**Transcript of Cyberseminar**

**Timely Topics of Interest**

**TBI: Ongoing Pharmacologic Trials**

**Presenter: David Wright, MD**

**March 28, 2013**

**TBI: Ongoing Pharmacologic Trials**

**March 28, 2013**

Ralph:It’s a pleasure to introduce David Wright, who’s Director of Emergency Neurosciences at Emory and an active Emergency Room doctor who’s been intimately involved with TBI. He will be reviewing the conduct and the rationale behind a very important trial of medication for acute TBI, and we look forward to this. Dr. Ruff may be on at a later time. However, we will have plenty of time for questions and look forward to hearing from Dr. Wright. Thank you.

Moderator:Thank you. And at this time I’d like to turn it over to you Dr. Wright.

Dr. David Wright:Thank you very much. Welcome. I want to thank the VA for supporting this webinar. As Ralph said there’ll be time for questions afterwards. The picture on this is not just to have pretty pictures. The significance is the huge chasm that’s between the basic sciences and the clinical sciences or between the basic sciences and what we’ve seen in basic sciences and what’s available for patients today for Traumatic Brain Injury. There seems to be a huge gap, and sometimes it seems this gap is getting wider and wider. I do have some conflicts of interest to discuss. I’m an inventor on a sideline assessment for a concussion with a device called DETECT that you see there. We’re not going to talk about that today unless you want to later. And then also on one of the drugs that I’m going to talk about today is Progesterone for Traumatic Brain Injury and that the company BHR Pharma has licensed the use of Progesterone for TBI from Emory University. I’m listed as an inventor on that, and therefore would be subject to royalties.

Let’s start first with the significance. I would imagine that everybody that’s on this call is already keenly aware of the problem of Traumatic Brain Injury and how significant it is. This slide is from the CDC and it’s been shown over and over again at many venues. I’d like to put this in a little bit more perspective. When you see a number of fifty-two thousand deaths that’s really kind of hard to put get your hands around. So I like to show this slide because it has a couple of different significances to it. One is that we all know what happens when a plane crashes in this country and how everyone comes together to solve the problem and figure out why in the world did the plane crash. But when you think about the number of deaths caused by Traumatic Brain Injury every year, you see that would equal a hundred and seventy-five airliners going down every single year. I can guarantee you that the FAA would absolutely shut down the airline industry until we figured out what was causing the crashes. Yet today we don’t have a single treatment for Traumatic Brain Injury. 

We classically think about Traumatic Brain Injury as Primary and Secondary. We’ve learned an awful lot about TBI over the past fifteen to twenty years. And indeed it’s not just that initial injury or that initial bruise, ripping, or shearing, or tearing at the time of the injury, but actually a whole cascade of events that occurs thereafter. As you see on the screen, initial work looked at the NMDA channel, N-Methyl-D-aspartate, as one of the initial effects after an injury that caused increased damage and much more long term damage over what the original injury would be. And so a number of very smart scientists looked at blocking this NMDA channel as a potential way to reduce the sequelae of that injury. However, we now know it’s much more complex than that. NMDA channels are only one of the many channels that are activated. Calcium influx into the cell and overwhelming the cell is only one of the ways of which cells die after Traumatic Brain Injury. So we’ve struggled along the path of trying to figure out how in the world we can do something about this neurotoxic cascade that is occurring, and therefore by intervening we can improve the outcome of our patients.

This slide shows a little more simplistic view where you can see all of the different pathways, and there are even more than what’s listed here. But certainly the big ones like Inflammatory Cytokines and Excitotoxic Cascade that I mentioned with the NMDA channel. Edema occurs both from intracellular edema as well as in the breakdown of the blood brain barrier and the vascular edema. Then there’s this curious thing called Apoptosis where self-suicide occurs after a cell is injured and some switch comes on to say, “Let’s go ahead and commit suicide.” Of course other things are occuring.

This next slide is a bit busy and I apologize for that, but it’s really just showing you the initial attempts at targeting the NMDA channel with the first drugs that were used and the clinical trials that were done to try to do that. The animal data looked pretty good, but when it went to clinical trial it failed. 

Here’s another list of a whole series of other drugs that were tried barbiturates, PEG-SOD, Cerastat, many of these you are probably familiar with. But again unfortunately this is where we are. We have many clinical trials that have been done. To date not a single clinical trial has shown any positive results at the Phase III level. Many of those trials you’re probably familiar with, even the more recent ones such as the Crash Trial with Methylprednisolone which failed. The Mag Sulfate Trial down here in the U.S., there was an increase of mortality by twenty-five percent in that treatment group which was quite a shock. Then of course we’re all upset that the Marijuana Trial failed that was done in Israel. I could go on about these failed trials. So this is where we are at present. We have no treatments. At some point you need to stop and think, “What is going on here? Why are all these trials failing?” Just for a very brief period I want to talk about some of the failures that have occurred and why we’re in this situation with Traumatic Brain Injury. There are huge gaps. One might think are our animal models really reflective of the clinical condition? That’s a legitimate argument. Unfortunately we can’t use human models in an active way. They won’t let us use the graduate student anymore for our studies. So is the animal model relevant? There’s a lot of discussion that can go around that. I think in the end when you look at it they are informative certainly from the concept standpoint. We’ve got to do a better job of modeling the human condition in the animals, and vice versa when we do our clinical trials we have to do a better job of narrowing the study design that we did in animals in our clinical trial is on when we go to humans.

Another issue is the classification and the definition of Traumatic Brain Injury, which has been really a problem for us in TBI. If you think about it, it’s almost a little bit silly. The Glasgow Coma Scale is what we currently use as a measure of Traumatic Brain Injury. But the truth is that this really has nothing to do with the underlying pathophysiology. It is simply how you react to your environment at the time which is supposedly reflective of the functional status of the brain. That’s how we classify it with Mild, Moderate, and Severe. The problem is that using it in the ultra-early stage is problematic, because there are so many other things that intervene such as drugs, alcohol, and medications that we give to the patient that can contaminate the Glasgow Coma Scale and give you a false reading. 

It’s a real problem, and it’s codified very well in this next slide which shows you six different patients. This was Alisha Jean’s work in San Francisco. It doesn’t take a neuroradiologist to look at these six different patients. All who had a Glasgow Coma Scale of four can tell you that the pathophysiology in the outcomes of each one of these patients is dramatically different. So we have a real problem with our classification. Imagine if we rated breast cancer for example as mild, moderate, and severe. And we approached our treatment based on that. That’s not the way we do it. We not only know the cell type of the breast cancer, but we know the genetics of it and therefore we can target it. We’re really living in the sixteen and seventeen hundreds when it comes to the way we diagnose TBI.

The other fundamental problem we have is our approach. The singular mechanistic approach is not going to work. You saw the slide of all the different pathways that are involved, and a mechanistic and a reductionistic way that we approached it to date is really simply not going to work.  You can think of it as a cup full of water and you have multiple holes, i.e. multiple pathways of demise. If you put your finger over one hole you’re still going to get wet and get an empty cup. So you have to find a multitargeted approach, and that’s where Progesterone comes in as you can see in the slide. It’s either multiple drugs or one drug that acts in multiple different ways. 

The last one I’m going to mention is what we call “The elephant in the room.” It’s our variability in management of TBI. We know that our clinical management impacts outcome fortunately, but unfortunately the variability has ruined many a good trial and probably sank a number of drugs that actually would work if we could standardize our treatment. You can look at this data of the difference in mortality across sites. Geography really does matter where you live, and it can depend on whether you survive the head injury. You can see anywhere from twenty to sixty percent mortality. What a huge variability. 

So what about current ongoing clinical trials, which is what I was tasked to talk about? There are quite a few things that are in the pipeline. I’m just going to very, very briefly look at these. This is www.clinicaltrials.gov data with all of the issues that may come with that, and they are Open Interventional Trials. I selected mainly the Acute Trials. For those who were in the rehab audience I apologize for that, but that’s my area of expertise. So I chose just to look at Acute Trials, neuroprotectant type of studies. And in the Phase I studies you can see a number of things that are out there. The data on the date is actually somewhat informative at the end where you can see that the date itself is often wrong and often already passed, yet these trials are still ongoing. That’s just the problem with enrolling subjects in these trials. In the Phase I stage there are a few trials. One of interest is the Bone Marrow Mononuclear Cell Trial going on in UT, Houston. That’s a DOD funded trial. At Phase II there are a few more studies. The Propranolol Trial that’s up there is really looking at sympathetic storm, and not necessarily the outcome of TBI. Although I think there’s a GOSE that’s going to be measured, but you can see a variety of other things like Lactate and Hyperbaric Oxygen. The BOOST Trial isn’t really a drug trial per se, but it is interventional based on data from the brain tissue oxygen devices. A Nerve Growth Factor Trial is interesting. Allopregnanolone, which is a derivative of Progesterone, is also being looked at by UC Davis, although they’re not open to enrollment yet. Under “Recruit,” “Y” means yes, and “N” means no for actively recruiting. NNZ-2566 is a growth factor that’s being looked at. That was developed out of military labs. 

In Phase III there are very few. There’s actually one that Claudia Robinson is doing it and it’s not on this list, but it’s an EPO Trial. She must be finishing this up, because it didn’t come up in the active studies. But there is still one going on in Australia and New Zealand. Then there’s a Prophylactic Hypothermia Trial. Hypothermia basically failed in this country in a couple of large studies, but it’s still being tried elsewhere and in children as well. We’re going to talk about one of the two Progesterone Trials, and then some Hemorrhage Trials that are going on. One is in Europe and one in Thailand. Briefly I’m going to switch over to the Progesterone Study and just talk about it for a second. So how in the world did we start thinking about progesterone as a potential treatment for Traumatic Brain Injury? You actually have to go back thirty-seven years. That seems phenomenal, but that is the development in this country of new discoveries. It was around thirty-seven years ago that Don Stein first discovered that in his female rats that they were doing better after a Traumatic Brain Injury that was induced in the lab when he was looking at neuroplasticity. And instead of ignoring this finding he pursued it to try to figure out why these female rats were doing so much better. There were a lot of different things and a lot of different reasons that you could postulate, including different brain areas, different brain functions. We know from looking in the animal world that certain parts of the male and female brain develop differently, depending on the use of that area. But what the bottom line came down to was that it was the hormonal cycling at the time of the injury that conferred the neuroprotection. When the female was in the state of her menstrual cycle when progesterone was high, she was most protected. And if you induced pseudopregnancy where the progesterone goes way up, you can almost eliminate the cerebral edema associated with the induced head injury. 

This work was done in Don’s lab, and you will also see Stuart Hoffman on this who is now with the DA System. He was in the lab working on this development. It turned out that the progesterone not only worked in females endogenously, but worked exogenously when given. You have to remember at the time it was thought of as a female hormone. And I’m here to tell you that it is not a female hormone, it is a neurosteroid. It’s only in the female cycle likely for neuronal development of the fetus. At least that is the prevailing thought currently. Just to show you that progesterone is unusual, it’s made in the brain by the brain for the brain. It’s one of the only hormones that’s actually produced within the brain from cholesterol. How does progesterone work? It’s multifaceted. It reduces inflammatory cytocons dramatically. It indirectly blocks the NMDA channel. It seems to affect blood brain barrier on edema, and it also reduces apoptosis as well. It has a multi-mechanism. There are now over two hundred publications that support this work outside of Don’s lab and within Don’s lab. So there is a lot of data.

The first “in human” trial was done in 2001 to 2005 out of a lab at Grady Memorial Hospital. Essentially its primary outcome was for safety. But what we found was that there was a fifty percent reduction in death in the treated patients, which was surprising to us. We didn’t expect anything quite that dramatic. It was a small number and it was not powered for efficacy, it was powered for safety. Since that time another trial in China basically replicated these results. The importance of that trial was that it showed improvement in functional outcome at six months, as well as improvement in mortality. So that led us to the Phase III Trial we’re currently undertaking, which is called ProTECT III. We now have seven hundred and twenty-nine patients enrolled. We had two enroll already today. It’s run through the Neurological Emergency Treat Trials Network, which is NIH funded network. Bill Barsan is the PI of the network and I’m the PI of the ProTECT Trial. 

This is just to show you all the different sites involved. We’re going to have close to forty-four sites involved by the end of this year. With blunt traumatic brain injury, GCS 4-12, the requirement is to get the infusion within four hours and age over eighteen. Progesterone is dissolved in a small amount of ethanol and then mixed with intralipid before it’s given. It’s given over a four day period with the last day being a taper. We’re going to get eleven hundred and forty subjects as I said; we’re at seven hundred and twenty-nine, and our primary outcome is a six month outcome on a Glasgow Coma Scale on a stratified dichotomy. We are on target with our enrollments, and we’re very pleased at how the trial is currently going. This is a very complicated trial involving lots of people. It’s not an ED trial. It’s not a trauma trial. There are a lot of people involved, and it takes a team approach to accomplish it. That’s all I have.

Moderator:Thank you very much Dr. Wright. We appreciate that. At this time I’d like to check with Dr. Ruff. Do I have you on the call?

Dr. Robert Ruff:Hi, this Bob Ruff.

Moderator:Excellent. Thank you for being able to get in here at the last minute. I will go ahead and advance through your slides for you and get that all set up. 

Dr. Robert Ruff:Okay, the first one is just the title.

Moderator: So we’ve got the title slide if you’d like to talk about you and your fellow researchers.

Dr. Robert Ruff:What’s the second slide?

Moderator:We are going to go to one of your poll questions. For your audience up on your screen now you should see a poll question. Before Dr. Ruff gets into his presentation, we would like to know, “What is your primary role in the VHA?” Your options are: VA Researcher, Non-VA Researcher, Clinician, Management or Policy Maker, Other. It looks like we’ve had about sixty percent of our audience vote, but the answers are still coming in. We’ll give everybody just another second or so. We’ve had a seventy percent respond rate. I’m going to close the poll and share the results. Twenty-eight percent of our audience are VA Researchers and five percent are Non-VA Researchers.  The majority, forty percent, are Clinicians. Thirteen percent are Management or Policy Makers, and fifteen percent are Other. 

With that we’ll move on real quickly to the second poll question. We would like to know what type of Traumatic Brain Injury do you encounter as a part of your VA Care Delivery? The options are: Acute TBI of all severity, veterans with sequelae of past TBI only, veterans primarily with mild TBI, such as with concussions. Then there are vets with problems associated with TBI and other conditions, such as PTSD, pain, etc. Or,” I do not see veterans as patients.” It looks like most of our clinicians have answered. We’ve had about sixty percent response rate, so I’m going to go ahead and close this and share the results. Thirteen percent of our audience deals with Acute TBI of all severity, thirty-four percent deals with veterans with sequelae of past TBI only, thirty-four percent deals with veterans primarily with mild TBI, such as with concussions. Fifty-five percent deals with vets with problems associated with TBI and other conditions, and thirty-two percent do not see veterans as patients. Obviously people were able to select more than one that applies. We’ll go ahead and move to the next slide, which are financial disclosures, grants, etc. 

Dr. Robert Ruff:There’s really nothing dramatic on that slide. I do have to disclose that I am currently sitting in this chair. I had a medical emergency come up and unfortunately this was the only time I could get. I couldn’t really put it off. 

Moderator:We appreciate you making the time to join us even under these circumstances. So the next slide is the Comparison of Annual Incidence. 

Dr. Robert Ruff:What you see is a circle diagram showing that TBI in the United States is extremely high compared to many other conditions. It’s one of the most common disorders requiring acute medical intervention. That numbers more than a million people in the United States with only people that get medical attention. It does not include people who have TBI that does not lead to a formal emergency room visit or hospital admission. It’s a small fraction and it represents probably the more severe of the TBI episodes.

Moderator:Thank you. And the next slide is talking about TBI Classification, mild, moderate, and severe.

Dr. Robert Ruff:This is fairly standard. This is from a VA/DOD cooperative. The standard criteria could be used between the VA and the DOD. Mild, moderate, and severe is based upon whether you’re at a loss of consciousness, alteration of consciousness, or post-traumatic amnesia. We see that mild is classified as having no identified injury on a MRI or CT scan, and those are more conventional imaging techniques, not DTI, fMRI, SPECT, or the PET scan. We need more sensitive imaging techniques as is possible to discern a small degree of damage in the brain after even mild Traumatic Brain Injury. Most of those can heal and some of the deficits remain. But in general, the neurologic efforts after mild TBI are trivial. The residual deficits after moderate and severe TBI on the other hand are very grey.

Moderator:Thank you. On the next slide we have the average annual rates for traumatic brain injury deaths, by age group and sex.

Dr. Robert Ruff:What’s shown here is that there is an increase in TBI incidents with age associated with more frequent falls. And falls are responsible for TBI’s in the very young and in the very old. In young adults, people in their twenties to their sixties, the majority of TBI’s are associated with motor vehicle accidents, injuries at work, and a fall. Injuries at work can also include falls, and there are also falls at home. As people get older falls become an increasingly frequent event and account for most of the geriatric traumatic brain injury.

Moderator:Thank you. The next slide is average annual rates for traumatic brain injury deaths, by age group and eternal mechanism of injury. I think you just went over that like with motor vehicles.

Dr. Robert Ruff:Yeah, I’m sorry. That shows the coincidental manner of the importance of falls in older individuals. I just want to make one editorial comment, which is that the residual deficit mild TBI is minimal, but there can be a fair amount of confusion and fatigue acutely associated with mild traumatic brain injury to the point that people can have a great deal of concern about how long this is going to last. What we’ve found is that in mild uncomplicated traumatic brain injury that the residuals don’t last. They will recover to their normal state. 

Moderator:Thank you. The next slide is of the brain injury and it talks about how mild TBI is not always benign.

Dr. Robert Ruff:The deficits that occur with mild TBI are usually transient. They’re almost always transient. There are problems that can persist. In a group of uncomplicated civilian traumatic brain injury, they find that ten percent have problems with headaches and concentration that persist beyond a six-month period. It’s difficult to know what causes that. Those can represent people for whom there is a secondary brain injury. But I think they also work within a slight group of people who are just more susceptible to a brain injury. There are some people who are prone for example to compression brain injury. With people developing something like carpal tunnel syndrome, the brain activity varies from person to person. Some people can do the activity with the wrist without feeling carpal tunnel, and others are more prone to developing a nerve injury. I believe that this is something that we will find. This is not something based on scientific study, but it’s more based on intuition from having seen people. That same imagery will result in different degrees of deficits and around different people. 

Moderator:Thank you. We’ll move right along. The next slide talks about diffusion-tensor MRI which reveals white matter pathway damage. 

Dr. Robert Ruff:This slide is pseudo-colored imaging where the technology is able to distinguish different fiber pathways. Diffusion-Tensor Imaging is a technology that looks at the ability of how protons move along the tube. A tube acts as an axon. The axon is attached and the protons are able to move at the beginning. The next one goes down the line and together move them at the end. If there is a break in the axon then that movement will not continue. The movement that they’re looking at is actually relaxation in a magnetic field. The magnetic field is perturbed by a low intensity electric field. It’s additional energy to the protons to move. And it is a very powerful technique that tells about the structural integrity of axons. You can see areas of damage that occur in particular with traumatic brain injury, because it’s a typical distortion of the brain that occurs in response either to a blast synergy that’s transmitted to the brain or a physical distortion that occurs. The axons to the brain are designed to be able to tolerate a small degree of stretch and contraction associated with just the regular blood pulsation. But they are not designed to deal with more rapid or more extensive stretching and contraction that would occur with traumatic brain injury. Contrast that to the nerves that are present in your arms and legs, they’re used to being stretched and relaxed. This has to do with the differences in the membranes that the membranes of the axons in the periphery are able to stretch and contract, whereas it is much less true for the axons in the central nervous system. Similarly the covering of the axons in the central nervous system is different than that in the peripheral nervous system. That insulation covering is less able to tolerate stretching and contractions. That’s why stretching and contractions can produce a brain injury which is something that occurs with traumatic brain injury intended to be detected by diffusion-tensor imaging. 

Moderator:Thank you Dr. Ruff. In the essence of time, we are going to need to move a little bit more quickly for the remaining slides. The next one is talking about neuropsychological deficits correlate with severity of white matter damage. You may have covered some of this in the last one.

Dr. Robert Ruff:What this shows is that the damage to the axons correlates with deficits of memory and executive functioning. The more severe the damage to white matter, the more severe is the damage between the quantitative in naturally different aspects of cognitive functioning.

Moderator:Thank you. The next slide talks about treatments for severe TBI with the medication trials and deep brain stimulation.

Dr. Robert Ruff:There are very few medications that are available that have demonstrated clear benefits for particularly severe traumatic brain in injury. Amantidine was something that was found to improve an individual’s ability to concentrate, focus attention, such that the person could more effectively participate in rehabilitation. Deep brain stimulation is used for a very small fraction of people in whom there appears to be isolated areas of cortex that are functioning, but are under stimulated. DBS is able, by stimulating critical areas of the subthalamic, to stimulate those cortex’s that tend to awaken the person and again enabling them to participate more effectively in rehabilitation. These affects are in one way minimal, but in other ways can be dramtic for an individual who has no functions. So they might be able to improve an individual for example to be able to eat, whereas prior to improvement they could not eat and they had to have a feeding tube.

Moderator:Thank you. We are going to go ahead and skip forward to the trials at this point so that we have time for questions with the audience. We are going to skip over the Midbrain RAS Activate Cortex and Intralaminar Nuclei. Here we have a paper about the behavioral improvements with thalamic stimulation.

Dr. Robert Ruff:That was when I talked about an individual who after using deep brain stimulation was able to participate in rehabilitation. 

Moderator:Great. And would you like to talk about your trials now?

Dr. Robert Ruff:There was a trial that was published in *JAMA* last fall in November, early winter. It was a multi-centered clinical trial of an agent, Citicoline, which had shown great promise in animal studies of traumatic brain injury. The clinical trial however, failed. This has been true for many trials where there are agents that have been shown to be effective in animal models, but not effective in clinical trial. It likely represents that the human brain is more complicated, and that recovering may require a higher degree of structural improvements to enable a person to gain appreciable functional skills. I think that the other thing that will likely be done in the future is that agents that are shown to be effective in animal trials may have mechanisms of action that can synergize. In other words, one may reduce information following traumatic brain injury, and another may help with recoupling damage to axons with those treatments that potentially were synergized might be used in concert with each other, rather than as individual agents. It’s much in the same way those cancer chemotherapy individual agents, which prove to be effective in treating animal models of cancer, that those agents when used individually were not as effective as they were when used in combination. I personally feel that the future for different interventions for traumatic brain injury are going to involve trials that are a combination of not just a pharmacologic treatment, but also of treatments such as different forms of electrical and magnetic stimulation, as well as perhaps innovative rehabilitation techniques that may more effectively engage an individual’s attention enabling them to more effectively engage in an activity. So I feel in the future we’ll be using multi-modality and multi-agent treatments, rather than just with modality stimulation. 

Moderator:Thank you very much. That does take us to our final slide. So I’d like to move onto audience questions. For those of you that joined us after the top of the hour, go ahead and just type in your question or comment for the presenter using that “Go to webinar” dashboard on the right hand side of your screen. The first question came in I believe during Dr. Wright’s portion. Has progesterone been tested after the acute phase of TBI?

Dr. David Wright:That’s an excellent question. We have looked at a little bit longer than acute. I believe the last study was a five or six-week study in animals. There are a number of problems with studying non-acute drugs in rats. Rats tend to recover from anything. If they survive by the time we’re six weeks out, they just seem to have an amazing ability to recover to the point that you can’t measure differences in function. I think that most of us who have worked in basic science with rats, it’s just one of the phenomena about them. The answer to that is yes in a rat model, and didn’t see a huge improvement with delayed onset longer term use of progesterone. That’s a single study in the rat model with the caveats I just explained. It has not been tried in any other species or other models. 

Moderator:Thank you very much. We have a question that has come in for both of you. Dr. Wright, what is the most promising for severe TBI?

Dr. David Wright:Most promising drug? Is that the question?

Moderator:I believe it’s the most promising treatment, but it could be a drug. I’ll wait for the questioner to write in.

Dr. David Wright:I’ll go ahead and talk while we get a clarification.

Moderator:He’s asking for both.

Dr. David Wright:Okay. I’m biased. I’m running the ProTECT Clinical Trials, so I certainly think that Progesterone is one of the more promising treatments. It clearly has an enormous amount of pre-clinical work that has been done on it. As I said before, there are over two hundred publications up to this point. We designed the clinical trial in a way we hope that we can overcome some of the failures of previous, which is a whole another discussion. I think standardizing care and following treatment guidelines is another really non-pharmaceutical way that we can dramatically improve the outcome. In fact, in centers where they follow guidelines and follow aggressive treatment of care, you can reduce the mortality in severe TBI down into the teens. That’s a rather amazing achievement. We know that if you have one episode for example of hypertension you double mortality. So just standardizing care and being aggressive with these patients and thinking of the trauma patient as a brain injury first and not with the current approach. It would go a long way to achieving better outcomes. 

Moderator:Thank you. And Dr. Ruff, would you like to comment on what is the most promising treatment or drugs for severe TBI?

Dr. Robert Ruff:I think that I totally agree. I would add that as a person advances to the point of starting to be interactive, once they’ve reached the phase where you can begin to reach out more effectively and engaging experienced therapists, particularly speech and language pathologists, with the person and to adapt the treatment to the individual’s needs based on what their deficits are combined with very aggressive and effective early treatment so that the person has more residual cerebral capacity at the point when they start to engage in rehab. I think that’s likely to lead at least at the present time to the best outcome.

Moderator:Thank you both for those replies. We have another question that came in for Dr. Wright. Does injury severity score correlate with TBI in intervention?

Dr. David Wright:Yes and no. The injury severity score for those who aren’t familiar with it is broken down by body systems. You have the injury scoring zero through six for head and body and other different systems. And then the four worst are added up and squared and you get the injury severity score. It’s reflective as its name is of severity of injury, but how well it correlates with a traumatic brain injury is a little more difficult to get your hands around. There is a head injury component, and unfortunately the standard neck is included in that. So it’s not a clean way of looking at the brain only, because a head injury under the head injury portion of the injury severity score can include non-brain injuries. It’s not a really good measure of traumatic brain injury, and it also doesn’t reflect the underlying pathology.

Dr. Robert Ruff:I think the thousand pound guerilla in the room when you’re talking about veterans and military TBI is for stress reaction such as PTSD. I think what separates out mild TBI in combat from milt TBI that occurs on a football field is the relatively high incidence of Post Traumatic Stress Disorder associated with mild traumatic brain injury that occurs due to a combination of injuries that can even transiently affect function of the veterans medial prefrontal cortex, and thereby disrupting the normal regulation that now the frontal cortex exerts on the amygdala resulting in the amygdala operating somewhat in a disinhibited way, resulting in exaggerated or excessive fear actions, flight reactions, overly exaggerated reactions to situations which are manifestations of PTSD. I think for me the challenge in treating veterans with mild traumatic brain injury has really been the need to address the combination of TBI, which I think is really a minor component. I think what the TBI has done is more that it increases the likelihood to have a psychologically traumatic as is in war time event would result in the establishment of PTSD, rather than the sequelae of the mild traumatic brain injury. It’s a totally different situation for people with severe TBI where physical consequences of the brain injury are paramount in terms of determining the sequelae. So I think that the severity of the injury in people with moderate and severe TBI is what determines the deficit. In people with mild TBI in the military or from military combat, the severity of the PTSD that determines the amount of problems that the person is having. 

Moderator:Thank you both for those replies. We have two questions left. By what receptor system is progesterone mediating its effects?

Dr. David Wright:Multiple. It has a gabinergic GABA receptor, which acts to cool down the brain of sorts. Not cool it in temperature, but the GABA receptor is a benzo type of receptor. The sigma receptor is another one that it acts upon which has an indirect effect on the NMBA receptor. Then there is a number of intracellular, maybe even some intranuclear, but intracellular receptors including some that are involved in the apoptotic pathway. So there are multiple different receptors that it seems to hit. We have looked at things that would block some of those receptors to see if we could lock it down to just one or two, and we haven’t been successful in that. In fact, when we block some of these receptors in a lab, we still get an effect, so it’s probably a lot more complicated than what we currently understand.

Moderator:Thank you very much. I’m not sure who this next question is directed at. Is there any difference between Europe and U.S. in outcome data?

Dr. David Wright:Outcome data with reference to what?

Moderator:Not entirely sure, but while we wait for them to write in clarification, do either of you have any concluding comments? We can start with you Dr. Wright.

Dr. David Wright:I’d just like to thank everyone for hanging in there for the hour. If anyone has any questions outside of this, they’re welcomed to contact me. I presume my contact information is up.

Moderator:It is available in the handouts I do believe. I really want to thank you for sharing your expertise, and also a special thanks to Dr. Ruff who joined us from an emergency dental visit. We know that must have been a difficult balance. Dr. Ruff, do you have any concluding comments?

Dr. Robert Ruff:I would say that what’s important in dealing with traumatic brain injury is that the brain is able to more than recover. It’s able to compensate. TBI is challenging, but it can be very rewarding. It’s important when dealing with people who have mild to moderate TBI that you need to not only deal with an individual but also with an individual’s family. We can provide education so that they can anticipate what’s going to happen and to help them through the course of recovering. It’s important to help the family understand or anticipate which patients are likely going to show better recovery than not. It’s an influence that people who are used to treating this condition understand. Thank you.

Moderator:Great. Thank you both once again for sharing your expertise with the field, and thank you to our audience members for joining us today. This is part of a mini-series on TBI. The next session is going to be on the fifteenth of April. It’s going to be on Cognitive Rehabilitation Assessment and Drug Therapy. So please go to the cyber seminar registration catalog and sign up to join us on April 15th. Thank you to our audience members and our presenters, and this does conclude today’s presentation. As you exit the session, please do fill out the feedback survey that will pop up on your screen. Thank you and have a great day everyone.

Page 1 of 12

Page 11 of 11