I want to welcome everybody to AAP Virtual Didactics today. My name is Sterling Herring. I'm a PGY3 here at Vanderbilt. As always, we want to recognize and appreciate those of you who are on the front lines of this COVID-19 pandemic. We recognize that the burden of this disaster has not been shared equitably. So we appreciate those of you who are carrying more of that burden, either professionally or personally, than the rest of us. The goals of this online didactic series are to augment didactic curriculum that are ongoing at your home institutions, to offload overstretched faculty. We recognize that there are a lot of logistical challenges associated with this pandemic, to provide learning opportunities for off-schedule residents. Again, we know that many of us, myself included, have been pulled off of some clinical schedules and that has, at times, made things difficult and put learning opportunities at a premium. So we wanted to assist there and to develop more digital learning resources and support for psychiatrists in general during COVID-19. We're gonna keep everybody's video and audio muted over the course of the lecture, except for our presenter. And if you have any questions, if you click on participants, you should see my name up near the top, Sterling Herring. If you double-click my name, you'll be able to send me a message directly and I can pass that along to our presenter. If you have any questions about the series itself, concerns, suggestions, please feel free to reach out to Candice. Her email's there on the screen or you can track her down on Twitter. So without further ado, we're excited to have Dr. Pinto here with us from Carolinas Rehab. Thank you for joining us. All right, thank you. So I'm just gonna see if this works so that I can share my screen. Are you guys able to see it or did it just go away? There you go, perfect. Oh, perfect. So again, so sorry about the delay and the technical difficulties on this. This is my first time using Zoom for giving a presentation. So thank you for the introduction, Dr. Herring. Just want to go over disorders of consciousness because it is a very important and very unique population that we see in rehabilitation. So we're going to just go over kind of the definition, the pathophysiology, the clinical assessment, prognostication, some ideas on med management and what we can do from a rehab setting. To start with patients with disorders of consciousness, we think of it as a spectrum for different levels of consciousness. So patients on the very lowest end would be in a comatose state, and that means that they have absolutely no sleep-wake cycles or awareness of the environment. This is typically very self-limited after any type of acquired brain injury, usually no more than about two weeks in this state that you would see that in typical settings. Vegetative state is the kind of next progression in the spectrum of disorders of consciousness. There is alternate terminology of unresponsive wakefulness syndrome, which definitely describes what you're seeing more in these patients. So they are awake, meaning that there are sleep-wake cycles present, but they do not have any awareness of the environment. So everything that you're seeing from a movement perspective are going to be reflexive and not purposeful. Progressing from that standpoint, now you get to the minimally conscious state where the sleep-wake cycles, again, are still present. Now the patients are starting to have increasing awareness of the environment, so you'll start to see inconsistent command following, some more purposeful movements, and so that's still progressing towards emergence from this. The emergence from minimally conscious state also is known as an acute confusional state in some of the most recent literature where people are more consistently following commands, and then the big things to take away here are that there's either functional object use or functional communication, both verbal and nonverbal forms of communication. We'll look at some of the scales for assessment and dive into this a little bit further in some of the other slides. Some of the things just to be aware of is you sometimes will see patients, especially in the consult service where you'll be asked to assess these patients for a DOC-type program for rehab because they're felt to be having a disorder of consciousness. Some of the mimics, particularly pharmacologic sedation, I will tell you just definitely review medications. I remember during fellowship and residency particularly having some patients come from some more rural hospitals, being told that they are vegetative or minimally conscious, and when we looked at the meds they were getting high doses of opiates around the clock, high doses of benzodiazepines, antipsychotics, and so they were in a lot of things, and as we took off the medications they appropriately woke up, and so it seemed to be more of a pharmacologically induced phenomenon rather than true disorders of consciousness due to the injury. Locked-in syndrome is another one to think of, and to remember that is usually a stroke, either hemorrhagic or ischemic, involving the basilar artery, and so you're going to have a lot of damage to the brain stem and patients are only going to be able to have vertical eye movements in a true locked-in syndrome. It is rare to see somebody having so much damage that they aren't able to move either the arms or both the arms and the legs, but it can happen, and these patients are completely aware they just are not able to respond to you because they cannot move, they cannot talk, they cannot communicate. I've seen one true locked-in syndrome in my life, and it was a very kind of unfortunate gentleman that he was able to answer questions completely appropriately with his vertical eye gazes, and so we did a lot of communication with up is yes, down is no, and that's somebody that, again, was very aware of his surroundings but just could not interact at all. Akinetic mutism is something that is also fairly rare, and that is going to be that the patient has a complete lack of motivation and so a lot of significant frontal lobe damage, and they're going to look like they are unable to interact with the environment because they just don't have the motivation. Like I said, this is very rare. The most recent times that I've seen it is when patients have what's called toxic leukoencephalopathy from inhaled heroin abuse, and it just causes such fibrosis of all the white matter tracts, and so they completely are unable to motivate. Those patients tend to respond well to dopamine, such as Sinamed, actually just giving them pure dopamine, and one of the interesting things with these patients is that they're the classic ones where you say that they cannot talk, they can't interact. You give them the phone, they can actually talk on the phone, and so they can do kind of reflexive things that are very socially appropriate. Anatonia is something you see more in patients that have underlying psychiatric illnesses, particularly like a schizophrenic patient, and these patients can get completely mute, completely rigid at times too, just absolutely not reacting, and those patients actually respond really well to benzodiazepines, so it's like a Zolpamid trial, or not a Zolpamid, actually an Ativan trial for these patients. It is something that usually you start thinking about catatonic if there's not like an actual stroke or a traumatic brain injury or anything that's actually causing them to have the underlying physiology that you're seeing where they become completely unresponsive, and again have that underlying psychiatric disorder as well. So when looking at the pathophysiology of disorders of consciousness, think about having patients that have severe damage, either globally throughout the brain or to specific subcortical structures that are important for arousal. These in particular, the reticular activating system, the thalamus, the basal ganglia, particularly the striatum of the basal ganglia, and then also the corpus callosum. So you're having these structures that are really very much a relay center of the brain, which I'll show you in a picture in the next slide. The traumatic brain injuries that you see this with, they typically have diffuse axonal injury, and that's going to be something that goes all the way down into the brainstem, so the more severe diffuse axonal injuries. So these are patients that usually are more high-velocity injury, motor vehicle accidents, fall from a significant height, usually not your typical, like I had a ground-level fall, usually not an assault unless it's some penetrating trauma that gets the brainstem with that. You can also see it with severe anoxic brain injuries. For people that are in the high areas of opiate overdose, we luckily in North Carolina are not, but if you go up into like the Pennsylvania, Ohio, West Virginia areas, a number of other places in this country where you see a lot of heroin abuse, those patients definitely you can see a lot of people getting into a disorders of consciousness state due to their overdoses and subsequent anoxic brain injury. And then severe strokes, especially again if it is impacting bilateral structures in those subcortical regions or you're going to have some brainstem involvement. So looking at the anatomy of consciousness, so when you look at this slide, there are a lot of different areas to look at. So this whole area up here, the cerebral cortex, that's going to be the cortical structures. Usually damage just to this does not cause a disorders of consciousness unless you're going to have like a global insult to all those structures. Where you start to see it more are in this right here that I'm highlighting with my marker, that's the corpus callosum, so that's the relay center of the brain. But once you start, so you can get, if you have a lot of damage there, which you usually don't have damage there in isolation to some of the other structures, that in theory can be an area. But the big spots are going to be the thalamus, which right here is the relay center of the brain. So any sensory input you're having coming in comes up through the brainstem, comes to the thalamus, goes out into the cortex. At the same time, if you want to do any type of movement, you're having input coming down from the cortex going through this major relay center and coming through into the brainstem. The reticular formation also is a big area. I always think of this as like our wakefulness area. So if this is impacted in any way, that is an area that you're going to see people with decreased arousal from that standpoint. So this is the COBA Recovery Scale revised. A lot of times you'll hear it referred to as the JFK because that was the center where it was developed initially. Really, we should be getting used to calling it the CRSR as the abbreviation. And looking at breaking it down even further, this is a good assessment for these patients where you're hitting very different aspects of their function and their arousal. So we're looking at different scales, looking from the auditory function, whether or not they can hear us and take in the sensory information processing. The visual function, how much they're able to take in kind of with the visual stimulation. The motor function, whether or not they're moving. The oral motor and the verbal function, that I will make sure you understand is differentiated from the communication because oral motor is whether or not you are able to provide any type of oral reflexive movements. So like if I would stick a toothbrush in somebody's mouth, an oral reflexive movement would be them trying to suck on it or trying to chew on it. It's very, again, a very primitive movement. Like as you see with children, if you have a newborn baby, you stick a finger in their lips, they start to reflexively suck on that. And that's, again, very primitive movement. Versus communication can be either verbal or nonverbal. So whether or not they're able to try to answer questions using yes, no responses with head nods, thumbs up, down, lifting an arm or a leg to indicate a yes or a no response. Those are two very different things. And then the arousal is just kind of looking at when you're doing this structured assessment, whether or not they're able to maintain their eyes opening with you stimulating them and then they fall asleep or if they're able to keep their eyes open the whole time without you constantly stimulating. And whether or not they seem to be attending to kind of the tasks and are responding much quicker. I'm not going to go into kind of how to do this assessment and kind of belabor it because it can get very long and it definitely is better doing it as a hands-on assessment. But if you search for the Coma Recovery Scale Revived online, you can get the, I think it's about 20-page packet and the PDF of how to go through the assessment. The big thing to note is that anything that's got a star, which are the ones that are highlighted in this blue box, are ones that indicate a minimally conscious state. And so if you look at the any of, if you have any of these things, like you're moving to a command that you're hearing, the auditory command you're starting to do some movement to, that means that you're interacting with the environment. Visual function, again, if you're starting to fixate on objects, looking, pursuing the object as it's going for a smooth pursuit in the visual field. The motor function, if you're starting to do things where you're manipulating objects or localizing to noxious stimuli. One thing I will note when you're doing your assessment of patients, when you want to determine if they're localizing to noxious stimuli versus doing a flexion withdrawal, for localizing to noxious stimuli, they need to cross midline. Because if you just pinch them on their finger and they pull away, that really is a flexion withdrawal. So what I always try to do with these patients, if I'm trying to determine whether or not they're localizing versus just having a flexion withdrawal, is that I usually will also pinch kind of in the armpit area. And what you want to see is that they're taking the contralateral limb and trying to push you away. That's more of a localization where they're crossing, rather than just having a flexion response where they come in and come up. Intelligible verbalization, again, that's very different than looking at the communication, because verbalization means that you're making some sounds and words, but it might not be appropriate as a communication strategy for being able to answer questions appropriately. And then when you want to document whether or not patients have emerged from the minimally conscious state, again, the biggest things to look at are whether or not they're doing function. So with communication, that one's pretty easy. You're trying to get yes-no responses, and they're accurate. So they can give you a yes for very simple questions like, is your name Bob? If their name is Pete, and they give you a yes to, is your name Bob, then that's obviously an incorrect answer. But if they say no, and then when you ask them, is your name Pete, they give you a yes response, that ends up being functional. And, again, it's in whatever manner they are able to do it. Functional object use, so this is something where within the realm of what they can do from their physical limitations, being able to attempt to use an object. So, you know, if you give somebody like a comb, trying to take it and go up and brush their hair, whereas if you give them a washcloth, they're washing their face or their body, a toothbrush trying to brush their teeth. And as you can see, this is kind of an assessment that can be very tricky to do in patients that have focal deficits. So if they have, you know, blindness due to their brain injury, you know, they had some kind of an orbital injury, your visual function scale is not going to be accurate in being able to assess them on that. And if they're hemiparetic and they don't use their left side at all, it's going to be very hard for some of this motor function. So you're just going to really be focusing your motor function on whether or not they can, you know, utilize their functional limbs. So you always want to make sure you're tailoring it to the area that they're able to do if they have some specific limitations. Other things to also note with this is that this is an assessment that, you know, should be going, you know, you should try it multiple times a day at different times. You want the patient to be as awake as possible. If you get them first thing in the morning while they're still in their bed, and you just open the blinds and try to do the assessment, they probably aren't gonna be awake. Whereas if you do it a little bit later, when they're upright up in a chair, you're probably gonna get a little bit of a better response. And so it's really important to be able to do these assessments multiple times. And the reason why it's really important for that is that the rate of misdiagnosis is very high. This study is from 2009, and this is actually an update from a prior study that was done. And in both of them, they found about 40% of people with minimally conscious state were misdiagnosed as having a vegetative state. And the way they did this assessment is that they had a bunch of experts in the field come to the single center, and they each graded how they rated the patient on their assessments, and they did it at different times of the day. And so that's one of the things to be really, really important to think about. When they looked at why patients were misdiagnosed, a lot of times people were missing some of the very primitive visual fixation and visual pursuit that was present, but some people were missing it. And again, the patients vary so much based on their level of fatigue and what's going on that it's really important to get these assessments multiple times. There was one study in 2015 where they actually found that there is significant variability within time of day, and people tended to do better in the mornings. And so that's something to just kind of think about it. You know, if you're doing it in the afternoon after they've had a lot of therapy, you're probably gonna get a different assessment than if you would have done it when they're more fresh and more awake, but, you know, after they've gotten up for a bit. And again, the reason why this is particularly important to make sure we have an accurate assessment of the patient is that withdrawal of care is pretty common in acute care with severe brain injuries, because, you know, you look at the patient and just thinking about how severe their injury is, whether or not they'll survive, put them through kind of the procedures that you would need to do for full care and what the function would be long-term. So this one study that was done in 2011 was done in six different level one trauma centers within a province in Canada. And they looked at just all patients with severe TBIs, they came into the trauma center, and then they looked at the deaths. So these are all patients that had died due to their injury. They found that 70% of the deaths that were in the severe TBI populations were due to withdrawal of care. And based on the center you went to, there was a very large difference based on what percentage of the deaths were due to withdrawal of care. And nearly half of these were withdrawn within the first three days of injury. I don't think you guys had as much on the acute neurosurgical complications after brain injury, because I know that there was the one lecture on kind of long, a little bit longer once they come to rehab. But within the first three days, a lot of times these patients have had multiple surgical procedures and are on sedation. They're working on getting the ICPs, the intracranial pressures controlled. If there is an immediate seizure, working on that. And so there's a lot of different things that are going on within the first three days that patients are on and off sedation. And it's whether or not you can even get an appropriate exam in that time. It can be a little bit tricky with that. And a lot of the reasons when they looked at it was that families were being given, they have a poor chance of survival. Their prognosis is grim. They look at it as it's not compatible with the patient's wishes, and they're saying a poor long-term neurologic prognosis. And again, it's very hard with these patients if you're putting them on and off meds that are gonna sedate them, suppress their exam. And as that prior study showed, even when they are more stable, there is still a lot of mixed diagnosis for that. So it's one that I just be very aware of some of the gravity of being able to have good assessments and good evaluations of this patient. When looking at prognostic information, we don't have great evidence of like, if I would have this patient based on these clinical factors, know exactly what their burden of care is gonna be long-term. That data we just don't have at this time. But we do know that these are factors that are associated with better prognosis. Younger age, which makes sense. The brain is more pliable, more malleable with younger individuals. In general, they're healthy versus the older population has more medical comorbidities that are gonna make their acute care stay more tenuous. They do better. Traumatic brain injuries definitely do a lot better than the non-traumatic brain injuries like the strokes, the anoxics. The SSCPs are the somatosensory evoked potentials. These are some assessments that you can do where you take the median nerve and you send a sensory impulse through the median nerve and you track it all the way up, up to Erb's point in the shoulder is one place. They do a subcortical one in the neck. And then they also look at the cortical areas and with an electrode on the head. And what you're looking for with that is you're looking to see whether or not you have a cortical response by stimulating the median nerve. If you do, that actually is a good prognosis. If you don't have it, the one thing you do need to check is to make sure that they had the active points further down the road, so at the Erb's point and subcortically, because if those are absent, then they probably have a median nerve injury at the wrist or had a history of carpal tunnel syndrome. And so those aren't gonna be too reliable. You can also do them in the tibial nerves, but most of the evidence is looking at just the median nerves itself. EEGs, a lot of these patients get put on EEGs right away just because of the severity of the injury. You wanna also make sure that they're not having non-convulsive status, which is something that needs to be treated and would also depress the mental status. And when they're talking about reactivity of the baseline, what you're looking for is if you would do some stimulation to the patient, like you pinch their nail bed or something, you wanna see the baseline of the EEG change, and so that means it's reactive. The EEG is also very helpful at times to see if there is sleep-wake cycle information there. So if you don't see any sleep architecture or if you don't see any awakening architecture, then that will tell you that they're probably still in the comatose period, versus if you are seeing that, then that means that they have progressed and the sleep-wake cycles are restored into the vegetative state. There are times where you'll not actually see the eye opening for patients that have progressed to the vegetative state based on having some injuries to the eyes or having like an eyelid apraxia, something that they are unable to actually open the eyelids themselves. Obviously, patients that are minimally conscious are more likely to improve and then the exam improving is also, it shows that there's a better prognosis. When we're looking at kind of labeling where the patients are, and this does show up on your boards, is that there is a terminology for permanent vegetative state, which we are trying to get that in the lexicon more to be a chronic vegetative state because we know that some of these patients do after these time periods progress, even though it's a small number. So on the boards, you'll likely get asked about this. If they are a traumatic injury, you don't consider them to have a chronic vegetative state until one year. If they're not traumatic, you're looking at it at three months just because we know that the traumatics do a lot better than the non-traumatics. And again, one of the big things that we need to talk about when we're looking at prognosis is that from the most recent Disorders of Consciousness Guidelines, the recommendation, which is a level A recommendation, as in the highest recommendation you can give, is to not provide a universally poor prognosis for these patients just because, again, we know that a lot of these patients can make good gains in rehab. And that whole part of the guidelines does come out from a few different studies from the TBI model systems where they looked at five-year outcomes for patients with disorders of consciousness at rehab admission. And based on the way that the model systems codes things, the studies define it as people who are not following commands at rehab admission. So what they then looked at is two different trajectories of patients, those who had early recovery, which is defined as commands were followed by discharge, and late recovery for those who did not have commands followed by discharge. And when you look at those that follow commands by discharge, almost a quarter of them actually emerged from post-traumatic amnesia by rehab discharge. And about a fifth of them were able to have independence in at least one FIM domain by discharge. And typically that's been in their transfer abilities. And 86% of them are independently mobile at five years, which that's a really large number of patients that come to rehab not following commands from that standpoint. Those that have a late recovery, and so they were not following commands at rehab discharge, about 60% were at one year and almost three quarters of them at five years were following commands. You look at the independence on FIM domains, you're still seeing some independence in at least one FIM domain. And again, that's gonna be typically transfers. I would just give you a clinical case. I did have a patient that I did a virtual visit on yesterday since we aren't doing a lot of in-person visits right now. The patient had left us minimally conscious from rehab a few weeks ago. He was not following commands. On the video, his mom was showing me him following commands with his left arm, which is the side that he had a shrink on. He was a hemiparetic on his right. And so even since the patient left discharge, and a lot of times with counseling these families, they get really scared that they're leaving rehab and this is gonna be where they are. I mean, that guy in less than a month is now following some commands on one side, which is really, really good to see. So they continue to make progress even once they've left us. And when they're looking at patients that had left rehab, this study did not break out between the early recovery versus the late recovery. But at the five-year point, roughly a fifth of patients were able to live independently and almost that many were also able to be employed in some type of competitive or sheltered employment. And so even though it's not back to the complete independent, being able to be a breadwinner, care for your family type situation, having 20% of patients with this level of injury being able to progress to an independent level where they can live alone is quite a number of them. And even a lot of the patients that don't even achieve independent living still live good lives and get a lot of purpose from their lives. So medication management, just like a lot of things in rehab, we don't have great guidelines on it. So this is kind of my approach to looking at medications. The first thing I always want to do is just look at the current medications. Like I mentioned, a lot of times you can see significant pharmacologic sedation in these patients that end up suppressing their mental status. So big things to look at. First off, anti-epileptics after seven days following injury. There was a large study in 1990s when it's published by Tempkin that is a classic article that should be read during residency on brain injury where they put patients on phenytoin after brain injury and did not find any benefit for having phenytoin for seizure prophylaxis outside of that first seven days. So patients should not be on anti-epileptics over seven days after injury unless they have had a seizure. Those are the only people that should be. Their follow-up study actually found that those that stayed on it longer actually had worse cognitive scores than those that were on placebo. So again, it's something that we should make sure that they are off. Antipsychotics and benzodiazepines. I'm sure you're all aware, we try to avoid both of those after brain injury and they can impair cognitive recovery. Usually when I see patients, if they come to me and they're on doses of these, especially decently dose, I have a feeling they probably are able to do a bit more functionally than being considered to be in a disorders of consciousness state. And so these are probably being used to suppress some of the behaviors that are just more of the patient waking up. Narcotics, without any indication of pain, if the patient has a lot of fractures everywhere, yes, you do anticipate that they're gonna have pain, but if it's more just an isolated head injury or the fractures have healed, narcotics aren't really the greatest medication for that. And so there are times to use them and use them also in a scheduled fashion for these patients that cannot tell you that they have pain. But I definitely would try to avoid using these medications in those situations. And then anything else that's centrally acting, I personally am not a big fan of H2 blockers like simodidine, I'd prefer people on PPIs if actually needed for that because they can be a little sedating. But anything that is centrally acting, you sometimes find some weird medications on people. You know, quantadine's also one that I'm not a big fan of because that can be pretty sedating because it's centrally acting as well. So another big thing to look for is you wanna look for paroxysmal sympathetic hyperactivity or storming in these patients. And this manifests as episodes of the tachycardia, tachypnea, fever, diaphoresis posturing. And it's something that you can see these patients can definitely have these symptoms appear, especially when they're weaning off of the sedation from the ICU. And people might mistake that as agitation because they're getting tachycardic, tachypneic, they're posturing and things like that. And then start putting them on benzodiazepines or antipsychotics and stuff. And really, they just need to have their storming treated. The big thing with this syndrome is that it's actually, it's a diagnosis of exclusion. So you need to first assess for what could be causing it. Infection is going to cause a lot of these symptoms. Venous thromboembolism, particularly PEs, are going to cause tachypnea, tachycardia, can cause low-grade fevers. If you're hypoxic and having symptoms, you can start posturing from that too. Wounds are another thing to look for. Sometimes drug withdrawal for patients that are abusing alcohol or opiates can also kind of manifest with some of these symptoms as well. So just make sure you're ruling out other causes. If it is an infection, treating it will likely make the symptoms go away. But the appropriate medications to put on it are going to be things like bromocriptane, which we'll talk about a little bit later as well from the medications. Propranolol is a good non-selective beta blocker that's gonna cross the blood-brain barrier. So it'll help with a lot of these symptoms, also help with the agitation. Gabapentin will help with some of the aledinia to be able to decrease that. Also the gabinergic helps with the storming. And then if they have any signs of tone, especially posturing, Dantrolene has pretty good efficacy for these patients as well. If their LFTs are up, then I'll go to Baclofen, but I haven't found that the Baclofen itself will help some of the other PSH symptoms as much. The other big thing when thinking about meds, so if we've ruled out any of these other things, they're not being overly sedated and the PSH is being well-controlled, is that you can definitely start to have some dopamine deficiencies is one of the big things that we see with patients in triadic brain injury. So the areas of the highest rate of damage are gonna have most of the dopamine receptors, and that's gonna decrease the cognition, attention, processing speed, and arousal. And I think that you guys have had a few different talks on the different neurostimulants in brain injury, so I'll just kind of keep it brief with us, but these are the big ones to think about. Amantadine's gonna be a indirect dopamine agonist. It also antagonizes NMDA, so it's kind of a dirty medication. Some of the early research was in all patients with moderate to severe TBI that were a little bit more higher-functioning, and they found that it helped with recovery within the first three months. The big one from the DOC perspective is the Giacino article in 2012 where they did a multicenter randomized controlled trial where they took patients with disorders of consciousness and gave them four weeks of treatment with amantadine versus placebo and a two-week washout period. And what they found is that those that were on the amantadine had a much more rapid rate of recovery during the treatment period on, and when they took them off the medication, it kind of plateaued, whereas the placebo group did recover, but not as quickly, that washout period, they still recovered, and they got back down to where the amantadine group was. And so this kind of highlights that amantadine helps speed up the recovery, but doesn't necessarily get them to a point where they wouldn't have necessarily gotten there based on this evidence. The one thing with the study, since they did the washout period in everybody, it would have been great to see if only half of them did, and then they would have continued on to see if we saw a continued trajectory during these four to six weeks. They did not really have much side effects with the medication, which is great. There is absolutely no difference in the seizure rate, which is really good, because that's usually the biggest concern from people in the acute care setting is whether or not we precipitate seizures. The maximum dose of amantadine is 200 milligrams twice daily, which is what they went up to in the trial. But I usually don't go above 100 milligrams twice daily, just because I've seen a lot of side effects, more the nausea and vomiting that doesn't really kind of counteract with increased benefit above the 100 twice daily. You do have to be very cautious about this medication in that it's renally cleared, so patients with renal insufficiency, the doses need to be lower, and I don't use it in patients with end-stage renal disease because it just, it stays around too long. The GI distress is the big one, and then levator reticularis is a nice lacy rash that you can see on the skin. It's usually more seen in patients that are a little bit with paler skin tones, and it's not something that's gonna be troublesome unless they just don't like the appearance of it. Rheumocryptine is going to be a very interesting medication because it's got mixed agonist and antagonist effects at the D2 receptor. So it helps with, you know, it helps because of its presynaptic binding. It actually helps push out a little bit more dopamine into the synapse, and then you're also directly binding the postsynaptic receptors. But at higher doses, it's not necessarily better because you're gonna start getting some of that antagonist effects. I don't go above 10 milligrams twice daily just because of that process. It's really good for the storming patient, so if you have subarachnoid sympathetic hyperactivity, definitely use it. And orthostasis, it's gonna be the most common side effect, and I definitely see that even at the doses that I use. Methylphenidate is Ritalin. It's gonna be a dopamine and a norepinephrine reuptake inhibitor, more of dopamine versus norepinephrine. Very good synergistic action with the imantadine and bromocryptine, which are both helping kind of push the dopamine into the cleft. This is helping keeping it in the cleft. And it's definitely good evidence for improvement in processing speed, attention, and memory, but we just don't have enough studies in patients with disorders of consciousness. Big thing with it is just definitely make sure you're checking the vital signs. It can cause tachycardia and hypertension. I'm particularly concerned in patients with PSH because I have had that kind of trigger those symptoms again. Modafinil is provigil. It's really only approved for OSA-related fatigue as well as MS fatigue and cancer fatigue. Very hard to get it covered for our brain injury population without the diagnosis of OSA. It hits a lot of the neurotransmitters. The biggest ones to note are going to be orexin and histamine. It increases both. And those are both highly active in the reticular activating system. And so that's how you get arousal. Really don't get much other than arousal, not the attention, not the processing that you see with the true dopaminergic agents for that. Zolpidem is one that's very specific for our DOC population. It is a positive allosteric modulator of the GABA-A receptors. There was this trial where John White had looked at patients with DOC of chronic duration, a little bit more chronic. So it's going to be four months. They did some with anoxic and a lot were traumatic. So the anoxic hit that chronic stage if they were vegetative. And the traumatic are still kind of in that thought that we're going to recover. And they found that if you gave them Zolpidem versus placebo, they actually did have about 5% have a response to Zolpidem. The problem though is that the placebo response was close to about 5%. And so we just don't know. We don't think that it's going to be one that that's definitely going to help, but there might be a subset of population of the patients that it can help. The reason that we think it can help is that this is kind of a whole theory of a framework of how one of the pathways that causes disorders of consciousness. So if you have a lot of damage to the basal ganglia, particularly in the striatum to the globus pallidus, this inhibitory pathway inhibits the projections from the globus pallidus interna that are inhibitory. And when you want to do a movement and are awake, you need the thalamus to be fully functional and active. And by having these inhibitory pathways firing, it's inhibiting what's happening here. So when we have this loss of inhibition on the globus pallidus interna, that is causing more inhibition at the thalamus and the structure stimulating the thalamus. So the idea is, sorry, and this is the loss of inhibition. And the idea with zolpidem is that it's going to restore this inhibition here. So now these two pathways are inhibited and that's going to allow the thalamus to work. There are some studies using deep brain stimulation on the thalamus to be able to directly stimulate this and have seen in small single cases that you're seeing a little bit of improved arousal with the bigger studies that are still ongoing. So just briefly, just because we're getting close on time, looking at what we can do from an inpatient rehab setting, the biggest things we want to do is we want to make sure we're optimizing the medical management. And a lot of these patients have respiratory care needs as they usually come with tracheostomies. So, you know, trying to get those decantilated in a safe fashion, working on nutrition, skin protection, their spasticity, because a lot of them are severe injuries that have a lot of spasticity and the PSH symptoms. Therapy is going to help with, you know, sensory stimulation to help improve arousal during the mobilization. We know that upright positioning seems to make people more awake. And so kind of working at that, doing a lot of things to kind of, you know, give them a lot of sensory stimulation with therapy interventions. And then work on equipment evaluation, as well as the extensive caregiver and family education, because even the patients that do progress and emerge, a lot of them are still going to have some significant functional deficits at time of discharge from rehab. This is a study that was just actually just came out in the Journal of Head Trauma in print this month from our center where we did a study where we put people in the locomat. And we had four individuals with DOC due to TBI. It was a feasibility study to see whether or not we could safely put them into the locomat. And so we did, for each patient did at least one trial where they're going up to 20 minutes in the locomat with 100% body weight support and guidance force. And we found that they were able to safely do it without any adverse defense. Their vital signs were stable. And all patients actually emerged during the study, which is when the study was ended for them. And then three of them actually started overground walking during their rehabilitation stay. And so we don't know whether or not this is a feasible, we know that it's feasible, and we don't know if it's effective for making these patients progress quicker. But it is very interesting to see that we have tools that we can use for these patients that can be helpful from a therapy intervention. And just the key points I want to make sure that you guys remember because these are highly board relevant. Coma is going to be the no sleep-wake cycles and no awareness of the environment. The vegetative state is when you have the sleep-wake cycles return, but you still don't have the awareness of the environment. And then the minimally conscious state is when you start to interact with the environment. And to emerge, you have to have function, either functional object use or communication. Again, this is, you'll likely get at least one question on the boards related to these definitions. Other big things, the chronic or permanent, which is probably the terminology you'll see on the boards, vegetative state is going to be three months for non-traumatics and 12 months for traumatics. And then the amantadine has the best evidence for treatment. And with that, do you have any questions? Thank you very much. This has been fantastic. Great review kind of across the board. Congrats on the Lokmat study, by the way. I don't see any questions coming in now, but as I mentioned yesterday, many of our viewers are now viewing in kind of a delayed format as people are returning to clinical responsibilities. So we're seeing an uptick in our viewers of the recordings after the fact that has kind of correlated with the feedback we're getting that people are going back to clinical responsibilities, but still don't have some of the didactic opportunities that they had prior to COVID. So that said, just because we don't have any questions right now does not mean that they will not come up, but it's likely that they will come up. Oh, it looks like we are getting a couple of questions. One is, are you titrating amantadine or are you starting at higher doses? So that's a great question. I am one that I like to start amantadine at 100 milligrams once a day. And then if they're tolerating it, usually about five days a week, somewhere in there, increasing it up to the twice a day in the morning and at noon. Again, I usually don't go above the 100 twice a day because I haven't seen much benefit at those doses, but I do know that there are a lot of people that do. If I get to the point where I'm at the 100 of amantadine twice a day, and we're still obviously needing something, that's when I start adding the ritalin to be able to get the synergistic effects with it. Okay, any thoughts on the relation of genetic markers like apolipoprotein E with poor recovery? So the genetic markers, there is a lot of evidence that's starting to go out there, but it's not anything that is to the point that we can see whether or not it is directly associated. I think that most of the apolipoprotein E has been looking at more of a cognition kind of long-term and not as much as in this population. Okay. What are your next steps in your research? So we would love to be able to do a comparative effect in this trial with the local match study. So that's something that we have talked about reaching out because that would have to be a multi-center study because we don't have that many patients at any one center just to see these patients coming in and seeing if they're going to be able to do it. So that's something that we would love to be able to do at any one center just to see these patients coming into rehab. A lot of what we've been seeing, a lot of patients that come to us with a designation of disordered consciousness, we get them up and doing therapy and like, oh, you're actually emerged. So it's something that we have talked about being able to eventually down the road, put together, work with some other centers to be able to do a comparative trial with looking at just doing standing frames versus the local match. Okay, interesting. I'm looking forward to that. And just to clarify, when you're doing your amancetine dosing, there's some question about the New England study, the New England Journal study did 9 a.m. and 5 p.m. versus some folks do BID breakfast, lunch. What are your thoughts on that? I'll have to double check their study because I thought that they also did the breakfast, lunch. We do breakfast, lunch. I actually don't know anybody that's done something other than breakfast, lunch with it because the goal is after that time, you want them to be able to sleep. So I usually do the breakfast, lunch and I always tell people to do it with food because I have had patients throw up when they don't have, when they don't eat with it. Okay, that's helpful. I'm double checking that Giacino study. Yeah, I'm not seeing it yet. Okay, I think there was one other question. No, I think that's it. I will, oh, and we're right up against our time anyway. Thank you so much for joining us. I have, I think right here, here we go. So I have your email address. Or if anybody watching this later has any questions, they can reach out to you directly at that email address. Yep. Awesome. Thank you so much for joining us. We appreciate it. For everybody else, we want to remind you that this recording and the schedule for the rest of our lectures are available at that website, physiatry.org slash webinars. You can reach out to our presenter, Dr. Pinto or me, Dr. Pinto, and we'll be happy to answer any questions. You can reach out to Dr. Pinto or me or the AAP directly on Twitter at those handles there. Again, thank you so much for joining us and we will roll right on into our next lecture.

disorders of consciousness

coma

vegetative state

minimally conscious state

prognosis

medical management

therapy interventions

amantadine

rehabilitation setting