Hi everyone, thanks for being here today. Welcome to the Pediatric Rehab Medicine Lecture Series. So today we're really excited about a topic pretty relevant to a lot of folks' practice, so the other half of spasticity with Dr. Ray Stanford. So he's coming to us from Phoenix Children's Hospital and he has asked that if you guys have questions, you can put them in the chat or you can put them in the Q&A. Megan and I are going to be monitoring that and then at the end we can ask those questions for Dr. Stanford. So without further ado, I'm going to pass it along to him and we can take it from there. Thanks so much. All right, thanks again for this opportunity. This is a topic that's very interesting to me. It's still heavily under research right now, so there's still a lot of things in the work but I think these things have a lot of potential and it's some interesting topics I think that's important for anybody that treats spasticity or injects Botox or other phenol ethanol, things like that, something good to keep in mind. And I'll explain the title and everything, but basically the focus is on soft tissue changes that we see with upper motor neuron diseases. Just as disclosures, I will be talking about some off-label uses, specifically with the medication of hyaluronidase and collagenase. So my main objectives like I said are to explain cellular changes that we see in soft tissue with the immobility from upper motor neuron diseases and then I'd like to go over some research that, some investigations on what we can do with these biochemical explanations to try to improve range of motion. And just as a spoiler alert, just to not leave it until there's a big climax at the end, the reason that I'm so interested in this is because we do know that Botox or other botulinum toxins, although they can improve range of motion, they can also cause weakness. So in a patient with for example cerebral palsy or recovering from a stroke, we're trying to improve strength and things like that and paradoxically we're weakening the muscle. Or also things like muscle relaxers like Botox or Baclofen or Tezanidine if we're giving a really high dose it can cause sedation. So the fascinating thing that I, the reason I'm so interested in this subject is because if we can target these soft tissue changes, what's going on with the biochemical alterations with these, then in theory it shouldn't cause any weakness and definitely no sedation. So if we can figure these things out I think they have a lot of potential to help out our patients. But going back to my first objective I want to talk a little bit more about soft tissue changes and why it's called the other half of spasticity. I call it the other half of spasticity because whenever we're talking about spasticity we focus a lot on the neurologic side of things. So this is just a little shout out to my classmates in residency. So in residency we learned a lot about how to treat spasticity and to no fault of it I think they did a great job at teaching us, but the focus was quite a bit on the neurologic side. Upper motor neuron damage leads to, just to summarize it very basically that uninhibited unopposed stretch reflex leads to spasticity. We can target those upper motor neuron issues, the neurologic issues by blocking GABA-AARB, blocking semacolonial altitude. We know the mechanisms of all the muscle relaxers that we use target the nerve side of things. So another thing that was mentioned a lot in residency was untreated spasticity can lead to contractures if we focus on reducing the spasticity, reduce the risk of developing contractures. Sorry I have these little reaction shots here. I'm sure a lot of people are looking at the camera here, so just some little reaction shots to give some context because this is how I felt in residency. I was very confused because I started seeing some patients that had contractures that didn't have some kind of neurologic disorder. Perfect case is an amputee, somebody that has an amputation. We can say it's traumatic so it wasn't even from diabetes or something because you could have some neurologic changes from the diabetes, but we can say it's traumatic. There was no neurologic injury at all. And I'm sure plenty of you saw this in your prosthetics clinic, there's a patient that comes back, lost a follow-up, hasn't been seen in a long time, they come in with a knee contracture because they've been sitting in a wheelchair most of the day. I started wondering what is actually happening in their muscles? Why is that getting stiff? It's nothing new. Everybody knows that if you don't move a joint around it's going to get stiff. So that just made me think of we see the contraction of the upper motor neuron, contractures without upper motor neuron. One of the keys was time. It takes some time to develop, but another commonality is immobility. So just that lack of continuous motion we see leads to a contraction. So here we go, sorry I just have some of this extra stuff to make it more interesting, but that made me think is how much of this resistance, the range of motion that I'm feeling in a patient that had a stroke or cerebral palsy or something like that, how much is this resistance true uninhibited stretch reflex spasticity and then how much is that just from changes seen from immobility from disuse? Obviously that's a very open-ended question and it's going to be hard to be able to piece that out, but it made me wonder how much of soft tissue changes are contributing to this range of motion. So we do know that there are soft tissue changes in multiple areas. We see changes in muscle, we know that there's muscle shortening, that there's tendon shortening, we know that. We can see joint capsule adhesions, so those are just some basic things. I won't go into too much of those specifics, but what I want to focus on is connective tissue changes. This is a review, the connective tissue has a lot of different layers especially in a muscle cell. We have all the different groupings of muscles and there's connective tissue in between each one of these. So the muscle fibers we know they all don't contract at once so that means that they have to slide on each other and they have to have some connective tissue around to be able to slide along each other. So what's keeping them sliding well, is there some kind of lubricant? So obviously there is, hyaluronic acid is a very important one of these that I want to talk about. So pretty recently there was a new type of cell, the fasciocyte was described, the paper was in 2018. They were able to find a cell that seems to be, they ended up calling fasciocyte, they found it in the connective tissues. They see this hazy stuff around the cell is the hyaluronic acid, that's how you get the glycosylic acids show up. So they could see that this cell here was actually producing the hyaluronic acid. So we could just picture these little molecules in between all of the connective tissue surrounding the muscle fibers to help lubricate it. And there have been studies looking into hyaluronic acid and its correlation with immobility because we have found that hyaluronic acid actually builds up with immobility and there's a special MRI series that they've been able to find. For example, on the top part of here the control is a normal patient without a normalized arm. The more red there is, the more hyaluronic acid there is. So after a stroke they found there's a lot more hyaluronic acid buildup. So what's the big deal about having more oil? It's not like just adding more grease or more lubricant, things start to change when the hyaluronic acid builds up. So that's something that I'm really interested in. So indulge me here, we're going to do a little science experiment to explain all of this and try to make it more tangible because there's a lot of physics involved here. I'll admit I do have a little bit of an engineering background so I hope this isn't too complicated, but I just wanted to make this, to explain this in a way that isn't too complicated. So hyaluronic acid actually has a lot of uses and it's all over the body. It's in the extracellular matrix, it's in connective tissue, fascia, cartilage, synovial fluid, and the first thing that might come to mind when you hear the word hyaluronic acid is the VSCO supplementation that we do for knee injections. There's a lot of different brands and that was definitely the first thing that came to mind when I heard of hyaluronic acid. Hyaluronic acid is actually also used as cosmetic fillers as well. So we're seeing that it's extremely versatile, you know like how does it do all these different things, and the key is it's a non-Newtonian fluid. So stay with me here, I hope I don't lose too many people talking about physics. This is my undergrad physics book so we're going to go into a little bit of it here. If you just remember the different states of matter, gas, liquid, solid, those are the basic states and we all know that some things don't fit exactly in those three categories. So if there's anything, so a fluid that doesn't fit exactly into the Newtonian definition of a fluid, we call non-Newtonian. So it has some properties that are a little different than a typical fluid that we would say that we would expect. So the classic non-Newtonian fluid is you mix cornstarch with water and then you get this very strange substance that when it doesn't have any pressure applied to it, it acts like a liquid where it can run through this person's fingers and drip down into the bowl, but when you squeeze it, it's a solid and because of that, they can mix in with water and you can actually run across it because you're putting enough pressure on with your feet that it will actually act as a solid, but without the pressure, it will act like a liquid. So I wanted to try this out myself and see how that worked. So I made my own cornstarch experiment. So sorry if this toy has like some image copyrights or something, I just grabbed one of my kid's toys to demonstrate this. So I started out with a pretty low concentration of cornstarch. It's just five mils of cornstarch and water and I pushed it along this plate and it's actually pretty slick. So I'm assuming that's kind of like a hyaluronic acid at a low concentration. We see that it's a good lubricant. So I gradually increased the amount of cornstarch. This is three, four mils, so we have a lot more concentrated and you can see the toy doesn't slide quite as well. It kind of gets stuck. And then this other picture I'm showing on the other side is me trying to do that video of the person squishing it and making it into a solid. Even though you see that it's already providing some resistance to the toy, it's actually still pretty liquid. It runs through my fingers pretty fast. So I was increasing the concentration quite a bit and I wasn't still getting anywhere close to that video of the person being able to squeeze it. So I poured my entire bottle of cornstarch in and mixed it all in and even with my entire bottle, I still didn't get to that amount it takes to squeeze it and form a solid. You can see that it doesn't run through my fingers quite as well, but it still does a little bit. You can see when I push the toy, it completely gets stuck. So you could imagine an immobilized muscle accumulating hyaluronic acid and just not sliding, the different fibers not sliding as well. I mean, if you could imagine a substance like Synbis or Orthobis, or what's the one that's like a... Sorry, I have a resident here. What's the one that's like a one injection, like Synbis one? I don't know if any of you have injected that, but it's hard to push it in. You have to go slow because if you try to slam it in, it's a non-Newtonian fluid. It's not going to go in. You have to go slow and it's very stiff. There's very viscous to put in. So if you could imagine a fluid like that building up in the muscles, it's not going to be flowing. It's not going to be a smooth motion. So I don't want to lose too many people here and I promise I'm not showing a bunch of graphs or anything. I just wanted to let you know that the study of non-Newtonian fluids and their properties, how they change is called rheology. And just as a basic example here, they have a rheologic properties of tomato paste and you can just see that as the tomato juice is a lot less concentrated. There's not as much of the tomato pulp and everything in it. So it's not going to have as much resistance versus tomato paste as it becomes. There's more things dissolved in the fluid and like my experiment showed, the more concentrated it is, the more of these rheologic changes we start to see under pressure. You can get similar graphs and there's very technical papers that are way over my head explaining the rheologic properties of hyaluronic acid. But it's interesting because this is really nothing new, but I did not hear a lot of people talking about it in my training because if you look back in the literature, even in 1997, that Meyer talked about the rheologic changes in chronic spasticity. So people have been thinking about this for a while and I think there's definitely a validity of paying a little bit more attention to it. And then this is another very interesting thing. So it goes back to my thought of we're seeing resistance to stretch in a patient that might not be, for example, they're right hemiplegic cerebral palsy, they're not using the right arm a whole lot, it's not moving a lot, sure they definitely have an upper motor neuron injury and they could have that spasticity, but how much of this resistance to stretch is also from a soft tissue change? And if we're talking about a velocity-dependent stretch, we know that hyaluronic acid under more forces when it's built up in concentration is going to cause more resistance. Kind of sounds like a velocity-dependent stretch there also. So this goes into a hypothesis that's been described as the hyaluronan hypothesis, hyaluronan is just another name for hyaluronic acid. And like I said, it's the hypothesis that immobility that we've seen with the MRI findings has an accumulation of hyaluronic acid and you can have these cartoons here of it forming around the muscle fibers and eventually leading to fibrosis. The theory on why it accumulates, I haven't been able to find an exact explanation or an in-depth study on trying to figure out exactly why it's accumulating. One theory is that it's due to decreased lymphatic turnover. It's just pooling in there, it doesn't have anywhere to go. Maybe the muscles moving around helps cycle it through so it doesn't build up. So we also know that inflammation and mobility and muscle stiffness initiates this fibrosis pattern. And the hyaluronic acid is actually replaced by collagen. That leads to thickened, you know, all the different muscle layers and we also see much muscle atrophy with this. So one of the thoughts of this hyaluronan hypothesis is that the stage between A, like a normal muscle fiber, and B with an accumulation before it gets to C with fibrosis, can we get rid of this buildup of hyaluronic acid and get back to A? So we do have medication that cleaves hyaluronic acid. So there's hyaluronidase, which is FDA approved to increase tissue permeability, I mean that's exactly what we're talking about. It's going to lyse the hyaluronic acid that we see in so many other tissues and it's going to be able to make other medications be able to permeate a lot better. It's used with chemotherapy so that it has the FDA approval for that. So of course if we're going to inject it into spastic muscle that's off-label and it's still under review and being studied, but there was a pilot study that had injected hyaluronidase. It was a smaller study though, the pilot study being 20 patients, but it was injected multiple sites. The results of that study, there were no adverse effects and they saw that 78% had a reduction of approximately 2 points at 2 weeks of the modified ASHRAE scale. They also saw that treatment remained over about 3 months. I don't remember off the top of my head how long the follow-up was, but they were able to at least report these findings. A different study was injecting hyaluronidase. This is the same study that I showed earlier showing the MRI findings, but they demonstrated that with injecting hyaluronidase into biceps and triceps they saw a reduction. I'm not sure exactly why they said, about the outcomes they said the biceps showed a significant difference, but they didn't see a significant difference in the triceps, but they were able to show that the biceps had a significant change. Oh wait, sorry, that was the control slide, so here's the pre- and post-injection slide here. I'm sorry, I have a lot of these question slides and a lot of the intent of this lecture is just to get people thinking about how soft tissue changes affect patients, loss of mobility, loss of function, things like that. One of these other thoughts that I had is we see range of motion as one of the huge mainstays to improving function, just basic passive range of motion with our therapists, with the patients doing a home exercise program. Definitely during the height of the pandemic when our patients were at home getting teletherapy and they weren't getting as rigorous therapies, I saw so many patients with this range of motion. So we know that this is an essential part of treatment, but if we know that immobility leads to increased hyaluronic acid, is mobilizing people, keeping them moving, is that another way that we can prevent the accumulation or maybe decrease some of that hyaluronic acid, so is that maybe an explanation for, another explanation for why it's so important to keep these sort of treatments, the range of motion treatments. Now this is another burning question that I have. So in the other studies with hyaluronidase, we talk about going from A to B, normal muscle muscle stiffness, which is an increase, but the theory was once you get the fibrosis, that's it, the muscles are better and it's two ways, so if you want to do a hyaluronidase injection earlier on before you get the fibrosis, but there are some other thoughts about what you can actually do with more fibrotic muscle, increased stiffness, stiff muscles have an increased amount of type 1 collagen in the extracellular matrix. So I'm not going to get into molecular biology like we did with our physics textbook, we don't have to dive in deep about all the different collagen fibers, but we do know that a large amount of the passive load on muscles is taken by the extracellular matrix and the stiffness of the entire muscle, it becomes more stiff when there is a higher collagen content. So if a stiff muscle is accumulating this collagen and it's becoming less mobile, can we do something to get rid of that collagen? So you may be familiar with collagenase injection, it's FDA approved for Dupuytren's contractures and I've heard it works very well for that, but what was interesting to me is that it's actually also approved for Peyronie's disease, so it's being used in more applications than just Dupuytren's contractures because I always was wondering like if we inject it into the muscle, what is it exactly going to do because in Dupuytren's we're putting it right in the tendon sheath, so it's a pretty confined space, but it's been used in Peyronie's disease which is not as confined of a space. And so a key about the collagenase is it doesn't destroy all of the collagen. It only does type 1 and type 3 and it seems to pretty much preserve type 4 collagen. So type 3 and type 1, they're in those connective tissue layers, the endomysium and the paramecium, but a key is that the sarcolemma, the actual cell membrane of the muscle cell is primarily composed of type 4 and type 5. So when I first thought about it, if we inject collagenase into a muscle is it just going to splice everything and destroy the cell, but possibly, I mean from what we know, it would be more of that type 1 and type 3 that we see with the muscle stiffness and it should be good for the muscle cell. Also we do know a little bit about how it's going to diffuse. Like I said, this is all very theoretical, but you should definitely be thinking about what's going to happen if I inject something that destroys collagen to muscle fiber, absolutely. So I was just talking about the diffusion of collagenase and there was a study about using it in uterine fibroids, so even though it's not skeletal muscle, they do know that it has been pretty effective for treating fibroids and that it has a good diffusion to the fibroids. That wraps everything up for me, so I'm glad that it wasn't cutting out too much maybe just at the end. I did want to explain that even though I ran out of all of the cornstarch and being a poor fellow's budget, I didn't go out and buy more cornstarch. I was able to actually decant some of the water off and I was able to make it thick enough to be able to squeeze it and form it into a solid and then you can see when I stop squeezing it, it just slips through my fingers. If you want to try this at home, I mean if you have kids, I'm sure they'll love it, but definitely do it outside because even though you're pouring cornstarch in the water, you think it'll stay and it gets cornstarch all over your house and for days we're finding it everywhere. Hopefully that sparked some interest and gets you all thinking about exactly what we're seeing when a patient starts to develop stiffness in their muscles, resistance with range of motion, and I'm really interested to find out about applications of collagenase. There was a paper that was published in 2019. I know that's not too long ago, especially in the research world, but I've been really waiting to find out if somebody has started at least a pilot study to see what the effects would be. So these are my references and then they wanted me to put my contact information, so I'm happy to answer any questions if anybody's watching this after the fact and they want to email me, feel free to reach out. This is my work email, which I'm checking more frequently, but yeah, and if anybody wants to collaborate on some research on any of this, I'd be very interested. All right, are there any questions? Perfect. No questions so far, but if anyone has questions, go ahead and put those in the chat or in the Q&A. I think you bring up some interesting food for thought for sure for folks and kind of thinking a little bit more deeply on the topic. So I know we have a decent number of people on. If anyone does have questions, go ahead and put those in the chat or the Q&A. In the meantime, just a reminder that you can get TME credit for this, and so if you go on the APMNR website, you'll be able to claim it there. So we do have a question that just came through. So would you be able to pass along some of these references as folks are interested in learning more or show the reference slide so someone can screenshot it super fast? So I know we have been able, Megan, you can kind of speak to it more, we have been able to kind of upload additional resources. This one down here is, wait, no, not the Menin one. Yeah, we can speak about uploading it, but this one right here, Howard, injecting the collagenase, I mean, we haven't actually injected it, but they did a lot of the literature review seeing what would potentially happen if we did it and then make it sound like theoretically it could be safe to do. And then, that was a good one for that. If there's a question about the hyaluronidase study, Dr. Raghavan has been doing a lot of that research, so she has several papers on that as well. Excellent, yeah, I think that... Oh, sorry, you're on mute, Mary. Thought I pressed it, sorry about that, thank you. So I said it's a very interesting topic, so we have another comment, just kudos for reminding folks that there are issues of contractions, spasticity and contracture, loss of length and or elasticity of soft tissues. So, some gratitude. All right, yeah, you know, and when I'm teaching residents, it's very common for them to when I'm teaching residents, it's very common we'll see a patient and they'll have some spasticity and so I'll say, okay, what do you think is going on here? And the first thing they always talk about is upper motor neuron damage, you know, uninhibited reflex arc, they have spasticity, but I'll show them, I'll say like, well, it's pretty early on and they've had their arm like this for a week now, you know, there's something else going on here too. We got to focus on range of motion and make sure there's positioning, so. Great, and Megan just commented that we can upload the references to the online learning portal. I'm guessing there's been several other people that are going to be interested too and if you're cool with that. Yeah, I think that Howard article is really good, one of the Ragavan articles is really good and then I have another one that was a really good literature view on the soft tissue changes that we see after with immobility, so yeah, I'd be happy to load those up. Perfect. It looks like no other questions right now, so thank you so much for really letting us all kind of think a little bit more about topics that we probably haven't been thinking about as much, which is great and giving us a little information about some stuff to read more about. So, thank you so much and thanks to everyone who's here and hope everyone has a good rest of your day. Oh, there's one more quick. Just came through right at the end here. Yeah. So, when ViaFlex first came out, it seems like the perfect way to perform non-invasive tenotomy, but I could not get any drugs from the company. Has anyone looked at that? Okay, so that is a good question. Yeah, I don't know. Let's see, that's definitely something that's a great idea. I was going to put it in this presentation, but I forgot. I remember looking up the cost difference between ViaFlex and like Botox or Dysport and I remember it being a lot more, so I'm wondering if that's another limiting factor to some of these studies. Thanks. All right, you guys. Well, thank you so much again. Claim your credit online and then do you want to just put your email slide up there one more time so folks can reach out? Perfect. All right. Thank you guys again. Hope everyone has a good rest of your day. All right. Thanks, guys.

soft tissue changes

upper motor neuron diseases

spasticity

immobility

hyaluronic acid

fibrosis

range of motion