Good morning, or good afternoon, depending on where you are. Welcome to the 2020 AAPM&R Virtual Annual Assembly. This session is a live session, point-counterpoint, debating controversial topics related to brain injury. There's an update regarding CME claiming for the AAPM&R 2020. Let me read this. We are aware that due to the high volume of CME and high participation, there is a lag in transferring your participation data to the online learning portal for certain sessions. Rest assured that your participation in all sessions is recorded. We are currently working on the backend to speed up the data transfer. We will send a notification to all registrants once the process is updated and all data has been transferred. To get us started, I first want to thank the Academy staff for everything they've done to put this virtual session together. All of the participants, we thank you for attending. The speakers all wish we could see you live, but I think we will have an interesting presentation in any event. We'll be discussing two cases and topics in a point-counterpoint style. The case will be presented, then two presenters will present rather opposing views, and then there'll be a minute or two for rebuttal for those views. The discussants for the first case are Dr. Brian Greenwald, the medical director of the Center for Brain Injuries and associate medical director of JFK Johnson Rehab Institute. He's a clinical associate professor in the department of PM&R at Rutgers Robert Wood Johnson Medical School and a clinical associate professor in the department of PM&R at Hackensack Meridian School of Medicine. He's also director of the Brain Injury Medicine Fellowship and the JFK Johnson TBI model systems research grant. He will be discussing with Dr. Ivanhoe, who is the director of the tear spasm program for asbestos C management and clinical professor at the University of Texas McGovern Medical School and an admitting physician to the Brain Injury and Stroke Program at Tear Memorial Hermann. I could spend the rest of the session talking about other accomplishments for each of them, but we want to move on to the cases. So case one, managing post-traumatic agitation. This case is about a 22-year-old man who sustained a TBI after falling backward on a skateboard two weeks prior to admission to acute rehab. Initial GCS was eight, had CT demonstrating a left occipital and bilateral inferior frontal injuries, no other surgical intervention, no other extremity injuries, and upon admission to rehab, he is still in post-traumatic amnesia with an orientation log score of 16. He's verbal but has decreased insight regarding his deficits. He can state basic wants and needs accurately. He has minimal assist for transfers and ambulation on a level surface, but he's hard to redirect and at times combative. ABS scores are typically in the high 20s, especially high for distractibility, impulsivity, resistance to care, restlessness, and changes in mood. Evangelos-Megel scale scores range from four to six with no clear pattern from day to night. He has also not been sleeping well at night. He's been on the unit for two days. Neuromedical causes for agitation have been ruled out. Initial behavioral interventions have been initiated by participation in therapy, tolerance of needed nursing interventions, and preparation for discharge to home with his parents are being affected by this behavior. There may not be much time for trials of a number of different medications to help. So the team is split as to whether a more sedating medication, such as an antipsychotic, should be trialed as opposed to a psychostimulant. Dr. Greenwald, first, what is your position? Well, thank you very much. I'm certainly not looking at those palm trees here in New Jersey, although the colors of the trees changing is very beautiful here in lovely New Jersey. So I have no significant disclosures. I will be talking about medications, off-label medications, but no financial disclosures. So let's just go over a quick summary of this case, so the key points that I'm going to be discussing. So it's a 24-year-old male. He's pretty early on after a severe traumatic brain injury, only about two weeks post-severe traumatic brain injury. He had injury to his left occipital lobe and the bilateral inferior frontal lobes. He's still in post-traumatic amnesia with an OLOG of 16 out of 30. We see that he has poor sleep, that he has poor insight. He's higher level physically, which always makes these cases a little more challenging. His RANCHO score ranging from four to six. Neuromedical causes of agitation have been ruled out. Neurological interventions have been tried, all important things to think about in agitation management in these patients. So just to remind people about the RANCHO-SLOSA-MEGLO stages of cognitive recovery, we can see that he's kind of vacillating here, right? So he's woken up, he's not in that one to three, but he's vacillating between sort of confused and agitated and confused appropriate things to be thinking about, right? Because your management might be different if the person was more consistently confused and appropriate versus the person who's confused and agitated. So when we look at what we're talking about neuroanatomically here, so we know that this gentleman has his frontal lobe damage, so common in this population, right, because of where the frontal lobe sits in the skull base and it's high risk of injury, especially in the inferior frontal region. We know the effects of frontal lobe damage, and we'll talk about those a little bit more. We know that it's likely that his hippocampus is injured also, so we have both the frontal lobe damage and also a loss of memory functions, secondary to hippocampal damage, and all that leads to an unregulated limbic system, an unregulated amygdala, and secondarily some of the agitation that we see in this case. So damage to the dorsolateral prefrontal subcortical circuits, so this relates to many of the challenging behaviors that we see in this population, right? So we see poor judgment, impaired problem solving, impaired higher level thinking, impulsivity, impaired awareness, and that in itself really relates to the agitation that we see, but these are some of the underlying cognitive challenges that are causing that. Again, that combined with this unregulated limbic system. What are some of the classic characteristics of agitation like we see in this case? So it's thought of as a subtype of delirium, we'll talk about that a little bit more, usually associated with a period of post-traumatic amnesia or confusion, and we'll talk about that a little bit more, but they're just doing a whole bunch of things that we don't want them to do, right? Excess behavior, disinhibition, aggression, akathisia, lability, just some of the things that we think about. These are some of the common behaviors that we see in this population. So I think this is an important article to familiarize yourself with. I'm lucky enough to be an author on this article, an article by Mark Shearer published this year talking about the post-traumatic confusional state. The point of this being that it's not all post-traumatic amnesia, that there's a lot of components to this post-traumatic confusional state, and we've got to think about those things, because those are going to really guide our treatment, and the point of creating this definition is to be able to better treat cases just like this. So we see disturbances in attention, and that's one of the key things. These are some of the core neurobehavioral features, disturbances in attention, disorientation, disturbances of memory like we were talking about, but then like what we see in this gentleman, fluctuation also in the character and the severity of the disturbances. Like they were saying, he was vacillating between a Rancho 4 and a Rancho 6, and these can occur during one given day, even from a morning to afternoon. Other things that we might see is emotional behavioral disturbances, like we see in this case, sleep-wake cycle disturbance, delusions, perceptual disturbance, confabulations. I think these are all important to think about those, because those will guide some of the pharmacologic thoughts that we have in a case like this, looking at these different components. So it mentions that neuromedical causes are ruled out. This is critical, honestly. You don't want to think about treating anything with agitation until neuromedical causes are ruled out. I won't go into this so much, but certainly medications can cause this, delirium from infectious causes, and sleep-wake cycle issues, and epilepsy, and intracranial complications. Certainly pain, always want to be thinking about pain, especially in a population who might not be able to express well the pain that they're having. Metabolic issues all need to be thought of before we start any treatment for agitation. I like this slide from Dr. Silver's book from 2013, just going over all the things. These are the things that we need to be thinking about when we think about an agitated patient. We want to make sure that we're looking at or addressing all these different things, especially before considering any pharmacologic intervention. Where is the agitation potentially coming from? So what's the evidence for pharmacologic interventions in agitation after traumatic brain injury? If we look at this Cochrane review, which looked at actually acquired brain injury, since there wasn't enough evidence in traumatic brain injury, it looked at all acquired brain injury and looked at sort of what the evidence ... This is from 2008, but I'm not aware of a Cochrane review that's been done since then in this population. It really only found that beta blockers had the best evidence for treatment of agitation and aggression after a traumatic brain injury. They didn't find so much that some of the traditional things that we use also, including valproate and carbamazepine and amantatine, had much evidence behind them. Some of the things that we think of as traditional management in an agitated patient like this, like Depakote and carbamazepine and trileptal and limictal. So these are all considered mood regulating antiepileptics. Their primary mechanism is thought by inhibiting GABA. Their level of events overall is quite modest, although so commonly used in this population I couldn't help but mention them. Part of the challenge being is the heterogeneous population overall that they've been studied in and of course their heterogeneous population in traumatic brain injury overall. Certainly in patients with epilepsy or bipolar disorder, it'll be something I would consider. With all these medications, you've got to think about the cognitive and sedative risks, but in particular with Tegretol or carbamazepine. So Trazodone. Trazodone is so commonly used in the brain injury population. I have here that the starting dose is 25 milligrams PRN, but really I more commonly start patients who need to think about if we overshoot the potential of sedation the next day or the static hypotension, the dose range is generally somewhere between 25 to 150 for sleep, although higher than that when we're thinking about depression. Benzodiazepines usually only used for acute escalation of violent behavior. Generally should be avoided for prolonged use due to its cognitive and sedative effects and the risk of paradoxical agitation. The psychotropic medications. So when we think about the older medications like Haldol, they're really a strong D2 antagonist. They've been shown to worsen or prolong post-traumatic amnesia in humans. Some good evidence of worse motor and cognitive outcomes in animal models. And it's really, I think what we see it used for in acute care is its sedative properties to deal with problematic behavior. The typical antipsychotics on the other hand have much less D2 effect or D2 receptor effect. They mediate their effects through other neurotransmitters. This class of medication works through serotonin and dopamine and alpha-1 adrenergic receptors and muscarinic receptors and histaminic receptors. And this reduces their side effects and some of the negative effects on recovery after traumatic brain injury and some of the fears that we had as far as recovery worsening in traumatic brain injury from some of the older medications. These are the medications that should be considered as the primary agents for the management of psychosis or significant agitation after traumatic brain injury. Some of the animal and human models have actually demonstrated the neuroprotective effect of these medications after traumatic brain injury. So I go through some of each of them here. These are some of the ones that are commonly used. So I'll point out, you know, a respiratone, it's considered the most typical of the antipsychotics because of its high dopamine blockade, need to secondarily be concerned about extra extra pyramidal side effects, orthostatic hypotension, Seroquil, we'll talk about a little bit more, but in this medication, obviously used during the day, the concerns about sedation, Zyprexa and its metabolic risks, including weight gain and diabetes mellitus and hyperlipidemia and sedation. Geodon has the advantage of that, it also has IM dosing, Abilify is an interesting agent. It's partial dopamine agonist at D2 and D3, seems to have a relatively favorable side effect profile with low incidence of weight gain, extra pyramidal side effects and alteration of lipid levels and diabetes. So here's a recent study looking at the neuroprotective effects of Quetiapine, which is Seroquil. So this is a study done in the ICU, it was a database study of adult patients in the ICU who were all there for more than 48 hours with isolated traumatic brain injuries. It looked at patients both who did receive Quetiapine and those who didn't, it was a matched cohort and they looked at about 116 patients who received Quetiapine and 232 that did not. They looked at ICU length of stay, discharge, Glasgow Coma Scale, mortality, ICP, CPP. They found, interestingly enough, when they looked at this group, that there was a lower mortality in the group that had gotten Quetiapine, that the group that got Quetiapine had higher mean GCSs at discharge. No difference with regards to ICU length of stay, but there was a dose-dependent lowering of ICP with secondarily higher CPP, exactly what you want, with regards to improving, with the hope of improving outcomes. The proposed mechanisms, now this is a recent study, which is why I brought it up, but there have been a number of other studies that looked similarly at this. The proposed mechanisms for this were the anti-inflammatory effects of this medication, which decreases the blood-brain barrier hyperpermeability, which is such a problem early on after traumatic brain injury. Vasogenic edema is due to blood-brain barrier disruption, resulting in extracellular water. The hope of being able to decrease ICP and increase CPP is prevention of secondary brain injury. In this case, what we see is that this is very early on, this jumps right in after brain injury. It's not in the ICU, but certainly very on after a severe traumatic brain injury. We know that early on, there's a neurochemical storm and acute increases in excitatory neurotransmitters, including glutamate, acetylcholine, dopamine, norepinephrine, and serotonin. When you look at the study that was done on amantadine, one of the reasons that they waited four weeks before they started any amantadine, the Giacina study from 2012 that is so widely used is because they knew that the patients are in this storm period and they didn't want to add more fire to that storm. To manage agitation early on after traumatic brain injury, we want to control the storm. Like Thor here, we want to control that storm. We want a trial of trazodone for sleep, again, a sedative medication, trazodone to get this fellow his sleep-wake cycle restarted, the consideration of an atypical antipsychotic and or a mood-regulating antiepileptic for agitation management. Just like Nancy Reagan said, just say no, we want to say no to stimulants. We know that early use of neurostimulants will add to this neurochemical storm. When we think about some of the risks of neurostimulants, we know that they increase risk of irritability, seizures, insomnia, anorexia, headaches, dysphoria, psychosis, tremor, perseverations, all the things that we're concerned about anyway. I think it's a real risky choice in this population to consider a stimulant for management of his agitation this early on after his traumatic brain injury. Thank you. Okay. My turn. Let me get centered. I'm going to present the opposing view of the use of stimulants. I can't get myself centered here. And I'm not advancing, guys. I have nothing to disclose, at least relative to this particular presentation. I'm still not advancing. In general, in this population, and I need to apologize because when I transferred my slides into the template for AAPMNR, it cut off the title of each slide. So this slide would have been about your general philosophy of medication use in this particular setting. So medications are generally selected somewhat based on our own biases, our physician discretion, experience that we've had, how we've interpreted experiences that we've had with different patients and I will totally own that I have had patients with side effects to neuroleptics even second generation or atypicals. Off-label does not necessarily mean that a particular medication is not warranted for use in a specific patient and I still encourage people to base a lot of their medication selection based on the patient in front of them as opposed to a lot of theoretical information because for the most part on a day-to-day basis that's what we get. Behavior is not just pharmacologic and how we treat our patients, we should not forget that there are other aspects to how we treat patients, what irritates them, who irritates them, this patient has occipital lobe injury, is he having issues with vision that are also contributing to his in quotation marks agitation. And then let's consider the goals of inpatient rehabilitation. We're trying to get this patient to learn, to progress motorically, cognitively, behaviorally and we're also concerned about his length of stay. There was a time where we used to say and we still theoretically do start low and go slow but how much time do we really have to play with some of the medications particularly since a lot of what we do still in brain injury is trial and error. So we are trying to facilitate new learning, focus, concentration and attention. Next slide please. Okay. So Brian went over a lot of this. The part of the issue to consider is that these are not mutually exclusive levels in terms of the sorts of issues that we were seeing. Basically we have a confused patient who has trouble focusing, who's restless and as I had said a lot of how we use medication is based off of studies that have been done in other patient populations. Next slide please. Something about neuroleptics where I have already owned some of my own biases is that as the doses do escalate and certainly I've had patients transferred from acute care who are on very high doses of even atypical neuroleptics. As the doses do escalate, the risk of the side effect profile probably not as bad as Haldol and Reglan but close. That does increase. Some of those side effects include agitation, Parkinsonism, which can happen later. A lot of the movement disorders that you can see associated with neuroleptic use can develop as tardive syndromes later on in the patient's life and if you go, if these patients end up in a movement disorder neurologist's office, one of the first questions is going to be have you been on any of those neuroleptic agents. What are the potential adverse effects? Dr. Greenwald and I can both find documentation or literature that will support our own biases. Next slide please. Dopamine agonists, noradrenergic agonists, let me move my slide, are used to improve arousal, attention, neurobehavioral deficits, and stimulants have been found to decrease fatigue, irritability, and anger. Next slide. So why would we want to block those things? Why would we want to block things that help with attention, mood, concentration? I put this study up, it's from 1982 and I think that it's an important study for people to be aware of. There was a slew of several studies anyway at the same time and the short take home point in the interest of time and granted this was done with Haldol versus amphetamines and it was done in albino male rats who had their cortex removed and basically what was demonstrated and in subsequent studies what was demonstrated is that Haldol blocked recovery even if recovery was achieved by patients being, rats being on amphetamines. Also that the amphetamines or stimulant basically helped improve recovery and actually shortened essentially the rat's length of stay or the rat's time to recovery. And this was amphetamine and practice. So it was basically combining the stimulant with physical therapy for rats, if you will. Next slide, please. So in terms of some of the other studies that we can find and this is done in PMNR and basically it was a retrospective review of 182 consecutive patients with moderate to severe TBI like the patient in our current case. Neuroleptics were associated with longer post-traumatic amnesia and longer lengths of stay. Next patients, next slide, please. Psychostimulants in general are used in an effort to improve arousal, attention, memory, and associated behaviors which is exactly what we are seeing. And this is specific to methylphenidate, for example. Dopamine and norepinephrine reuptake inhibitors, especially in the frontal cortex and throughout the brain. And that's exactly, again, typically what we see and what we see in this patient. Relatively short term side effects as opposed to the potential side effects with neuroleptics. And if you're using short acting as we usually do in the at least inpatient setting, that can wash out pretty quickly. And again, we all know that these are agents used for fatigue, lethargy, depression, and ADD and ADHD. Next slide. There has been a positive effect on sustained attention with the use of methylphenidate. And isn't that what we want to improve in this patient in his ability to progress in rehab? In general, cognitive improvement even in the TBI patient population. And again, very often in different studies. Next slide. Very often in different studies, the patient populations are mixed. In our patient, we have pain that can be contributing potentially. Hypoarousal, executive functions are impaired due to his frontal lobe injuries predominantly. I have no particular issue with making it easier for him to sleep, though Seroquel would not be my particular go-to, at least based on what we're seeing here. But his motor planning is impaired and the stimulants can certainly help with that. Next slide. So what are we hoping to get? Some of the goals of this inpatient stay and medication selection as a part of his rehab process are improving his cooperation, his sleep, his mood, his attention and awareness, and hence his participation to help improve his motor control. As short a length of stay as any of us can possibly get these days. Maintain a more neutral interpretation of his behavior that is on us as rehab professionals. Improve his focus and cognitive processing. Decrease his irritability and improve his mood. Facilitate his discharge and in preparation for that discharge, help with his family's training. Next slide, please. So what drives medication selection in general is going to be the setting, the clinician's biases and the treatment team's experience, the safety profiles, potential of the patient to do harm versus the potential of that patient's recovery to be slowed. Remember that medications are usually just part of the problem. And what will happen if we do nothing should always be considered. Next slide. I'm running out of time. In short, take-home points. Stimulants improve attention, improve mood, improve awareness. There's a low risk for short or long-term side effects. And additionally, what I'd like to add is sometimes by giving patients stimulants during the day, you actually can facilitate improved sleep. Drugs that are sedating can increase our length of stay, which is a big issue these days in health care, can actually increase fall risk, can decrease the ability for new learning, and can be associated with tardive movement disorders. Next slide. Methylphenidate has been shown to improve many of the cognitive and behavioral issues that we see in our particular patient. Neuroleptics represent sort of the antithesis of the goals of rehabilitation and can also increase lengths of stay and have longer potential for side effects. The cognitive behavioral deficits described in this patient could potentially be managed in other additional ways as well by improving his sleep, improving his awareness, shortening his length of stay, and improving his rate of recovery. Next slide. And I put this up if any of you want to go back and look at those initial studies that made neuroleptics sort of verboten, you can look up some of Feeney's work and then a couple of others, Klein as well, Dr. Zephant's on that article. And then next slide is just more bibliography for you all. Thank you very much. Thank you, Brian and Cindy. For the sake of time, we are going to pass on time for rebuttals. Time for rebuttals. I also see that at least one question was submitted. We'll try to hold those to the end if we have time. But what I'd like to do now is move on to case number two. And before I do that, let me introduce Dr. Ross Zephant, the Earl P. and Ida S. Charlton Professor and Chair in the Department of Physical Medicine and Rehabilitation, Harvard Medical School, Senior Vice President, Medical Affairs, Spalding Rehab Hospital, Chief of PM&R Massachusetts General and Brigham and Women's Hospital. And again, I could spend the rest of the session talking about his multiple accomplishments. I will be opposing his view. I am the Clinical Director of the Drucker-Brandrew Center, Director of the Stroke Program as well at Moss Rehab in Philadelphia, Associate Professor, Department of Physical Medicine and Rehabilitation at Temple University. So case number two, and we will be looking at stem cell therapy after TBI. You're asked to consult on a 34-year-old woman involved in a high-speed motor vehicle crash nine months ago. No significant past medical history, married with two children. And you can see from the details, this is clearly a severe traumatic brain injury, including diffused swelling, she required a craniotomy with cranioplasty, diffused external injury, and even more recently, some evidence of cerebral atrophy. After three weeks of acute care stay, she received acute inpatient rehab for eight weeks in a facility with a specialized disorders of consciousness program. So she had a fairly robust rehab course. From there, she was transitioned to a skilled nursing facility for two months, but then discharged to her parents' home and has 24-hour supervision assistance from paid caregivers and family. Let me just give a little bit more detail regarding her presentation now. She can communicate basic wants and needs, is out of post-traumatic amnesia by formal testing. She transfers with max assist, but is dependent for self-care and ADL. Upper extremity movement less than anti-gravity at the elbows and wrists for flexion and extension. Some mass flexor grasp bilaterally. She has not had any documented seizures, was weaned off of seizure meds within two weeks after injury. You meet with her parents and spouse. Husband is a firefighter, mother is an elementary school teacher. Patient and spouse are, I'm sorry, father is a firefighter. Patient and spouse are school teachers. Friends and coworkers have raised $20,000 to help with care. The patient and family have read about stem cell trials on the internet and ask about using this money to help cover ancillary costs, for instance, child care time from work for her husband, et cetera, because this will be a clinical trial with some expenses covered. The trial and follow-up are not local, but will be within the United States. Wanted to make that clear. And they are concerned about, or they just want to ponder use of funds and other things for this therapy. So, Dr. Zafant, what do you advise? There we go. Okay. Thank you, Tom. And thanks to my three dear friends for allowing me to present with you today. I think this conference is a clear example of the resilience of team physiatry. So we're going to focus on the yes. And I'm going to explain my rationale. I have no disclosures that are related in any way to stem cell-based therapies. So let's think about this for just a second. We have a limited ability to really jump ahead. And what I mean by that is there aren't that many motor therapies that really work. And I'll go into this in just a second. There are caveats. Tom touched on a few of them. People should not be involved, I think, in out-of-US proprietary studies or proprietary therapies. But there is some nascent evidence that we will show that we've got signal here. And that signal could be quality of life changing. So let's examine this in a thoughtful manner. Why for this person? They're young. Checkbox. Their cognition's improved. They can function at a higher level if given the opportunity. They have a fixed focus deficit. That fits right into some of the studies we'll talk about. They've already had a significant course of rehabilitation but still have deficits that they and their family are worried about. And they don't have a history of seizures, which would put us perhaps in a different category. Now, quickly, when we think about this, I think about it in two different ways. When we think about stem cell therapies, we should think about A, the delivery mechanism, and B, what cells are you actually getting? So what are we putting away? That really does matter. We should also consider another fact. There aren't that many motor therapies that work after brain injury. There hasn't been an overwhelming pharmacologic or interventional study that really has led us all one direction. So now let's go to A, delivery. We could, and studies in the past, have done intravenous therapies. Those kinds of therapies are helpful. They are befraught with challenges. Among them, they require large numbers of cells. Those cells are generally cleared by the lung or the livers, and the ability to cross the blood-brain barrier is not so much there. Intra-arterial therapy has shown some promise in stroke, and we'll take some of our information from stroke. The problem here is there still may be blood-brain barrier issues, and there's possible clumping into microthrombi that could really deliver a huge problem, theoretically. Some studies have considered intrathecal therapy, and the problem with this is it really requires active movement of the CSF, and in relationship to that is the dispersal of the cells. Do you get it where you want to put it? And lastly, intracerebral therapy. There are no blood-brain barrier issues. You put it in an exact location under stereotactic guidance. The problem is there's a 1% to 2% risk of hemorrhage or tract damage, at least so far. So let's look a little further. What are these cells? What are they doing? Well, really, we've had disturbance to the milieu, so they result in further protection. They provide a trophic function. They seem to result in angiogenesis. They produce an anti-inflammatory effect. They change the extracellular matrix. And there is some sense of a production of neurostem cells, migration, and differentiation. So historically, what you give really does matter. And now there are really two cohorts of cells, but all the way back, I was involved in a study peripherally in which immortalized N2 teratoma cells were washed with retinoic acid to become marked like neuronal cells. And we were worried that that would move or be carcinogenic or something. Well, not so much. The PET site changed as we wanted it. And while we didn't see significant motor improvement, we did see cognitive change. More recent studies have focused on bone marrow stem cells and the use of fetal progenitor cells. And in essence, these SB623 cells are transfected cells that produce these kinds of mesenchymal stem cells that differentiate. And the PICE studies have been based on fetal cortical progenitor cells that are changed over and labeled as CTX cells. These are a summary of some of the recent studies that are going on and been looked at. And one of the things you see here, I think, is they're all trying to create a variable menu with different dosing. As we'll show you in a little bit, there's very few really nasty outcomes. What you do see is a hint of efficacy. Now, these are a summary from stroke, where the experience is high. The experience is much greater than it is in brain injury. But I will show you in just a second that brain injury now has a fair number of clinical trials ongoing. Okay. So now let's look deeply at just a few of them because of our time constraint. And this is the SB623 study, SanBio studying stroke. They released the data in January 2019. They didn't meet their primary endpoint, but many of the other things showed a tendency for Fugl-Meyer motor recovery that would not exist or did not seem to exist in the sham surgery group. A further ongoing study is being planned. So what we can think about is, hey, there's signal here. We may be changing the environment, the milieu, and producing functional change if only by that and not even by neuronal connection. One of the things to consider, and I think we do, is what other reparative therapies, whether that's stimulation, whether that's active physical therapy, would be the right answer for this group. Safety is always a big issue when we think about this. This is Steinberg's review. And in this early review, and I'll show you in just a second some caveats to it, the biggest concerns were seizures and track bleeds, but really, really low in number as one would expect in stereotactic surgery. So what is going on now? Well, what's going on now is many clinical trials. I found at least 11. There might be more. Scorepi et al has a lovely review. And what one can see is that at least in some of the studies that were reported out recently, the side effect profile is not so much. And there's a tendency for motor benefit. Now we're weighing a young person. They don't have a lot of other opportunity. They're worried about their functional status. They have the opportunity to enroll in a study. And this is just another slide that really lists some of the studies that have not yet been reported, almost all of which looks for motor stability at a fixed period of time that is chronic and with significant impairment. So it's impressive that they're getting any signal. Now I want to drill down quickly on two, one of which is out of UT, Cindy's shop, in which they were able to use bone marrow, mononuclear stem cells, and actually showed a change in the inflammatory environment, upregulating the good inflammatory signal and downregulating the bad inflammatory signal. Next, we're going to go to the opposite side of the slide and talk about the SEMTRA study. And this one is yet to be fully published. It is a study that enrolled what we believe is about 61 people. The primary efficacy for people with brain injury was a Fugl-Meier score change of greater than 10. And there were various treatment dosages of SB263 neurons. These are these bone marrow stem cell neurons that have been in some ways converted. So what's the population? It's 18 to 75. People greater than 12 months. It's a focal brain injury with, as I said, fixed motor deficits and no seizures within three months. So what did they see? Well, we're waiting the final publication from Lew et al that is to come out shortly. But we do know a little bit about what was presented at ACRM. And I thank Steve Kramer for allowing me to have this study because he's a co-author. There appears to be a dose-related effect. No control patient achieved greater than 10 points at six months. So it's not a placebic effect. And there were significantly more SB623 patients who got over 10 points. The theme is similar, whether it's stroke or whether it's brain injury. Fixed motor deficit, change in milieu, enhancement to some extent in motoric function. Adverse events, what we've heard so far, again, we're waiting for the final structure on this, no difference in serious AEs, no relationship between cell dose and headache. A lot of people get headache. And that may be the real problem with this. We do appear to see headache in the both intervention group and control group, perhaps more in the intervention group. So when we think about these things, we have to think about ourselves as clinicians and physicians. We have unique elements to think about. Hey, what does it mean to get a sham surgery? That's not so good. What do we expect? Many people expect the end. I'm going to solve the problem. And it's unlikely that such an intervention would do so. What are the cautions? And as Tom will bring out, what are the costs? But a good clinical trial, a well-sponsored one, should cover all of the medical costs. And what are the alternatives? Right now, I might argue that this person doesn't have much. They have the opportunity to get better. And if it's a focus of their life, there's a rational basis to move forward. So lastly, everyone wants magic. The evidence is really leaning in one direction. Informed consent is really important. Are there other benefits? We don't know. There may be systemic benefits as well. We need to know what not to wear, who not to give this to, and the role of therapy and stimulation afterwards. Thank you so much. Thank you very much, Dr. Spahn. I'm going to thank you ahead of time because as you'll see, although I'm going to present a why not view, we're actually going to use some of the same information and I guess maybe just interpret it a little bit differently. Let me just start by saying I have no relevant disclosures. There we go. Okay. No disclosures. And by way of introduction, I want to say that I am actually very excited about the prospects of stem cell therapy. So the point here is not that the therapy does not have potential. But what I want to do is really take a look at where the state of the science is now as we educate this patient in terms of how to make the best decision. So as I mentioned before, Dr. Spahn quite ably explained the case for the patient to pursue stem cell therapy, but I'm going to look at some of the reasons why it may not be the way to go at least at this point. So for me, in considering the recommendation for this patient to pursue enrollment in a stem cell clinical trial, there are several things to consider. What is the evidence? How applicable is the evidence to this case? And what are the anticipated outcomes? We also need to consider risks and alternatives. And as you will see, I'll broaden the concept of risks and alternatives beyond just the scope of the procedure itself to some other elements to consider. So considerations, as Dr. Spahn pointed out, I can't disagree. Relatively young, extensive motor deficits with some cognitive deficits. This is the type of patient that should be most appropriate for stem cells, whether or not we're really ready to invoke that or not at this point. Extensive interventions, but this does not, up to this point, this does not mean she can't get better by a number of means. Nine months out, clearly room for further improvement again by multiple mechanisms. However, this is a severe injury, so we need to consider long-term needs and also in this case, consider the modest financial means that the patient and family may have. The goals are not specific. We kind of left that loose to help with our discussion, but the overall goals that the patient and family might have would also need to be considered. So what is the evidence? Dr. Spahn presented much of it quite nicely, but mostly evidence in acquired brain injury is from stroke, and we would have to ask whether that is at all comparable to traumatic brain injury, and we know that traumatic brain injury has a number of characteristics that are often different than stroke. Also, we need to consider outcomes and figure out how we're going to measure outcome, both for this patient, but then how have outcomes been measured in the studies that have been published so far, and what does, quote unquote, improved outcome really mean? Dr. Spahn mentioned this study, which is probably the most compelling one to date that would have a relationship for this patient. The results are promising, but I might suggest that perhaps the bar has been set a bit low. So Fugl-Mars motor scale score of greater than 10 has been mentioned by several researchers as a, quote unquote, clinically meaningful degree of change. If I took a little bit of a look at this, and for instance, there's a study from Wagner in 2008 that identified in Fugl-Mars minimal detectable change for the upper extremity portion is 5.2, and that's minimally detectable for research, not necessarily meaningful. There's also an interesting article from 2001 that took a look at improvements in Fugl-Mars and related them to improvements in FIM, and in this study, they equated 10-point improvement in upper extremity Fugl-Mars score with a 1.5 change in discharge FIM in self-care, and self-care encompassed six different items on the FIM. So 10 points equaling 1.5 point change in overall self-care FIM. I think it's worth considering whether that's really the robust type of outcome that we would want to consider. There are some ongoing studies regarding acute stem cells to address TBI in the subacute to chronic phase, which is really what we're talking about for this patient. Dr. Safant reviewed several of them, and he mentioned that there are several. In my mind, there are relatively few, and I think the other thing to consider about these studies, and two of them are highlighted here, is that there's still a lot unknown that is trying to be sorted out with these studies. So you can see that we're talking about varied delivery, again described nicely by Dr. Safant, varied diagnoses, so we're not sure how applicable these results will be to a person with a traumatic brain, severe traumatic brain injury several months after injury, and varied outcomes and outcome measures. So my point here is that some very fundamental, at least to me, questions are still being asked, and many of the studies, because they have vague outcomes, I believe that these are important studies, but they're studies that need to be built on further as we hone down on things like delivery types, cell types, and outcomes, which again is not at all clear at this point. Again, some of the questions that are still ongoing have been discussed by Dr. Safant, so I just want to highlight some of the issues here. So my summary from this slide is that we're not sure how to administer the cells, we're not sure when to administer the cells, and we're not sure how many cells to administer, and seem like fairly basic questions that still need to be answered if you're going to encourage somebody to move forward with this type of intervention. And again, as discussed by Dr. Safant, we don't know what types of cells to inject at this point. And we have to think about some of the risks here. So risks do vary depending on the type of cell. Embryonal cells carry ethical considerations, as I'm sure you're well aware of. Also, there is the risk of rejection and the potential for tumors. Adult neuronal stem cells carry less of a risk, but they're also less plastic, if that's one of the things that you're trying to accomplish. And survivability is in question. And induced pluripotent cells, which have some intriguing qualities, including the possibility of being supplied autologously, getting around the problem of rejection, but still have very limited data to date regarding utility. And for what goal? And you know from Dr. Safant's discussion that different cells are administered with different goals. So the mesenchymal cells, for instance, were primarily exogenously trying to stimulate the endogenous repair, where some of the other cells are more for replacement of damaged cells. I would have to agree with Dr. Safant. I think the risks and complications overall are fairly low. And we highlighted in this case that seizures, this patient doesn't have a seizure history, so I think the risk of that is pretty low. But there are considerations, seizures, immunologic problems, tissue overgrowth, as I mentioned before, depending on the type of cell, craniotomy, and injection of cells. Obviously, there are risks with this invasive procedure, the risk of anesthesia, and as mentioned before, that there are headaches. Another risk that I'd like to point out is that in a clinical trial, which we are both espousing, there is a risk that the patient might receive placebo and not the actual cells. So if they're enrolling with the purpose of trying to have an improved outcome, there's a risk that they may not even get the intervention that they're hoping will have the desired effect. I do want to point out, too, that there are some alternatives to consider. The patient has received relatively intensive care in a specialized brain injury center, yet there are still cognitive and motor deficits, but there are other technologies and interventions that are available. Certainly, it's not that you have to choose one or the other, but as I'll get to a little bit later, there is the issue of indirect costs for all these and weighing the risks and benefits of different interventions. So there are exciting robotic technologies, some non-invasive stimulation technologies like TMS, TDCS, which can also be considered, brain-computer interfaces, and a whole host of other interventions, which we don't have time to look into. There's also the issue of considering whether we would want to put our resources into compensatory technologies and interventions, and there may be some costs associated with those, and again, with limited resources, maybe it would be more efficacious functionally to go in that direction. Further therapy could be warranted and could produce more neurologic recovery, and there may be costs associated with these interventions. You probably all have patients who have fairly, in my mind, extravagant co-pays for therapy. There's transportation involved in therapies or some of these interventions, child care, time off from work. So again, with limited financial resources, the patient and family may want to consider these added costs. A few other costs to consider. Again, I'm not trying to make the point that care for severe traumatic brain injury is a chronic condition, so costs that at some point often have to be absorbed by families include nursing, home health care, home services, home modifications, wheelchair, wheelchair accessible van, and these are just some general prices that I found to make consideration of the financial implications of how you'd want to go in this case. So in my mind, there are exciting but preliminary studies regarding stem cells. The efficacy to me is a bit unclear. There are many uncertainties regarding methodology. The risk-benefit ratio may not be favorable if we consider, depending on what risks and benefits we're considering. So I would say it's not yet ready for prime time, and with one exception, if the primary goal of enrollment for a patient like this is to help move the field forward, and we've worked on studies like this, and we've really emphasized that, you know, this, an intervention may not help you, but it may really help people down the road. If that's a primary motivation, I could, I would be more comfortable with that. But if the primary motivation is, I think this is the intervention that makes the most sense to help me move forward long term, that's where I have some questions. Severe TBI is a chronic long-term condition and has long-term needs. So is this the best way to use limited resources? Also, there's this question that I've mentioned a little bit before, unmet expectations. What's the cost of an unmet expectation? We all have patients and families who have spent years trying to, intervention after intervention, place after place. It's not necessarily wrong, but to me, there is a psychological cost in addition to financial costs for people trying intervention after intervention. So for some, the strategy is worth the cost, but not for others, and I would just throw that into the equation as something that should be considered. Here are a few references to help us. All right. I'll hold that up for a second. So we are almost out of time. We were going to do a point-and-counterpoint, but maybe what I think I will do is ask Brian. He's been monitoring the QA part of this, and I know people had some questions. Brian, can you identify maybe a question or two? We can start with your set of talks and see if we can answer one or two. Sure. Let me start with this question from Michelle Gitler. At what time given his age do you consider new onset mental health diagnoses? This comes up sometimes when we're thinking about depression or psychosis or Parkinson's disease or a host of other things that the person can look like early on after brain injury, and I personally would wait a period of time before I would consider any new mental health or even neurologic diagnoses like Parkinson's disease or such as far as it being a long-term permanent problem for the person. Most of what we're doing in this early period is more symptom management, more than actually making a new diagnosis, and I think that's whether you're using stimulant medications or using sedating medications. It's more symptom management than anything else. This next question, Cindy, what do you think of this question? Once these patients are discharged from inpatients and are no longer receiving daily therapy or physician supervision, do you have a recommendation how to wean these patients? Stimulants have been very hard for me to wean in this population even months or years later. I think it really depends on what benefits the patient is receiving from those medications and what the other issues are that make it difficult to wean. A lot of patients will potentially benefit from being on those medications long term, and there's sometimes comfort levels with who will or will not prescribe stimulants long term. So I think you have to focus on those sorts of things. Sometimes there's value depending on the patient and the situation and doing neuropsych evaluations further on down the road, but identifying what it is. We're physiatrists and physiatrists, so it's always about what the goals are and looking at how that medication helps, but you can start decreasing it to see if there are responses. Okay, great. Looks like our time is up, so we just want to all thank you again for participating in this unique format and hope to get a chance to see people live soon. So have a great meeting. Thank you to everybody. Stay safe.

brain injury

CME claiming

post-traumatic agitation

severe traumatic brain injury

pharmacological interventions

risks and benefits

neuromedical causes

stem cell therapy

limited evidence

delivery mechanisms