Good afternoon, everybody. We're very excited to see everybody here. My name is Lauren Fetsko, and today with Drs. Justin Ramsey and Edward Wright, we'll be discussing botulinum toxin type A injections for pediatric spasticity about optimizing information sharing and consent for our families and our practices. Just as a little bit of housekeeping, if you have any questions, please, as we go through the presentation, place those within the chat box, and then we will have some poll questions that'll come up just to get an idea of our audience, and we'd love for you to answer those, and we'll discuss those afterwards as well. We do not have any relevant disclosures. We are a group of pediatric physiatrists that practice across the United States. I'm at the University of Wisconsin in Madison, but I recently finished my fellowship training at Texas Children's Hospital and Baylor College of Medicine in Houston where Dr. Wright practices, and then Dr. Ramsey was recently at Children's Mercy and is currently at the Children's Center Rehabilitation Hospital in Oklahoma. A lot of what we're discussing today is actually based off an article that was recently written by Dr. Wright and myself within the Journal of Pediatric Rehabilitation Medicine, so if you have additional interest in this topic, we would also love for you to check that out. Today, we're gonna discuss the timeline of botulinum toxin FDA indications and pediatric dosing trends. We'll also examine FDA drug labels of botulinum toxin products, review some pediatric litigation cases, discuss elements of informed consent in the use of the toxin, and then explore implementation of quality standards to decrease unintended medication doses and frequency. So this is a timeline for FDA labels for type A botulinum toxins. So we're looking from 1989 and to 2020 within this graph right here. In 1989 was actually when Botox was the first drug on the market in the United States, and it had its FDA label for blepharospasm and strabismus. We then had the FDA black box warning after the alerts, and Dysport and Xeomin obtained FDA approval in the United States after that. In 2016, we got our first pediatric indication for botulinum toxin type A, and that was with Dysport. And then subsequently in 2019 and 2020, we had extensions of the label and the additional Botox and Xeomin indications as well. I think when I look at this, I look at the gap between the first introduction of the toxin to the market and the first pediatric indication. So the toxins were first introduced to the market in 1989, and we had our first pediatric indication in 2016. And for Botox, it was a 30-year gap before they were able to get a FDA approval for a pediatric indication. All right, this is a graph that's a little bit complicated, so I'll go over it a little bit. We're looking at published dose studies, FDA warnings, and then the FDA approval of the medication. And this one is specifically looking at Botox or onobotulinum toxin A. So we're looking at a timeline here on this axis, and then the units of Botox per kilogram body weight right here. And so the initial studies really looked at dosing, efficacy, technique, and muscle distribution. This Graham study was the first consensus statement for dosing within this population. And then the Molinars and Heinen studies here are where we had some of the first studies that looked at single-event, multilevel injections. So this is where we see a dose escalation. We then have the case reports of systemic events, followed by the FDA alerts and box warnings. As a whole, as a community, we kind of had safety review and consensus papers. This love article is really nice because it looks at risk stratified based on GMFCS level. So the GMFCS one through four without risk factors, looking at potentially a higher dose of the medication and a lower dose for the GMFCS-5 patients. And then in 2019 is when we got the Botox label for PEDS upper limb. And that was at eight units per kilogram body weight. And this was then extended to 10 units per kilogram with the addition of lower limb. And that's where we are currently. Similarly, here is a graph looking at the same thing for Dysport. So these are the published dosing studies and this darker gray area is the current FDA label. It's important to keep in mind as we're looking at these and discussing toxins that one unit between toxins is not equal. So one unit of Botox does not equal one unit of Dysport. And then that Dysport was introduced into the market in the United States after the black box warning but had been used outside of the United States prior to that. In 2016, Dysport was the first toxin to get a pediatric label within an extension of the label to include upper extremity spasticity. And their label is for 30 units per kilogram body weight. And then to round out our studies, this goes through the early part of 2021, I think in the published research papers that were just discussed, there was an additional study on Oncobotulinum toxin A, but we had limited studies when we were initially reviewing the literature for Xeomin within the pediatric population. Again, Xeomin had its first FDA indication after the black box warning and was introduced in 2010. And the current label is for up to 16 units per kilogram if you're using bilateral upper extremity dosing. And there is no current lower extremity indication at this time. So next I will pass it off to Dr. Ramsey to talk about Botulinum toxin labeling, warning and adverse events. All right. So let's get into the Botox labeling and adverse events. When we start talking about Botox, most of you are familiar that it has many different uses. We wanted to point out today that it has a separate insert and labeling specific to cosmetic use. In pediatrics, it has used in spasticity in patients two years of age and older. And in neurogenic, detrusor overactivity. Next slide, please. When we look at the Botox insert warnings, it has warnings against unapproved use, pre-existing neuromuscular disorders, caution in patients with compromised respiratory status, specifically with spasticity, pre-existing dysphagia, drug interactions such as aminoglycosides and anti-cholinergic medicines. It makes note that it can play a role or complicate pictures, including autonomic dysreflexia, urinary tract infection and urinary retention. Next slide, please. When we look at the common adverse events and effects of Botox, the most common one in pediatrics is basically flu-like symptoms, so pharyngitis, nasopharyngitis, and fever. When we look at serious adverse events with off-label use, the label notes possible weakness, dysphagia and aspiration pneumonia. Now looking at Dysport, it has an FDA label for spasticity in patients two years of age and older. When we look at its insert warnings, it warns against pre-existing neuromuscular disorder, dysphagia. In pediatric patients, it makes notes of potential roles in bone growth, delayed sexual maturation, decreasing fertility, and points out that some animal models point to the risk of muscle atrophy. There's a notation of a milk allergy specific with this product. They note that the geriatric population is potentially vulnerable, particularly with the risk of falls. And again, recommend caution with aminoglycosides. Next slide, please. Probably not unexpectedly, it has a similar list of common adverse effects, including those flu-like symptoms, fever and nasopharyngitis. Next slide. Looking at Xeomin, it has a label for chronic hypersalivation in an upper limb spasticity in patients older than two. There's language that excludes the use in cerebral palsy, but as we understand that, that is an orphan label exemption in which the other two toxins receive their FDA approval before Xeomin. It has specific warnings against dysphagia, neuromuscular disease, and corneal ulceration. Next slide. Again, I think we're proving a pattern that it has common adverse reactions of flu-like symptoms, bronchitis, headache, nasopharyngitis. Next slide. When we look at serious adverse events, all three toxin types have a black box warning. And those warnings include risk of potential spread, dysphagia, respiratory suppression, which may produce a life-threatening condition. All three botulinum toxins report that there's increased risk with therapeutic and pediatric use as opposed to, let's say, cosmetic Botox. The FDA defines a serious adverse event as it relates to Botox as death, meaning adverse drug experience, inpatient hospitalization, or prolongation of that hospitalization. There's two types of events, temporal or time-based. Two events, two types of temporal events have been seizure and bronchial spasm versus a causative event, which basically means that intervention A caused event A. Next slide, please. Sweeney et al looked at adverse events and they based this on gross motor functional classification. And as you can see, they basically divided this into two groups, a GMR-CS one through three versus four through five. And we want to attend to the first box here, looking at systemic adverse events. Basically, if you're a four or five, you have two to three times the risk of a systemic adverse event as opposed to ones and threes. Next slide, please. Medication guides. Medication guides are a language for the patient. This is opposed to the medication insert, which is that large, nearly 40 pages of information. That's a language for the medical professional. It extends the drug label and the FDA deems that it is necessary for patient safety. It's typically done as an aftermarket add-on. Basically a box warning equals a need for a medication guide. A medication guide is included inside of every box of botulinum type A. The medication guide is required to be issued with drugs when the FDA determines that certain information is necessary to prevent serious adverse effects when it may affect patient or family decision-making or patient adherence to directions for the use of that product are essential to its overall effectiveness. Next. So basically we're required to give out a medication guide. In many events, such as antidepressant medications, the dispenser is a pharmacist, but in the case of us in pediatric rehab or in physiatry, we are the dispensers. We prescribe the drug and we administer it. Next. Here's a graph created looking at when you may be required to give a guide. We feel that the first row is the most important. It's required at the first time of dispensing, upon a patient or family request, or when the guide has substantially changed. Next. Again, we wanted to look at dosing as it relates to the botulinum toxin injections and wanted to point out a few things. Again, as Dr. Fesco had indicated, all three toxins make it clear that their units are not interchangeable. But when you look at the minimum intervals, there's difference. Botox recommends three months, Dysport and Xeomin recommend 12 to 16 weeks. And when you look at how the dosing label is suggested, Botox talks about units per kilogram, whereas Dysport, for example, talks about units per kilogram per extremity. Next. I'll go over briefly US litigation and we'll go into this in much deeper detail. But basically the points are that lawsuits are uncommon, therapeutic Botox has more risk with litigation than cosmetic use. Typically those claims have been against the manufacturer. We would point out that that was before the FDA labels. There's a higher rate of adverse events associated with dosing, comorbidities, polypharmacy, and specifically in children that have had Botox injected for spasticity. All labels have been, all lawsuits have been against Botox and we believe that's a function of the amount of time that Botox has been used in the US market as opposed to the others. Risk reduction could be considered by basically thoroughly reviewing the process with families, withholding treatment when there's a known contraindication and considering an adherence to on-label use. Next. Generalized conclusion. Each label has indicated increased risk with spasticity and especially in pediatrics. Caution has been noted in dysphagia. URI and bronchitis, which are respiratory symptoms are listed as common adverse side effects and caution has been proposed with certain medications such as amino glycosides and anti-cholinergic medications. Now we'll transition back over to Dr. Fitsco who will review cases. Thank you. Thank you, Dr. Ramsey. All right. So we are going to now be discussing some three cases that were noted in federal court. One is a case of systemic botulism. The second is a case of an idiosyncratic reaction resulting in a seizure. And the third is a temporarily linked death following a series of injections. These cases are unsatisfying to us from a provider standpoint. There are not enough details that would kind of quench our thirst to get a really thorough chart review but these details are taken from legal documents. And the reason we're discussing these cases is to gain further understanding about the court's perception. And so it's not necessarily to satisfy our own understanding of the complications that occurred but to really get the legal standpoint. Before we talk about that, it's important to talk about the two different types of adverse events that can occur with medication administration. The one that we're most familiar with would be the dose related or type one reactions. Those tend to be more common and mild in nature, can have an extension of the therapeutic effects, are predictable but sometimes unavoidable, can be related to the introduction of the drug to the patient and can be reduced or relieved with dose reduction. So I think commonly of medications that we have known side effects of sedation. So this would kind of be within that class that you try to decrease the medication, hopefully still have effect but may have that side effect. The second is an idiosyncratic reaction which is a type two reaction. It's generally a lower frequency type of reaction as compared to type one but the reactions are more severe. Generally thought to be an allergic reaction or immunologic in nature, less related to time of when the medication was introduced, can be more unpredictable, is not thought to be a dose response. And so if an idiosyncratic reaction occurs, the drug should then be avoided in future. So we're going to review the three cases of litigation involving pediatric injection of botulinum toxin type A in researching for this project. In the article, we did look to see if there were any other cases and these were the three that we found. Allergan was the defendant in each case. It's important to note that each case occurred after the black box warning was introduced but prior to the labeled indications for pediatric spasticity. So it is a different time point when we're thinking about today versus when these cases occurred. And each case represents a different type of potential adverse event that can occur with these injections. It's also important to note that in some of these cases, the injectors were listed as co-defendants to the cases as well. The first case is a preschooler with leukodystrophy and lower extremity spasticity. The patient underwent 200 units of Botox injected for a total dose of 18 units per kilogram total body weight. After the injections, the patient's legs and body began to swell. The patient then required hospitalization, ventilator support, as well as nutritional support. And the presentation was thought to be consistent with botulinum poisoning. The second case is a five-year-old boy who was a GMFCS level two diaplegic cerebral palsy patient. This patient had mild to moderate lower extremity spasticity and had undergone previous injections with Botox at six units per kilogram total body weight into the bilateral caps. Two years later, the patient and family were hoping to repeat injections. The previous injections were thought to be somewhat successful, but not necessarily the most successful as they had hoped. So the dose was increased to 12 units per kilogram into the bilateral calves. Soon after injections, the patient, about a day later, the patient developed facial swelling, slurred speech, difficulty with respirations, increased secretions, head drop, vomiting, and different parts of the patient's body began to twitch. The patient was then treated in the emergency room. The thought was, is that the presentation was related to an allergic reaction, and the patient throughout that time was treated with an EpiPen and steroids. The patient was then monitored in the emergency room after he had been found to have status epilepticus. Similar episodes occurred months after the injection, and an EEG months later noted seizure activity, and the patient was diagnosed with epilepsy and placed on AEDs. Much of our subsequent discussion about litigation is going to actually be pulled from this case, focusing on a new seizure disorder after Botox injections. The last case is a 21-year-old female with a past medical history of microcephaly and cerebral palsy. She had been treated with Botox previously since the age of 14, with doses ranging from 10 to 17 units per kilogram. Throughout the years, a functional decline had been noted. The parents had noticed dysphagia, and the child had had hospitalizations for aspiration pneumonia. She had also noted upper extremity function loss, more difficulty breathing, seizure, or seizure-like spells, and then ultimately the patient died in her sleep as a result of atypical pneumonia. And the litigation was brought forth as a temporarily related link to Botox injections. So, you know, we have to think about legal considerations. We practice, we want to make sure that our practices are safe. If you were to have a serious adverse event in your practice, you would think about what kinds of information you would bring to the court. So for me, I would think about our literature, the practice that we have, my training. I would think about the doses that we're injecting, the injection technique that we're performing, and then the consent that I'm performing with families before I do an intervention. All of this information that's on this slide was presented to trial, and it actually all relates to evidence provided by Allergan. Recall that Allergan was the defendant in all three of these cases. This is elements that were presented in our second case involving seizures following Botox injection. Elements, when I look at this, I have to think that elements may be presented at a trial that you may not have access to as a physician. So this is looking at core data sheets from the company, internal emails, sales representative call notes, and maximum dose consideration or review. So the maximum dose that the company would consider safe for injecting. All of this information was found in the judge's opinion and order. Essentially, it's a legal document, and it's when a judge is asked to review a case that was already decided by a jury. So the judge reviews the evidence that was presented in the court and writes an opinion and order on whether the jury from the evidence presented had reached a reasonable conclusion. So when I look at this information when I was first exposed to it, it helps me come to an understanding that our training, experience, academic learning, and literature can help demonstrate our competence, but may have little bearing on the outcome and future risks if the case would be brought to litigation. I know that we've all at least watched one or two lawyer-type shows in our time for leisure, and we always talk about juries, and we talk about a jury of our peers. When we think about a jury and a jury of our peers, it really is a jury of people within the community. It's not a jury of medical providers who have a deeper understanding similar to our own. And so as that's the case, we have to really think about how could the practices that we're performing be perceived by a jury of people within the community? So when we think about things and think about botulinum toxin from a provider perspective, we think that, yes, botulinum toxin is a potent toxin, and adverse events are usually transient and mild. However, a jurist might say, this is the most lethal substance on the planet. We also might say, yes, some dose-related risks are present. There are thousands of treatments that occur without any serious adverse events. And we know that there's a standard of care, and that's based on our experience, our training, and our literature. However, a juror might say risks are dose-related, and this is a fairly vulnerable population, and that the dose can be characterized as an overdose. I think that what we have to really think about in looking at our practices is that perceptions in healthcare can differ between a provider and a jury. In the second case, the jury determined that Botox had caused a seizure. We might differ in our opinion. This is what the judge wrote in his opinion in order. The jury was instructed at the time of trial that a preexisting condition that makes the plaintiff more susceptible to the event does not destroy causation. And the judge felt the jury could have reasonably concluded that Botox either caused the seizure outright or lowered the child seizure threshold sufficiently to cause the seizure. The jury might have reasonably drawn that conclusion from the plaintiff's evidence. At the top is a quote from the jury that said that from which reasonable jurors could have inferred that it was more likely than not that Botox was to blame for the child seizure. This is the data that was presented at trial that isn't necessarily available to the public. So they were looking at seizure rates in clinical trials done within the company, FDA guidance in the Botox label, adverse events in anecdotal evidence, adverse events in anecdotal reports, biological plausibility and theoretical mechanism of action and temporality and lack of alternate explanations. Prior to the trial, a jury wouldn't likely have knowledge on botulinum toxin dosing. So there were several pieces of evidence that would have been given in testimony at trial regarding dosing, including the maximum dose consideration review that was from the company. In his opinion in order, the judge noted that the maximum dose consideration review determined that Allergan would keep the pediatric dose at eight units per kilogram. Again, this is at the time of trial. The judge also noted that the jury could have reasonably inferred that Allergan has significant evidence in its possession suggesting that doses above eight units per kilogram were more dangerous. So after looking at the legal portion and how judges and juries might look at our practices, how can we keep our practices and patients safe? And I'm gonna send it over to Dr. Wright to discuss that further. I'm gonna steer the conversation in the direction of risk reduction for providers. And as we've already seen in the Corman article for 2013 that reviewed botulinum toxin litigation in the US, they recommended that provider behaviors that could influence our risks would include how well we review adverse events. Are we withholding treatment if there's a contraindication? And are we adhering to the on-label use? Now this was written in a dermatologic journal. And so that's a little easier statement for the dosing associated with cosmetic Botox. But they also recognize that our population was the most at risk of populations such that children with spasticity and cerebral palsy have higher dosing needs and they have higher comorbidities. So Falings authored a practice review comparing pediatric spasticity practice in Canada to international consensus guidelines. And from that, the panel recommended that we should be providing both verbal and written parental information about adverse events prior to obtaining a written consent. And that we should also be implementing adverse event monitoring programs within our practice. So a good question for us to ask is how well are we meeting this standard of information sharing? What's the quality of what we share and are we sharing it ahead of time as opposed to the day of? And how specific is our, and consistent is our consent for botulinum toxin? One thing I see pretty widely is that in the outpatient setting, there's one consent process and the inpatient setting or in the sedated setting, there might be a completely different consent process. And then lastly, how intentional are we being in surveying for our serious adverse events? So the Journal of American Medical Association, a journal of ethics, provides us with two definitions that we need to consider as we work towards a quality consent. The first is of shared decision-making. And this points out our role as physicians, as educators. Dr. Ramsey actually pointed out to me that the Latin root of physician is teacher rather than healer. So I think that what we need to do is if we're gonna have a family that's gonna play a significant role in decision-making that reflects their values, we need to be providing them ample information about the disease and about the treatment options. Then regarding consent, the Journal of American Medical Association suggested that we must disclose information that a reasonable person would want to have for decision-making. Even if that might lead the person to choose not to use the treatment that we're suggesting. So this emphasizes that for consent, we're to provide the key facts and then respect patient autonomy. So where do we go then for guidance for our risk language regarding informed consent? And we've spoken to the literature and to the labels and we've spoken to the literature and to the labels as well as litigation. And we've discussed population comorbidities and we'll dive into those a little deeper. But I also wanna suggest that our experience is a very useful place to go for the information we provide in informed consent. I've found that experiential dialogue helps families understand that a serious adverse event occurring after an injection may have a temporal association, but that does not equal causation. So let's look a little deeper at the litigation standards. Most of us remember from medical school, the statement of, did we follow the standard of care? And that's an important element of litigation, risk reduction, and it speaks to the technical side of what we do. So things like what's our training and how are we credentialed properly? How do we localize? How many sites do we inject? And more recently, I would say it suggests that we need to have better comorbidity awareness and we need to have good dosing awareness and how that shifted over time. But the other half of litigation is consent. That is, what did we say? And there the standard is, what would a reasonable person want to know? What would a reasonable person want to know about serious adverse events, about comorbidity risks and temporal associations and about dose? Let's talk a little bit about comorbidities. If I have GMFCS5 cerebral palsy, my symptom sets that go with that are I have risks of dysphagia and aspiration. I have potential for unplanned hospitalization or physician visits. I have a potential for seizures or a change in seizure status. And I have a potential to die as a result of that level of cerebral palsy. If I look at botulinum toxin as serious adverse events, all I have to do is add weakness to that list to come up with a description of a serious adverse event for Botox or botulinum toxins. So the list is not different. Our kit, the comorbidities of GMFCS5 and the serious adverse events of botulinum toxin are essentially the same. And I would suggest that weakness in a GMFCS5 cerebral palsy child might be pretty hard to discern. So this led Sweeney and colleagues to describe it this way. Children with severe CP have increased rates of comorbidities that may predispose them to complications after botulinum toxin injections. So if we'll remember then by the FDA's definition, a serious adverse event implies a temporal association but not necessarily causation. And as we've seen in the eyes of the court, a predisposition to a serious adverse event does not destroy causation. So regarding dose, should we share information regarding dose? And if so, what dosing threshold should we use? Paulson did a review recently and looked at the label as it relates to the relevance in our practice. And he suggested, I'm sorry, I don't know if it's a he or she suggested that 86% of we pediatric physiatrists exceed the maximum dose of Botox above the label as part of our practice. So there are other dosing thresholds we can certainly use besides the label. We could use our practice guidelines or consensus guidelines within the literature, multilevel injections or serious adverse event case reports. There's a number of places we can pull from. When I look at the label and ask myself, is it really relevant if 86% of us are dosing above the max level for a drug? I have to step back and recognize that the treatment of pediatric spasticity, that in the treatment of pediatric spasticity for the last over 15 years of international experience with Dysport in 25 years of Botox product experience in the US before the drug companies designed and executed a drug study that would gain the FDA label. That's a lot of years of experience that led to a study design that would demonstrate efficacy with low risk of serious adverse events for a drug that had a black box warning. And that might be an indication that the label is more relevant than our collective behaviors would suggest. So what would a reasonable person want to know regarding dose? JAMA has suggested, and the courts have suggested that that's an important question to ask. And unfortunately, the answer is a subjective one, and it's really not ours to decide. And I would contend that if you ask an individual before a serious adverse event, they might say, I would like to have known this. And if you ask them after a serious adverse event, they might say something different. And if we look at the three cases that we presented at 18 units, 12 units, and 10 to 17 units per kilogram, were those doses standard of care? I think we as physiatrists would look at them and say, yes. Were they an overdose? In each case, the plaintiff's complaint suggested that their child was overdosed. And in the maximum dose consideration review, we suggested at the time was eight units per kilogram. So this prompted the plaintiff's attorney to ask the injecting provider at deposition this following question. If you're planning on exceeding the maximum safe dose with a medication that's a lethal neurotoxin, would you at least let the parents know about that so they could consent to that? So if we look at, let's assume we have a serious adverse event within our practice. What are the things we can do to mitigate our risks? I think the common wisdom would say that the strength of our relationship with the family and the quality of our consents are the two things that we really get to control in minimizing that risk. And so towards that end, just remember your role as an educator in the purpose of shared decision making. Be great at sharing with information, sharing with families information about Tome, about the treatments, about the risks, the benefits, the alternatives of those treatments, and about non-intervention. That takes time and that time builds a relationship and that relationship minimizes your risk. Then regarding consent, what you have documented is exceedingly important. But I would also suggest that what's also important is the consistency with which you provide that consent process. Your capacity to say, I know I did this because this is what I always do, because if you're an injector of this drug, it's an important part of your practice. So towards that end, to simplify things for myself and my own practice, I like to keep the initial focus of consent on serious adverse events. So I choose to inject on label for a first injection. And then later, if we've had a successful injection event without an adverse event, then the conversation around dosing can emerge. So as a result, I move faster in focal injections because those tend to be kids with lower GMFCS levels, lower dose needs, and lower comorbidities. And I tend to move slower in kids with more systemic needs because those tend to be kids with higher GMFCS levels, higher comorbidities, and need higher dosing for the number of muscles involved. So let's look at the consent as a process. My consent starts on the day that we determine that injections are going to occur as opposed to the day of the injection. So once I've established a goal with a family for the injection, then I turn the discussion to risk and I start softly speaking to needle breaking the skin risks, infection, bleeding, bruising, swelling, pain. And then I tell the families that we're trying to make an overactive muscle weak. That's how the medication works. There's a risk that it's going to make the muscle too weak. There's a risk that it may not make it weak enough. There's a risk that it might spread to an adjacent muscle, cause that muscle to become weak that wasn't intended. In a very rare circumstances, there's a risk that it would spread through the whole body and cause a botulism-like illness. That can be a severe weakness that would cause difficulty with breathing, difficulty with swallowing, difficulty with clearing secretions and could be life-threatening. And I tell families that I've done around 7,000 injections and I've seen one case. And I tell them that my colleagues who've done that as equal number of injections have most of them have never seen a case. So it's a very rare phenomenon. And then I speak to the notion that we're injecting a foreign protein into the body. And just like with any foreign protein we might inject, the person could have an immune reaction to that. And in this case, cause a change in neurologic status such as a seizure. And I tell families of the cases I've had where I've injected a child and had a subsequent seizure and had to wrestle with the question of this trigger the seizure. Was this an at-risk child who had happened to have a seizure after an injection? And then I tell them that I've had two cases of children that it happened twice in a row where we determined the family and I not to proceed with this treatment as appropriate for this particular child. If you don't have those kinds of experience, so that's what I meant by experiential dialogue. If you don't have those kinds of experiences and you're a younger injector, I think you can lean on the practice experience that you're involved in or the place where you trained and the practice experience there to give bigger sort of sense of numbers of how rare these serious adverse events are. I then provide a medication guide. I provide an information sheet. And I ensure that there haven't been any recent botulinum toxin injections. Here's a copy of the information sheet that we use at Texas Children's Hospital. It's fairly generic and but freely shared. And I point out that this is an elective non-curative procedure. And if your child's had a recent illness or immunization or a change in seizure status, that might be a good reason to postpone. If a family has deeper questions about risks, Dr. Fretz will actually develop this from the Sweeney study that splits the serious adverse event risks into GMFCS levels 1 through 3 and GMFCS levels 4 and 5 and helps families see those risks as it relates to their child's functional level. Then the day of the procedure actually becomes a review rather than an introduction of risks, unless there's a new family member present. And so we'll review the child's interval health. And then I'll perform written and verbal consent for the procedure. And at this time, I provide another medication guide and a discussion of the weakness severity again. But the purpose of the medication guide in this case isn't meeting an FDA requirement. It's really to discuss bulbar weakness. So if you have a GMFCS 5 child who has botulinum toxin injections, we've already seen that that comorbidities list and that serious adverse event list overlaps significantly and that weakness is the only difference. But it's the bulbar weakness that is probably most recognizable in that population. So I give the family the medication guide because there's a nice list for bulbar weakness. Gives them something they can use as a resource if they're concerned. Here's a copy of our consent that we use. It's one page and it covers multiple of the areas of off-label dosing, of local weakness, of systemic weakness, and contents of the boxed warning, and seizures. So that's all on one page, again freely shared. Then the post-injection follow-up is another opportunity for learning about the adverse events as they've occurred, as well as educating ourselves and our families about those adverse events. And I used to be pretty nonspecific in my questioning. I would just ask an open-ended, any side effects kind of question. But I realized that if I, since I wasn't really asking, was I really finding out? And as I started asking specifics about, you know, dysphagia, or seizures, or illness, or hospitalizations, or things that happen, I started to discover, well indeed there are quite a few events that are happening. Doesn't mean there's causation, but there's nobody better than you and I to work through the notion of, did something we did in our injection trigger this event? Or is it just a temporarily associated event? The FDA says it's a serious adverse event. So then we'll review our treatment options, our goals, and then if necessary, to increase the dose, we can talk through dose escalation. Here's a copy of an active surveillance that was used by Blasek, and they're in an article in their practice. And I like this. It's simple, and it asks, in the past four weeks, has your child experienced any changes in the following symptoms? You can do this the day of the injection, for the prior four weeks, and you could do this four weeks later by phone, or by telehealth, or by staff member phone call, and see if any of these adverse events have emerged. So next, Dr. Ramsey is going to talk through best practice in a multidisciplinary, multi-specialty clinic setting, and I think the value here is that, you know, we have a greater number of indications, we have a greater number of toxins with a pediatric indication, and we have a greater number of different providers providing botulinum toxin injections, and these things increase the risk of an overlapping time injections, and multiple injections in an overlapping time interval. All right, thank you. Thank you, Dr. Wright. Here's a slide reviewing off-label uses of botulinum toxin injection. As most of you know, there are several. I saw that there was a paper recently published looking at some of these uses. Our purpose of this talk is not to go over a specific use, or dosing with that use, but to point out that the multiple off-label uses of Botox indicate a plethora of specialties which use Botox for multiple reasons, and that there's an importance to be aware of other reasons why other specialties may use botulinum toxin injection. Next slide. At Children's Mercy, we had the ability to use an intranet, and we had to the ability to basically break down how many providers had privileges, and in which departments or divisions were those providers. Basically, this math breaks down to 65 providers at Children's Mercy Hospital, which is a large tertiary quaternary hospital in the Kansas City area. Next slide. At Children's Mercy, recognizing this risk, we tried to create an alert within the EMR. This alert flagged if the EMR believed that Botox had been ordered for that patient in the last 12 weeks. If it flagged, it prompted questions to ask if any provider had used Botox for any reason. It asked the physician to do a document review. It asked it asked the ordering provider to ask if there were any future plans in using botulinum toxin by other providers, and it asked about drug reactions. Because of awareness that the alert may fire inappropriately, the providers have the ability to override the alert. Next slide. Next slide. All right. So there's nearly 200 times in which the alert fired between March and July of this year. 130 of those times we felt that were a mistake. It likely represents a process error in that there was an error between when the nurse took the drug out of the patent system and the provider put in the order. But there were at least 55 events recorded for review, and those included nurse practitioner orders, neurology, and pediatric rehab. Some divisions use nurse practitioners to inject the botulinum toxin. In my discussion with the other departments, it was clear that the individual departments did not have a universal practice in asking about other departments' use of botulinum toxin. Some weren't aware that there was importance to screening for gentamicin, for example. Next slide. At right, Texas Children's prompted a six-month review with their pharmacy department, and what they found was that there was 600, I'm sorry, 700 patient injection events. There were 64 identified unique injectors, 13 patients were dosed by multiple providers, and there was 200 events in which botulinum toxin was injected above label. 11 events were dosed above consensus guidelines. Next slide. So, in consideration of multi-specialty care, I want to bring up a point. We discussed two larger pediatric institutions and the risk for unintentional dosing beyond what an individual provider intended. But even if you own your own practice and inject Botox, you're injecting a patient with multiple medical comorbidities that has multiple reasons for injections from different specialists. So, it's important to be consistent about if another provider is using Botox for any reason. If you have an EMR that you're able to interact with, it is useful to ask the question of if you can use that to reduce the risk of unintentional dosing. And it's important to be aware of the overall breadth of which botulinum toxins are being used beyond your individual uses. Next slide. Conclusions. Pediatric dosing has evolved with an effort to provide a safe and efficacious treatment for our population. The relationship between serious adverse events and cerebral palsy is complex. And what we mean by that, as Dr. Wright had pointed to, the risk profile of the botulinum toxins and cerebral palsy themselves are very, very similar. It's important to have a patient and family-based education with the intention of building a safe practice. A black box warning, which all three botulinum toxins type A's have, necessitates the provision of a medication guide. A consistent written and verbal communication process with families before, during, and after the injections is important. Next slide. Lastly, we'd like to thank you all. Dr. Fesco will soon go over the poll results, and we'll try to address the questions that came up during our presentation. Thank you all for your time. Thank you, everybody. I have a section of the poll results, and so I think we got a subsection of the people that are here joined with us today. So I have 26 responses total. So the first question we had was regarding the consent process when injecting botulinum toxin type A for the first time and talked about consent. I would say the majority, it's kind of, it's actually evenly split. So four out of 20, 15% said they obtained verbal consent and documented in their note. 35% said they use a generic consent form. 19% said they use a specific botulinum toxin consent form. 4% said they provide a written information sheet and toxic-specific consent on the day of injection. And 27% said they provided a written information sheet prior to the day of injection and a written toxin-specific consent on the day of injection. And then going through what we share risks-wise prior to injection, the most common was 100% in risk of bleeding, bruising, infection. 92% said systemic weakness, 88 dysphagia, 65% mentioned death or life-threatening. 23% mentioned risk based on GMFCS level, 23% seizures, 42 medication dosing above the label, and 31 talk or provide a medication guide. And then I discussed botulinum, dosing of toxins with family if, and the majority was if a family asked at 35%, everything else was 23% or lower. So less likely if they, for other, the other choices. Just going through this in the interest of time. And then 88% of people that were polled said they regularly asked families if a botulinum toxin products used by any other providers. And the majority of people when asking about adverse events, 65% said they generally asked if there were any complications at a follow-up visit rather than like specific or not routinely asking or things like that. So 65% ask any complications. So just in the interest of time, cause I know we're coming up on five minutes. Oh, and you guys can see that all there. Sorry. Thanks, Carla. Looking at my phone. I know Dr. Wright and Dr. Ramsey, it looks like Dr. Murphy has a question or what, how you guys want us to do that? Thanks guys. Hope you can hear me. Okay. Is that all right? Thanks. I really appreciate your work. A beautiful talk to everybody. I'll be brief here. You know, those of us that see adults to lifespan care, there's a good literature, Dr. Hurwitz and others on that. The decreasing muscle mass in the adults, the adipose tissue, the animal studies on fibrosis from too much Botox are getting very credible. The American Academy of Cerebral Palsy and Developmental Medicine had a nice symposium on that this year and some of last. So I guess I just want to throw it out there to be careful with Botox in my own opinion. And I think some others too much, too frequent over time can potentially add a lot of weakness in the adults and cause crouch gait and loss of mobility over time. And it really is a scary thing if you take care of the 40, 50, 60 year olds and others. The Botox every three months for eternity, I think is a rule that probably is not a good one, but I just throw it out there for discussion and I'm very careful with the long-term perspective in mind. Thanks again. Great talk, you guys. Thanks, Kevin. You know, one thing that I was a little surprised to see how few people are providing consent information ahead of time. And I think one of the side benefits that I've noticed from that process is how few cancellations I have. And so a family has a chance to sort of digest that information rather than being taken aback by it at the time of an injection. And it also I feel like increases their awareness about other illnesses, other injectors, other surprises that might say, well, we really can't do that injection today. So I've found that really valuable on those two fronts. I agree. Since I've started doing that, it has been helpful in avoiding the canceled procedure. In going through the chat room, a lot of the audience answered questions that were asked. So thank you, audience members. There were questions about off-label use and BPI, which I think there was guidance to an article. There was a long discussion about flu and COVID vaccines and if there's a length of time. And I think that has been well discussed in the chat already. There was a general pattern of two weeks followed by there's not much evidence behind that. And I doubt if we have more to add. There was also a, hey, we need to come up with a consistent way to do consent in education. I would say that we largely agree. There was a request for consents and education forms, which I believe that you have seen that Dr. Wright provided in his portion of today's talk. And it's my interpretation that you plan to be able to share those upon request. Yeah. And we have Spanish versions of the same for the information sheet and the consent. And we have them that include phenol as part of the injection procedure. Dr. Fitsco helped a lot with those. Anybody else want to raise their hand and ask a question? I will say that I've been practicing outside of fellowship for over a decade now, and only recently began to use medication guide. So as Dr. Wright invited me into this talk, and we've had our multiple meetings preparing, that's something that has changed my practice pattern over time. I think we have a hand up. Yeah. Hi. I was just wondering if when you were talking about risk of seizure, is there a timeframe if someone has a seizure after injections, like if it's the next day versus a week later versus three weeks later, whether you would say that would be attributable to the injections or not? I think in the second case that was presented, there was just this unusual immunologic response was the early response that happened, and then seizures may or may not, in looking at that report, may or may not have been a part of the initial presentation, but definitely developed subsequent. And this would have been in a GMFCS2 kid with, you know, a cognitively intact kid without a prior history of seizures. And the doc who was doing the injections actually reported it as a serious adverse event. So those were kind of the factors that went into that. More broadly than that, I don't have a timeline that I look at. I do ask about it specifically and try to listen to, you know, do I believe there is a link between what I did and that event? And then certainly if it happens a second time, and so it doesn't necessarily mean I don't do an injection subsequently, and the family and I will have that discussion. And if we decide to proceed and it happens a second time, usually I'm ready to sort of check out and say this, we probably need to go in a different direction for your treatment. So I don't have hard data on what would drive the timing of that. I think you just have to look at each case individually. I believe we're over our allotted time now. So thank you, everybody, for attending. Thank you for the questions and the discussion in the chat.

botulinum toxin type A injections

pediatric spasticity

FDA indications

dosing trends

labeling and warnings

informed consent

adverse events

risks

consent process

patient education