreciate if you could hop on the Poll Everywhere so that we could make this somewhat interactive even though we're not together. You can either go on your phone or you can scan the QR code to get to the website or open a browser, but just get that going in the meantime. So as far as disclosures go, I have no financial disclosures. However, I do have a NIH R01 that is pending council review that's investigating intrathecal baclofen's variable effects on dystonia. So hopefully I will have a conflict soon. As mentioned, I am a board member of AACBDM. I am also an investigator with the Cerebral Palsy Research Network, and I also serve on multiple editorial boards. One thing to keep in mind as I go through this talk, I was being a little dramatic here and saying that every single treatment is off-label, but very seriously, with the exception of Botox and Dysport, which are FDA approved for cervical dystonia and deep brain stimulation, which is FDA approved for certain types of dystonia, everything here is off-label use. So I think one of the takeaways you're gonna see in my lecture is that there's not a lot of evidence behind what we're using. It's a lot of common sense and anecdote. So there probably is good reason to be using some of these medications and interventions, but we don't have enough data to really back all of this. So learning objectives. These seem really simple, but we're gonna define dystonia, talk about how you identify it, how do you qualitatively and quantitatively measure dystonia as well as how do you develop strategies about managing dystonia, particularly in cerebral palsy. These seem really simplistic, but dystonia is obviously a very complicated topic, which is why it was such a hot button topic that everybody wanted to talk about. So I hope that you'll feel more confident in at least identifying dystonia in your patient population and having a clearer understanding of what actually has evidence and what doesn't as we go forward. All right, the first Poll Everywhere test. Go ahead and place a pin for where you currently are right now. If you happen to not be in the United States, go ahead and throw yourself in an ocean. Here we go, got a few people responding. Like, I'll log in and put myself in there too. All right, we'll see as people log in and chime in, but it looks like Poll Everywhere is working. Okay, we will move on. For right now, we have no one on the West Coast. I guess it is still pretty early over there. Okay, first real question. What do you think when you hear dystonia? So this is a word cloud, so you can put in a single word response, a short phrase, you can put in multiple responses, throw it out there. Movement disorder, posture, what else? All right, more people thinking about posture. So again, with the word cloud, the more people say the same word, the bigger the word gets. There we go. I was hoping people would chime in, otherwise I was gonna start calling people out by name. Excellent. Now here are some of the themes that we see. Difficult, I saw bad. It's moving very quickly. Uncontrolled, twisting. We see velocity, challenging. Awesome, thank you guys for participating. I appreciate it. Okay, so yeah, so let's dive into what is dystonia. So dystonia was first discussed in medical literature that we are aware of back in 1911 by a German physician with last name Oppenheim, who called it dystonia muscularum deformans. And as he was describing the case that he defined this term with, he commented that this patient had muscle, that their muscle tone was hypotonic at one occasion and in tonic muscle spasm at another, usually but not exclusively elicited upon voluntary movements. So not too much has really changed in how we define this from back in 1911. It's abnormal muscular contraction that's triggered by voluntary movement. It could look like rhythmic twisting with tone fluctuations or it could be something that's more slow with uncontrolled movements and fixed postures. We find that dystonia typically affects the trunk and proximal limbs and less so the distal limbs. I'm going to embarrass Dr. Kraskiner or maybe he's not embarrassed by this, but I think he had the best commentary on what dystonia is or how you identify it. He said this at the Pediatric ITV Network meeting earlier this year, but he said, it's like the Supreme Court said about pornography, difficult to define, but you know when you've seen it. And I still sometimes feel that way, even though this is what I study even from a research aspect of like, I feel like there's dystonia there, but I'm trying to put it into words, what am I seeing? So I'm hoping that as we talk through this, you'll feel more empowered about identifying it. One of the big things I want you to take away from today is knowing that dystonia is a network phenomenon. There are some things we know, like a single pinpoint brain injury in some nuclei causes one specific problem. Dystonia is different. Dystonia is looking at a phenomenon where you're controlling multiple muscles and coordinating that movement together. So it is an entire network or a pathway that's going through the brain. From what we understand so far from animal modeling and some human modeling is that it involves the basal ganglia, the thalamus, the subthalamic nucleus, the cerebellum, as well as higher cortical regions. We used to think that all dystonia was coming from injuries to the basal ganglia that's now been very well disproven. The other thing to really keep in mind is that the network is not just a motor network, but it also includes sensory inputs. So it is a multi-sensation network. So it's much more complicated than some other issues that we deal with in cerebral palsy. So a injury to any part of this network could present as dystonia, which then raises questions of, should we be treating all dystonia the same or is dystonia that's arising from an injury to the basal ganglia different from dystonia that's arising from an injury to the cerebellum and so forth? So a question to ponder. And also before I keep going, I am very casual in my presentation style. So please feel comfortable to unmute and interrupt verbally if you feel so. You can also be throwing questions into the chat. I am able to see that, so I can answer that as we go along as well. Okay, let's dive into how we identify dystonia. First off, I wanna know a little bit about what you are currently documenting. So when you see a patient in clinic, how often are you regularly documenting whether or not dystonia is present? Your choices will be yes and no. And you can be honest here, because I can tell you a lot of people don't. and pardon me as I sip on tea because I've managed to have a lovely allergy call. We're going to give it 10 more seconds. Our final results, we have about three-quarters saying that we do regularly document whether there's dystonia or not, and maybe a quarter saying that they don't regularly put this in their note. Then next, how many of you put it into the problem list? Again, it's a yes, no. All right, so this one's a little bit more of an even split. The reason I highlight this is for us to really begin to tackle dystonia in our patient population, we need to do a better job of identifying it overall. And some of the times we're not even, it's not even that we're not identifying it, we're not putting it into the documentation. This is really important if we're trying to do QI initiatives or research initiatives. In fact, CPRN had an entire initiative around dystonia and trying to improve identification of dystonia. When I did a recent poll of our patients, Texas Children's, we have about 2,500 patients who have CP. Some of those are adults that have aged out of our system but are still semi-managed here. But only 300 of them had dystonia marked in their problem list. And we are now finding that a significant chunk of patients that we think of as just being spastic is truly having components of dystonia and it's just not being picked up on. So this is step one that we gotta work on. So how do we talk about dystonia? We talked about the definition, but how do we speak about it, like describe it? Technically, a lot of us use the old lingo. I quite frankly am still using the old lingo of primary versus secondary. So primary dystonia is when we think of a genetic origin dystonia or a dystonia that has a focal segmental component or it's idiopathic. We generally think of these types of dystonias as being more amenable to treatment. And then secondary dystonia is often what we think of as being implicated in cerebral palsy where it's resulting from a lesion somewhere in that network that I showed you, some sort of acquired brain injury. And we find that these are more difficult to treat. In 2013, there was a movement amongst movement neurologists, I guess, pun fully intended on that one, of changing the lingo and being more descriptive of what we're seeing with dystonia. So just like our movement with cerebral palsy of not just saying this child has cerebral palsy, but going further to say, this is a child with spastic diaphoretic CP who has a GMF CSO2 secondary to prematurity and periventricular leukomalacia. In the same way, there was a movement to try to be more descriptive of dystonia and not just clumping it as primary and secondary where you're focusing on the clinical characteristics as well as the etiology of dystonia. So something to think about when you are trying to, in your mind, think through it. So say dystonia that I see in one of my patients with CP might be a birth onset generalized persistent dystonia that's also associated with spasticity that's resulting from say hypoxic ischemic encephalopathy at birth. So start thinking about it that way. I think this has not been able to catch on quite as much as the neurologists would like. I think a lot of us are still really just talking in primary and secondary. This is from a paper that not a lot of people talk about, but a lot of the movement neurologists talk about. Any of the papers that I think are key papers in this lecture, I've put one of the scan me QR codes over here. So it's a little bit easier for you to grab that paper, but this paper comes from Terry Sanger, who is a movement neurologist out of Children's Hospital of Orange County. He also focuses his work on deep brain stimulation for secondary dystonia to use the old term. And he wrote this paper as he was working on his patient population with DBS of the common dystonic postures that they were seeing in their patients. And I think this is really helpful, especially for trainees and for people who are more junior who are on this call to understand what you should be looking for. So he identified seven very common postures that are associated with dystonia. Basically, sorry, I'm trying to left-hand drive my second computer over here. We have the swan necking positioning of the hand. This one, which I think if you think back to your patient population, you've probably seen this before. I was glad that he put words to it. He calls it the one, two, five, because it's the first, second, and fifth digit that are going together into sort of this extension posturing and the third and fourth going into more of a flexion at the lumbricals. Internal rotation of the arm. He doesn't comment on the extension of the arm, but I feel like the extension of the elbow is a common component. So it's like shoulder internal rotation and then elbow extension, fisting, straddle toe, or also great toe extension, foot inversion from some post-TIB involvement. And of course, epistatonics fits into this category as well. So a good paper to look at when you're just trying to get your feet wet and is this dystonia, is this not? So trying to tease that apart. So now you're trying to get more sophisticated. You're thinking about those patients where, man, I really think that they're just predominantly spastic, but is there dystonia? It's not one of those cases where it's slam dunk, they're totally epistatonic and with their limbs extended and things like that. Really, the hypertonia assessment tool is one of the best ways to tease this apart. So this measurement tool was created by Darcy Failing and her team. Darcy Failing is a developmental pediatrician out of Canada at SickKids in Toronto and Holland Bore View Rehabilitation Hospital, whose entire career research focuses on dystonia. So she, along with a bunch of other movement neurologists, created the hypertonia assessment tool. Hopefully this is not new to you, but it allows you to distinguish between dystonia, spasticity, and rigidity. And you can see that those in like the golden yellow rows are the ones that are specific for dystonia. And in fact, items one and two have actually been found to be able to stand on their own without item six on here. But to review those things, the first test that you would be able to do as part of this tool is you see if there is increased involuntary movement or postures of a designated limb with tactile stimulus of another body part. So imagine I'm investigating the right leg and I gently touch the left shin and I see that right foot invert in. That's a sign of dystonia. The second item is increased involuntary movements or postures with purposeful movements of another body part. A classic technique that you can see done is distracting the child with another activity, whether that's scribbling with a crayon, manipulating an iPad while they're watching YouTube, things like that. And then while they're busy with their hands, you see what's going on with their legs and the hand that they're not using. Sometimes you can see some posturing start to happen in the non-dominant hand that they're not using to manipulate whatever device. You can see their legs extend, you can see their feet invert. So other signs of dystonia. Then that last item, number six, increased tone with movement of another body part. This can be things like if you have an ambulatory child and you start to see that flexion posturing of one of the upper extremities, even though you thought of them as a spastic diaphoretic patient, some would argue that's a sign of dystonia. So if this is something that you have not seen before or want to be more familiar with, Holland Bloorview Rehabilitation Hospital on their website actually has clinician education videos that takes you through that entire assessment and actually has demonstration videos of how to administer the tool, as well as showing you what a positive exam would be. So I find these to be really helpful and I think it's super useful to go through. All right, let's talk about measuring dystonia. So there are a ton of quantitative tools out there. So far we've talked about the hypertonia assessment tool, which is really more dichotomous, right? It's a yes, no, there is dystonia or there is not dystonia. And of course it also comments on spasticity and rigidity. Why do we want to quantify dystonia? So obviously I'm biased, I am a researcher, I'm all about quantifying outcomes and it's really nice to know if there's a change happening with the intervention that you are prescribing. However, the literature has numerous scales out there for dystonia and when you talk to pediatric movement neurologists about it, none of them are really a slam dunk for measuring dystonia in children who have cerebral palsy. A lot of them are really based off of children who have like adobe responsive dystonias or primary genetic dystonias. So they're not really slam dunks, but some common ones that you will see as you're reading the literature is the Barry Albright dystonia scale that was created by Barry Albright and his partners, Barry Albright, sorry, Leland Albright, I apologize. Leland Albright was a very famous world-renowned pediatric neurosurgeon who really pioneered intrathecal baclofen and he created the scale really to be able to quantify the changes that he was seeing with intrathecal baclofen. Then the dyskinesia impairment scale is meant to be somewhat more sensitive in the CP population. However, it's a very tedious scale. The original version, the first edition of the scale takes about 45 minutes to administer. The second edition that's been recently published is about 30 minutes. And then there's the Birkbahn-Marsden dystonia scale, the BFMDS, I'm sure you've seen that mentioned in papers about tone, still not a great tool for really capturing the essence of dystonia in CP. So then what do I propose as an alternative if I'm saying that all of these are not ideal? There is a newer tool that just came out. I believe this was published in 2022 and it is the Dyskinetic Cerebral Palsy Functional Impact Scale. I think as rehab physicians, this will speak to you more than some of these other tools that are purely quantifying changes in dystonia because really this is getting at how does that dystonia impact your function, your life, your participation, pain, things like that. So there are 18 different domains on this. It's a patient reported outcome. So it can be done by a parent, a caregiver or the patient themself. And it goes through 18 different areas. So here I just show you an example of standing and sitting and you can see that it goes everywhere from no impact to extreme impact. And if they think that there's difficulty in this area but it's not due to dystonia, then they can say NA and not answer that. What I like about this is that it allows you to have a measure of how impactful the dystonia is. Is it something that is worth going after and treating knowing the side effect of some of the medications that we're gonna prescribe? It also allows you to really see what are the priorities for the family because there are 18 different areas. You can really tailor it to a child and their family. What's important to them? Is it the fact that one of the areas is your ability to use technology? Is it really that they're just frustrated that they can't communicate with their child because the dystonia is getting in the way of them being able to use their augmentative communication device? Or is it really that they're having trouble sitting in their wheelchair? I like the idea of using the scale clinically, not just in research. And it's something that we're trying to implement here at Texas Children's, especially when you're doing things where you're acquiring titrations of medications so that at least I don't know how it is for all of you guys. For me, I often get these sort of vague responses from families where they're like, yeah, maybe that medication made it a little bit better and they can sorta tell me maybe they're not scissoring as much when I'm trying to change their diaper. They can't quite give me concrete feedback to really know if it made a difference, but I think this type of tool would help them put words to what they're seeing and what gives meaning in their life. So something to think about. Okay, now let's get to the meat of this, the management of dystonia. And again, please throw any questions that you have into the chat if you don't feel comfortable interrupting. When I think about dystonia, I like to step back and think of it in terms of the international classification of functioning and disability and health model that was proposed by the World Health Organization. It's a nice way to take a holistic view of the situation. So here you have body functions and structures. So we know that dystonia causes involuntary muscle contractions. It can be painful. It can lead to dysphagia. There's bulbar involvement. Unchecked dystonia can cause joint contractures. While it's controversial and still not technically proven, a lot of people implicate dystonia with worsening hip dysplasia as well as neuromuscular scoliosis. And the presence of dystonia makes activities such as self-care and mobility, fine motor skills, interactions with peers very difficult. It can interfere with your ability to participate in activities that have meaning. And of course, there's environmental and personal factors that can play a role in dystonia. One thing that I didn't mention as I was defining dystonia is that it is fluctuating. While there can be some kids that every time they're awake, they are in a dystonic fixed posture. Quite a few individuals have fluctuating tone and any type of high stimulus can cause dystonia to appear. It could be a negative stimulus like being ill, having a bladder infection, a pressure wound, just like when you're thinking about AD with a spinal cord injury, a broken bone, a hip out of place. And then on the flip side, it could also be good things like any high emotional state. So positive emotions can also cause this. I have one patient who I love to death who every time her birthday is coming, she's so excited about her birthday party. Her mom told me that they need extra doses of medicine for that week leading up to her birthday party because she is just so dystonic that week because she's so excited for the birthday party. So there's a lot of things to be thinking about when you're thinking about the management of dystonia. So hopefully this little clip here is not something that is new to you, but there is this amazing paper called the State of the Evidence Traffic Lights 2019. This comes to us from the Cerebral Palsy Alliance in Australia with a team led by Iona Novak, where they did a systematic review and meta-analysis of every possible intervention for cerebral palsy so that they could give guidance as to the evidence that's available for things. So this is a clip of just the tone section. For those who are not familiar with this paper, it's essentially you have red, yellow, and red, sorry, green, yellow, and red, hence the stoplight phenomenon. So anything that is green has enough evidence that you should be doing it. Anything that's yellow is in the, where there's weak evidence, we should talk about it. And then if there's anything that is red, it's a absolutely do not be doing this. Thankfully, tone doesn't have anything that falls in the red category, but as an example, something like hyperbaric oxygen, that's something that has a red on this. When you look at the yellow, there's also this dashed line that's a worth it line, love this. They basically drew a theoretical line where they felt that there was enough evidence to say that something was worth trying versus maybe not trying. So when you look at this, I know this might be hard to see on your screen depending on the size of your screen, there's nothing green for dystonia. Botulinum toxin, as I indicated in the disclosures, is effective against cervical dystonia. The evidence is still weak enough that it's not a green. That's really due to the size of the studies that are available. One thing to add is the bigger the circle, the stronger the level of evidence. So these giant circles up here are essentially three plus RCTs that are available. And then as you come down here, interestingly on the research side of things, transcranial direct current stimulation has been shown to reduce dystonia. Deep brain stimulation has been shown as well as gabapentin amongst the medications. And then below the worth it line, one thing that's important to point out and we'll talk about more, trihexafenadil or Artane is below the worth it line. So maybe not use it with dystonia. If you don't see a medication listed here, it's not because they're not being used for dystonia, it's that there's no evidence to even make a circle for them. So with this data, so remember this is from, this was published in 2020, but the data comes from 2019 and onwards, or sorry, in previous. Based off of that data, there was an original care pathway that was created by AACPDM for dystonia. This is actively being updated, about to be published. Some of you might've looked at the public review of the new pathway, but there's a lot of good elements of this pathway that I wanted to take us through because it gives you a thought process on how you should formulate your plan for a child that has dystonia. But there's definitely some things that are going to change in this and things that need more evidence. And so it's important to point out that anything that is purple has inadequate data and it's only the ones that are yellow that have probable benefits. So one big thing, they start off with an assessment, truly identify whether there is dystonia. You consider using something like the hypertonia assessment tool to make sure that it's there. Find out if it's consistent with what you're seeing in their CP diagnosis. If it isn't fitting, then you might need to be thinking about additional workup. And then how much is that dystonia actually impacting the child? We don't want to treat dystonia just because it exists. There's not enough data yet to say that it's just bad, bad, bad. We should just be treating it. But if it's impairing function, if it's impairing quality of life, it's causing pain, those are times that we need to be taking it seriously and treating it. We know that we're not going to be able to stamp out all dystonia, but it's important to be making sure we have a good purpose when we start to treat it. And again, as I mentioned, dystonia is triggered by many different things. So it's important to take a look at, again, holistically at their overall health. Is this a patient who has bad sleep apnea and it's not being managed and that's a big trigger of their dystonia? Do they have severe anxiety and depression? Do they have dysphagia and they're still taking PO instead of having a G-tube placed? So think of things like that too, because a lot of times by controlling these other secondary health issues, you can actually tamp down some of the dystonia that you're seeing. So say you've done all that and you're still having dystonia that's causing pain and interfering with function, then it's time to start thinking about our bread and butter rehabilitation strategies, getting our therapists involved, thinking about how we're positioning the child to break the pattern of dystonia, seeing if there's splinting options that are available like AFOs and so forth. And then once you get past that, it's worth thinking about, is this a child who has focal dystonia or generalized dystonia? If they have focal dystonia, then botulinum toxin is probably the way to go. It is FDA approved for at least cervical dystonia and it does allow you to get control of that limb. Now, one thing that I do always point out is that much like what Ian Malcolm, Jeff Goldblum's character says in Jurassic Park, that life finds a way, dystonia finds a way. So oftentimes if you knock it out in one area, it's gonna show up somewhere else. And that's one of the big issues with trying to treat dystonia. So something to keep in mind, because there's definitely been times where I've heard of people noticing that a patient was always extending their arm and they might take out the tricep and a wrist flexor and then they go the other way and they flex and they're getting stuck that way. So something to keep in mind. Now, once you get into generalized dystonia, that's where you should be thinking about something that is a enteral medication that can have more global effects. This is where the pathway starts to be very weak in data and note that this pathway was set with things that have evidence behind them. So some of this is not gonna mirror what you do in practice. The first line that was recommended was Baclofen. Remember that Baclofen does not actually have an FDA indication for dystonia. The second line at that time was Trihexafetidyl, which is a favorite amongst movement neurologists. However, it has now been shown to not be effective. It actually have quite a bit of a side effect profile. So people are poo-pooing this and I can tell you that it is gone in the new updated guideline that'll be coming out. And then again, because dystonia is so personalized, it's worth thinking about specific indications such as is this child having pain that we think is triggering dystonia? Gabapentin seems to be effective here, especially if we're having undiagnosed centralized pain in these patients. We know within the adult group within the Cerebral Palsy Research Network, there's a lot of undiagnosed pain out there where it's just not being reported because it's not being asked about. So there's a significant amount of pain in children with CP and adults with CP, so something to think about. If you get to the point of having status dystonicus, which just like status epilepticus, if you've never heard the phrase, is that you're stuck in this fixed posture, then it's time to be thinking about benzodiazepines and clonidine or other alpha-2 blockers. Here at Texas Children's, I know we're at the point of ICU. We really like Presidex, which is an alpha-2 agonist as well because it's quick on, quick off, and not sedating to the degree that something like midazolam or fentanyl drips would be. And then if there is sleep disturbance that is also associated with dystonia, the guideline was recommending clonidine and or benzodiazepines. I will say that the original guideline really shunned benzodiazepines because they were worried about the long-term neurocognitive effects of benzodiazepines. If you're not getting sufficient control there, then at that point you would be considering a trithicobaclofen and deep brain stimulation. All right, so that was where we were until a updated systematic review of all pharmacological and neurosurgical interventions for individuals with CP and dystonia came out in 2021. So this group also led by Darcy Failings, again, she's one of the main experts in this area, rehashed all of the drugs and neurosurgical interventions to really get a feel for where things are. And it's this work that the updated guidelines are gonna be based on. So first off, I wanna know what you guys are using as far as enteral medications go for the reduction of dystonia. So this is anything that is being given by mouth or by G-tube, again, go to your poll everywhere. It's a word cloud, so you could enter things multiple times. And the more people say things, the bigger the word gets. We'll give it 10 more seconds. For the last people, we're almost there. On the battle to see which one's going to win out for the biggest. We're calling it. This is our, right as I hit the button. This is our final word cloud here. The reason I ask this is that you can see that there is a lot of medications that are being used for dystonia. Not a single one of these has an indication for dystonia. I am part of, I'm leading a group through CPRN to actually do a multi-site adaptive clinical trial to actually investigate which of these medications is most efficacious in reducing dystonia in cerebral palsy. And as we're building preliminary data for putting, oh, I thought I had frozen that one. Okay, someone getting in the last minute votes there. As we've been building this trial, we did two different preliminary studies for it. One, one of our partners, a movement neurologist was able to access the Cerner database and look at what medications were being used with the diagnosis code for secondary dystonia. And then we also did a provider survey, which some of you might've gotten emails to participate in asking for what medications you had been prescribing for dystonia in cerebral palsy. Josh, you might still be able to squeak it into the word cloud if you want to, but yes, tetrabenazine as well. So when we did that survey, the number one medication that 96% of providers used as first line was Baclofen. And I should point out that that provider survey went to peds rehab physicians, child neurologists, developmental pediatricians, and then a hodgepodge of other physicians who managed CP. So Baclofen was number one. And then the next top five were Levodopa because a lot of people felt strongly that you needed a test to see if it was a dopa-responsive dystonia before you gave up on it. Amongst the benzos, diazepam and clonazepam were an equal tie, I think at like 55% and 56% of people were using it. Partain or trihexapenidyl was high on that list and then gabapentin. So it pretty much follows what you have seen in this word cloud. So we are going to be hoping to test Baclofen and those top five in the study. Unfortunately, I know that there's more drugs than that, but we will be able to at least start there. Okay, so what did the systematic review show? So here in the box outlined in red are the medications that actually had some sort of data behind them or that we knew were commonly being used so they wanted to highlight this. Oral Baclofen, remember 96% of us use this first line, zero studies out there looking at its effect on dystonia. Artin, the favorite drug of all the child neurologists as well as some peds rehab docs, seven studies across the board, little to no difference and there's possible increase in adverse events, which is why the new pathway is going to be advising against using Artin. Now this is with a grain of salt because every child is different, right? So if you've tried every drug and nothing is working, is it worth trying it to see if it's different for this child? Absolutely, there's not enough evidence to say no to that. Benzodiazepines, zero papers. Clonidine, one single study, but it was the most successful out of all of them but also had possible adverse events associated with it. Not a single study looking at gabapentin, only one looking at levodopa specifically in cerebral palsy, which really didn't show much but also didn't show any adverse events or minimal adverse events, so worth trying. And because everyone gets excited about cannabis, no papers. So you can see that it's sort of the wild west when it comes to trialing these drugs, which goes back to even more of a reason why you should think about quantifying it for your patients in some ways, such as the DFIS, the patient reported outcome that I had mentioned, because here you can see you could try all of these and maybe one drug works for one child and one drug works for another child and we don't understand the pathophys just yet, but if you're tracking it, you might actually be able to be like more, trying to think organized with how you're thinking through that process for a child and actually know what's making sense. Now botulinum toxin. So this is FDA approved for cervical dystonia. Interestingly, when it comes to goal achievement, there is possible improvement here, some improvement in pain, some improvement in ease of caregiving, but again, possible risk of side effects, but that's not surprising, right? And I should have pointed out, this is the summary, what's written in text, and then what's here in the plus signs is the certainty of the level of evidence. So you want it to be four plus signs all the way, but obviously a lot of this data is not strong studies, they're not high levels of evidence, so it's hard to get that. But the one grain of salt to think about with botulinum toxin is the data that has been presented by Kerr-Graham and Walter Herzog that shows that there's positive, sorry, there's possible negative impacts of botulinum toxin on accelerating fibrosis and CP muscle, but the data is still very, very early with a lot of it being animal-based, but just something to be keeping in the back of your mind. So to review, especially for trainees who are on this call, botulinum toxin A causes presynaptic blockade of acetylcholine. It provides focal tone reduction, so the idea is that it's affecting only the muscles that you are injecting. The duration of effect is anywhere from three to six months, depending on the product that you're using and what the FDA approval says, although I do feel that this varies child to child. Your big issue here is that you're limited by weight, but it is covered by most insurers and it is FDA approved for cervical dystonia at least. And for people who still have board exams coming up or any MOC, classic PIMP question, botulinum toxin A is binding your SNAP25 vesicular protein and that's why the acetylcholine vesicles are not able to fuse at the synaptic cleft. There are multiple commercial preparations of botulinum toxins available for toxins A. You have Botox, Dysport, and Xeomin, and again, both Botox and Dysport are FDA approved specifically for cervical dystonia. Now, none of these studies or systematic reviews or the guidelines have touched on phenol injections. And having done a practice variation study that's soon to be published on provider use of botulinum toxin and phenol for toad management and cerebral palsy, it really seems like it's us, the rehab physicians who are predominantly using phenol injections. For those of you who are at centers that don't use phenol, because I know there are a few out there, phenol was around for long, long, long periods of time and they existed pre botulinum toxins. So this used to be how we would be targeting muscles, sorry, targeting nerves to be able to relax specific muscles and get focal tone management. So it causes a neurolytic injury up to the target nerves. You can't use it on nerves that have sensory input, otherwise you end up with a dysesthesia. So classically, you're thinking about using it for the musculocutaneous to the biceps, the obturator to the hip adductors, sciatic nerve to the hamstrings. You can also use it for the tibial nerve, but you need to make sure that you're distal to any sensory branches. The effect is longer because you're causing this neurolytic injury, thought to last about six months, not limited by weight, covered by most insurances and most places dirt cheap. There are some places that we started to hear were having really high costs associated with phenol and compounding it, storing it. But I think I could be totally wrong on this, but I feel that most of those issues have resolved. Now, last but not least is neurosurgical tone options for dystonia. So this is where we get into intrathecal baclofen and deep brain stimulation. And where you see here is obviously there's a lot of studies that have been done on both of these at this point. So intrathecal baclofen, interestingly, has all these areas where it might make improvements. However, when you look at motor function, little to no difference. And I highlight this because there's so many families that go into getting a pump, thinking that it's going to be that tipping point that changes some motoric outcome for their child. I think many of us have had patients that are still holding onto hope for walking, even when their GMF-CS4 or five. So this is something to keep in mind as you're counseling your patients. What a lot of people don't realize is, remember, these are studies, the studies they included here are specifically for cerebral palsy, not the genetic dystonias. And here, these studies across the board may improve in all of these categories. So, and it actually has about the same adverse event profile. Interestingly, some of these studies, they don't talk about it in this review. Some of the deep brain stimulation studies show that there's less impact on worsening axial hypotonia when you use deep brain stimulation. So something to think about as well. So, another poll. For the statement, intrathecal baclofen is an effective way to control dystonia. I want to know if you 100% believe that. If you think, meh, it's hit or miss, depends on the kid, choice B. No, you don't really think it does much, but there's really no alternative, so it's worth trying. Or no, you think it's actually useless and you don't even counsel patients that it's going to affect their dystonia, you just focus on their spasticity. Jolene, I see the question, I'm getting there. Okay. Let's see if a couple more are going to chime in here. We won't judge you if you're an early adopter and you're going to choose D. Yes, we have Dr. Vova commenting, or choice F, if you use it early enough, it's better. Also, a very interesting commentary between intrathecal baclofen and DBS, which we can talk about. All right. We're going to call it here. Looks like significant majority of us see that it's variable. That some kids, it's an amazing tool, and then other kids, you just don't get a good response. You have Jolene Brandenburg, Dr. Brandenburg, commenting on a huge hassle factor associated with intrathecal baclofen. Absolutely. Again, this is more geared towards the trainees than those who are already in practice, but intrathecal baclofen is used for global tone reduction when you have severe spasticity and dystonia. Again, not FDA indicated for dystonia, FDA approved for spasticity. The idea is that by delivering baclofen intrathecally, you are getting across the blood-brain barrier. You can use much lower doses of it. One-thousandth the dose of what you're taking by mouth and have more effect. You can control what areas are being relaxed based off of the catheter placement. You can think of this as similar to a traditional garden hose where the tip is where the baclofen sprays out. It's not that this is sprinkled like a kid's water toy, where there's spray coming out all over. It's not like a garden sprinkler system. Where you set the tip, the idea is that it might go a couple levels above, but not really hitting much higher than that. But you can place that catheter anywhere along the spine, cervical, thoracic, high lumbar. You can even go intraventricular or go into the foramen magnum. There's questions as to, are you changing the targets of where that baclofen is working? Very serious question. Not something that has been well-studied, but something to know about this. Now, why would you be doing this? Improving functional mobility. I just told you in the systematic review that intrathecal baclofen is not shown to improve function. However, if you're using intrathecal baclofen in ambulatory child who has significant dystonia who would otherwise not be eligible for something like a selective dorsal rhizotomy, then it's possible maybe you would improve gait characteristics. Something to think about there. You want to improve comfort and ease of caregiving, improving positioning, but it's not going to change if you already have fixed musculoskeletal deformities. Another big question of how early do you want to use this? One of the reasons to think about intrathecal baclofen is that you might unmask weakness when you take away that tone. You can titrate with intrathecal baclofen, so you can back off or take more away depending on what you see. Now, this is what Dr. Brandenburg mentioned in the chat, the ventral dorsal rhizotomy or palliative rhizotomy. I am a huge fan of this procedure. It is still something that is highly debated amongst our neurosurgeons. Our neurosurgeons here do like doing this for the right patient population. I assume that most people on this call are familiar with selective dorsal rhizotomies, where the idea is that you have this aberrant reflex loop going on in the sensory rootlets that causes spasticity. Neurosurgeons can go in, section the root into rootlets, and then they can further section some of these that are considered the most abnormal and therefore eliminates spasticity. Now, if you also cut ventral motor roots, you are permanently weakening the muscle, but now that muscle is not available to participate in a dystonic contraction. You can also eliminate dystonia. Now, if you are cutting out the motor roots and the sensory roots, you're getting rid of spasticity and dystonia, but you're also leaving the child essentially flaccid in their lower extremities. This is really something to be thinking about in the GMF-CS5 population, where they're 100 percent dependent on their caregivers for mobility. This is where you're really thinking about pain and ease of caregiving and comfort. For the right population, this is an excellent choice. Again, not enough data or anything to be talked about in any of these pathways or any of the systematic reviews. Then finally, deep brain stimulation, originally thought to be for genetic origin dystonia, things like the DYT1 mutation, classic responders to deep brain stimulation, but now being used for secondary dystonia. Tell me what you guys are doing at your institutions. Your first option is, no way, Dr. Thomas is taking crazy pills, why would we do that? B, being you've thought about it but haven't tried it. C, being that you've tried it in the child who has not had good results with ITP. Then finally, you're using it as first line in a sub-population of patients. Go for it. Oh, someone was about to be, oh, there it is. I was wondering about D because I know there's a couple of centers out there. Oh, someone else chiming in for D. Oh, this is getting very interesting. All right, giving it 10 more seconds. And we're going, okay. Wow, I'm not gonna lie. We had, I had just, what, two years ago, still where I'm working on writing it up, sorry guys, done a practice variation study looking at the use of ITV, dystonia and rhizotomy, especially in non-ambulatory children with mixed tone. And we were finding that only a handful of centers were really using it as first line. So I know that Gillette had a couple of centers Gillette had some patients that they were choosing, Sick Kids in Toronto was choosing some as first line, but that most people generally fell in B and C. I can tell you at Texas Children's, we fall in the C category and are working on going to the D category. For those of you who are using it as first line, if you feel comfortable putting it in the chat or unmuting, I would love to hear what populations you are using it in. Okay, I'll let people put it in the chat if they feel confident. But for those of you who are less familiar with DBS, essentially a neurosurgeon is placing a lead into the area that is thought to be affected in the network or a downstream or upstream area from the area of insult. And then they snake these wires similar to a VP shunt subcutaneously, and then it connects to a stimulator pack that's in the chest like a defibrillator. Then this is able to be titrated just like an ITV pump, but it's a little bit more sophisticated than just choosing a dose. You can choose pulse width, pulse frequency. There's a few ways that you can program these. And the idea is that you can then block the aberrant signals coming out of the injured area of the brain. The classic area that was typically implanted for dystonia is the globus pallidus internus. However, this is an area that's usually the injured part in our children who have cerebral palsy, especially if they've had a hypoxic ischemic injury. So what a lot of neurosurgeons or centers are trying to do is go after thalamic inputs or subthalamic nuclei inputs. I'd be curious if anyone is trying other nuclei outside of that. I'd heard some rumors about red nuclei in Europe, but I know that our neurosurgeon has not tried it here yet. So last but not least, when should you be thinking about the neurosurgical interventions? When you're not getting adequate control with enteral medications and injections, if there's intolerance to medications and injections, if you have clear goals for further intervention, if you're trying to prevent orthopedic deformities or perhaps make sure that the orthopedic surgeries that do happen have a higher success rate, if you think that you can prevent the need for repeated medications and injections, but also very important to think about access to care. As Dr. Brandenburg was pointing out, ITP can be quite the hassle. So can TBS as you're going through that titration process. So if you have a patient who would also be eligible for something like a ventral dorsal rhizotomy or palliative rhizotomy, something to think about because that's a one and done intervention. The other key thing that people were hinting at in the chat, you want to be doing this early. So you want minimal to moderate contractures because if they're already severely contracted, you might be able to impact things like pain and some comfort, but you're not gonna make much difference in other areas. And I do see Dr. Boba saying that pre-pandemic, they started looking into it as far as TBS goes. And yes, I think it would be really interesting to see what others are thinking. And then for those who can't see the chat, Dr. Brandenburg has added that dyskinetic CP involving whole body or upper extremity or had a palliative rhizotomy and still has lots of tone, but not many families elect to pursue, but it's increasing there at Mayo. They have a strong adult program, so it's trickling down, but it's a big commitment from the family. Agreed. So we have just a few minutes left. I am happy to take any questions you might have. And I can also read out these questions in the chat. So I have Don Dikey mentioning that they have a multi-DPMNR movement neurology therapies clinic for surgical tone management, which I love. We have that here as well. And the neurologists there are pushing for when patients with lesions identified causing dystonia for electrode placement, but they have not seen one get implanted yet. And that's sort of where we're at right now about trying to decide on areas that lesions, like areas to target. I will say that there is a subgroup within the CPA research network that is looking at this and part of that group as well so that we can have better guidance in how to target. And it looks like Dr. Brandenburg again, I used to believe that they had to have a targeted lesion too so you held off. Yes, okay. And Dr. Akamaguna, how do you propose incorporating some of those family patient reported outcomes into our clinical practice? The way that I would like to do it as the intrathecal back lip and pump program director here, I am hoping that we can use it pre-implantation so that we have an idea of what the family's goals are so we can make sure that we're really capturing that as we work on titrating the pump dose because we might be seeing something as the provider as being the primary problem, but then you talk to the family and they don't care about what we're seeing. We're seeing them having trouble fitting in the wheelchair. They're like, dude, we just want them to be able to sleep well at night. The dystonia is getting in the way and they can't sleep. So that way we're targeting the right thing. So, and it's a patient reported outcome. So if it's able to be built into my chart, if you have an Epic, sorry, if you're on something that's not Epic, but it's something that could even be sent out as part of the pre-check-in. It's 18 questions, but it's actually not that bad to fill out. I think the first time the family does it, it might be difficult. If there was a way to build it where the family knows what they clicked the last time and then they can just update if they think that there's been any changes, then that would be a time saver as well. But I think that would be the best way to start. Honestly, just knowing where individuals are scoring on the DFIS as we start to treat them is useful to know. Are we just treating really low level dystonia or are we just treating everybody who's got really severe dystonia and ignoring other populations and so forth? So that's what I would think. All right, awesome. Thanks guys. All right, we're right at the one o'clock hour. I'm happy to stay on for a couple of minutes if others have questions that you want answered. Otherwise I will let you get back to your day. Sridhi, this is Didem. Hey Didem, how are you? Hi, I'm doing great. Thank you for this wonderful, wonderful talk. Quick question, not a question, but maybe a comment. I am somewhat disappointed to hear 3-hexafenadil artanase going away because honestly, my personal experience in the last 20 plus years, I get better results with using artane versus baclofen. I've had some results to gabapentin and for the last five, six years, I've been trying that as a first line when it's the mixed tone or dystonia being more predominant. But now I'll have a harder time justifying use of this one medication that I feel is more helpful in my medically complex population, where I'm always feel like I'm challenged by our hospitalists or pediatricians when it comes to me starting medications. So just curious, what are your thoughts on how should we approach this? Yes, well, I'm hoping that we can get our multi-site trial going because we've heard this from so many people after we did that survey that we felt that we had to include artane in a trial because there's, I think that all of the data that's out there, none of those studies are massive RCTs. They're all small studies. Most of them are observational, but there are some adverse events that the movement neurologists were seeing as they were using artane to a higher degree than any other group. Excuse me. So I think that's what gave them pause when they, yep, and I see Susan McDowell commenting that you have to be willing to push the dose of the artane and manage the side effects. And exactly, it's that give and take, right? And that's why I said, take everything with a grain of salt because I can think for every drug where I'm like, that didn't work in this child, I can think of another child where it might've actually made a difference in the eye of that family and the patient. But I do believe that there was enough evidence against artane that the new guideline is going to be saying that they recommend not using it. But there's enough naysayers that we felt strongly that it needed to be in the actual trial. So we are taking that into account. And I'm waiting to hear the results. So thank you for all the good research. One question I had from in-house counsel is a question about peripheral nerectomy coming to us from Dr. Gabby Wynn, who's on the couch over here. So there is some interesting data that was being presented to ACPDM as well as in some of the orthopedic conferences and I think plastic surgery conferences as well about using highly selective peripheral nerectomies for tone management, including both spasticity and dystonia. I don't know if anyone has gotten into that territory. Oh, you were actually very early for being on trial site. Dawn, we have you in mind. We are at the point of just trying to find a mechanism. Like, sorry, when I say mechanism, not a dystonia mechanism, I mean a grant mechanism. We're running into a tricky territory because we think of this as within appropriate comparative effectiveness research. However, when you go to comparative effectiveness mechanisms because there's no efficacy data for the majority of these drugs and it's not FDA approved, they don't consider it effectiveness or they don't think that an effectiveness study is appropriate. So we're running into some issues with that because we're probably going to have to set it up as efficacy. But yeah, okay. But yes, please stay posted because we're hoping that we would be able to get that trial submitted within the next year. So hopefully enrolling in the next two years. So something to keep in mind. It is going to be a pretty big undertaking with a lot of sites. So something we would need a lot of participation in. All right. Don't think anyone else had any thoughts about the peripheral anorectomy, but that can perhaps be a separate talk then. Would love to hear people's ideas there. But thank you guys so much for joining. Bye again. Thank you. Thank you guys.

Dr. Shruti Thomas

dystonia management

abnormal muscular contractions

voluntary movement

network phenomenon

motor and sensory inputs

treatment options

deep brain stimulation

cerebral palsy-related dystonia

patient-reported outcomes