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Virtual Didactic - Neurostimulant Use After Recove ...
Neurostimulant Use After Recovery From Traumatic B ...
Neurostimulant Use After Recovery From Traumatic Brain Injury Led by Heather Ma, MD, MS
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virtual didactics today. My name is Sterling Herring. I'm a PGY 3 at Vanderbilt. We're excited for today's speaker. I want to welcome everybody and appreciate you participating. The goals as always are to augment didactic curricula, to offload overstretched faculty due to some logistical challenges that we're all facing due to this COVID-19 pandemic, to provide additional learning opportunities for off-schedule residents, again with some of the logistical challenges associated with this pandemic, and to develop more digital learning resources and support for psychiatrists in general during COVID-19. I neglected to say this at the beginning, but of course we always do want to recognize and appreciate those who have been more personally or professionally affected by the COVID-19 pandemic than the rest of us. We recognize that this has not been, the burden of this pandemic has not been equitably distributed, and so we appreciate those of you who have borne the brunt of this. Housekeeping wise, we're gonna keep everybody video and audio muted. If you have any questions, if you click your participants list and find me up near the top, again my name is Sterling Herring, you should be able to double click my name and send me a message. So if you have any questions related to the lecture itself, any content, any questions for the speaker, please send those to me and at appropriate times I will ask them either at the end of the talk or at any time that our speaker has time set aside for questions. If you have any general questions related to the lecture series or anything related, please reach out to Candice Street, her email is there on the screen or you can find us on Twitter. And without further ado, we're excited to have Dr. Heather Ma here with us from the University of Rochester. Welcome, Dr. Ma. Thank you, all right. You should be able to click the green arrow and you see perfect. That works? Perfect, looks great. Okay, all right, perfect. All right, so I'm Dr. Ma. I am, I'm here to talk about the use of neurostimulants in brain injury rehabilitation. So just before housekeeping things, Sterling did a good job, but I'm just, please be sure to not copy these slides. A lot of the medications I'm going to be talking about are really for off-label uses and that's going to be part of the, hopefully what turns into somewhat of a discussion by the end of this. So this is, this is a big interesting topic. There's a lot of little tiny pieces of research, but there's not really good consolidated randomized control trials. And so the first part of this is just going to get kind of setting the stage and then we'll talk more about the uses of these medications. All right, so that we have pauses at different points, Sterling, for you to ask questions. So I have no disclosures. So in general, I'm going to talk about the purpose of prescribing a neurostimulant and then go over kind of the basic science, how the physiology is supporting their use, clinical evidence supporting neurostimulant use, and then opportunities for research. There's lots of opportunities. I'm really personally interested in research. If anybody else is interested in listening to this, I'd be more than happy to talk with you offline. And I'm, I completed a brain injury, a fellowship in brain injury rehabilitation medicine. So most of what I'll talk about today relates to traumatic brain injury, but there is some uses of these medications in stroke recovery also. So to give you some context, this is a little bit of an aside. So this is not going to be on your specialty boards or anything like that, but I think this is something that really helps to put everything in context. So if you've ever seen this article, this was published in the British Medical Journal in 2003. They talked about how parachute use to prevent death and major trauma related to gravitational challenge. They did a systematic review, a randomized controlled trials, and they concluded that while everyone may benefit, there is no devil-blind, randomized controlled, placebo-controlled trial of the use of parachutes. So how do you know that the parachute is actually going to save you? But then, believe it or not, a couple years later they did the study. Again, this is the British Medical Journal, we don't make any assumptions. But they, they did a randomized controlled trial on the parachute use to prevent death and major trauma when jumping from an aircraft. And what they concluded was that parachute use did not reduce death or major trauma when jumping from an aircraft. So they actually randomized it and concluded that the parachute did not work. However, they were only able to enroll participants if they kept the plane on the ground. People were not willing to jump out of an airplane without a parachute. And so they actually argued that when beliefs regarding the effectiveness of an intervention exists in the community, randomized controlled trials may not, may selectively enroll individuals with lower proceeded likelihood of benefit. So there actually could be a bias in enrollment into a randomized controlled trial if there's already kind of general belief in the population about the effectiveness of the use of the device or the medication and whether or not it's useful. And then they did also say that, you know, that they felt the people who are the most pragmatic people involved in pushing randomized controlled trials as the standard, the gold standard of medicine, the clinical medicine, should be the ones to enroll in this kind of randomized controlled trial. But really, in my, what I try to explain and emphasize is there's, it's a risk, everything that you do has risks, as physicians, everything that we prescribe, everything, every procedure that we do has a risk, but it's a risk benefit. As long as you understand the risks very well, and well as the benefits, it's, you're always weighing those two things. So the aside is over. So in 2010, according to the CDC, about two and a half million people suffered a TBI in the United States. Of those, about 400,000 are mild concussions, 53,000 resulted in death. Okay, so this is the number of ED visits, hospitalizations, deaths over the past several years, up to 2010. And in 2013, the most common causes were falls. And then second was being struck by an object, whether that's a bullet or some other sports object. And the third was motor vehicle accident. Now this is all traumatic brain injuries included. But if you only focus on the moderate to severe TBIs, which is really my, my area of interest, 40% of those hospitalized reported an issue, an ongoing issue at least one year after their injury. So even though we save their life, we get them back to their community, they still have one ongoing issue at least a year later. And then most commonly, the issue they reported was mental fatigue, followed by disurbances with sleep. I know there was a good lecture the other day, I was caught parts of it on medications used to treat sleep disorders after traumatic brain injury. And so that was really helpful. And then balance problems and irritability. And then two years after a moderate to severe TBI, 34% of people still required some supervision. Either a good percentage lived in private residence, but they often require supervision at least during the day. All right. So clinically, first I address sleep, there was a great and again, I'll let you see the other lecture that was done the other day about sleep disorders and TBI. But really, if somebody isn't going to be awake and alert or be able to focus, it could be just because they're exhausted. And the analogy I often give is if you're a resident and you're on call and you have one bad call night, the next day your attention or concentration, that next morning is terrible, or at least mine was. And so, you know, if you if you're not sleeping well at night, several days in a row or several weeks in a row, that can cause problems. So my recommendation usually is that you should wean opioids and benzos first. So wean the sedating medications during the day, opioids and benzos being the most commonly prescribed and most sedating. So pathophysiology of a traumatic brain injury. So there's an immediate injury that occurs, and it's disrupts brain tissue and function at the moment of impact. So there's shearing, there's this acceleration, the coup-countercoup concept. But then hours to days later, there is a secondary injury. So it's like a physical force that causes a downstream kind of cascade of biochemical processes that's caused cell function, cell death. And then we're really involved in, I'm really involved in the recovery process, the, you know, degeneration, repair, regeneration, what can we do? So there's neuroprotection, to the injury cascade. And so there's, there's been some thinking, I'm sure you've heard things about hypothermia or progesterone, testosterone, some of this endocrinology and pituitary function. And then there's neurorepair, and that's really a part of the recovery process. And that's really where neurostimulants come into play. It's a neurorepair. So cognitive deficits after a brain injury are among the most debilitating and complex. So they involve arousal and awareness, like, you know, cognition is arousal and awareness, are you awake? And then are you able to be aware of what's going on? That's consciousness. So awareness can include attention, concentration, memory, and then the executive functions, initiation, planning, execution, problem solving, the various executive functions. And so neurologic, neurobiologic bases are not completely understood. But this is really what's often, what is often injuries that are most often reported. And you can argue that that's possibly because the frontal lobe of your brain is the softer part of your brain that's most exposed to the skull. And so when the when there's acceleration, deceleration happens, the brain, the softer part, which is involved in executive function, attention, concentration is going to hit something solid. And so that's more likely to be damaged. Current treatment applies neuropharmacology principles for Alzheimer's, dementia, Parkinson's, ADHD, and narcolepsy. There is not a whole lot that we have that's really FDA approved, or directly for TBI recovery, but we kind of use a lot of off-label medications off-label. So clinically, I first address sleep again, right? We go back to the basics, means all daytime sedating medications, opioids, and benzos first. And then second, are there cognitive deficits and are they interfering with function, which, as a physiatrist, you're using a patient's ability to participate in therapy, especially in the inpatient setting. You're looking at that as like your marker for function. So there's neurostimulants in brain injury rehabilitation. They became popular, you could argue, after this 2012 paper. And I happen to have had some personal mentors on the author list, which was great. It was a really well done randomized controlled trial. The interesting thing to note is that they went to 11 clinical sites, and they only enrolled 184 patients, subjects, from 11 different places across the country. To put that in perspective, I'm sure at some point, if you were an intern and you rotated through neurology, you'd be familiar with some of the stroke preventions trials, and they all have acronyms, and they'll have several thousand patients, or several thousand subjects have enrolled. And usually they, I think they only go to probably about the same number of sites. And so when this paper came out, it was great. It was very well done, but they went to a lot of places for not that many subjects. So neurotransmitters are involved in wakefulness. There's actually six. That paper targeted one, but there's six. And so norepinephrine, histamine, dopamine, serotonin, hypocretin, or orexin, and then acetylcholine. We actually have medications that target all of these now. I used to say most of them, except for histamine, because of the kind of systemic responses, or you know, you wouldn't activate histamine systemically. But then they came up with a new medication this past year, it actually targets histamine. There's different histamine receptors inside your brain. I have not actually personally used it yet with any patients, but. So these, this is, these are the locations where they act. And so you talked about these, I'm sure, yesterday, or a few days ago with this, this sleep lecture also. But these are where the neurotransmitters are thought to mostly be most active. So this is a list of medications that's neurostimulants or neurostimulant-like medications. I tried to make it as comprehensive as I could. I'm sure there's others, there could be others that people have used in the past that are not on here. This is not meant to be completely exhaustive. And I'm gonna really focus on the ones that are in the boxes, the ones that I am more familiar with, the ones that I've seen more commonly. I really just, as far as like the traditional stimulants, I'm going to talk about methylphenidate or ritalin. I'm not going to talk about Adderall or Vyvanse, although I know that both of those have been useful also. In my mind, they kind of act pretty similarly. Actually, the doses of Adderall and dose of ritalin is kind of a one-to-one, seems to be a one-to-one. So I think that they all, there isn't a whole lot of research with Adderall and Vyvanse, but there's enough to say that they support the ritalin research also. All right, so the first neurotransmitter would be dopamine. So dopamine we use through amantadine, memantine, and then cinnamate, carbidopa, levodopa. So the goal really is to downregulate this mesolimbic pathway, big red arrow, and to upregulate the mesocortical pathway. So the mesolimbic pathway is kind of considered the subcortical structures that are involved in emotion, motivation, learning, memory, but also then upregulate this pathway involved with motivation and activation, planning, organization, attention, kind of cortical tone. And so the dosing is usually morning and midday, and dopamine can be a little, the medications can often cause some nausea, so if patients are nauseous, I give them with food. And they're actually thought to be, essentially they're thought to be effective because they work through NMDA, this N-methyldeaspartate receptor, that causes an excess glutamate release, and so it's kind of excitatory. And so the NMDA antagonists, so these are all antagonists, and NMDA antagonists are anti-excitotoxic. So there's this excessive glutamate release that happens when you have a TBI biochemically, and this NMDA antagonist is thought to prevent that, or is kind of slow that glutamate release. So in the 2012 paper, that I made on maintaining how to become a common name that's thrown around in the neurologic world, the big outcome was that these 184 subjects, when they enrolled them, they were either in vegetative state or a minimally conscious state. They were enrolled 4 to 16 weeks after traumatic brain injury, okay? So all of these patients were in some sort of disorder consciousness, and I don't know if this DOC lecture has happened yet, but if not, I'm sure that will be coming soon. So a man today, they gave him 100 milligrams twice a day, morning and midday, again because it's an NMDAR antagonist and a dopamine agonist. Everybody had four weeks of treatment, and then they were followed for a total of six weeks. So what you can see is that this is the DRSRO score, the disability rating score. So this is just a very big picture, how disabled are they? Zero being no disability, and 29 being extreme vegetative state. And so when they were enrolled, most of them were in this vegetative, minimally conscious, and then the placebo subjects kind of got better over time, but so did the patients who were given imantadine. And what you can see is that the curves did separate, and so they said after four weeks of following these patients, those with imantadine improved faster. Now the argument could be that if you extrapolate these two curves out further, they would at some point meet. So you would think that at some point, the patients who were treated with placebo would get, would arguably get, become just as good, recover just as much as those treated with imantadine. So we really use imantadine to help accelerate the rate of recovery after a traumatic meningitis. so there's, that led to a really good practice guideline update recommendations from the American Academy of Neurology. And so they said that clinicians should prescribe imantadine for adults with traumatic vegetative state or unwakeful state or minimally conscious state 4 to 16 weeks to hasten functional recovery and reduce its disability early in recovery. And it was only considered a level B evidence because the study only had 184 subjects. But one thing that you should think, keep in mind, if you don't aren't familiar with this, is there's a Rancho Los Amigos scale. This is the Rancho Los Amigos scale of cognitive functioning. This is a scale that we use to talk about where patients are in the recovery spectrum after traumatic brain injury. So initially they're comatose, and then they become devegetative, minimally conscious, and then they actually go through this period of confusion and agitation. And they actually are confused and agitated, then confused and inappropriate, and then they become confused and inappropriate, so that eventually they become out of what we call post-traumatic amnesia. So the first six stages are really those patients that are in this post-traumatic amnesia phase. And then once you become out of post-traumatic amnesia, you're starting to be able to make new memories again. You're not as confused anymore. So pretty much almost all of your patients after traumatic brain injury are going to go through a period of agitation. So when they gave imantadine to the patients who were vegetative and minimally conscious, they all needed to pass through this series of agitation. Everybody had to go through an agitated phase. And so the question of whether or not imantadine is going to make patients more agitated is a, well, probably, possibly, if they're in a vegetative or minimally conscious state and they're just having gone through this agitation stage. But that's not necessarily a reason to stop the medication if they become agitated, because you're helping them to accelerate that. You're helping them to move through the agitated phase first, and then hopefully to become less agitated as time goes on. So an important thing to know is that imantadine is actually, again, risk versus benefits. A relatively safe medication unless you have renal failure. If somebody's on dialysis, if they have any kidney problems, then that's actually arguably a contraindication. But otherwise, it's relatively safe. And you can see that in the journal paper, more of the patients in the placebo group had side effects than those who were treated with imantadine. So then there is actually, is imantadine useful in concussion? That's the next question. And I know that there's been some talk about concussion treatment, too, in this lecture series. And so this was a retrospective case control series. They had 25 adolescents. They treated them for three to four weeks. And they showed that it helped with some of the cognitive symptoms. Verbal memory, reported symptoms, verbal memory, and reaction time. Again, this was retrospective, and it was case control. And then there were only 25 subjects. But it did show that that's some improvement. So dopamine or imantadine may help irritability and chronic TBI. So there's been a lot of studies out by Dr. Flora Hammond, and she has a large chronic TBI population. All these subjects were enrolled at least six months post-TBI. So in this study of 168 subjects on day 60, 74.7% in the imantadine group improved at least three points on the neuropsychology inventory is the irritability, on how irritable they were. But then at the same time on day 60, 68.3% in the placebo group improved. So their P-value was not statistically significant, but there was a tremendous placebo response. And so the large placebo effect may have masked the treatment effect. I don't know if the placebo lecture series has happened yet or not, but placebo is actually thought to be working through the dopamine pathway. So the argument is that maybe giving imantadine versus placebo to patients who are cognitively able to understand that they're taking something that's supposed to help them get better and not know whether it's imantadine or placebo is not really a good placebo, because the placebo does actually slightly increase your dopamine level in and of itself. And then another study that came out recently by the same group of getting chronic TBI showed that imantadine did not positively impact cognition. So this was looking at 119 subjects, and they looked at overall composite scores and learning memory index. And those are statistically significant. But then if you look closer, you'll see that the placebo group actually did better than the imantadine group over time. And so the statistical significance is actually that the placebo group was doing better, not that the imantadine group was doing better. But again, you don't know, we don't know if the placebo is actually a placebo. So clinically, again, I go back to addressing sleepers. And then I look at whether there's executive function, concentration, memory problems, are they interfering with a patient's ability to function in therapy or in life if you're in outpatient clinic? So one of the biggest misconceptions out there is that imantadine could cause a seizure. And actually, I wrote a review article, which I'll show in a few slides. And so I did the digging. I did the find the study that sources another study, find the study that sources another study, kind of went back through the literature. And if you go back to the beginning, in 1969, in JAMA, an article on imantadine in the treatment of Parkinson's disease said in their discussion section that they observed no convulsions in their series, but convulsions have been reported with doses of 800 milligrams a day. And so they talked about their advice that convulsions had occurred in patients receiving doses of 800 milligrams a day. And so my argument is always that honestly, really, I've looked, there is no other evidence in the literature of imantadine causing a seizure at doses of 100 milligrams twice a day, so 200 total, or 200 milligrams twice a day to 400 total, which is as high as they went in the New England Journal paper. The New England Journal paper never did more than 400 milligrams a day. So I would argue that at 400 milligrams a day, you're not going to actually cause seizures. And believe it or not, in the pediatric literature, imantadine is useful to prevent seizures from happening in children. So I think that that's just really interesting that the adult neurology literature and the pediatric neurology literature are saying two different things. So imantadine. We'll do one more and then I'll pause for questions. So imantadine, imantadine is similar, it's thought to be similar mechanistically to imantadine. They're both NMDA antagonists and dopamine agonists. But imantadine, there's much less that's known about imantadine. Imantadine is NMDA, that's the brand name, it's FDA approved for dementia. And actually there is, imantadine has been used in some constraint-induced aphasia therapy in chronic post-stroke aphasia. So it's going to be shown to be helpful in post-stroke aphasia. Again, these are all, this is 27 subjects only, and these are subjects that had a stroke. This is, you know, their stroke was several weeks or several months before they were enrolled. And this is looking at the mean change in western aphasia battery quotient, WBQ. And so they give imantadine 20 milligrams daily, and then they were treated with constraint-induced aphasia therapy and then drug treatment alone, and then there was a washout period. It was an open label extension phase. And so they actually showed that the patients who were getting the medication did better when they were on imantadine. And then this is, this is a graph showing event-related potentials. So bilateral brain reorganization happens, or they argue happens, with memantine and chronic post-stroke aphasia. This is looking at event-related potentials. So the graphs are root-mean-square obtained during a silent reading task. And they showed that essentially there's bilateral activation in the patients, subjects who were given memantine versus placebo. And they were able to quantify that. So I did have an, I do have a review article that came out recently, and the brain injury about imantadine, imantadine and memantine. It's just a review for the uses or the evidence behind their uses for acquired brain injury, both TBI and stroke. All right. And then levodopa, carvodopa. So if they're thinking Sinemet and, you know, enhancing dopamine, why not just give them dopamine itself, or why not give them levodopa and carvodopa? And so this is, this is a series of five cases. The patients were either persistent, vegetative, or minimally conscious, so they were all in a disorder of consciousness still. And the injury was to the cerebral pedicles or the dorsolateral midbrain. And so if the injury is really in the area that causes Parkinson's disease, then why not just give them something to, you know, to help with that? And then there was a series of five cases, and they were all in a disorder of consciousness still. So if the injury is really in the area that causes Parkinson's disease, then why not just give them something to actually to help their, to treat, why not just treat their Parkinson's? If their injury was in a certain location in their brain, and they have symptoms of secondary Parkinsonism, they have tremor rigidity akinesia, then why not just try it? Again, risks versus benefits. So in conclusion, following a severe TBI, imantadine treatment does hasten functional recovery and reduce disability early in recovery. Following a mild TBI, just a concussion, imantadine treatment may improve reported symptoms of verbal memory and reaction time. And following a stroke, imantadine may help improve aphasia, but again, the sample size was very small, it was about 20. And Sinemet or levodopa carbidopa can be considered if there's anatomical and exam findings suggest some sort of Parkinsonian features. So Sterling, if you want me to pause for a second, that was a lot of information. If people want to have specific questions. Yeah, we do have a couple of questions. Thanks. One is, so theoretically, if we believe that imantadine works in part, at least in part through non-competitive NMDA antagonism, could this have any detrimental effects in the long term since NMDA transmission is necessary for many neurologic processes, including long-term potentiation? That's a good question. And actually, I do get a little nervous when I see patients who've been on imantadine for long term. If I see a patient in clinic, an outpatient clinic, for example, and I start them on imantadine, and their symptoms improve, and then we just can't, I'd say, you know, we'll try it three months, because that's what the New England Journal of Study did, three months, okay, so we'll be getting it for three months, and then they should be able to stop it and continue on. If they have regression, and they feel like they need it, then we have the conversation, maybe you have a secondary attention deficit disorder, maybe we should try something like Ritalin or Adderall or something that we know longer term won't have any negative consequences. Okay, and so along those same lines, I know you mentioned the Joe Giacino study is three months, but is there a consensus on length of treatment for imantadine post-EBI? Is there a point stop or anything? No, there isn't, and so I'll tell you that what I quote is honestly a case report from about 30 or 40 years ago, I bet. I won't tell Dr. Zafant how old I think he is, but Dr. Zafant wrote a case report, and he showed that they stopped imantadine, and the patient had a functional decline, and then they resumed it, and the patient went right back and picked right back up where they were, and that's kind of what I've seen in my practice is that if you stop this in patients, it's like, oh, you stopped it too soon, let's give you back it, and so after three months in outpatient clinic, you know, after three months, I will say, you know, we'll stop it, and if they feel like they need it again, we'll have the conversation. You want to try it one more time, and if they do want to try it one more time, okay, fine, and if one more time, and then we stop it again, it's like, whoa, okay, then we really need to think about something longer term, but three months is a magic number. If you, imantadine is this weird drug, and that if they're a patient is in acute inpatient rehab, and they're doing well, and they've made progress, and they're, you know, range of seven, they've gone through post-traumatic amnesia, and they've started, they're on their way out, it's, when it's helping them is the time to try stopping it, to see if they have a functional decline, and embellish it. I had, I worked with a great attending who had, who would stop it, and then if the therapist did not come up to him the day before they left, and say, hey, they need, they're, they're not with it, they're exhausted today, they're not focusing, they're not paying attention, they're really struggling, then he'd say, okay, fine, then they don't need this. They've completed their treatment, so we don't have a good marketer for this, but less medications is better. Okay, and then on the other end, when would you start this in an MTBI setting? Is this like as soon as somebody shows up with an MTBI, and they're having some difficulty, or is this like they're continuing to have difficulty down the road? That's a good question, so fixed sleep first. Rule number one is fixed sleep first, inpatient or outpatient, and in MTBI, if you fix sleep, and you treat their headache, often they get better. Often in MTBI, all you need to do is fix sleep. That should be like your golden brain injury, is all about like regulating sleep-wake cycles, just doing as much as you can to artificially regulate it until they can do it themselves again, and so it really, MTBI, I, it's usually several weeks afterwards, and I'm thinking if they're, if they're talking about they're sleeping well, their headaches are fine, and they have cognitive fatigue, it really, really exhausts them to do something for longer than a few seconds or a few minutes. Then we start talking about trying this, and I have the same conversation, knowing that side effects of this, right, so what's your side effect of a stimulant is it can make your anxiety worse. It can make you more anxious and more on edge, and so in MTBI and concussion, a lot of times you're dealing with depression and anxiety they happen at the same time, and so starting amantadine without, in somebody who's not sleeping well and who's very anxious, it's just going to make them worse, so you got to take a few steps back in MTBI and think about them from a psychiatry perspective also. Okay, perfect, thank you. That's all the questions we have for now. All right, sounds good. Okay, so what we know, interestingly enough, is that because of this beta-6 hydroxylase, the question whether you should start amantadine or ritalin, because when I was a resident, that was a big question, which one do you start with, which one, you know, and I have, I actually had one attending who I worked with who would start amantadine on all of his patients, and the other would start ritalin on all of his patients, and that was just, that was what they did, but the answer is maybe it's not, they're not as different as we think because of this enzyme, so except in dopaminergic neurons and in the adrenal medulla, dopamine is actually converted to norepinephrine, so you're giving them amantadine. Maybe you're just giving them a slightly weaker version of methylphenidate or ritalin as opposed to, you know, it's, maybe it doesn't necessarily work, it isn't as necessary to differentiate as we think it is. So norepinephrine, we know that norepinephrine works in the pons, mostly the locus ceruleus, and so within 24 hours of following a brain injury, cortical norepinephrine levels are decreased, but the question of timing is like, well, actually in the 2012 Joe Giacino study, New England Journal of Study, their, one of their post-hoc analyses looked at timing, and they found that the patients or subjects who got the amandine started a few weeks later than the ones who got it started earlier, and I don't know the exact number, what they differentiated for earlier versus later, but those who got it later actually did better. I don't know, that was a post-hoc analysis, you can take it with a grain of salt, but within 24 hours after a brain injury, cortical norepinephrine levels are decreased, and so augmentation early after TBI is considered neuroprotective. It regulates cortical plasticity and promotes neuronal sprouting. So there's a lot of smaller studies, smaller magnitude studies on methylphenidate, on Ritalin. Methylphenidate does improve processing speed and attention after TBI. This was a double- blinded, randomized controlled trial of 34 adults, TBI, where four months to 34 years prior to enrollment in the study, and they had a moderate disability with a mean DRSS of about four. They were given methylphenidate for six weeks, and what you see is that it did improve processing speed and attention, but their effect sizes were relatively small to medium. And that was probably because of how small the study was. However, these authors also concluded there's no treatment improvement with divided attention, sustained attention, or susceptibility to distraction. So it helped processing speed. There was really no treatment-related effects in other aspects of attention. So then there is actually a meta-analysis, because there's been a lot of studies about methylphenidate. And it showed that methylphenidate does improve attention, especially sustained attention after TBI. So again, you have these smaller studies that are kind of contradicting each other and what they conclude. But there was no significant positive impact noted in the facilitation of memory or processing speed. But there was a difference with the attention and sustained attention, again, in this meta-analysis. So prophylactically, prophylactic use of methylphenidate in patients undergoing radiation therapy for brain tumors, this study says it did not improve fatigue. Anecdotally, I have used it for patients for attention after a radiation and therapy. And I feel like sometimes some patients feel like it's helped. There is not good evidence to support the use of it. But at the same time, there are risks of it, right? So what if it either works or it doesn't work? A lot of times, these medications are minimally risky. Usually, if you make sure that the patient doesn't have certain risk factors, in a manginese case, not like kidney failure, then using this medication either may help you or may do nothing. Again, it may make them a little more anxious if their anxiety is not controlled. But otherwise, it may help them or it may do nothing. So why not try it, especially when they're in the inpatient setting? That's kind of what I often teach residents. Why not try it? You're watching them closely with therapy and with nursing. Why not give it a try? So there's other neurosimulants, OK? So if we move on, acetylcholine. Acetylcholine is important with memory, particularly in the hippocampus. And actually, dinapazol has been shown to enhance recovery in short-term memory and sustain attention after TBI. So this study, they had 11 subjects that were less than a year post-TBI. And group A was dinapazol for 10 weeks. And then there was a four-week washout and placebo for 10 weeks afterwards. So A was 10 weeks of dinapazol, four-weeks washout, placebo. Group B was the opposite. These are tables that can be kind of confusing. But essentially, patients did better after they were given dinapazol for 10 weeks. And then what you see, too, is that they were given dinapazol for 10 weeks. They did better. And then when they stopped it, they still actually maintained that. So you could argue that, again, the 12-week, 10-week, how long should this medication go on for? We don't have any good answer. But we know that usually, if you stop it, you should either continue the benefits that you've gained on it, or you should get worse. But then when we restart it, you'll go right back to where you were. All right. So this is cholinergic augmentation by dinapazol. Shows a cortical metabolic effect associated with clinical response. So this is a PET scan study. There were 26 adults. They were all five months, about five months post-CBI. And then there was a significant increase in cortical glucose metabolism after treatment was found in both the bilateral, frontal, parietal, temporal, and occipital cortices. So actually, in their entire brain, there was an increase in glucose metabolism. But there was a decrease in glucose metabolism in the parahippocampal gyrus. So possible reasons why memory could be impaired. And possible reasons why dinapazol could help. Again, so clinically, you make sure they're sleeping OK. And then really, I often start, just again, because I am most comfortable with, because most of my mentors and people I've trained with have started with either amitadine or methylphenidate. And I guess in the outpatient setting, it's either amitadine or amitadine or amitadine or ritalin versus amitadine or Adderall. But then otherwise, is there an isolated memory problem? Is one of the amitadine or methylphenidate not enough? Maybe we should add dinapazol. Maybe we should target another neurotransmitter to help with their memory. All right. Any questions on dinapazol before I move on? None. Thank you. All right. So if we get into the modafinil, this is one that's actually not as commonly used with the podiatrists I've worked with. But it's neurologists seem to use this a lot. So this is actually a really well-known study. In the grand scheme of things, what I'm talking about, this is pretty large. 232 adults. They were over three months post-stroke. So all these adults had stroke. And they looked at the multidimensional fatigue inventory. This is a stroke-specific quality of care fatigue inventory. This is a stroke-specific quality of life scale. And they found that there is a treatment effect of modafinil on post-stroke fatigue after the intervention period, commendable SIBO. And it was statistically significant. Their p-value was significant, but overall. But then the question is, does modafinil improve the level of consciousness in people with a prolonged disorder of consciousness? And this is a retrospective pilot study. And so again, retrospective, take it with a grain of salt. But they looked at, this is the Wessex head injury matrix. And what they really concluded is that it really didn't do a whole lot. Modafinil didn't seem to help patients emerge from a disorder of consciousness. So clinically, I think about amantadine or methylphenidate first. Those are often the things I think about first. And then maybe I think about adding denapazole too. And I personally don't have as much experience with modafinil. And so that's not something that I think about using either. And I feel like, aside from what I've shown you, there really hasn't been a whole lot of research done into that medication. Partially in part because the question is, how does modafinil work? And the answer is, we don't really know. It's kind of through this orexin pathway that nobody really knows exactly what the details of that one is. Any questions? Not at the moment. OK. All right. So the last one that I think I'm going to talk about most of, OK, zolpidem or Ambien. This is the one that everybody wants, right? Because every brain injury attending seems to have their one Ambien-responsive patient, their one paradoxical Ambien response. So the idea is neurodormancy. This is GABA-mediated. And so zolpidem is GABA-mediated. It's selective agonist with a certain subtype of the receptor, the GABA-A receptor complex. This is an inhibits-the-inhibitor. So you're thinking, honestly, paradoxically, if you give a patient who's in a disorder of consciousness, zolpidem or Ambien, that can cause them to be awake. So it inhibits the inhibitor. It is inhibiting a GABA, which is inhibiting their arousal. And so it causes normal metabolic activity and can restore functional connectivity. The thing with zolpidem or Ambien is that this is really short-lived. So this is a really interesting study. I looked at it. And there was a review that was published in 2017. And I looked at it. There was 67 articles on the use of Ambien for neurologic disorders. But nine were randomized controlled trials. 28 case reports. Only 11 studies had more than 10 patients. So anyway, in 2009, all of these patients were in vegetative or mentally conscious for at least a month. And they decided they were going to give them an Ambien trial. Let's give them a try. Let's see how it works. And they had 1 in 14 patients respond. And this is a graph of the responder. And so what happened is, if you look at the CRS, this is the Coma Recovery Scale Revised Edition. This is the most commonly used marker for tracking patients functionally as far as their progression out of a coma, out of a disordered consciousness. So the CRS is. And then the assessment time is the x-axis is hours, actually hours. And so what they found is that with zolpidem or Ambien, there is a person who transiently emerged from vegetative to minimally conscious. So this person was able to track, essentially, around the room or to follow commands for about three to four hours. And then they would go back to vegetative state. And so this is a very short-lived thing. It's a very temporary thing. But for whatever reason, it seems to work and have a very, very good, clear explanation of why. All right, last one is serotonin. OK, so serotonin is also thought, actually, to be a little bit arousing or stimulating. It's active in the midbrain, the pons, and the medulla. And I know that there was a sleep lecture. And they talked about using trazodone. Trazodone at lower doses, you're using it more for the side effects, not for the serotonergic effects of it. All right, so fluoxetine. We've all heard of the FLAME trial. The FLAME trial was done in stroke recovery. And it showed that there was motor recovery after the acute ischemic stroke. And then there's been some studies since then that have questioned whether or not the FLAME trial was real or whether or not the FLAME trial actually had any effect. There was some suggestion that maybe giving an SSRI post-stroke can increase the bleeding risk, increase the hemorrhagic inversion risk. But the question is, using a TBI, is fluoxetine going to help for a TBI? So actually, there hasn't really been any studies in humans for TBI. But in mice, you can give 78 mice a TBI and then do a sham surgery for 70 of them. And three days later, you can give them fluoxetine at 10 milligrams per kilogram per day, for four weeks, which is a much higher dose than ever given to humans in the FLAME trial. 10 milligrams per kilogram. That's tremendous. And they looked at the dentate gyrus within the hippocampus. And they found that fluoxetine did not reverse the spatial TBI-induced gait parameters. And it did not reduce TBI-induced impairments in spatial learning memory. So I actually argue that fluoxetine is not helpful for TBI. It's been shown to be helpful, again, with the FLAME study for motor recovery and stroke. But there is no indication right now for it to use fluoxetine in traumatic brain injury recovery. So again, going back to this evidence-based medicine concept, the idea that really, we're kind of in the archaic side of things. And we're not yet in the future. Traumatic brain injury or brain injury rehabilitation medicine is the hole, or it's the gap in our medical understanding, our understanding of health medicine as we know it. Probably a few times a week, I have a conversation with patients about how they hit the hole, the nail in the head or the gap in our medical understanding. And I cannot explain exactly what is going on. But I can treat the symptoms. And I can kind of do my best to guess. And I know the risks or potential risks of the medications that I'm suggesting. So in summary, research is limited. Comparison ratios is very, very limited. Is more better? Which drug is more effective? When should you start it? What's the dose? When should you stop? Comparison ratios are very limited because research is so limited. We do not yet know how to characterize responders from non-responders. Maybe there's a genetic component. We don't know. We don't know. Patients are not often in acute inpatient rehab facilities at the time of the studies. So think about how many times you've started imantadine on a patient who's in acute inpatient rehab or an outpatient. And then you've cited the New England Journal study, the 2012 study, as the reason or your evidence behind that because it's accelerating the rate of their recovery. However, in that 2012 study, all of those patients were still in a disordered consciousness. So they would not have been in an IRF at that time of starting the medication. Studies include a mild, moderate, and severe TBI or stroke. But there's rare focus on lesion anatomy. We really are not. Stroke is stroke. TBI is TBI. Mild, moderate, or severe. It's just a very, very big picture. We don't yet have the specificity. I do a lot of neuroanatomy. I think it's really important to look at imaging. And I do think that your time with radiology, I hope as residents, is really helpful. There's large placebo responses or very small medication responses. Again, is a placebo-controlled trial really a real trial of amalgadine or of any dopaminergic medication? Or is it really, should we do something, do we need a different trial design? So you need the right place with the right time and the right patient. So there needs to be a supportive environment, like acute inpatient rehab, where the most active neuroplasticity is going on. You have to have a patient that's sleeping well. And then it's just that we've done everything given them the best chance to make the fastest recovery possible. And if one doesn't work, try another. Because we don't know. Maybe methylphenidate works for one patient. Maybe imantadine works for another one. Maybe modafinil works for one. And maybe donepezil works for another. We don't know. We don't know. It's a lot of trial and error. A lot of what we do is trial and error. There's a tremendous need for research. All right. So that's my email address. If you have any questions, any further follow-up, this is an area that I find absolutely fascinating. So I'll open up now to starting for questions. But if anybody wants to reach out to me later directly. Thank you very much. This was fantastic. I appreciate lectures that tell us not only the what but the why and the evidence behind it. So I appreciate that very much. One question that came in is in reference to Joe Giacino's New England paper. Specifically, there appeared to be the placebo group had more narcotic exposure than the intervention group. So any thoughts on that as a possible confounder? No. I'm trying to think if I was supposed to go back to that. I'm glad you paid attention. If you're in residency in, that was such a pivotal study. If you're in residency in physical medicine rehabilitation, you should know that study. You should have read that study just so you're aware. Because I was really wanting to consider one of the most, I think, one of the most pivotal studies from our field. Margarine narcotic use. I don't have any good suggestions or any good thoughts. Sorry. The questioner is saying it's in the supplementary data. OK. I was like, oh. I was like, OK, yeah. I don't have a good answer. I know that Joe Giacino really spent a lot of time trying to figure out why certain people responded and some people didn't. And he really couldn't. He really spent a lot of time thinking about what were the responders and non-responders and why do certain people respond. And I really, I've worked with another mentor. And he really, his concept, and a different possible, his concept is that he really thinks it's down to genetics. We don't know what we're testing yet because we don't know what we should be looking for. And so we don't know who will respond. OK, that's interesting. And he's a smart guy, too. Yeah. OK, I appreciate that. So if we're doing an amantadine RCT, we should be narcanning everybody, just to clarify. Just to make sure. All right. That is all the questions that we have right now. Again, thank you so much. If anybody has any last minute questions, feel free to send them in. Otherwise, your information was there on your, I think, Yeah, it was on the end, at the very end. OK, yeah. Here we go. Right there. So anybody has any questions, please feel free to reach out. That is her email address. And you can track us down on Twitter as well. Any questions, or if any of your colleagues want to see this, or if you want to review this later, the recordings are there on physiatry.org slash webinars. They're not downloadable, but they are watchable at that website. Oh, Sterling, how long will the recordings be available? These recordings will at least be available through the end of this calendar year, because we've gotten feedback from a lot of folks, especially up in New York. Some of the programs that are busier than others, we'll say, have not been able to watch these live. So these will be at least available through December 2020. Awesome. OK? So thank you again for joining us. This was a fantastic lecture. Thank you, all of our participants, for joining us today. And if you have any questions, please feel free to reach out. And we will look forward to having everybody tomorrow. Thank you again.
Video Summary
The video transcript is from a virtual didactics session on the use of neurostimulants in brain injury rehabilitation. The speaker, Sterling Herring, introduces the goals of the session, which include augmenting didactic curricula, providing additional learning opportunities for residents, and developing digital learning resources and support for psychiatrists during the COVID-19 pandemic. Herring also highlights the importance of recognizing and appreciating those who have been more affected by the pandemic.<br /><br />Once Dr. Heather Ma from the University of Rochester begins her presentation, she discusses the use of neurostimulants in brain injury rehabilitation. She focuses on medications such as amantadine, memantine, levodopa carbidopa, methylphenidate, dinepam, modafinil, and fluoxetine. She presents the research findings for each medication, the potential benefits, and the limited evidence available. For example, amantadine has been shown to hasten functional recovery and reduce disability in patients with traumatic brain injuries (TBI), while methylphenidate may improve attention and processing speed in TBI patients.<br /><br />Dr. Ma also mentions the use of zolpidem, or Ambien, as a GABA-mediated medication that can restore functional connectivity and improve arousal in patients with brain injuries. However, she acknowledges the short-lived nature of this medication's effects.<br /><br />In conclusion, Dr. Ma highlights the limited research available on the use of neurostimulants in brain injury rehabilitation and emphasizes the need for more studies in this area. She suggests that clinicians consider individual patient factors, such as sleep quality and cognitive deficits, when determining the appropriate neurostimulant to use. The session ends with an invitation for further questions and discussion.<br /><br />No credits were mentioned in the transcript.
Keywords
neurostimulants
brain injury rehabilitation
virtual didactics session
medications
research findings
functional recovery
attention
cognitive deficits
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