presentation today. Hello everybody and welcome to our presentation today. We're very excited to talk about the top papers in pediatric rehab medicine. This has been an long-going annual tradition at the AAPMNR annual assembly and we greatly appreciate the AAPMNR support in allowing us to do this. Talking about some people who have previously presented at this presentation are just absolute giants in the field, including people like Amy Houtrow or Stacy Suskow or Sue Apkon in Colorado. We have some other people like Molly Fuentes and Mike Green who have worked on this in the past, Justin Burton and Stacy Stibb. And then this year, very fortunate as last year, to be joined by my co-presenters Dr. Mary Dubon and Dr. Saruthi Thomas out of Boston and Houston respectively. Houston is one of those cities that I absolutely love visiting and they always brag about their weather like they were doing yesterday, their community session day. I didn't hear Mary bragging about the weather in Boston unfortunately, but I absolutely appreciate the work that both of them put in into this presentation and hope that we find some of the best articles in pediatric rehab medicine that we're able to talk about today. So with all of that being said, I'm Matt McLaughlin and this is my portion of the presentation. We ask that people during this presentation please try to keep your microphone muted. If you'd like to have your camera on during times, you're welcome to do so. We will be having enough time at the end of this presentation for some question and answer sessions as long as I don't speak so long that we don't have any time for any question and answer to occur. But please place your question and answer in the chat feature and I'll be monitoring those which we will address kind of at the end of all three of our presentations as we have a firm cutoff of 60 minutes for this presentation to occur. So we hope we're able to address and answer as many of the questions as we can, but please feel free to engage and interact in that way and talk back and forth to different people during these presentations. This is solely articles that we have chosen that are related to what we feel would be high implications for clinical practice and that was one of the main metrics that we utilized as to whether or not an article could or should or should not be included. The methods that we did and as researchers or all of us are researchers, so we greatly appreciate the methodology and how we did this. We systematically reviewed articles from the top pediatric and PM&R journals. Approximately 12 journals were always included, so we reviewed the last issues from June of last year to June of the next year. That allows us enough time to review the articles in full that we feel like the abstracts are reasonable enough to continue to review and then cross-reference these with other article searches that we have on roughly the 12 to 13 top diagnoses we feel that occur in pediatric rehab medicine. As this is a research, top research article presentation, we try to focus as much as we can on original research and try to limit the amount of systematic reviews or other types of reviews, articles that we don't feel are as original as research and so that's primarily why we focus on the original research in general. Once we select all of the abstracts, we look at those. We had 88 abstracts that we reviewed as a group this year and individually each one of us ordinarily ranked those abstracts between one being a lower quality article, five being the highest quality of article, and then from that we ranked them and I essentially included the top 12 to 13 articles of those as articles that we would consider and reviewed the entirety of those manuscripts to decrease this number down to six today to present which was one of the comments that was received at the last top papers presentation was that we'd like to have fewer articles but more in depth and so we hope that we're able to accomplish that task this year. You see the numbers down there at the very very bottom which makes me extremely happy. These are the average scores that we all ranked the articles from one to five. I was 3.8, Mary is 3.09, Sruthi was the closest to being as average as possible with this as you can see her score there but one thing to note is that we all got better compared to the year prior when Mary was the harshest at that time but as you can see Mary is also still the harshest or excuse me, Sruthi is the harshest technically I guess right but she's also the most mean and unbiased. So with all that being said, the honorable mention articles that we did not select unfortunately for presentation today but those that I know many people always continually ask about and sometimes utilize for journal clubs at their own individual institutions are the the six articles here that were within the top 12 that we did not actually select for presentation today. Two or three of those actually are on cerebral palsy, one of those is on Duchenne muscular dystrophy, another on concussion, and another on limb differences and as you can see what we try to do also is ensure that we're not solely presenting on one singular topic during the entirety of the presentation as this is not a top papers in cerebral palsy or top papers in myelomeningocele, this is a top papers in pediatric rehab. At the very bottom there is an article of interest that I thought was extremely fascinating which was slackline training in children with spastic cerebral palsy which was a randomized trial out of Spain. I thought it was extremely fascinating that they got kids to do slackline because I've tried to watch people do that and all I do is have an increased heart rate, increased respiratory rate and feel like unfortunately that person may end up going to our emergency department after trying a slackline because I know I certainly would be going into emergency department after that but with that being said those were the articles that unfortunately did not make the top six that we are going to present about today but the top articles that we will talk about or at least I will specifically talk about is an assessment of cognitive and neural recovery in survivors of pediatric brain injuries in a pilot clinical trial utilizing metformin and then the second article I'm going to present about today is incobotulinum toxin A for treatment of lower limb spasticity in children and adolescents with cerebral palsy which was a phase three study. The first article we're going to talk about is an article talking about the cognitive and neural function of neural cognitive and neural recovery in survivors of pediatric brain tumors in this pilot clinical trial utilizing metformin and this was published within Nature Medicine which I believe has an impact factor in like the 50s something unbelievable so it's nice to see an article that has some kind of pediatric brain tumor cognitive and neural recovery stuff that is now being brought about in some of the largest journals or most highly cited journals in the world. There's a theory that activation of neural precursor cells may promote specific areas of brain repair. That is one of the things that this group has had a significant background and work on in the past. They feel that metformin as a well-established oral hypoglycemic agent also has some unknown mechanisms acting in unknown aspects of improvement of cognitive recovery. This is both a mouse and human study so pay attention here as I may switch between mouse and human data as we're talking. The mouse studies that have previously performed have shown metformin actually increases some of this neurogenesis from those neural precursor cells and they hypothesized in their mind that the pediatric patients with brain tumors treated with radiation were their quote ideal population as most of those neural precursor cells remain present and viable but for the most part a smaller area of the brain compared to maybe a traumatic brain injury would have actually been still affected. So most of those neural precursor cells may have not been actually affected by the presence of a tumor. This is a parallel rodent and human study assessing cellular and behavioral outcomes and it's also a pilot clinical trial measuring the safety and tolerability and specific memory measures in the population of pediatric patients that they were able to enroll. They received or they utilized juvenile mice and had cranial radiation assessing both this early and late time periods. Mice started to receive this metformin one day after the radiation and essentially their neural precursor cells were unchanged from the control mice which was different than some of the other mice they had in the study. They had 24 human participants which then they put into the randomized double-blind placebo-controlled trial and I'll show you how they enrolled and tiered those patients. They used a 12-week cycle of treatment or control or vice versa so essentially utilized 500 milligrams per day increasing up to 1,000 milligrams per day after that first week. They had desired 30 participants to reach their statistical power their a priority power analysis revealed that they needed to reach 30 participants but they did not actually reach that level enrollment. Still I feel like there might be some important information that we can gleam from the data if we're able to look through some of that. The results specifically first looking at the mouse portion of this study is looking at the number and change in neurospheres and the full change in neurospheres between the mice that were treated in the control which is in the white box and the group treated with metformin which is either in the blue purple or magenta box. As a colorblind individual I cannot identify those so please bear with me as I'm looking through a colored graph. They also kind of to look at a wonderful kind of thing which was quite interesting to think about the difference between our mouse cohorts of patients being treated in this study and what we actually do in practice but there's a time split exploring objects in novel space which was a test that they utilized that is a little bit better explained by this graph itself. This graph on the right hand side or the figure I should say I'm sorry on the right hand side that looks like a y is exactly supposed to be that and the idea is they track and measure the length that a mouse walks during a specified period of time and also the time they spend in the quote open arms as opposed to the time that they spend in the middle of the y and one of the more interesting things is that in graphs b and d which is represented on the left hand side are female mice those on the right hand side are male mice and as you can see that there are some kind of differences between the group that is irradiated which is the ir group versus the group that is irradiated but receives metformin. In graph b specifically that's one of the most interesting to see that the mice that were irradiated and received metformin had very minimal difference between the control group and the female cohort of patients but if you look at the male cohort of patients it's always very fascinating to see that there's kind of a discrepancy and I think that the group itself had questions as to whether or not this might be a sex as a biological variant as to determining whether or not metformin may help female mice versus male mice. For the actual human portion of this which I found a little more interesting they essentially consented and randomized to 24 pediatric aged patients they sequenced them or treatment perspective either as an a b or b a essentially meaning a meaning that they received the medication first and then and then pretty much did not have any intervention after that versus b they received the intervention second but then didn't have any initial treatment to begin with. So those initial patients in the control group received actually a placebo for those 12 weeks probably very very similar to what we're currently doing within clinical practice. And then as you see that was for 10 for 12 total weeks there was a 10 week washout meaning that neither patients received any of those medications between those time periods and then those were switched. So if you were in the control group you're now in the treatment group if you were in the treatment group you're now in the control group. They ended up with 11 patients continuing all the way through the end of the study and the a b group and 12 that continued all the way through the study in the b a group. One of the interesting aspects of things is that in my mind looking at those for most of the batteries of tests that they utilized we can talk about those a little bit later more in depth if you if we want to but for most of those and the sequence of variation groups so the a b versus b a group most of the a b so those that received metformin at an earlier time period during the course of their treatment performed better on the studies than those that received metformin second. This kind of supports the potential for a metformin mediated promotion of this cognitive and neural recovery. The neurogenesis as we were talking about improved in female mice but not in male mice. They said metformin was safe for use in pediatric patients with brain tumors although I think we've been utilizing metformin maybe with more increasing frequency for other conditions other than brain injury in the world of pediatrics lately but it does as they indicate support phase three study kind of based on this initial phase one and phase two evidence and it kind of has a potentially introduces in my mind a new evidence that repair of an endogenous stem cell might be a viable mechanism for some promotion or some recovery after brain injury. The second article I'm going to present today comes from the journal of pediatric rehabilitation medicine. As interesting as it is to say one of the wonderful people in all of pediatric rehab medicine is the last author or final author in there as you recognize Dr. Gabler Spear's name there. So I don't know if she's on the call today but I will tell Dr. Gabler Spear what she wrote in her own study which is always quite humorous to do. So this is incobotulinum toxin A for the treatment of lower limb spasticity in children and adolescents with cerebral palsy. So this was actually a phase three study and just a wonderful study to see included in the journal of pediatric rehab medicine. Spasticity as we all know affects a large portion of pediatric patients with cerebral palsy and also is really associated with a challenged aspect of quality of life. It's been botulinum toxin type A has been shown to be an effective and well tolerated treatment as part of a multimodal approach to cerebral palsy and I'm very thankful that they wrote that multimodal approach comment in the article. This was a phase three study so remember phase one, phase two, and phase three type studies all have different priorities. The first study that we reviewed was a phase one and phase two study which was essentially talking about safety in phase one. Phase two is kind of a safety tolerability and is there any kind of clinical benefit type study. The phase three study is almost entirely or primarily focused on what is the clinical benefit as I think we've all started to understand phase one, two, three, and post-marketing surveillance phase four studies with all the medications and vaccinations that have been coming out within the last several years. This is essentially a phase three study that evaluated three tiered doses of incobotulinum toxin type A to a heterogeneous group of patients with cerebral palsy and that was one of the things that I liked about this study is that I felt that it was a quote real world sample of patients. They utilized patients who were ambulatory and non-ambulatory from ages 2 to 17 both with uni or bilateral spasticity as it was talked about within the article due to cerebral palsy. Inclusion criteria is that they would need to have had at least a possibility of receiving 16 units per kilogram and I'll tell you why in a moment. Their modified ash word needed to be greater or equal to two at both screening and baseline and needed to be botulinum toxin naive so greater than 12 months since a botulinum toxin injection. Other exclusion criteria were fixed contraction, dystonia, prior surgery within 12 months that was an orthopedic or neurosurgery thing that would have affected tone. The only other thing that I did not mention on here is a migration percentage that was greater than 30% as well. This was a wonderfully done study from a statistical perspective as they estimated that they needed a sample of 300 to get a 94% power to note a difference between the higher and lower dose groups. The way that this study was enrolled was in a one to one to two ratio meaning that if you can see those patients down at the bottom were either enrolled into group a receiving a maximum or receiving four units per kilogram of body weight up to 100 units group b receiving 12 units of body units of kilogram per body weight or up to 300 units or group c which was 16 units per kilogram of body weight or up to 400 units. You can see that there is a screening and enrollment period which is approximately two weeks in duration and then injection occurred with multiple visits control visits phone visits and options for re-injection at the end of the study period for continued analysis and secondary outcomes. As I said I think I said everything that I wanted to say in the last slide on this slide so for those of you who are more readers than graphical presenters or graphical readers this is the way to kind of look at it. So this was as you can imagine a pretty big study 45 different sites through 14 different countries anytime you undertake something like that it's obviously quite significant. Patients were allowed to utilize usual therapies usual pharmacotherapy and medications and their usual type of bracing their main outcome measures that they were focusing on were changes in modified Ashworth scales and global's impressions of change and just for reference and if somebody were to do a global impression of change you essentially ask somebody how they feel that that patient is doing whether it's a patient themselves the family or the actual medical providers from a perspective of negative three being the worst to three bearing highly improved function. This was how they were able to randomize all the patients as I said 311 participants initially entered the study they were all randomized in that one to one to two fashion as I discussed earlier. 69 completed the four units portion of the study 70 from the 12 units and 139 from the 16 total units. So there was quite a good mixture of patients as we talked about that this was including both ambulatory and non-ambulatory patients. Looking at the ambulatory patients so essentially patients GMSES level one two and if you want to include three those represented the largest majority of the participants within the study but also they continued down to GMSES level four and had 53 participants GMSES level five had 26 participants. There were slightly a little skewed towards a male population in this study, but I think this is always a nice thing to be able to look at to compare the groups themselves when talking about if there are any differences between groups when starting. Lots of wonderful graphs. As I told you, I love graphs and I'm more of a graphical presenter. On the left-hand side, we're looking at Ashworth scales and the plantar flexion, and we're seeing that those participants that received botulinum toxins at lower doses primarily had a less effect than those that received it at the secondary level of a dose or the highest dose. In the middle graph itself, what we're looking at is a global impression of change scale and plantar flexion. It's looking at essentially the lower dose, mid dose, and the high dose groups. You see there's an increasing amount of compared thoughts of global impression of change when looking at the higher dose indicating potentially higher global impressions of change. Then there are other components looking at knee flexors and thigh adductors. As we were talking about, each participant represented much more of a real-world sample and real-world patient, as some were more hemiplegic and some were more diaplegic patients. As you can see, there are fewer participants that were able to capture knee flexion change in spasticity or thigh adductor change in spasticity. Looking at global impressions of change, we already talked about this a little bit, but this was a nice thing to see and interesting to look at. The investigators versus the caregivers versus the child's report. Of note, similar to all the other graphs which I showed, there was a great change from baseline on all of those. This is a really fascinating thing as you got to see those participants that could provide a global impression of change score where they felt like they would receive the highest amount of benefit. As I said, this was a very large phase 3 study showing there was benefit for improving muscle tone with those series of injections. It was effective up to a total dose of 16 units per kilogram per body weight. It appears to be well-tolerated and some muscles had some dose-dependent changes while some may not have. A big strength of this article is that it was a real-world study that these would be kids that would be coming into your clinical practice as opposed to being only hemiplegic kids in a small cohort of hemiplegic kids. Also, I like that this was a large prospective cohort. One of the challenges of this is it obviously lacked a placebo cohort, which was one of the things that when randomizing the number of patients that they were looking at doing, they had a hard time or you could have imagined having a hard time to also include a placebo cohort group. With that being said, I also wanted to mention that there is a great talk coming up in the next hour by Drs. Ed Wright, Lauren Fetsko, and Dr. Justin Wayne Ramsey talking about botulinum toxins that I want you all to be able to tune into and be aware of some of the comments that they will be discussing, which is obviously toxins at a much higher level. With that, I'm going to be going ahead and passing this off to Dr. Sruthi Thomas for her portion of the presentation. All right. Thank you, Matt. That was wonderful. My name again is Sruthi Thomas. I'm a Physician Scientist and Pediatric Rehabilitation Doc at Texas Children's Hospital in Houston, Texas. As you can see, I have been described as the most average of the three presenters and also the meanest, so I'm honored to have that title. Diving right into our next series of papers. The first one that I will be presenting is Long-Term Upper Extremity Performance in Children with Cerebral Palsy Following Selective Dorsal Rhizotomy. This paper was published in the Child's Nervous System Journal and comes to us from Dr. Steinbach's group from Vancouver, Canada. The problem. Selective dorsal rhizotomy is used to alleviate lower limb spasticity. In this neurosurgical intervention, a neurosurgeon transects the dorsal portion of the lumbosacral dermifluids. Typically, they do starting as high as L1 or L2 and going as low as S1, S2. Now, you would think that would only be affecting the legs. However, there are some studies that have shown that the upper extremities have benefits as well. In particular, there's a previous study with Engale et al that comes to us from the UK that had a cohort of 54 patients, GMFCS4-5, who had all received selective dorsal rhizotomy. Interestingly, one of their surprising findings was that the upper extremities showed a modified Ashford scale decrease of one to two points, which you can imagine is a significant improvement. There was indication that there might be some suprasegmental effects of selective dorsal rhizotomy in the lumbosacral region. Steinbach's group wanted to evaluate long-term changes in upper extremity function post-SDR. They performed a retrospective review of prospectively collected data. This is a cohort study without blinding and randomization, but it was collected prospectively. All children in this study had quality of upper extremities skills tests or QUEST assessments done pre and post-operatively. They had a lot of foresight because they started doing this on all children back in 1992, which allowed them to get some very long-term data. Their primary outcome was the QUEST dissociated movements in grass domains, and their secondary outcome measure was the total combined score. The creators of QUEST, when they were validating the study, found that the minimum clinically important difference on the QUEST scale was approximately 3%. If you saw a change greater than 3%, you could imagine that there would actually be a functional change in the individual. Since the QUEST is not a common OT intervention that we see, I wanted to review it with all of you. You can see here that there are four domains, dissociated movement, grasp, weight bearing through the arms, and protective extension of the upper extremities. To remind you, the first primary outcome focuses on dissociated movement and grasp, and then the secondary outcome was the total score. They used descriptive analyses, repeated measures ANOVA analyses to determine the change in QUEST, and then they went one step further to actually perform logistic regression analyses to assess for correlation between certain patient characteristics and changes in the QUEST. In their chart review, they found 150 children had received selective dorsal rhizotomies from 1992 to the time of their data collection. 39 were excluded because they had not received a pre-assessment. Out of those 111 children, 75 were lost to long-term follow-ups. This is nine years or more after the initial rhizotomy. They had a cohort of 36 patients who had pre- and long-term post-assessments. Four of these children did not have early post-assessments. Early post-assessments were generally one to two years after rhizotomy, and long-term assessments were nine plus years after rhizotomy. They published on both of these cohorts separately. This shows you the overview of all of the patients. You can see that at the age of pre-op assessment, on average, there were four years and nine months. So the younger population, but a very typical population for receiving a rhizotomy. You can see here, what's really exciting is the age at long-term assessment. On average, this long-term assessment was done 12 years and four months after, and some were as long as 26 years after the rhizotomy. On average, that works out to two years and two months. Also, to point out here, a lot of people often wonder what percentage of the dorsal roots were they cutting. They cut dorsal roots L2 to S1, and they cut on average 55%. To give you a perspective, based off of practices in the U.S. and Canada, most surgeons are cutting anywhere from 30% on the conservative side to 75% on the aggressive side, so this is right in the middle. This shows you the Quest scores for the 32 patients where we had early and long-term post-op follow-up. Again, the dissociative movements and grasp were the primary outcome measures, and you can see here that there was a significant increase in these scores at the early post-op assessment, and at least the grasp increase was maintained at the long-term assessment. Now, the total Quest score, which was their secondary outcome, also showed improvement, and this also was sustained at the long-term outcome assessment. One thing to note is the average percent change was an increase of greater than 3%. If you remember earlier, the minimum clinically important difference is greater than 3%, so we would assume that this level of change would have given these children functional gains. Now, it's important to see that there's some variability in this group because a certain percentage showed increases greater than 3%, and some did show a decline during this time. However, the decline was less than 3% of the Quest score, which means that it probably was not functionally important. Now, they performed logistic regressions to look at certain patient characteristics to see if they could potentially predict how their Quest scores changed over time. When they looked at their early post-op assessments, they found that the younger you did the surgery, the better the improvement in the Quest scores. And then when they looked at long-term scores, they actually found that having a lower GMFCS score, meaning more function from a gross motor standpoint, led to better long-term outcomes in the Quest. So, the work by Steinbach's group shows, again, that there are super-segmental effects that are, in this case, maintained over a long time, but the response is variable. I would say this is really exciting information because now we have two large cohorts of patients, one set from the UK and one set from Canada, that are all showing improvements in the upper extremities with just doing lumbosacral selective dorsal rhizotomy. So, this is clearly an area that we have to investigate further, and also hints that perhaps we don't fully understand the pathophys of what's going on at the level of the spinal cord with spasticity. So, the next article is the use and safety of intramuscular midazolam during in-office botulinum toxin injections in pediatric patients. This article was from the Journal of Pediatric Rehabilitation Medicine and comes from a group of authors from various locations, including one author who was in Dubai. We all know that doing injections can be really traumatic to children and can cause a lot of distress, not only for the child, but also for their caregivers. And, of course, if these children are benefiting from injections, they're going to have to be coming back for these injections repeatedly, and that can really lead to quite a bit of anxiety. So, this group wanted to know if intrathecal, sorry, not intrathecal, changing topics, intramuscular midazolam administration could be beneficial for angiolysis with botulinum and phenol injections in children. So, for their approach, they did a descriptive study of retrospective chart review. All of the children had neurological diagnoses. The injections were performed by a single practitioner. They followed the pre-sedation protocol of the American Academy of Pediatric Sedation Guideline. And children were asked to fast after midnight, just as they would with general anesthesia. They were monitored with continuous pulse oximetry and non-invasive intermittent blood pressure monitoring. The safety was assessed with the respiration, energy, alertness, circulation, temperature, or REACT post-recovery anesthesia scale. For statistics, they used the student's T-test to evaluate for correlations between prior respiratory or seizure diagnoses with the duration of sedation. Now, most importantly, I know this was going to be a hot topic question, was what was the dose of midazolam that they used? So, for six months and older, they were using 0.1 to 0.15 milligrams per kilogram. And you can safely administer up to 0.5 milligrams per kilogram with a maximum dose of 10 milligrams. They found 72 charts that met their initial criteria, and 71 ended up being analyzed. This led to 120 episodes of injections where intramuscular midazolam was used. 40 of these patients had one injection, and 31 patients had come back for repeated injections with midazolam. So, this had 71 patients total, but 120 injection encounters. The average age of the children included here was about 11 and a half, but you can see that there's a large spread in the age here, including some young adults here. There's modes around four to six, and then modes again in the early teenage years. As far as their diagnoses go, the majority, 86%, had cerebral palsy, and then you can see that there's a variety of neurological conditions represented in this population. The investigators were concerned that having a respiratory diagnosis or a seizure diagnosis could potentially affect how the intramuscular midazolam worked, particularly in the duration of sedation. So, they tracked a number of respiratory comorbidities here. You can see that asthma was the most prevalent, and then they also looked at epilepsy versus no epilepsy, and out of the 71 children, 59% had epilepsy, which fits with this population overall. Out of the 122 injection episodes, there were 26 episodes of breakthrough crying. They defined this as any type of crying or sign of irritability after the midazolam had been given. 47 of these episodes had prolonged sedation, which they defined as greater than 30 minutes. However, no one required reversal of flamazenil, which is a reversal agent for benzodiazepines, and none of the children had to be transferred to the emergency room for evaluation. When we look at the midazolam dose, they group it by small, medium, and large, small being up to 0.09 milligrams per kilogram, medium being 0.1 to 0.2 milligrams per kilogram, and large being greater than 0.2. The majority of the children received medium to large doses. Unfortunately, they do not go into how they decided upon these doses. You can see here, for the average sedation time, it was as low as 24 and a half minutes, as high as 32 minutes. It's important to note here, you know, they highlight prolonged sedation as being greater than 30 minutes, but based on this average, it's not much more than 30 minutes. They found that intramuscular midazolam resulted in an average of 29 minutes of sedation. There was no statistical relationship between prior respiratory diagnoses or seizure diagnoses and the duration of sedation, and there were no adverse side effects. This is really exciting because a lot of us are in a position where our choices are doing it in clinic with maybe a topical anesthetic or doing it under general anesthesia. So now you have a hybrid that we might be able to use on a more regular basis. One question I had is that while the title says botulinum toxin, the paper itself says that they were doing botulinum toxin as well as phenol injections. And I was curious if the breakthrough crime might have been when there was phenol also being used because, one, phenol would take longer to do, it's more noxious when you're injecting it. So I wish they had broken that down a little bit further, but hopefully there will be some future studies coming on this so that we have better options of doing injections in our children. So I will now stop sharing and pass the baton to Dr. Mary Duvon. All right, perfect. Thanks so much, Ruthie. That was a great review, as well as the review done by Matt earlier. So I'm going to be finishing up with our last two articles here. And starting off with an article from GEMMA Pediatrics. So prenatal repair and prenatal care. And starting off with an article from GEMMA Pediatrics. So prenatal repair and physical functioning among children with myelomeningocele, a secondary analysis of a randomized clinical trial. And this is by Dr. Howtrout and team. So as we all know, myelomeningocele is a fairly common cause of physical disability in children with about one in every 1,500 to 3,000 births. The MOMS study, or the Management of Myelomeningocele Study, was a well-known study that was done a number of years ago that was a randomized controlled trial that looked at prenatal repair versus standard postnatal repair. In children with myelomeningocele. And they looked at initial outcomes, and then they also looked at outcomes at 30 months. Some of the things that were found were that in the prenatal repair group, there were fewer individuals who needed BP shunts for hydrocephalus. There was better motor levels compared to anatomic levels. So actual functioning of the motor component versus on imaging what the anatomic level looks like. More of these children walked independently at that 30-month assessment. And then there were also noted to be better self-care skills. Then fast forward, and they took that same group of individuals and they looked at them at school age. So now these are a follow-up of studies of patients in the MOMS study at ages 5 to 10. And that data was collected between 2012 and 2017. Lots of information was collected at that snapshot of those children, and that included adaptive behavior, cognition, urologic functioning, physical functioning, quality of life, the impact on family, and then adaptive behavior. So what they found with some general principles that were found with the MOMS 2 study were that there were no differences in the adaptive behavior scales and the composite score there. Individuals in the prenatal repair group were actually less likely to require catheterization and more likely to actually void on their own. And then more individuals in the prenatal repair group actually walked independently, which was also seen at the 30 months, and so that was also seen here. And then in one of the scales, the Functional Rehabilitation Evaluation Sensor of Neurologic Outcomes, or the Fresno scale, looking at the composite scores, there were better composite scores for the prenatal repair group versus the postnatal repair group in both self-care and in mobility. So the objective of this branch of the study was to look at physical functioning at school age between prenatal and postnatal repair groups. So this was a pre-selected study that was going to be done based on the mom's data and looking a little bit more closely at these outcome measures. And so the hypotheses were to, that there was an assumption that the prenatal group, prenatal repair group would have better self-care skills and mobility skills, and that the prenatal repair group would also have better motor levels compared to anatomic levels. So again, looking at the motor functioning, what the level amounts to versus on imaging. And so again, this is kind of saying like, hey, are we seeing the same things that we saw at 30 months when we fast forward to that school age timeframe? So again, it was a secondary analysis of the moms to data, which I presented some of the general trends that we're seeing, but this is a closer look on it. There were 161 study subjects, again, who were aged five to 10. They were all part of the previous mom study. And again, the data was collected between 2012 and 2017. The three centers for the data were Children's Hospital of Philadelphia, Vanderbilt, and UCSF. So looking again more closely at what the relevant factors for this version of the analysis would be. So physical examination was performed. There was a functional assessment that was done by either a PT or a physiatrist. Demographic information was collected. Again, that Fresno scale, which had, they broke up the components into self-care, motor, and recreational skills. Functional mobility scale, which looks at how much assistance folks need for mobility at different levels. And the Hopper classification system, which breaks people into community ambulators, household ambulators, or non-ambulators. The 10-meter walk test, which can look at the quality, but most importantly, the speed also of walking. And then the Brogdon scale, which is that scale that looks at the motor level. This flow diagram goes through the enrollment and the follow-up. And so looking at the top number up there, that was the 183 individuals who were in the original MOMS trial, which was about 50-50 assigned to prenatal and postnatal surgery. There was some dropout due to patient deaths and also due to loss of follow-up. And then at the bottom there, you see the individuals that participated in MOMS II, which was 161, and not all actually did the in-person physical examination. So 154 of those individuals did the physical exam component. So looking at baseline characteristics between groups, just some things to point out, and this is pretty well cited in the MOMS and MOMS II papers, that it actually wound up that there were more female sex in the postnatal group compared to the prenatal group. So the statistics for this study actually adjusted for that. And then there also was a difference in the average gestational age of birth with the average gestational age of birth being 37.4 for postnatal and 34.4 for the prenatal repair group. So looking at other measurements between the groups, there really wasn't a difference between most of the measurements except for contractures. So there were more contractures seen in the postnatal repair group compared to the prenatal repair group, which actually can speak a little bit to the mobility. Now looking at the Fresno. So looking at how folks are doing in terms of self-care, motor, and recreation. Down to the bottom there, the recreation total, there really wasn't a difference between groups, but looking at self-care and looking at motor, we are seeing some differences there. And so we're seeing that the individuals in the prenatal repair group were able to perform a higher percentage of their self-care skills and that they had a better motor assessment as well. We're also looking at how much assistance folks need and how independent they are with their mobility. And so we're actually seeing that there's an increased independence in the home, in the school, and in the community environment. If you're looking here, you can kind of see the different levels of assist and see that actually in our first column, which is our prenatal group, you're seeing less assistance needed. Also of note, the prenatal repair group was about two times as likely to ambulate without bracing. So the prenatal repair group, prenatal repair group rather, in looking at the Hoffer classification, you actually see more community ambulators as well. Looking at the 10-meter walk test, you're seeing a quicker gait speed. And then with that more exam assessment, you're actually seeing better gait quality as well. So that last component that they were looking at was the motor levels versus the anatomic levels. So again, looking at the Brogdon scale for the motor level versus looking at imaging for the anatomic level. And there actually was some really great findings there as well. So the adjusted relative risk for motor level worse than anatomic was 0.44. So individuals who were in the prenatal repair group were actually less likely to have a motor level that was less than their anatomic level. So any study obviously has its limitations. And so there was obviously not 100% follow-up, but it wasn't a significant dropout rate really. And there were some individuals that didn't do that physical exam component in the MOMS-II trial. There was not full blinding. So parents were obviously not blinded to what the repair group was. And so that may have affected some scales. And then the demographics were mostly white non-Hispanic individuals. And so it did not necessarily line up with the demographics of a general population with spina bifida. So certainly something to look for for future studies. So in summary, really looking at school age, there was that same pattern that was seen earlier on and that the prenatal repair group had better motor and self-care skills than the standard repair group. All right, and with that, I'm gonna move on to our final of our top articles, which is Constraint-Induced Movement Therapy for Children with Neonatal Brachial Plexus Palsy, a randomized crossover trial. And so this is with Dr. Warner's group and it was published in the Developmental Medicine and Child Neurology Journal. So again, another diagnosis that we see fairly commonly in our practice, and it's 1.4 in every 1,000 life births, which is neonatal brachial plexus palsy, about 10 to 14% of those individuals wind up with ongoing functional impairments. So most of us are fairly familiar with constraint-induced movement therapy, which we often think about in the hemiplegic cerebral palsy population. And so with an individual who has less function in one of their arms, the idea is to constrain the arm that is more functional to encourage use of the arm that has more weakness or impairments. And so it's been pretty well studied in patients with hemiplegic cerebral palsy, with patients with stroke, but not as well studied in this population in individuals with neonatal brachial plexus palsy. The authors point out that there were some case studies, case reports, a retrospective study that did show some trends, but obviously not high-level evidence. And so they did show trends towards improved bimanual hand function, improved unimanual hand function, as well as improved active movements and function of the arm. There was actually one prior study prior to this one that was a prospective study, but the authors comment that there were quite a few limitations that made it difficult to interpret the results. So this project really sought out to address that gap in the literature and to assess the impact of CIMT on bimanual hand function in children with neonatal brachial plexus palsy, and then to see if this translates to the child's own environment. So does CIMT improve upper extremity use and the quality of use in the child's environment itself? You know, in the paper, they did point out one hypothesis for their initial objective, but not their secondary one. They pointed out that their hypothesis was CIMT improves bimanual hand function. When reviewing journal articles, I'm sure as all of us do, I always like to look for hypotheses. So I would have loved if they would have pointed out one for their secondary objective as well. But I think it was kind of presumed that they would hope and think that CIMT would also improve upper extremity use at the home environment as well. So in terms of the methods, this was a 16-week study. It had a crossover design. So that means that everyone was in the control group and everyone was in the intervention group at some point in time. So folks did eight weeks of one arm of the study and then eight weeks of the second arm. So they either started with control and went to an intervention or started with intervention and went to control. And it was randomized which group that they were in. There was some blinding. So the occupational therapists themselves were not blinded. They were the ones administering the tests, but they video recorded their session of administering the tests. And an individual researcher who was not associated with those sessions was blinded. And that was the individual that actually did the rating. The recruitment was from a large urban pediatric hospital that had a multidisciplinary brachial plexus clinic. And so when folks would come in for their routine care, they were recruited from clinic and approached about consenting for the study. So this kind of shows a bit about their enrollment and we'll start over here looking at the inclusion and exclusion criteria, which I felt were fairly reasonable. So they included individuals with unilateral brachial plexus, neonatal brachial plexus palsy. The minimum age was 12 months of age and they needed to be walking at the study inception. They need to be able to cooperate with the assessments. They pointed out family's willingness to participate in intervention and control arms. So certainly I think as part of their consent process, they needed to make sure people were committed to being part of both arms of the study. And then they actually had to be receiving OT because of their brachial plexus palsy for about an hour a week and expected to continue for the entire 16 weeks of the study. So it's interesting in this study, they actually kept with their own occupational therapists. The exclusion criteria were if they had another diagnosis that was unrelated to the brachial plexus palsy that could confound the results a little bit, if they had complete plasticity of the involved upper extremity or if they didn't have any observable hand function. If they had a surgery or a procedure coming up during the study period, they were excluded. And then certainly if they were alerted to casting materials, which I feel like is a fairly reasonable exclusion criteria as well. So there were 22 individuals who were recruited. One was excluded because it sounds like after consenting, they decided to decline to participate. And so there were 21 individuals that were ultimately randomized to either sequence A or sequence B. Sequence A being intervention, then control and sequence B being control and then intervention. The 10 individuals in sequence A completed all of their assessments. So after intervention and after control, and then the 11 in sequence B, there was a little bit of a dropout. And so they all completed their assessments after control, but they had a dropout of two individuals before assessment after intervention, but they did analyze it with an intention to treat model. So again, here's the sequence A, intervention, then control and sequence B, control, then intervention. And some here is kind of what the intervention and control consisted of. So all individuals were receiving occupational therapy one hour a week with the expectation of doing two hours of home exercises throughout the study. And the individuals that were at that time in the intervention group got three weeks of casting. Families and therapists were kind of taught about emergency procedures to make sure that there weren't any concerns that the cast needed to get removed. And then the cast was removed after three weeks and then they were kept in the intervention phase for continued occupational therapy for the additional five weeks without the cast. So the measures that they used were the AHA, which is assisting hand assessment and the pediatric motor activity log revised. So the AHA is testing the use of the affected arm in bimanual play activities. And so it's ultimately converted into a hundred point scale with a higher scale meaning more function. And five points is considered, five point difference is considered clinically significant and that's based on studies in individuals with cerebral palsy. And this has not been, it has been validated for brachial plexus palsy but the five points piece came from the cerebral palsy literature. And then the pediatric motor activity log is looking at 22 activities and the parents and caregivers are ranking it on how well and how often they did the activities on scale of zero to five with five being more function. And 0.39 and 0.38 respectively are the clinically important changes. Demographics and baseline measures for brachial plexus injury were also collected. And then looking at the baseline characteristics there really were no significant differences at baseline between the two groups. So looking at their outcomes, the big thing they were looking for was, is there a change in that AHA or use of that affected arm in bimanual activities? And they did find that there was an increase. And so again, with that AHA the clinically meaningful difference would be a change of five. And we actually see a change of 7.1 in the CIMT group which is great. We see a difference of 2.3 in the control group which is just of note. And there was about a 4.8 difference which was actually statistically significant between groups. There actually was no difference between the control group and the CIMT group in terms of caregiver assessment though. And so limitations here, obviously hard to standardize therapy. Not every OT that every patient is gonna have is gonna do exactly the same thing. And so there's gonna be some individualization there. And then the occupational therapists performing the assessments were not blinded, but the video analysis was blinded but could occupational therapists have unintentionally affected it because they knew what group the patient was in. And then the actual scale that the caregivers fill out is not validated in individuals with brachial plexus palsy. And could that impact the fact that there was no difference between groups? It's possible. But really this was a good start in terms of a prospective study to tell us that this could actually be a good treatment option. And so they did show that there was improved scores on the arm function for individuals with brachial plexus who had CIMT treatment. And so future studies I think should be looking at kids that have more impact because I think that they did not include kids that had a little bit more severe brachial plexus injury and then also looking at treatment dosing and more specifics. So with that, I'm going to stop my share screen here. And then I think we can have a couple of minutes for questions. Yeah, great job both Sruti and Mary. We have a few questions other than why are my eyes so blue on this screen? Which is just the fact that my eyes are very blue. I apologize for that. The first question was from Dr. Ed Wright primarily to you, Dr. Thomas on the question regarding the SDR study and whether or not the comments or the changes in the scales or the outcomes were essentially related to changes in the expected number of chest quest to change the scales or not. I guess that I should have not paraphrased that and actually read something intelligent that he wrote. But I think that was the general gist of what he was asking. No worries. Sorry, I'm laughing. Yes, I think that was a humble brag about his eyes. I was going to joke that the ocean behind me matches his eyes. And that's a wonderful question. I think some others also brought that up. So they actually pointed out that there was a 2003 article in DMCN that used quest to develop a growth curve essentially for hand function. And that paper found that the average peak was actually just shy of four years of age. So they argue in their discussion that because the majority of the rhizotomies were done after age four, that they would not expect those changes in the quest to be developmental and that it was likely actually a change based on the rhizotomy. Additionally, there was some future studies that they mentioned. One was from 2013 that showed that in many cases there's decline in hand function, not just a plateau over age. So the fact that those changes were sustained 10 years out or greater, they were actually assuming that that even maintaining would be a sign that the SDR potentially was having some effects. Great, thanks for answering that. And then my question actually to Dr. Dubon, as I think that there was quite a lot of comments in there, also to Dr. Thomas about your midazolam article as to whether or not they used oral or intranasal or intramuscular. But Dr. Bonner, I wanted to ask you your thoughts regarding your upper extremity BPI study and the length of time during each day that each participant was required to utilize constraint therapy. You felt that there would be any higher amounts of dose dependent changes in outcomes if they were utilizing it more than what was recommended. Yeah, I thought it was kind of interesting design because they had them fully casted for three weeks and then they removed casting after that and then they were doing more standard therapy after that. So maybe not necessarily the way that people would traditionally do it. So I think it would have been more interesting to have them do more like, I think folks are familiar with the CIMT camps where they'll do a number of hours during a certain number of days a week. And so I think that future studies actually should probably focus on doing it a little bit more that way because I think that's more standard. Great. And Dr. Thomas, any quick comment regarding the midazolam before we're done here at 145? They did not have a good explanation for why they chose intramuscular or intranasal and they made no commentary on the time of onset because that was one question that I had. So perhaps at some institutions, IOM midazolam would meet qualifications for being done in clinic and that's why they thought to use that. But I'm not 100% sure they didn't go into. All right. Well, wonderful job, Dr. Thomas and Dr. Dubon. Thank you for all of the engagement, even Drs. Clamar and Bova talking about their singing voices within the chat. Thank you for everybody who had interacted and we greatly appreciate that. The only final comment I will say is to Dr. Sinha is that I'm sorry that we're not all tall and handsome like yourself. Some of us have to rely on our eyes who are just as beautiful as being tall and handsome. Thank you all for joining and please, as I said, try to attend the next sessions hosted by Drs. Wright, Fetsko and Dr. Ramsey. So thank you very much.

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