My name is Elaine Tsao. I'm one of the pediatric physiatrists at Seattle Children's Hospital, and I'm very happy to be here to talk about pertinent topics in pediatric cancer rehab with you all. My co-presenters are Jared Levin, who will be talking about chemotherapy-associated adverse outcomes, and Dr. Kelly Giaviano, who will be talking about graft-versus-host disease. And so I will start the morning by talking about posterior fossil syndrome. Hey, all right. So I have no conflict of interest associated with this talk. So we'll start by going over, doing an overview of pediatric brain tumors, and then dive a little bit more into posterior fossil syndrome. And then in there, we'll be peppered with literature, the more recent literature on posterior fossil syndrome, and then we'll also talk about some research ideas for the future. So childhood brain tumors are the second most common tumor in childhood. They consist of about 16% of all new cases in childhood cancers. And over the last few decades, new cases of brain tumors in childhood have only increased. These are graphs from the National Cancer Institute. So on the very top line, it indicates that each year, that trend of new cases have only increased. However, that second line there is the death rate. And so with advances of chemotherapy, of immunotherapy, all these treatment options that we have for childhood cancers, the death rate over the last several decades have reduced, which is great. And along with that, on the third line there, the bottom graph shows that the five-year survival of childhood brain tumors have also improved over the last several decades. Now, again, that's great news for our patients and families, but that also means that we're seeing a lot more survivors of childhood cancers that are growing into adulthood, and they're dealing with long-term effects that we have to help them with. And so one can think about brain tumors in several ways. You can categorize them by histology. That's the most obvious way. But another way to think about it is by location. Now, location of brain tumors is important because one, it can determine whether that tumor is operable or not. And so, of course, if a tumor is deeply seated in the brain, in the brainstem, it may not be operable, even if it's a benign tumor. And two, of course, the location of the brain tumor can also affect what the functional outcome or the functional deficits of that child. And so it's sort of good to think about where that tumor is located in the brain as well. One sort of easy way to describe location of a brain tumor is think of a dividing line along the tentorium. The tentorium is this transverse fold of dura that's in between the occipital lobe and the cerebellum. And so all the tumors that occur above the tentorium are called the supratentorial tumors, and these are the tumors that occur in the cerebrum, in the pituitary gland, in the optic nerves, in the third ventricles, the lateral ventricles. So these are the supratentorial tumors. And supratentorial tumors tend to occur either in the very young or the older adolescents and young adults. Whereas the infratentorial tumors, the tumors that occur below or in the posterior fossa tend to occur in the kids anywhere from one to 10 years of age. And as you can see, they actually make up the vast majority of the kids with brain tumors. And accordingly, we see a lot more kids with posterior fossa tumors in our practice. And the posterior fossa area consists of the cerebellum, the brain stem, the fourth ventricle. And so with that, we also see a lot of kids who have posterior fossa syndrome. There's a reason why the word posterior fossa syndrome is in quotation marks, and we'll get to that a few slides down. But essentially what happens, it can happen after cerebellar or fourth ventricle tumor resection. The incidence varies from eight to 39% depending on the study that you read. And what's interesting about posterior fossa syndrome is that there can be a delay in onset of the syndrome. And so a typical story might be a child comes out of posterior fossa tumor resection. The day after, they're fine, they're talking, they're moving, they're eating. And then a day or two after that, the parents describe them as very irritable. They stop talking, they stop moving. And of course, the neurosurgery team wants to rule out complications like bleed or hydrocephalus. And once all the complications are ruled out, oftentimes the diagnosis of posterior fossa syndrome can be made. People also describe posterior fossa syndrome as having this acute stage that can last anywhere from one day to several months. There are various, a spectrum of symptoms that can fall under posterior fossa syndrome diagnosis. The most pertinent one, the most obvious one that people talk about is this reduced speech or even mutism. There's also an alteration in their speech pattern. One can also see some motor difficulties. So they're diffusely weak, they're hypotonic. They can have balance problems, apraxic. They're also ataxic. You can definitely see some emotional abilities, some irritability, or some kids are just very flat in their affect. You can also see some cognitive dysfunction. There can also be dysphagia requiring a feeding tube. You might also see cranial nerve palsies as well as some ocular abnormalities, nystagmus, eye bobbing, and opsoclonus, which is rapid, multi-directional eye movement. So again, posterior fossa syndrome is in quotation marks for a reason because it can be known by several other different names. Cerebellar mutism, cerebellar mutism syndrome, pseudobulbar palsy, and this can be problematic in that are we all calling the same syndrome by the same name? And even if you're calling the same syndrome but by different names, it can also be very confusing to the families that we're trying to educate them about this. And so with that mindset, this group of people, they're called the Posterior Fossa Society. They came out with a consensus paper and proposed that instead of posterior fossa syndrome and all the other names that were used in the past, they coined the term postoperative pediatric cerebellar mutism syndrome. And they based this consensus on a lot of surveys amongst their group. They also came together and had in-person discussions, presentations, and they surveyed yet again. And so this is the term that they coined. I think it's very descriptive in that it shows you how it happens, postoperative, who it happens to, pediatric, where it happens, cerebellar, and what happens, mutism. And so it's very descriptive, and I think it was purposely designed that way. But I can see that with a very long name like this, it's very difficult to remember. And I worry that it might be challenging for people to sort of remember what this full term is. And when it's hard to remember something, it's hard to sort of use it consistently, which then, you know, we're back to square one. But this is the sort of more recent proposed name. And I'm going to try to use this name throughout my talk, but I'm not making any promises. So just, yeah, bear with me. All right, so in this consensus paper, they also proposed a set of definitions describing this syndrome. So they said postoperative pediatric cerebellar mutism is characterized by delayed onset mutism, or reduced speech, and emotional lability after cerebellar, or fourth ventricle tumor surgery in children. Additional common features include hypotonia, and oropharyngeal dysfunction or dysphagia. It may frequently be accompanied by cerebellar motor syndrome, cerebellar cognitive affective syndrome, and brain stem dysfunction, including long track signs and cranial neuropathies. Mutism is always transient. And that sort of alludes to that sort of acute stage. But recovery from cerebellar mutism may be prolonged. Speech and language may not return to normal. And other deficits of cognitive, affective, and motor function often persist. I like this part of the definition in that it alludes to the fact that there may be long term effects. And I think it's helpful, because it's not all the time that you're diagnosing somebody with postoperative pediatric cerebellar mutism syndrome a day or two after surgery. It might be two years after surgery that you're meeting the child for the first time. And after you do your history, you find out that, oh, when they're presenting with their neurocognitive, neurobehavioral issues, this may be very much part of the spectrum of postoperative pediatric cerebellar mutism syndrome that they have. And so you might make that diagnosis, which I think helps with the clarity of their diagnosis, and helps you to sort of think about what are some of the appropriate interventions and resources that the child needs. So there's another group coming out of St. Jude's that also surveyed 56 specialists in the area, in the country, and internationally. And they came out with this paper last year. Now, they called it posterior fossil syndrome, so I'm gonna use that. And so what they did was ask the specialists to characterize what they think should all fit under the diagnosis of posterior fossil syndrome, and then rank these symptoms based on what is the most diagnostic symptoms. And so 3 quarters of them felt like, 66% of them felt like there can be a pathognomonic symptom, and 3 quarters of that 66% felt like mutism was it. But then there are many others in the group that felt that mutism doesn't have to be pathognomonic, because certainly not everybody has mutism. And so if you have some sort of speech dysfunction, emotional ability, and apraxia, those combined alone might be pathognomonic for posterior fossil syndrome. And with that, they also proposed their set of diagnostic criteria for the diagnosis of posterior fossil syndrome. So what they said was, if you meet criterion A and B, then you are good, you should feel comfortable enough to make that diagnosis. So criterion A is you have to have an acquired cerebellar injury, with symptoms in criteria B, C, or D that are emerging within the first two weeks after surgery, after injury. And they also said that if you meet criterion A and B1, that's also enough, so B1 is mutism. If you have mutism and then a little bit of other symptoms, then you're good. But if you don't have mutism, you have to meet criterion B2, as well as C or D. And so B2 is there's a significant impairment in their language, and then C is they've had mood change, and D is they have had some motor dysfunction. Okay, moving on. So why does posterior fossil syndrome occur? And in the past, there had been several theories and risk factors associated with this syndrome. For example, the size of the tumor. If it's more midline, you're more likely to have posterior fossil syndrome. A medulloblastoma can have higher incidence of posterior fossil syndrome. In the old sort of neurosurgery articles, they mentioned if the vermis is sort of split in half or disturbed, you could have sort of higher incidence of posterior fossil syndrome. But not all of these risk factors have been sort of proven to be true. And so the more recent sort of accepted theory on why posterior fossil happens is that there is a diascesis, meaning a disconnect along the dentatothalamocortical tract, which is delineated in that tract that, I have a pointer, but I don't think I can reach it. Nope, not gonna happen, okay. In that picture, you see the green and the purple. That's the tract that they're talking about. And so the, oh, thank you. The theory is, he's doing the pointer for me. That's really nice. The theory is that even with local injury, more distally, there can be disruption. And the theory is that there's a trans-synaptic generation happening. And so at the local level, the cerebellum is disturbed, but all the axons that otherwise would be synapsing with the axons downstream are affected. And therefore, you might see symptoms associated with not just injuries to the cerebellum, but also in the cortex. And so there have even been MRI and SPECT perfusion studies that looked at kids who have had posterior fossa syndrome and they put them in an MRI machine. And they saw that, for those who are affected by the syndrome, has shown a hypoperfusion to their frontal and temporal lobe that's contralateral to the cerebellar site of injury. Okay, so I alluded to some long-term effects, and we're gonna talk a little bit about them. And so in this study, they looked at 450 kids with medulloblastoma. A quarter of them developed post-operative cerebellar mutism. And they also tried to quantify or qualify those who had moderate severity, which meant their symptoms lasted one to four weeks, or severe, which meant their symptoms lasted more than four weeks. And then they re-evaluated these kids a year after diagnosis and found that those who had posterior fossa syndrome that lasted for four or more weeks had really persistent impairments. So the vast majority of them still had ataxia. 66% of them had language deficits. And 59% of them had neurocognitive deficits. And more recently, similarly, this group, I think also out of St. Jude's, looked at 60 kids with medulloblastoma. And they did a lot of various analyses, but sort of the takeaway is for those who have had more severe symptoms associated with posterior fossa syndrome, specifically the ones that had mutism after surgery, a year out in their group of 60 kids, none of them had a normal neurological exam. I think just one patient, 2%, with no return of speech. 14% with severe dysarthria. 26% of them were non-ambulatory. All of them still had ataxia, but the severity of the ataxia was improved. But half of them still needed a feeding tube. And so, let me go to the next slide. There also had been a lot of papers highlighting the long-term effects on speech and language as well as neurocognitive effects that is part of posterior fossa syndrome and that can persist for the long-term. And so these are sort of well-known. And the conclusion on a lot of these papers say that posterior fossa syndrome or post-operative cerebellar mutism is a risk factor for long-term deficits compared to match controls without cerebellar mutism at 12 months after injury. However, I would take that further and characterize these long-term effects as part of the spectrum of cerebellar mutism rather than cerebellar mutism being the risk factor. Because again, I think this is all part of a spectrum that may change over time, but these are the long-term effects of posterior fossa syndrome. And so my little thought bubble is that I think we should sort of consider more inclusion of the long-term effects than the definition and diagnostic criteria for posterior fossa syndrome. So traditionally, the treatment for posterior fossa syndrome tends to be more supportive. We engage with our therapists, our neuropsychologists, help out with the neurocognitive and neurobehavioral effects. And certainly, we wanna make sure that from an educational standpoint, these kids are receiving the right services and being supported in their academic setting. But in the last several years, there have been more and more case reports on pharmacologic therapies and for the symptoms of posterior fossa syndrome. I highlight this case report that also did a little bit of a literature review. And granted, these are case reports, and so the evidence is low, but this is where the evidence is now. And certainly, there's a lot more room for research down the road. So I'm gonna go over some of them. So fluoxetine was used in a couple of cases, and these were kids who had posterior fossa syndrome and mutism for a few weeks. And the authors describe giving this fluoxetine to these kids and within three to four days, the mutism improved. In one of the studies, they stayed on fluoxetine for nine weeks and the other one didn't really comment on that. And there were no side effects. There are a lot more studies, case reports, on bromocriptine, which is the D2 dopaminergic receptor agonist. And in most of these case reports, these kids have had post-reflufossa syndrome with mutism for a number of weeks. And what's often described is that within days of receiving bromocriptine, they started talking, the mutism improved significantly. The duration of the treatment really varied. I think one person only received it for a few days because they had side effects, but others received it up to six months in one of the cases. Most of the time, they were on it for about a month. So for the most part, they had no side effects, although one person had a hallucination and the other one who was only on it for a few days had restlessness and agitation. Zolpidem was used in one case. And again, they describe several weeks of post-reflufossa syndrome symptoms and within a few days of receiving this medication, the patient was a lot more alert, that their emotional ability improved, their mutism also improved. They were on it for a month and interestingly, their side effect is insomnia. Benzodiazepine has also been used in certain cases. This one case, they used IV midazolam because the patient was just really irritable and I think really irritable. And they described that within minutes, all the symptoms associated with post-reflufossa syndrome resolved, but it was not clear what all the symptoms were and the resolution really only lasted for three hours. And so I think then they switched to a longer-acting colobizam and they were on it for 10 days and they report no side effects associated with this. And at last, this present paper used haloperidol and dilirazepam, which is sort of a longer-acting benzo, and also found that within a few days, this child's irritability and behavior improved dramatically. He or she, he did develop some dystonic movements as side effects, so they switched to risperidone. And really took about 40 days before all of the symptoms of post-reflufossa syndrome resolved in this child. And so the authors sort of concluded that bromocriptine may be considered for use just because there's a few more case reports on this, particularly for those who have more of the sort of aconetic extrapyramidal symptoms, like mutism, and for those who are a bit more sort of flat-affected or have more sort of neuroaffective symptoms, you can consider fluoxetine as sort of your second choice. I think this is interesting. Obviously, these are case reports, and so again, the level of evidence is quite low. But for those who really have some problematic symptoms, instead of waiting it out, there may be some room for us to do some trials. And so I wanted to sort of bring this to this forum so that we can all sort of come together and talk about this. All right, and at last, this is definitely on the experimental side, but it was kind of fun, it was kind of fun to read through it. But anyway, so in this study, they used these like neuromodulatory device, and there's two components to it. One of them, there's this device that has this electric grid array that's very small. It's shown in the pictures there. That fits on the tip of your tongue. And what's connected to it is this sort of receptor, or they use this, sorry, I'm butchering this. So there's the tongue piece, and then there's another piece that goes around their neck, and they use this accelerometry sort of technology to detect the head position of the child, and then sense that head position signal to the tongue piece. And so if the child's leaning more forward, the front of the chip will then send an electric signal. If they're leaned a little bit to the right, then the right side of the chip will send an electric signal and essentially, it's sort of this sensory feedback to the child that gives them additional clues to what their body is doing in space. And then there's a second part that's also a thing that goes on your tongue that just sends this sort of non-directional electric signal. And the theory is it's using sort of that mandibular sensory nerve that goes back to the brainstem, and they sort of equate this to sort of deep brain stimulation, sort of using the tongue to kind of access the deeper part of the brain. So what they did was they also had these kids sort of wear these device and have them go home and participate in intensive home therapy for eight weeks. And there's sort of the static standing with the eyes closed component where they use the device that tell them direction of where their head is. And then there's another component that involves more sort of dynamic motor activities. And during those motor activities, they were aware of the other electric device that just sends that electric stimulation through the tongue. And after the eight weeks were done, these children sort of showed improvement in their motor skills and their balance. And of course, the obvious question is, was it really the device or was it the intensive therapy that really improved these children's functional level? And I suppose the easy study can be you can have a control group that does intensive therapy and another group that does intensive therapy wearing these device, but I don't think they're quite there yet. Anyway. So that's all I have. In conclusion, I wanted to introduce this new term, postoperative pediatric cerebellar mutism syndrome. I don't know if it will stick, but I'm gonna try. And I also wanted to talk about some long-term effects of posterior fossil syndrome. See, I already messed up. Postoperative pediatric cerebellar mutism. And would propose that there might be more consideration for incorporation of long-term effects in the part of the diagnostic criteria. And then I wanted to sort of highlight some of the case reports out there. That's kind of fun to read. So thank you. Thank you. I forgot to say that he is coming from Washington University in St. Louis at St. Louis Children's Hospital. And he's going to talk to you about, well, I'll let you introduce, chemotherapy-associated adverse outcomes. Good morning. So my name is Jared Levin. Today, I'll be talking about chemotherapy-associated adverse outcomes. I'm using this term because while we'll probably be focusing primarily on peripheral neuropathy, we're also going to be touching on some other adverse outcomes that we may want to address as physiatrists for our pediatric cancer patients. I have no disclosures, but I want to quickly thank my mentors, both during residency and fellowship, especially Kasia Ibanez at Memorial Sloan Kettering, who was my primary mentor in my training in pediatric cancer rehabilitation. I want to thank my colleague, Dr. Cherie Smith, at St. Louis Children's Hospital, who's covering today so I can be here. And I want to thank my co-presenters, who are lovely and amazing, and I'm very appreciative to get to work with them. A brief overview of today's presentation. We'll start by talking about chemotherapy as it's used in pediatric cancer patients. We'll move on to talking about some of the drugs that most commonly cause functional side effects and are thus salient to peds rehab. We'll then focus on chemo-induced peripheral neuropathy, move on to talking about some of the scales used to assess chemo-induced peripheral neuropathy, specifically in pediatric patients, and then we'll talk about some other adverse side effects outside of chemo-induced peripheral neuropathy. My goal on this presentation is to stay away from the basic and kind of talk about the available most up-to-date literature and point out the fact that there is not a lot of it and therefore help highlight some areas that we could really improve some of our knowledge base. So I think as part of every cancer rehab topic or presentation, we talk about the fact that there are generally three primary forms of treatment for most malignancies. These include surgical, radiation, and chemotherapy, depending on the type of tumor, the spread of disease, its qualities, sometimes chemotherapy is the primary or only form of treatment. The majority of chemotherapeutic agents work by disrupting cellular division, while there are a couple of other agents that have alternative functions. And then in most cancer rehabilitation presentations, we always bring up the fact that we're getting better and better in helping patients survive cancer, but that that often comes at a cost of higher and higher debility. In pediatric patients specifically, we're able to treat them more aggressively than in adult patients, and as we'll talk about later in the presentation, kids tend to be more prone to developing side effects from chemotherapy as well. There's also a pretty strong correlation between overall dose of chemotherapy, frequency, length of treatment, and the risk of side effects and side effects severity. When talking about cancer rehabilitation in general, it's important to point out that one of the things that makes it rather unique is not only is the acquired pathology causing functional deficits or affecting the patient's quality of life, but also the treatments often do. So chemotherapy is one of those treatments that can very significantly affect a patient's function, which is of course the point of this topic. And then what makes pediatric rehabilitation unique relative to adult is that oftentimes you have patients who are developing and learning, gaining milestones. Their body is physically changing, and so anything that leads to a loss of function can more significantly affect the patient's development longitudinally. So just talking about some of the chemotherapeutic agents most likely to cause side effects affecting function, there are the neurotoxic drugs, cardiotoxic drugs, and then I will briefly in this presentation talk about the pulmonary toxic drugs and its effect, our chemotherapy's effect on the hemopoietic stem cell line as well, but we'll keep that rather brief. In terms of the neurotoxic drugs, we primarily focus on the microtubule affecting, which are the vinc alkaloids, and then the platinum based toxins, which are the cisplatin, carboplatin. There are a couple of other agents. When people think of cardiotoxic drugs, they most commonly think of the anthracyclines, though there are some other drugs that can affect pediatric cardiac function as well. So according to some studies, including a study by Gilchrist et al., CAPN, chemo-induced peripheral neuropathy, also known as CIPN, can affect up to 80% of patients receiving chemotherapy. Some more recent studies show that number in kids can be as high as 90%. We know that there are a number of studies showing that kids are more prone to developing chemo-induced peripheral neuropathy relative to adults, and we'll talk about that a little more in detail as we move forward. Again, the two most common agents to cause chemo-induced peripheral neuropathy are vincristine and cisplatin. That's not only because that's their primary side effect, but also because these are two of the drugs most commonly used in most chemotherapy regiments across the board for the different pediatric and adult malignancies. Chemo-induced peripheral neuropathy can occur in all patients. So when we talk about risk factors, well, I want to highlight risk factors. I think it's important to point out that monitoring for chemo-induced peripheral neuropathy should be considered regardless of the patient's age, ethnicity, what treatments they're receiving. Again, probably the strongest exogenous correlate is the amount of total dose of drug the patient is receiving. We know that the use of azoles can increase the risk of CIPN, and we'll talk about some of the endogenous risk factors as well. So as I said before, kids are more prone to developing chemo-induced peripheral neuropathy relative to adults. However, interestingly, what we find is older pediatric patients are at a higher risk. So there's a lot of literature showing that kid children over the age of 10 are more prone to developing chemo-induced peripheral neuropathy relative to patients under the age of 10. I suppose there's some question as to how much of that has to do with our ability to study some of these patients in the lower age ranges, especially, for example, with things like the neuro-oncologic tumors, radiation is not an option for patients under the age of three, and so they tend to be treated primarily with surgery and then aggressive chemotherapy. We know that patients who have congenital neuropathies are at a much higher risk of developing CIPN, and so it's generally recommended to be cautious about using such medications as vincristine and cisplatin, the most commonly well-known is Charcot-Marie-Tooth disorder. As we've gotten better at doing genetic studies, there has been a push to try to identify what genetic factors may increase the risk of chemo-induced peripheral neuropathy. The majority of the literature right now is these genome-wide association studies. What they do, it's a cross-sectional cohort study, they take a large population of patients being treated with chemotherapy, they identify those who have peripheral neuropathy and those who do not, and they give everyone whole exome sequences, and they try to look for what genes come up in the patients who have significant chemo-neuropathy versus those who don't. These studies have identified a couple of genes, I'll just highlight two of them, CEP72 in vincristine neuropathy and RPRD1 in cisplatin-induced peripheral neuropathy. I do want to point out with some of the more recent literature where they go looking at patients specifically who have these mutations, the literature does not as strongly suggest that it increases the risk factor of developing these neuropathies, but these are still studies that are significantly underway, mostly from 2017, 2018, and moving forward. So vincristine-induced peripheral neuropathy, this is probably one of the better studied, more talked about chemo-induced peripheral neuropathies, both in adult and pediatric patients. Vincristine affects the formation of microtubules, which can therefore inhibit the metaphase of mitosis. Microtubules are also important for transport of material up and down the axon, and we believe that inhibiting both of those processes can lead to apoptosis of the cells. Because of this we get an axonotomesis-like picture within the nerves when using electro-diagnostic studies. Vincristine-induced peripheral neuropathy is significant because it's both a motor and sensory polyneuropathy. We tend to talk about it as being an ascending neuropathy, similar to a stalking love neuropathy, though I'll point out, both in my experience and in some of the literature, it tends to present in a more pseudo-fibular pattern, or pseudo-peroneal pattern. And what I mean by that is after the patient presents with some painful paresthesias and maybe some numbness in the feet, in terms of the motor symptoms they develop, you'll first generally notice EHL weakness, then tibant and eversion weakness, and then progressing more proximally. Not every patient presents like this, but that tends to be the most common motor pattern. We know that pediatric patients develop more motor deficits relative to adults, and they can also develop cranial nerve and autonomic deficits. It's also important to note that there's this phenomenon called coasting, which is where even after the drug is reduced or stopped, the patient can continue to get worse for two to four weeks. I think the majority of the available literature on VIPN is discussing the course of it. The literature is admittedly very, very varied, and that likely comes from the mix of different patient populations, the diagnostic criteria used to identify the peripheral neuropathy, whether it's patient-reported, just a diagnosis made in the chart, whether one of the peripheral neuropathy scales were used, or whether electrodiagnostic testing was performed. Most of the literature will say that chemo-induced peripheral, or VIPN, will develop within the first month of treatment, although some of the more recent literature generally will suggest in the first two weeks. The peak effect, or the peak of neuropathy can be anywhere between four to six months, and again, some of the literature is now showing that that peak can occur earlier on in the patient's course. There is some literature showing that the VIPN will start to improve within a month of holding or reducing the dose. However, there are other studies, including one by Tay et al., that shows that patients can show no evidence of improvement for up to one to two years. Again, I think some of this comes from what sort of study we're using to identify the neuropathy, as well as what sort of treatment the patient's undergoing. Again, the study from Tay et al. showed that about a third of patients still had peripheral neuropathies two after treatment was stopped, or two years after treatment was stopped, excuse me, via the MPEG's TNS, but via EMG was as high as 70%, or 68%. So in brief summary, the literature really varies in terms of talking about the risk, onset, and course of Vincristin-induced peripheral neuropathy, but I would suggest that we understand this is essentially a axonotomesis-like picture. The more aggressive the patient is treated, the more likely they are to have long-term deficits or even permanent deficits, and the more aggressively they're treated as well, probably the risk for that increases. However, we really have a paucity of prospective literature using standardized outcomes to try to identify this in pediatric patients, and there's a lot of opportunity for research moving forward. However, in general, we can say the prognosis is generally favorable. Most patients will have some degree of recovery, if not full recovery, after treatment is stopped, but that can't be guaranteed depending on the patient's treatment and their clinical course. Moving on quickly to talking about cisplatin-induced peripheral neuropathy, I apologize, I'm a little bit behind, so I'm gonna start speeding up. In terms of the platinum-induced peripheral neuropathies, the major difference from vincristine is that these are generally sensory neuropathies only, as these drugs tend to primarily affect the dorsal root ganglion. I like to bring that up with residents and then ask them if it only affects the dorsal root ganglion, what sort of neuropathy do you think they'll show? Again, it works by creating permanent cross-bridges between GNC bases, which inhibits the ability for the cell to divide, leading to cellular apoptosis. Again, that's gonna lead to an axonotomesis-like picture. Cisplatin-induced peripheral neuropathy is also evidence-coasting, and then patients are at risk of developing both ototoxicity and vestibular toxicities. There is a small amount of literature, actually, primarily in the adult population, showing that vibration may be the first or most sensitive finding, vibration deficits. In pediatric patients, salient to us as rehab physicians, because of the loss of their proprioception, they're at risk for kind of these ataxic-like gait patterns, loss of balance, although you will occasionally have the patient who can touch the hot stove and not feel anything. Generally, it's recommended patients receive hearing tests. These are generally performed or ordered by the oncologist. This tends not to be in the hands of the physiatrist. However, it is important to note that vestibulopathy is a possible occurrence, and being able to perform vestibular testing can be a very useful skillset to have. We actually have a little bit stronger literature in terms of the overall course of cispline-induced peripheral neuropathy. We know that symptom onset generally occurs around 300 milligrams per meter squared, with almost all patients having deficits by 500 milligrams per meter squared. And we also know that, again, these deficits can be prolonged even after chemotherapy is stopped. Another limitation in terms of assessing the cispline-induced peripheral neuropathy that we'll talk about in a second is that the majority of the outcome scales or diagnostic scales we have for these chemo-induced peripheral neuropathies focus on vincristine and, therefore, study motor deficits along with sensory deficits. And then, of course, most patients are gonna concomitantly receive vincristine and cisplatin at the same time, or depending on the protocol, many, many do, and so parsing out what is related to what can be very difficult. So because of this, I'm going to kind of talk about managing chemo-induced peripheral neuropathy more broadly in terms of things that you can do to affect the progression of the disease. The mainstay is dose adjustment. However, there's limited guidance guiding many of the protocols for this. This oftentimes is a decision made by the oncologist, but depending on your practice, you may be able to communicate with the team and help the oncologist make decisions. As a physiatrist, we're often involved to help with symptom management, help the patient walk better, help control their neuropathic pain, help improve their function, independence, and quality of life. So, again, most of the literature you will read will point out that it's highly advised that we have screening for all patients receiving chemotherapy to identify these deficits early. In practice, this is much harder to accomplish, and there isn't a lot of literature available showing improvements by doing this, but just speaking personally, I have a number of patients where you don't end up seeing them until they're very severely affected and you feel behind the eight ball, and of course, treatment for them can be much more challenging. The majority of the literature that we have supporting the things we do come from referring patients to physical and occupational therapy, which is shown to be strongly beneficial for patients. There's not a lot of literature guiding bracing and bracing management. In general, I would suggest the use of stretching braces early on because patients tend to be bed-bound for long periods of time. Plus, if they are receiving vincristine, they're at high risk of developing foot drops, so preventing Aquinas contractures can be very useful. And then bracing from that will be based on the patient's deficits and suspected likelihood of progression of their deficits. With the vincristine population, I tend to prefer AFOs that have a dorsiflexion assist component for this reason, either hinged AFOs with a dorsiflexion assist, or if you're gonna use something more like a posterior leaf spring or carbon fiber, something that can also provide some subtalar support as well because they tend to have pretty weak eversion control. In lower level patients, just speaking personally, we'll oftentimes also prescribe things like foot orthotics, but there's no literature for that. Again, I think a great opportunity for further study. So there's been a couple of studies looking at medication, medical prophylaxis for patients receiving chemotherapy to prevent peripheral neuropathy. And in short, none of them have been shown to do anything. Some of the drugs most commonly studied have been gabapentin, glutamine, and pyridostigmine. For neuropathic pain, probably the medication with the strongest literature behind it is gabapentin. Though there is a pretty interesting study from 2018 showing that opioids are non-inferior to gabapentin. I would suggest, of course, if you're gonna treat a patient with one of the two drugs, gabapentin may be in some ways more benign, but of course, if they can't tolerate it, that is an alternative option. There is far less literature looking into some of the other medications and some of the literature doesn't as strongly support their use. Just a quick mention, both because a lot of the chemotherapeutic agents are going to cause cytopenias as a result of affecting the bone marrow and because there can be concerns about recommendations for use of occupational or physical therapy while patients are cytopenic. There's a growing amount of literature now showing that involvement in physical therapy can be symptom guided with a low risk of developing things like a hemorrhage while a patient is severely thrombocytopenic. Letting a patient tell them, tell you if they're feeling out of, short of breath, if they're anemic, things like that, that those are safe ways of going forward with guidance for physical therapy and occupational therapy. Okay, I'm gonna move more quickly. So the original scale is the CTCAE. This is a guideline used in many chemotherapeutic protocols. It breaks down severity of all sorts of side effects into grades one through five with recommendations to hold or dose adjust with grades four to five or three to five, depending on the study. The main problem with this, especially with the peripheral neuropathies, is that these guidelines can be seen as rather obtuse and nonspecific. So grades three, four, and five here would be severe symptoms, limiting self-care and ADLs, life-threatening consequences, and death. So again, the specificity of what that means can be highly variable. In fact, a really interesting study from PASMA et al showed that the rate of reliability was really poor for deciding what grade the CTCAE was for peripheral neuropathy side effects. Furthermore, there's been a lot of studies showing that other forms of measurement are far more sensitive, especially early on in the patient's treatment course. Because of this, there have been a number of chemo-induced peripheral neuropathy-specific scales. I'll highlight two of them, both derived from the adult TNS scale, which is a scale meant for adult vincristin-induced peripheral neuropathy. Gilchrist's PEDS MTNS and the pediatric vincristin TNS are the two probably most common used scales, both probably clinically and in the research. They're overall shown to be more sensitive than physical exam or the CTCAE alone, and they tend to have the largest number of studies supporting them. They're rather complicated to perform and involve the use of a number of tools that aren't generally available in most clinics. You have to have a whole set of Seams-Weismann monofilaments, you have to have these MediPens, and you have to have a biothesometer, which is a type of vibrometer which isn't even available anymore. You can buy it on eBay, I looked it up, it was like $900 was the cheapest I was able to find. Because of that, there's more studies coming up more recently using more reasonable equipment, such as a general pinprick, a tuning fork. Specifically the TNS PV, there's a couple of studies now where they use the tuning fork, and the major difference between the MPEDS TNS and the TNS PV is the decision to move away from an actual needle or pinprick to using just cold sensation because we know kids don't like needles. While these tests are likely more sensitive and specific than some of the other things, they're not without their problems. They're broken down into a survey component and a physical exam component. The survey component has been shown to be highly non-sensitive or specific, especially a lot of these patients are gonna be receiving things like high-dose steroids, so they may be feeling unwell in many other ways, so asking them if they have any pain or feel weak may not be a very useful tool. Furthermore, with things like the physical exam, you identify their manual muscle testing score in every area and then only score them by where they're the weakest, which is generally gonna be in the toe. So if they're a zero out of five in the toe, it doesn't matter where they are distally. Because of this, there's likely areas for further research and probably things we could do to develop more convenient and sensitive and specific tests. Again, because I'm a little bit over, we're gonna move very quickly through some of the other adverse events. We'll talk quickly about the cardiotoxic drugs and the pulmonary toxic drugs. The anthracyclines, again, are the most commonly studied. In tyrosine kinase inhibitors, 3-ephate are some of the other drugs that have been shown to be cardiotoxic. Some of these drugs are more commonly used in the leukemia population as opposed to the neuro-oncologic or solid tumor population. They generally result in a congestive heart failure-like symptom, generally with a systolic failure. Most of those symptoms are generally managed by a cardiologist, but of course, this would be a good area to perform cardiac rehab. While there is some literature in the adult population on this, I was personally unable to find any literature on the pediatric population on cardiac rehab for cardiac toxicities. Again, a likely area that we could look for future research. And lastly, bleomycin can be used for some of the lymphoma population and some germ cell tumors. It's not commonly used in the pediatric population. It tends to cause a more obstructive than restrictive disease on pulmonary function tests. And interestingly, in the pediatric population, most of the time, the deficits are shown to be subclinical with the patient not reporting any symptoms despite findings on pulmonary function tests. We know that the younger the patient is and Caucasian patients are at a higher risk for this. But again, because these findings are generally subclinical, there's no research on doing any sort of pulmonary rehab for these patients. So I apologize for breezing through the last couple of slides. I think the main point is, while we do have a good amount of literature guiding some of our management, there are a lot of opportunities for us to move forward and try to identify ways that we can develop literature or studies that support the things we do. Especially in the cancer world, it would be very useful to be able to go to our oncology populations and show, look, when you put these braces on, patients walk better and I have studies to prove it. I'm not just saying it, that's what, you know. I'm not just doing it based on my experience. Thank you very much. Now we'll be hearing from Dr. Chaviano. Good morning, everyone. Thank you guys so much for being here today. So let's go on this journey together with graft versus host disease. All right, so similarly to my colleagues here, we're gonna go through diagnosis, differentiating some of the differences between acute and chronic GVHD. We will be describing and discussing some of the more recent literature and then talk a little bit about some room for being able to do a little bit more research in this area. I have nothing to disclose. All right, let's define some GVHD. So GVHD is an alloreactivity from allogenic stem cell transplant. And so, as a reminder, autologous is when cells are harvested from the patient and then allogenic is when cells are harvested from the donor. It's T cell mediated and, you know, kind of thinking back to med school and thinking about the cells that have the highest turnover rate. So we're gonna see that there's an effect in the skin, GI, and liver. Now, specific for pediatrics, there are certain risk factors to consider in GVHD, chronic GVHD. So prior acute GVHD, donor recipient, disparity in the HLA, and we'll kind of get to that in a second, and then patient age, a little older patients. And so, just again, talking a little bit about why the donor site matters and usually when I get these consults or I'm outpatient and I see some of these different patients, I do pay attention to how they got those donor cells. And so essentially, when we have greater HLA mismatches, we have a greater risk for GVHD. And there are very specific populations, black population, Hispanic, Asian Pacific Islanders, where we have these increased HLA polymorphisms. We'll notice that we have less GVHD in those that have matched sibling transplants. We'll have a little bit higher of a risk for those that use peripheral blood stem cell and then we all know that there is an impact on quality of life for those that have chronic GVHD. A little bit more research is needed in the haploidentical family donors, but hopefully that will be helpful in the future for quality of life. Okay, so we've got some classic definitions and then we have some subtle and more nuance on the right side that we're gonna go over. Okay, so we have classic definitions. So we have acute GVHD is less than 100 days post-transplant and typically when you see things like rash, diarrhea, abdominal pain, rising bilirubin, you can pretty much say yeah, this is acute GVHD. You can also have some histological confirmation of that and then you have kind of this general definition of yeah, greater than 100 days post-transplant, you can see chronic GVHD. But it's not that simple like anything else, right? So we have a NIH consensus criteria that goes into these subclassifications where you have it based on time and something called the diagnostic and distinctive features of chronic GVHD. And that's how we kind of get these nuanced subclassifications of classic acute GVHD, persistent recurrent late onset acute GVHD, classic chronic GVHD, and then an overlap or acute on chronic. And busy slide, can't really see it very well. Main point is we have diagnostic features which are pretty sufficient when you see those to diagnose chronic GVHD. And then over on the right side you see distinctive that you're like, eh, maybe this is seen in chronic GVHD but we're gonna need some more evidence. So for example, look at skin, sclerotic features, that's fairly diagnostic. Distinctive, not quite there, is depigmentation in skin. Okay, so in terms of diagnosis and grading, acute GVHD, we have the MAGIC criteria, we have the Glucksberg, and then we have the IBMTR. And so, again, it's a lot of type. But I think the main point that I wanna have you guys look at is, again, skin, liver, and gut are within those, really the organs that we pay close attention to, then do our staging on. Okay, so again, a lot, go neon this adventure. My favorite slide here is the ECOG versus Karnofsky and the Lansky, and for some of you guys who are not familiar with this, this is something that I use as a teaching tool and also helps us from a rehabilitation standpoint have a conversation with our oncological colleagues about what they define in terms of function and disability and how we can kind of have that crossover conversation. And so, on the left side, you see there's ECOG, in the middle, there's Karnofsky, and on the last bit, there's Lansky. And so, again, for some of you guys who aren't familiar, the difference between Karnofsky and Lansky is really adult versus kids. So kids is really the Lansky aspect of things, graded from 100 to zero, and then you'll see it's kind of like the opposite, where ECOG is zero, but if it's a Lansky, 100, and then it all goes, it goes all the way down to dead, so you know. But one thing to kind of think about is there's some sort of equivalence to this. So if we hire a Lansky 70, you can see we have both greater restriction of and less time in play activity, and then why I love this is you can go all the way to the ECOG and be like, okay, that's equivalent to a one. And why am I spending time on this? That's because when we have a chronic GVHD diagnosis, we use the NIH consensus criteria for organ scoring, and we help kind of determine whether we have a mild, moderate, or severe case, and we get to use these ECOGs specifically within them. Again, lots of type, but we're gonna go over the very top one, which is the performance score, which we just went over, and then over on that right-hand side, you see joints and fascia, and we're gonna go over the PROM scores. Again, you can see this involves pretty much all the organ systems, right, but we're gonna focus a little bit more on those. Okay, we've seen this slide already, but just so you can see a little bit better, you can see that it's a score from zero to three. Zero being asymptomatic, ECOG is zero, KPS or LPS is 100%, all the way over to score three, symptomatic, limited self-care, greater than 50% of waking hours in bed. So our ECOG is equivalency to a three or four, KPS or LPS is less than 60%. Again, I use a Lansky score for kiddos that are 16 and below, and just kind of a note on Lansky's and Karnovsky's. We all know that FEMS and WeFEMS, we have to go through a lot of training to do and kind of reduce a lot of subjective bias, but the Karnovsky and Lansky's, you don't need training to do, so there's a lot of risk for rater bias in this. All right, I promised we would go over this. This is kind of the musculoskeletal component of the photographic range of motion, or the PROMs. As you can see, it's a scale looking at different joints, the shoulder, elbow, wrist, finger, and ankle, and it's basically looking at the range of motion and then giving a scale from one being worst all the way to the right, seven being normal. And so once you add that up, you can see that little box over there that says the shoulder, elbow, wrist, finger, and ankle, and kind of how that's graded. You can then determine what that score is and then do a score of zero to three. So this is something I actually use in clinic or in consults when I see some of these different patients. And so with pediatric considerations in the most updated NIH consensus criteria of 2014, the two-minute walk is used in the adults but not as much in the kids. Also, there were particular scales, the ASC and the CHRI, that was used to assess quality of life. The PEDS QL has been suggested for actually continued use from the 2014 one on. Because they're kids, we may need to repeat the PFTs due to limited cooperation from kiddos. And then before, the Least Symptom Scale wasn't really useful or helpful for pediatrics, but now they're like, hey, you know what? If we get some help from the caregiver, have the PEDS help out a little bit more with some of these questions, then we may be able to use the Least Symptom Scale. And just for some of us who need to know what that is exactly, here it is. Again, it's not that great to see, but just to hone in on eating and digestion, energy, and mental and emotional as kind of functional components of this scale. On a scale of zero, not at all, having effects, all the way to extremely as four having a lot of effects. All right, we have talked about the diagnostic features and things to talk about for acute and chronic GVHD. Now we're gonna move on to treatment. All right, so as you can see here, I was very general in talking about just the different medications that we use. And you'll notice there's kind of an overlap. We have some in prophylaxis, we've got some of the same ones in treatment, and a lot of these that we recognize. I'm gonna take a moment, and for some of us and some of our learners who are not familiar with this, this is the ICF function of the WHO classification that kind of helps us determine function and disability. And I love this graph. I think this is a really good way to approach disability and function. And so I was actually really inspired by some of our colleagues in cancer rehab who have written kind of how to address this in terms of impairments versus activity limitations and participation restrictions. As a review, we have impairments which affect the body, activity limitations, which is ADLs, mobility, eating, kind of your basics. And then you have participation restrictions, which is more like how are your limitations affected within your community, how you're going to work, how you're going to school, things like that. And so again, a lot of type, but to orient you, we have prophylaxis slash treatment options here on that left side. And then I have rehabilitation considerations at the top. We have impairments kind of in the middle, talking about what's affecting the body. And then over on that right hand side, activity limitations and participation restrictions. So shout out to some of those. Actually, they're here in the audience that helped to create this graph. And basically what I did is I added a couple of different points and then I took some of the medications and then just mentioned some impairments and things that I've seen just in my experience. And so let's go over one that we definitely have seen before, some methotrexate. We definitely can see some neurotoxicity in terms of impairments, cognitive impairments, developmental delay. We can have osteoporosis, we can have bone pain. Then we scooch on over to the activity limitations, participation restrictions. We can have impaired school performance, impaired age appropriate ADLs, limited participation in athletics and sports, impaired self-esteem, impaired social incompetence, loss of motor function, which thus impairs more of your activities and limitations in terms of participation restrictions. I have some more. So again, this is here for your reference. We don't have to go over all of these. But again, this is just for your reference. When you get a patient, you're on a consult and you quickly look, okay, what have they had? This, this, this, great. What's the worst case scenario? These risk factors, great. Let's see what they have when we go in there. That's kind of how I approach this in real time. All right, we talked about treatments. Now let's talk about the updates, which of course, I think the theme of the day is there's not enough and we all need to get together and do some research so we can do some more on this. All right, I love this table. So if the authors are here, thank you so much for making this table. I use this for teaching all the time. Why do I love this? We have the organ systems, we have the clinical findings that are specific, and then you have the symptom and the impact, which is so functional when I'm able to be like, okay, I know this is involved, this is involved, worst case scenario is blank. What do I need to go in and do for education and what do I need to look for? We're gonna actually focus a little bit more on the neuromusculoskeletal system. I added a couple things just based on experience and then I'm gonna do a little bit more on the cognitive aspect of it. Again, very busy, but I'm gonna go over a couple of these, again, I base this on ICF WHO models. So you have impairments, activity limitations, participation restrictions. So on impairment side, you see we've got pain, arthritis, peripheral neuropathy, impaired sensation, so on and so forth. And the big one, of course, will be sclerodermal or lichenoid skin changes. Activity limitations, all your basics, all your bread and butter of rehab that you're gonna be concerned with. For our adult colleagues, I would pay a little bit more attention to how that child is playing and how that affects them. And so for instance, I've had kids who are upset that they can't brush a doll's hair or they can't play with their toys as well or they're not able to play with their peers or there may be peer and social concerns like cosmetic differences that they may feel a little bit more embarrassed about or things like that. Kind of teasing that out in the clinic setting is really important. And then of course, again, we have to think about school. What can they do or not do? So are we impaired in art, music, or is our handwriting or typing? Do we need some sort of accommodations for that? And then of course, a playground. If we have a lot of contractors, how does that affect the way they're able to be in sports or a playground, things like that. And so again, we're doing the same thing for neurocognitive effects. And so thinking about mood disorder, fatigue, depression, anxiety, slower processing speed, weaker verbal learning, communication disorders, speech delay, and just some of the same different things that we kind of talked about before. We have some activity limitations and participation restrictions based on school or how they're doing with peers, social concerns, things like that. And of course, biggest thing, concern for developmental delay. All right, so some updates in terms of specific treatments. So we have, in terms of the PTOT world, we've got some literature that suggests that aerobic activities, manual stretches, articular motion, endurance training, strength training, and yay for Nintendo Wii, it's pretty great for all the nerds out there, massage, parent training, ADL training, and gait training. Classics, but at least there's some literature to suggest that and have those updates up there. We need more on energy conservation techniques and contract, relax, contract techniques, which to my DO colleagues, that is within the same family of muscle energy, so that's pretty awesome if you wanna be able to do some OMM on the kiddos and maybe make some functional gains in the future. Who knows? Speech therapy, of course, kind of your classics. Orthotics, unfortunately, I put a little asterisk there because there's no specific research for PEDS GVHD, but yeah, we should totally do that. We're kind of doing, we're using all of our rehab and adult skills to kind of apply some of these thought processes. Kind of these classic modalities, things to think about, equipment. I'm doing a plug for OMM. So that's because, I actually had a couple of patients that I saw outpatient that I would do a pre-PROM score, do some muscle energy, indirect and direct myofascial treatments, and then I would have improvements of their PROMs after. Was it functional? I don't know, but it was a few degrees and the kids were usually pretty happy and the families were pretty happy after they got these treatments. So I think there's definitely an opportunity to look more into this. Mood disorders, again, lots of asterisks there in terms of treatment limitations and updates for things, school, pain, nothing specific. So man, we got some awesome work to do, you guys. All right, so opportunities for future research. I think a lot of this is leaning on our adult cancer rehab colleagues who have done a lot of work over the past 100 years or so. Kind of like starting to get their foot in the door and really start developing these beautiful chapters and research, like let's kind of, let's call them up, let's try to do something, let's make something PEDS-y out of that research. And I think there's a huge opportunity for that, to reach out to our cancer rehab colleagues. Honestly, just talking to oncologists and saying, so what studies do you have going on? You wanna insert some FEMs or WeFEMs, is that possible? Can we do something like that? Also one day, future research would love to do some sort of crossover between ECOG, Lansky, Karnovsky's, and how that equates to FEMs and WeFEMs, and if there's something prognostic to that. In my like, my very little experience of this and kind of doing this the past several years and what I've seen, I've seen things like if we are at a Lansky 40 for like two weeks, we have more likelihood of going into inpatient rehab. That is just me, that is just what I've seen. Maybe some of us have seen something similarly and we can do a research paper together. I think also leaning on some of the other research that's been done in other research, like contractor research, sclerodermal, so that way we can kind of crossover into doing some more for GVHD. Again, it's time to move on beyond some multi, some case series and reviews, let's do some multi-site collaboration. And of course, my plug for OMM, I will always do that. All right, humongous shout out to all of these awesome people that have been influential in my life. And I see some Michigan State colleagues in the back. I like am so happy that you guys are here. So thank you guys for coming in for support and really y'all's presence, just being here in this audience, every one of you are making a difference because there's obviously this interest in exploring and doing more with peds oncology. And so, thank you for joining us today on that adventure. Thank you. I think it's time for questions if you have any. Yeah, I was going to say, is this okay? Yeah. Dr. Shavano, don't worry. I think we all heard that y'all in there, so your Alabama is showing now that you moved. This question is for Dr. Levin. I had a question about as we are starting to understand and maybe the mechanisms of gabapentin a little bit more and its impact maybe on the dorsal root ganglion, have you noticed any difference in efficacy of gabapentin on like a cisplatin-induced neuropathy, which affects more that dorsal root ganglion as opposed to maybe a vincristin-induced neuropathy, or have you noticed other agents being better for peripheral-induced neuropathy or for chemotherapy-induced neuropathy either way? So, I'll be honest. I and my colleagues started our practice at our current hospital about two years ago, and so for the most part by the time we're still establishing ourselves with the oncology practices. So normally by the time we're consulted, the patient's not only on gabapentin but probably on an additional medication as well. So I would have trouble answering that because I would say with about 90% of the patients, we see by the time we're consulted, they're already on gabapentin. It sounds like you and St. Louis have the same thing we do in Kansas City. They put gabapentin in the water in the state of Missouri, so thank you. Thank you. So in regards to the new name for posterior fossa syndrome, which I've already forgotten, but there's definitely a lot in the literature about what's the best way to treat it. I know you talked about BROMO a little bit as well, but there is definitely those combinations of do you do an SSRI first or do you do a dopa agonist versus... And I think previous, prior to your BROMO, there was a couple of Mantadine studies. There was a Ritalin study and for at least clinically, we kind of use a combination. So personally, what do you use and has this literature affected how you do your practice? Good questions. I'll be honest. Historically, I haven't tried pharmacologic interventions. I think a lot of the really irritable kids, especially if they're really, really young, they tend to go home and then maybe later come back for inpatient rehab considerations. So I think if I were to start, which I might, especially if there's certain symptoms that are just so profoundly impactful to the patient's function, mutisms, for example, if they're super irritable, I think it probably just depends on what is the more problematic and prominent symptoms that child has and then sort of gear your therapeutic intervention toward that symptom. And so I think a lot of these case reports sort of indicate that if you have more of the sort of aconetic aspect to their symptoms, you might treat with BROMOcryptine, whereas if you have more of a neuroaffective type symptoms, then it might be the SSRIs. And there's also other sort of adult studies that use like Modafinil, for example. And specifically this one case report sort of used it on somebody who has sort of that really flat affect and SSRIs didn't really do anything and so they tried Modafinil and then within days they had an effect. Yeah, we've had some success, especially obviously a lot of these kids get the pseudobulbar and then switching to like an SNRI and then once you get that, then we work on one of the various dopamine agonists. And again, it varies just based on what you choose and if you're going to go for your rather antidepressant category, you know, you got your three main ones there and then once you know what your chemical component of that, then we kind of look at our dopa agonist category. Um, I have used imantadine. I personally prefer ritalin over imantadine if I'm going to use a dopamine agonist and I know we talked a lot about this at, you know, Stacey talked about it when she was doing her talk on brain injury and DOCs. I personally prefer to use a ritalin and looking at more of the norepi component first and then adding dopamine on top of that, because I think a lot we can initiate we have and I think there's a lot of initiation factors that are more of an issue than arousal. So I rather use more of that ritalin norepi component and then I start looking at if that's not working. To kind of piggyback off of that question, I think you presented a wide range for the acute phase of post-operative pediatric cerebellar mutism, PCMF. Do you have any thoughts on discerning from, like, natural healing or natural course versus medication effects? Yeah, I don't... I think in, well, in most of these studies that looked at the natural progression or the ones that hint at long-term effects, I don't recall them commenting on the use of any sort of pharmacological intervention. So my assumption is that this is more or less a natural progression as opposed to drug effects. Yeah. I'm going to piggyback off of the natural progression question. When do you start it? A lot of times I'll wait... a disservice to not start it earlier too, but every med has side effects. So I struggle with that a little bit sometimes and worry that I wait too long. Yeah, I think that's a good question and it probably depends on the child, the family, and what the circumstances are. In most of these case studies, I think at least the majority of them waited a few weeks or they tried something first and it didn't work and they tried something else. I guess it also depends on the severity of the symptoms. If truly something's so dysfunctional that the child just has a lot of dysfunction and the family is distressed, then that might be a good time to consider some of these interventions. But if things are okay, they're hesitant about starting a new medication with potential side effects, then might you wait a little bit? Yeah, I don't think I have a clear answer on that because I think that there isn't a clear answer. because I think we need to go to Plenary anyway. 50% of the kids still may require G-tubes when they have posterior opposing syndrome. So I've been in institutions that have... Preferred to wait, but then that's closer if they're getting chemotherapy or radiation therapy And then they don't want to pursue it because of healing issues So are there any true standard recommendations for long-term nutrition at this moment or? Not that I'm aware of I know at our institution People tend to be a bit more conservative when it comes to g-tube placement If truly the child has obvious sort of significant neuro neurological Dysfunction then yes that consideration is much more to the forefront, but I would say vast majority Knowing that a lot of these symptoms could potentially get better. They choose to wait and just have that ng2

posterior fossa syndrome

cerebellar tumor resection

mutism

emotional instability

motor difficulties

cognitive dysfunction

pharmacologic therapies

neuromodulatory devices

chemotherapy-induced peripheral neuropathy

graft-versus-host disease

neuropathic pain

pediatric oncology