**Transcript Of Cyberseminar Timely Topics Of Interest**

**Rehabilitation of Mild Traumatic Brain Injury in OEF/OIF Veterans: A Multidisciplinary Challenge**

**Presenters: Regina McGlinchey, PhD; Kris Siddharthan, PhD, MS; David Cifu, MD**

**October 25, 2012**

**Rehabilitation Of Mild Traumatic Brain Injury In OEF/OIF Veterans: A Multidisciplinary Challenge**

**October 25, 2012**

1:10:44 page 16

Molly: Today is the third in a four part series on TBI. Today’s topic is management of TBI and rehabilitation. We will be getting started ...um... actually right now. I would like to first introduce Dr. Ralph Depalma. He’s a special operations officer for VA ORD and he’s going to introduce this series for us. 

Dr. Depalma:  Well, this is the third seminar presented by distinguished VA scientists. We will discuss TBI management and some of the issues regarding treatment. It’s hoped that these practical matters will help to provide guidance to the field. Thank you, Molly.

Molly:  Thank you very much. We do have three presenters. Speaking first will be Dr. Regina McGlinchey. She is the director and principle investigator at TRACTS at the VA RR&D TBI Center of Excellence. Speaking secondly I have Dr. Kris Siddharthan. He’s a senior health researcher for Patient Safety Center at Tampa VA Medical Center. And, finally speaking we have David Cifu. He’s the national director of PM&R Services for the Department of Veterans Affairs. 

So, right now I’d like to turn it over to Regina. Are you ready to share your screen?

Dr. McGlinchey:   I am Molly.

Molly:  Okay great. You should see a pop up that says show my screen. Just click on that. Great. Now just go into slideshow mode and we’ll be all set.

Dr. McGlinchey:  Can we leave that open?

Molly:  I don’t see your slide yet actually. There we go. Okay, now you should open to slideshow mode. Perfect.

Dr. McGlinchey:  Okay. Are we ready to begin?

Molly:  Yep. Go ahead.

Dr. McGlinchey:  Okay, first of all I’d like to thank you for the opportunity to present today. I’m going to be presenting on the rehabilitation of mild traumatic brain injury and OEF/OIF Veterans. The title is a multidisciplinary challenge. Iraq and Afghanistan wars have raised a great deal of concern about the incidence and long-term effects of mild traumatic brain injury and how we’re going to treat these Veterans in the coming decades.

While this concern is certainly well founded, I am going to suggest to you today that it is unfortunately much too limited in scope. When you work with these men and women, what you learn very quickly is that their problems are not limited to what one would consider to be associated with post concussive symptoms. Yes, many of them do have persistent memory problems, but many of them also feel very detracted and withdrawn from their loved ones. Some are angry and impulsive. Some are hypervigilant. Some might have debilitating pain. I could go on. What I want to stress today is that when approaching strategies for treatment of mild traumatic brain injury in OEF/OIF Veterans, we have to look at the whole person – not just one or two of his or her problems. 

I hope to cover four main topics today: The scope of the challenge to treating mild TBI – in other words, who is the population for whom we will need to devote our rehabilitation efforts towards. Why does this cohort present such a challenge? I will then outline the considerations the caregivers should keep in the forefront of their minds as they develop new strategies for these patients. Lastly, I will mention briefly a few of the lessons that we have learned at the TRACTS program as we have tried to institute rehabilitation treatment programs. 

In the course of my presentation I’m going to share with you some of the data from our TRACTS cohort. We recruit our subjects primarily from throughout the Boston area with the inclusion criteria for the study simply being that they were deployed to either Afghanistan or Iraq, or that they’re in the National Guard and will likely deploy. I show this to point out that our sample is representative of the military population at large with regard to ethnic and gender distribution. I’d like to also note that the time since their last deployment – in other words, the time since they’ve been home – is nearly three years. So, I’m not talking today about acute effects of mild TBI. 

The most common physical injury sustained by OEF/OIF military personnel is traumatic brain injury. And, the predominant mechanism of injury for OEF/OIF is blasts due to IED’s and other explosive devices. TBI is classified by the VA and Department of Defense into three levels of severity – mild, moderate, or severe – and that depends on the severity of the symptoms at the time of the injury. 

Approximately 75% of all TBI’s are mild, which means that the individual experienced a loss of consciousness of less than 30 minutes and/or a severe memory loss or alteration of mental status surrounding the event of less than 24 hours. At TRACTS we further classify mild TBI, or what some would call a concussion, into three levels of severity – grade one through three. The primary difference between grade one and two is the loss of consciousness in a grade two. And then, from grade two to grade three the primary difference is in the duration of the symptoms. 

Now, why does this cohort of Veterans present such a challenge to the VA? Our bottom line is the issue of heterogeneity. In this cohort of Veterans we saw tremendous individual differences in nearly all aspects of their clinical presentation. We see this heterogeneity first in their lifetime history of mild TBI’s. These data are summarized from the first 200 service members from the TRACTS cohort. 

There are a couple of points to take away from this. First, replicating many other reports, the clear majority of our service related TBI’s fall into the mild category. Second, look at the number of pre-deployment TBI’s. Seventy-seven individuals in our sample, or approximately 40%, had experienced at least one TBI before entering the military. Now, in retrospect, this makes a lot of sense because you consider the kind of person who is going to be drawn to military service tends to be someone who is more willing to take risks than others – be it in a school yard, a football field, or a battle field. This fact underscores the need to consider prior histories of trauma in our Veterans because these early life events had latent effects on the brain and they actually act to exacerbate deployment related injuries. Third, there are many instances of multiple TBI’s in our sample, both during service, but also prior to service. These cases of multiple blasts and blunt TBI’s are critically important to their clinical care in the long run because it is these cases that could be at a high risk for the development of very serious, chronic effects of multiple TBI’s such as chronic traumatic encephalopathy – which we’ve heard a lot about in the general media lately.

This slide is an attempt to visually display the extent of individual differences in brain structure associated with mild TBI. The red and yellow areas of these brain models represent areas along the surface of the cerebral cortex where there is thinning to an extent that is more than you would expect just due to random differences between neurologically normal people. When looking at our group of control participants without TBI we do see some red spots, but they’re really not very localized and instead are more randomly disbursed across the cortex. 

But, when you look at our group of participants with mild TBI we see a brain model that depicts a high degree of individual differences in cortical thickness in widespread areas of the brain – including temporal, parietal, and some frontal region. All of these areas are important in the cognition.  Another factor as to why this cohort may present such a challenge is the fact that the very events that cause mild TBI – that is primarily blast exposures – are not only physically traumatic, but they’re also psychologically traumatic. We hear time and time again from Veterans how the world changes for them in an instant. Just one experience of a roadside bomb or IED puts an indelible mark on these men and women.

As a result, we now not only have relatively high rates of TBI in OEF/OIF Veterans, we also have high rates of PTSD – post traumatic stress disorder. In TRACTS, 60% of our participants have a diagnosis of current PTSD. When we consider pre-deployment history we see that 18% of our sample actually entered their military service with a lifetime diagnosis of PTSD. The fact that people are entering the military with pre-existing histories of PTSD, we think could be a very important factor in how they deal with the stress and trauma during service. 

In this slide, the blue color on the surfaces of the brain represents areas that are statistically correlated with PTSD severity – a little bit of a complicated concept. But, basically where you see blue indicates that the area of the brain is involved in and expressed PTSD symptoms. We see that for those with only current PTSD the blue is relatively limited to the parietal cortex. But, for those with a lifetime history of PTSD, the blue is much more widespread and includes areas of the frontal lobes that could be very important in the control and regulation of cognition.

The pie chart breaks up our sample into four groups based on whether or not an individual sustained a military TBI and whether or not that individual has a current diagnosis of PTSD. We were startled to find that only 8% of our Veterans have a mild TBI without co-occurring PTSD. By contrast, 60% of the entire sample – which is depicted here in the green and purple pie slices – has a diagnosis of PTSD, and over half of those – 33% - have co-occurring mild TBI. So, to us the big worry is not so much that Veterans are returning home with mild TBI, although 35% of them are – at least in our sample. But for us, the biggest worry is that so many of the Veterans are returning home with PTSD and that half of them have at least one complicating mild TBI. 

Here I present the same four groups again, but this time broken out on depending on whether or not they sustained a TBI sometime during their lifetime as opposed to simply the military service – during pre-service, during service, or post service, or similarly received a diagnosis of PTSD sometime in their lifetime. Now, the picture becomes even more complicated because what we see is that people who we thought were untouched by TBI or PTSD when considering current symptoms – the piece of pie colored in burgundy there – has shrunk considerably from 32% of the sample down to only 11% of the sample. So, in other words, out of a group of 198 Veterans only 11 of them are free from lifetime trauma. By counting for lifetime trauma, we also see that our group with mild TBI has now grown to 68% of the entire sample - this is the blue and purple slices - with a staggering 55% of those having co-occurring PTSD.

Now, PTSD is certainly the most prevalent comorbid condition with TBI, but is unfortunately not the only one – as we will see from this picture. So, this analysis is limited to only those Veterans with a mild TBI during their military service. We see that 80% of those have a diagnosis of PTSD. Seventeen percent have a diagnosis of an anxiety disorder other than PTSD. Forty-two percent with a mood disorder – primarily depression. Twenty-four percent struggle from alcohol abuse and dependence. Two percent struggle with other substance abuse – mostly narcotics to control the pain which is present in 73% of the sample. And then, chronic sleep disturbance is in 80% of the people in our study. 

This table is a simple count of the number of co-morbidities in our sample. Here we see that in the group with mild TBI, 70% of the sample has three or more diagnosed co-morbidities. This is compared to 54% in the sample overall. I think we can all agree this is a staggering percentage of Veterans who are suffering from multiple and often debilitating problems. 

One last point I want to make about co-morbid conditions associated with mild TBI in this population is the increased risk for cerebral vascular disease. This is a topic in a finding that was reported about a month ago in a piece in *USA Today.* In this table we see three cardiovascular risk factors that are normal in this group – body mass index, LDL, and HDL cholesterol levels. These findings are really quite alarming and raise the possibility that this cohort of Veterans may be facing a lifetime struggle against the development of chronic cognitive and physical problems associated with cerebral vascular disease much like what we see in Veterans who are much older than this particular group. 

Now, at this point you might be asking what does this all mean? Why is important for us to consider all these co-morbidities when we’re trying to treat TBI? The answer, and what we feel is the key to understanding or the helping men and women is that we have to appreciate that many of these co-morbid conditions share in the same underlying neural structures in functional brain systems. For example, here are three different studies from our laboratory. Again, these brain models are showing areas of structural change – in this case, cortical thickness – associated with a particular measure. In the upper left we see thickness correlated with cholesterol. In the upper right, thickness changes associated with alcohol abuse. And in the bottom, thickness changes associated with PTSD. 

Here, you can see that each of these risk factor or condition impacted some of the same cortical areas. Given that many of these conditions impact the same underlying neural tissue, it is probably not surprising that many of these commonly occurring conditions also share many of the cognitive and behavioral problems that we see. For example, some of the hallmark features of mild TBI - being memory disturbance, attention, concentration, fatigue, executive function deficit - are present in all of these other co-morbidities. Very few symptoms - for example – re-experiencing in the case of PTSD, can actually be used to differentiate one problem from another. 

So now, a major focus of our research in Boston is trying to understand what it means to the brain and brain function when you have several biologically significant processes - like TBI, like PTSD, substance abuse, and depression – impacting the same neural structures, does that make each of these conditions that much worse? Does it make each condition more resistant to treatment? Right now, we simply don’t know. What we do know is that you cannot expect to rehabilitate or treat mild TBI as if it exists in a vacuum. Its effect on the brain, cognition, and behavior are much too intertwined with these other disorders for that kind of strategy to be effective.

I just want to mention a few other things...a few things that we feel that caregivers might consider when embarking on treatment regimen for OEF/OIF Veterans with mild TBI. First, an office physical and blood work should be done to check for cardiovascular risk factors that we know do impact cognition and brain function, in particular the three I mentioned – hypertension, cholesterol levels, liver and thyroid function. Second, you really need a full assessment of cognitive functions to identify domains of decreased ability - that should be the target for a cognitive rehab program – and that will also help to identify areas of strength that can be used as a basis for rehabilitation. Third, we would suggest that you need a full assessment of possible co-occurring psychological and emotional co-morbidities, including PTSD, depression, anxiety, pain, sleep, etc. All of these need to be addressed and incorporated into a treatment plan if that plan is going to be successful. Lastly, it’s important to give serious consideration on how you might involve outside sources of support. Involvement of family, friends, and other sources of support we feel are likely to be critical for success.

Now, I want to just close with a few lessons that we have learned here at TRACTS on the basis of our clinical trials experience. First, I can’t stress enough – and maybe you're getting tired of hearing it – but you cannot think of mild TBI in OEF/OIF Veterans as something that can be treated in isolation of the other prominent co-morbid conditions. Mild TBI in this cohort rarely exists alone. 

We have also learned that his cohort is very difficult to engage and retain in therapies. This is especially true for trauma based therapies. Many Veterans are simply not ready at this time to take that painful step. We at TRACTS are considering more peer based approaches to at least get Veterans engaged in the process of some kind of therapy, with the hope that the experience might help them to take the next step.

Treatment compliance is effected by ongoing factors such as pain, sleep disturbance, and substance use and abuse. It is critically important to try to get these significant chronic problems at least managed before attempting cognitive and behavioral based therapies. It is also critically important to consider cognitive deficits, especially executive function deficits as moderators of the therapeutic process. Compromised cognitive systems are going to limit the amount of resources an individual can bring to therapy. Lastly, presence of such cognitive deficits will require flexible approaches to rehabilitation. For example, clinical materials and methods of presentation should be tailored to fit the needs of the patient. Strict adherence to protocols may not clinically be beneficial. 

So, our advice is to use a patient-centered approach and understand that not one size will fit all. I’d also like to thank all my co-workers for their help in all the work that’s gone into this trial. Thank you very much. 

Molly:  Thank you very much. Okay, next we have speaking, Dr. Siddharthan. Do you have access to your slides Kris? 

Dr. Siddharthan:  No. I don’t.  Can you do the slides for me Molly?

Molly:   I can.

Dr. Siddharthan:   Just tell me what the heading of the slide is because I can actualize as to what was in those slides.

Molly:  Not a problem.

Dr. Siddharthan:   I apologize tremendously because this has never happened before. I was able to set up yesterday morning, but for some reason the internet is down. I’m at a conference here in Orlando – a medical conference – and I just can’t seem to be able to get on the internet again. It’s just too late. Anyway, can we go ahead with this Molly?

Molly:  Yep, yep. Okay, so we have your first slide up now.

Dr. Siddharthan:  This study was commissioned by the Center for the....the CDMRP – the Congressionally Directed Medical Research Program – administered by the DoD. I am the principal investigator of this study. It is conducted at the James A. Haley Veterans Hospital in Tampa, Florida. For those of you who may not know this, James A. Haley or the Tampa VA is one of the four PRC’s, the level one polytrauma centers funded by Congress to especially care for our wounded Veterans returning from combat operations in Iran and...in Iraq and Afghanistan. 

The original study was supposed to be going for three years, but it’s now been extended to five years because they want to take the findings that we’ve had and transition them over to network wide applications rather than be constrained only at the Tampa VA. Next Molly.

Molly:  Great. Now, we’re on the background rationale slide.

Dr. Siddharthan:  Yes, the rationale for this – as mentioned by the earlier speaker – is that we have a lot of people coming back from combat operations, OEF and OIF. The number of people who have been wounded and have been evacuated as a result exceeds 35,000. And, the incidence of mental health disorders – such as PTSD – can range up to 60%. Many studies indicate that this co-morbidity may in fact be much more difficult to treat than the physical injury itself. Here at the Tampa VA we're constrained with respect to our resources – the number of beds we have and the number of providers, especially in the mental health area. So, we looked at all methods to provision of care for these individuals and one of the ways we could possibly do this was at a distance using telerehabilitation. 

Now, when the project started in 2008 it was very difficult to set up a secure messaging system by which we could communicate with the participants in this study. So, we were lucky to be able to connect to a secured VA server and essentially it was through this modality of internet that we are able to provide the telerehabilitation services that this research tends to look into. The next one Molly.

Molly:  The objectives.

Dr. Siddharthan:  Yeah, the objectives of the study are first to find out the efficacy of telerehabilitation. And, when we started this project we had in our mind our reasoning to essentially use My HealtheVet as the modality of care for these people. So, this worked as a good bench research with respect to traditional findings that we could then transport across populations and across the different modalities of provision of this care. 

We also wanted to look to see what utilization cost would be for this group of individuals if they were being provided care coordination compared to a group that was not. Essentially our hypothesis was that if they took their medications which we would be able to monitor as well as kept their appointment, then in fact they should have less problems than those who did not. And, we would see evidence of this with respects to hospital utilization as well as the cost of care for these people for a period of one year from the time of enrollment. Next Molly.

Molly:  The study design.

Dr. Siddharthan:  Yeah, the study design. We originally started this with a three year study. We wanted to have approximately 75 Veterans enrolled in this. It was not the classical RCP in that we did not have a control group. Our main objectives here were to find out if we could tweak the system to finally be able to provide a platform by which all of them would eventually be asked to use a modality like My HealtheVet for their needs. So, we started off with 75. Now, there were a few dropouts from this program. They moved out of the area because they were not seeking care anymore from James Haley, which means we could not follow them. Or, a few of them had to go back to service because a number of the people we recruited for the study were active duty military. Even though they were wounded and they expected them to become Veteran, a few of them decided to go back to the forces. So, in essence we ended up with approximately about...slightly less than 60% of the populations. I’m sorry. Slightly less than 60 Veterans enrolled in the study who did the entire evaluation for a year. We collected data on a six month basis – at baseline, six months, and at 12 months. That’s how we were able to gauge the efficacy of our study over a one year period. Next Molly.

Molly:  The inclusionary criterion.

Dr. Siddharthan:  Yeah, the inclusionary criterion – as I mentioned – was that they had to have a computer with secure messaging, which all of them did because all of them were really young, mostly male population. They had to at least call in once to the care coordinator. The care coordinator in our case was the polytrauma nurse. She was the fulltime polytrauma nurse at the polytrauma center and she essentially acted as the vehicle by which the Veterans would contact the other healthcare providers. So, in other words, she was the point of contact. 

They would have to ...um... we provided them with computers at the beginning of the study, and they would have to communicate with the care provider at least once a week. We’ve done the sthematic analysis on what they thought would be ...uh... on what they communicated with the care coordinator. It dealt mostly with care coordination issues – like scheduling appointment, drug therapy, adverse effects, and so on. But, I think in a few cases it also dealt with emergency issues. And, on at least two cases we were able to overcome adverse effects that could have taken place by timely intervention, especially with people who had suicidal tendencies. Even with that, we were not totally successful because one of the participants killed himself during the course of the study. Next one Molly.

Molly:  Telerehab intervention.

Dr. Siddharthan:  Yeah, the intervention itself...most of the care coordination dealt with scheduling appointments. The other issue we dealt with was drug therapy. This was a problem because of the pain involved. Most of them had muscular skeletal disorders as well as headaches. We published another article some time ago in Pharmacology where we showed that the ratios of these people being on opioids and other narcotics were about five times that of the (inaud.) civilian population. So, clearly we had... it was our intention to bring about a drug weaning programs because a lot of the problems of addiction associated with long-term use. In addition to that, we did a lot of counseling and we provided them effects of the other research that has been published in this area. 

In the course of providing this kind of contact a few of them went on to the next level of using the system very abruptly for a host of other needs – like getting information on the disease and the progression of the disease over time. We could actually send this over by email as an attachment. In a few instances we were able to do just that. Next one Molly.

Molly:  The care coordination.

Dr. Siddharthan:   Yeah, the care coordination... I’m sorry. I apologize once again. Since I don’t have the slides in front of me I thought I was speaking from that slide. Let’s go onto the next one.

Molly:  Monitoring of the health status.

Dr. Siddharthan:  Yeah, the monitoring of the health status. What we decided to do was use instruments that the VA uses in terms of monitoring the health outcomes over time. And, the two areas that we were interested in were monitoring their functional capabilities – the mobility and their physical function – as well as the mental health. Generally, what we found over time is that they have stabilized with respect to their injuries from TBI. But, it is the physical ones – especially the cognition and the memory loss and issues such as anger and inability to integrate into society – that they find most challenging. 

What we found in our cohort was, it was more or less a bimodal distribution. A large number of people were able to stabilize and eventually go back to society in the form of relationships as well as obtaining jobs and so on. But, a small minority had major problems. And, these things involved domestic violence, incarceration, and law and order issues. This is something that we’ve struggled with as to how we can help these individuals because the trigger mechanism that causes them to behave like that is something that we could never, ever understand. We spoke extensively with a lot of psychologists here but were unable to come up with something that we felt could calm them at the time when they needed it most because they were very prone to impulsive behavior.

We noticed this is quite a few individuals – four or five – that had problems with their neighbors, with police officers, and so on.  This group, this very small group is the one that needs intense counseling and intense intervention. The problem with intervention that we could see is pretty much limited to drug therapy and counseling them. But, we tried to go to the other level of having social workers involve themselves with domestic issues and try to resolve them. To some extent we were successful, but it’s still a very big challenge to deal with these aspects of the wounds from the war that they have encountered.  Next one Molly.

Molly:  Thank you. We do want to leave enough time for Dr. Cifu. So, we’ll try to wrap it up in the next five minutes or so. This is speaking on instruments. 

Dr. Siddharthan:  Yeah, the instruments. We used instruments like – as I mentioned before – we had instruments for physical functioning, for depression, for PTSD scale that’s used by the VA. Most of these are validated instruments. We borrowed some from the DVBIC – Department of Veterans Brain Injury Center. That’s the chart which provides for some elements of cognition and social integration. And then, the next chart will tell you about the trajectories themselves. Okay, go to the next one Molly.

Molly:  Okay, the Veteran demographics. 

Dr. Siddharthan:  Yeah, the Veteran demographics, if you look at the demographics you can see that a large number of them had...we broke them down into two cohorts – the cohort with just TBI alone and the one with PTSD. You can see that (inaud.) if our numbers are right, all the three female Veterans we had, had PTSD. And, among the male, a very large percentage did so as well. The reason why we have female Veterans is because even though they don’t serve in combat, they can come down with injury from indirect fire and so on. They were mostly young in nature. Most of them were about the age of my son, which is around 22. Go on to the next one Molly.

Molly:  The rehab trajectories.

Dr. Siddharthan:  This is essentially the fundamental thing, especially the difference within the groups. You can see that the TBI group is fairly flat with respect to its trajectory. But look at the fluctuations with the other – the one that has PTSD as well. It’s this noise - as we say in statistics – the up and down motion that causes the greatest concern because they are very well adapted at times and at other times they have to cope with problems themselves. And, if you look at the bottom of the graph you'll see the one associated with social integration. I’m sorry. I’m losing my voice. 

Social integration ...um... and what we did was, we did some statistical analysis on this – if you go to the next one Molly.

Molly:  The linear latent growth curve models.

Dr. Siddharthan:   Yes, we used the latent growth curve models to try and understand this change. We adjusted for variables such as age, the amount of disability, whether or not they had co-morbidities, and so on. And even with that, we found that PTSD played a very significant role in terms of their social function as well as their ability to integrate, which is shown on the next slide. Can you do that Molly?

Molly:  Yep. We have the results here. 

Dr. Siddharthan:  So, you can see, I just showed two of the instruments which you may be aware of. But, the results were pretty much the same with the other instruments as well. There was a very significant contribution of PTSD toward the issues; the cognition issues and the other issues that confront us.  The results of this will be published shortly in one of the journals, so anyone who’s interested can email me and I’ll send you the article. Next one Molly.

Molly:  We have summary.

Dr. Siddharthan:  Yeah, summary...the thing that we found most was that some of these people need individualized treatment. There is no one shoe that fits all. That’s one of the reasons why it’s been more of a big challenge in this because the way the injuries act on these individuals is very different. Both of them - in terms of severity - can be very same, but the causality between the severity and their action can be very different. 

So, we have to come up with individualized treatment. That was a huge challenge to us because it’s a huge learning curve for us. For example, the same counseling doesn't work for two individuals at a time. So, we have to cope with this but we are constantly refining this process. And, hopefully when we roll it out on a network basis we’ll have better results. Next Molly.

Molly:  You touched on some of these, conclusions.

Dr. Siddharthan:  Yeah, conclusion. The conclusion is basically what I touched on right now. What we are planning to do in the next couple of years is to move this to My HealtheVet where they will be able to look at their personal health record and they can monitor themselves as to their improvements and various function. We’re in the process of trying to get funding for that. We have already set up a panel of providers at the James Haley who would be happy to assist us with this. Hopefully, next time when I present this I’ll be a little better prepared than I am right now. Once again, I apologize. I don’t have the slides in front of me. So, I’ve had to do it on an ad hoc basis. I thank you Molly very much for your help.

Molly:  Thank you. And, we do only have a couple questions pending. So, I’d like to offer David Cifu these last 20 minutes. So, are you ready to share your screen?

Dr. Cifu:  I sure am. I think I have it up. Let me know if you can... I can see it. 

Molly:  Yep. Just click share my screen and then we’ll be good. Perfect.

Dr. Cifu:  Alright, fantastic. Thanks Molly. Thanks everyone. I’m going to condense what’s on these slides – there’s a longer version in your handout – so we can jump to the chase. I’m fortunate to carry the weight for the VA in the world of hyperbaric oxygen. We’re going to be talking about predominately the Department of Defense, but also VA initiatives in hyperbaric oxygen interventions for symptomatic mild TBI from the OEF/OIF conflict. I’m going to cover quickly why the DoD is even studying this, a little bit about the theory behind why it may work, and more importantly kind of highlight the last decade or so of literature, but then focus on the four trials that are ongoing – one of which was recently published, and we’ll cover that. 

The reason this is being studied is – as the last two speakers have talked about – the conflicts have generated a number of challenging Veteran clinical care scenarios, related to TBI and other factors. We’re seeing a persistence of symptoms in a significant cohort of these individuals. But, we don’t have evidence influence or evidence based interventions that would appear to manage some of their symptoms. Just as importantly, we’re getting lots and lots of pressures from the Veteran’s service organizations, from lobbyists, and from our constituents to do something more dramatic than we have been doing. And lastly, there are specific pressures from Congress and the DoD leadership to address both some of the Congress persons who have been injured as well as some of the need for troop readiness. 

You're all aware that there have been ...uh... hopefully that there have been TBI’s even before these conflicts. For about the last six million years humans have been getting injured in their brains, and certainly for the last decade or more it’s been more closely followed. But, the most recent statistics from the CDC published in the last two months is that we're seeing about 3.5 million TBI’s a year. The vast majority of them being mild TBI’s or concussions. From the current conflicts, the numbers that I’m seeing are closer to 95-99% of the injuries are mild – way more than has previously been discussed in the literature. These things are not cheap to manage, and challenging to treat. 

The military numbers are on the current screen and it varied depending what source you're going to look at. The larger slide...the larger bar graphs are from the DVBIC DECO. And, the upper corner is a breakdown of that. I’ll show the VA data in just a second, but again, we’re closer to 95% mild. But, regardless if it’s one patient or if it’s 200,000, if they’re not getting well it’s a challenge for all of us to care for. Here are some of the VA numbers that have been out there. Importantly, about 8% of all the folks who are being screened or coming into our system from OEF/OIF are screening positive for persistent systems with a confirmed MTBI. So, 8% of the just under 700,000 who have returned for OEF/OIF and come into the system. 

Note, as mentioned earlier, a large percentage of these folks within the MTBI diagnosis who have symptoms are also positive for PTSD as well as other mental health conditions. Again, it depends on what you read, but the numbers are high enough that this is a significant issue. There is a belief unfortunately that the current treatments aren’t working for a large number of folks, and more importantly even if they are working they’re not evidence based. I wouldn’t say that I believe that, but that’s the belief that’s out there. It’s something that is pushing forth the need for more research.

Just as importantly, as you've heard earlier and probably are aware, there’s a concern that long-term TBI’s – particularly the mild type, particularly those that are repeated...occurring multiple times, and particularly those that may be related to a blast type injury – may have some long-term effects. Whether we call this chronic traumatic encephalopathy, whether we call it some other variant of Alzheimer’s or something related to dementia pugilistica, there may be challenges with long term issues. As you may be aware, there are some anecdotal reports of hyperbaric oxygen treating individuals who have long term sequelae from neurologic injury. That’s been out there for 20 plus years, and more recently there’s been some case reports related to combat injury.

There’s certainly a lot of money to be made in the hyperbaric world, in the private sector. And, there’s been lots of testimonials from prominent individuals. So, all of these factors have kind of driven us to – let me click on this – to look at hyperbaric oxygen. Importantly, the majority of the literature that we're going to talk about briefly looks at acute traumatic brain injury with hyperbaric oxygen. Based on the acute injury – we're talking about within minutes to hours after injury – there may be some of the basic science/mechanisms that hyperbaric has been shown to work for other conditions such as skin breakdown as well as carbon monoxide poisoning. There may be some factors that the acute injury could affect. But, in the research I’m going to be covering in the last five to seven minutes, we’re talking about chronic effects. 

So, most of the basic mechanisms wouldn’t be likely to have an impact. The ones that may are highlighted in this table as possible. We can see correction of cellular hypoxia, which may be longstanding, and more likely, stimulation of cellular repair. So, that’s the basic science modeling that we’re hoping to rely on as an effect. 

When we look at the available animal literature, as I mentioned, a few studies have clearly shown impact in predominantly moderate to severe injury. It’s tough to cause a mild injury in most animals. But, certainly we’re seeing positive basic science as well as clinical correlates. We’ve also seen some research in animals in the more chronic deficit – particularly moderate to severe. And, we have seen improved cognitive outcomes in these rodents and K-9 models. 

Importantly, when we try to make this transition to humans, again, we are... we have a more ideal situation in an animal model. Even in the acute setting as well as in the chronic, the majority of acute animal models and TBI that have shown effect for intervention including hyperbaric, haven’t translated into human models. So, the 50 plus drug studies that are out there in acute rodent models and even larger animals have not translated well, if at all, to humans. So, we’re concerned about that. Importantly, there are no animal models in mild TBI for hyperbaric oxygen and we don’t even – as noted – we’re not even sure why they would be working. 

So, clearly there’s a great challenge. We don’t have a strong animal model to base this on. But, the urgency of the situation and some of the other stressors have pushed us to advance to the human model quickly. So, when we look at the human studies there are a handful of studies – actually up to ten of them – with four nice reviews. So, there have been four reviews of ten studies – which is always unusual. But, importantly there are 23 total studies, but really ten were looked at extensively, and then four kind of made the cut of being scientific. And these, as I mentioned, were in acute injury and they were acute ...um... moderate to severe. There have been two more recent reviews and two trials which have occurred since these systematic reviews and they haven’t shed any particular new knowledge. 

But, importantly if you put someone into a hyperbaric chamber acutely after moderate to severe injury, we do see some improvement particularly in survivability. We don’t see significant improvement in function, but the fact that they’re living is a good sign. We think the survivability and even some of the other effects that I’ll comment on are related to a reduction in intracranial pressure and enhanced pulmonary functions acutely after injury. But again, these are moderate/severe and these are acute. 

These studies were small and there was no sham for logistical as well as possible ethical reason. They weren’t blinded and the inclusion criteria were varied. So, importantly we’ve got some reason to be positive about hyperbaric oxygen, but just in a different model. And, more for survivability than for functional outcomes. So, with this scant background information available, the DoD and the VA pushed forward and said we needed a concerted program of hyperbaric research in the high valiant, high volume persistent symptoms after mild TBI cohort of individuals from Iraq and Afghanistan. And, a program of research was outlined that involved a number of demonstrations of feasibility trials and then a definitive trial. Note two of these studies are now completed. One has got the last subjects in chambers now. And, the definitive trial is beginning or has actually begun. I’m going to cover those in the last several minutes.

Importantly, the results were one non-DoD, non-controlled trial – which has been published and is also underway. They published a small sample of 16 or so and are doing a larger sample now. The first study was...the first study is the one I just commented on, the non-DoD study that originally was going to look at a very large cohort of individuals of 1,000, but did not get funding. And therefore, is looking at a smaller subsection or cohort...a subpopulation of these individuals. As I mentioned, they did publish on the 16 about a year ago – maybe nine months ago. And, they demonstrated positive outcomes for these individuals. But, this was non-blinded and the outcome measures were not the standard, mild TBI measures that are being used. So, there was some concern that perhaps there was some bias in the sample. And, it was nothing more than a possible pilot study to plan a more controlled trial. Note, these authors have since gone on and have completed 30 and have submitted for publication but have not been accepted in press to my knowledge. And, we haven’t seen these results. So, it’s hard to make much of it other than to say the importance of a controlled trial continues. 

The first of the military trial was published three months ago. It was a trial just demonstrating that certain measure...that the hyperbaric oxygen could be tolerated by individuals who had TBI, stroke, and hypoxia. And, that the clinical measures that were going to be used and that were typically used for mild TBI could be applied to these individuals pre and post chamber. The study was published and demonstrated, yes that we could recruit these individuals. Yes, they could tolerate the interventions. And yes, the measurement tools were reproducible and effective. Of note, there was no significant finding in this – again – open labeled sample. All the individuals knew what they were receiving. So again, of note, these are studies that can be done but we didn’t find much.

Let’s not move to the one study that was published about three weeks ago in the Journal of Neurotrauma. This was the study that had 50 – 25 in each group. One group received hyperbaric oxygen at 2.5 atmospheres. The other group received a sham at just above room pressure, but had an adjusted dose of oxygen. So, they were getting standard atmospheric oxygen. Of note – and I’ll show you the graph is a second – there was no difference in either group at time of initiation of oxygen.

So, it was a good, randomized sample. And, after the 30 treatments over an eight week course we say no difference in their outcome. But, of note, both groups improved. Both groups improved significantly using the PTSD screening tool – the PCLC. We saw a statistic of significant differences that persisted for greater than six weeks after the intervention as well as the sham were completed. And, when we looked at the impact symptom score – which is a validated measure of symptoms seen after concussion injuries – again, we saw both groups demonstrated improvement and both groups had persistence of these improvements past six weeks. But, of note, these two areas of improvement were not statistically different. 

So, we were seeing either very strong placebo effect or the effect of being in a very nurturing center for eight weeks or it’s for some other reason, but it was not related to the hyperbaric oxygen as can be determined by these outcomes. Of note, there were additional neuropsychological and physical measures that were applied and these did not show significance either. But, the primary outcome measures were those listed. 

I’ll just finish up by highlighting the other two studies that are underway and then we’ll go forward with questions. The one that you see on the screen is the one that I’m PI of. It’s through Richmond VA at our university as well as through the Pensacola Naval Air station in Florida. This is an N of 60. In this case we have three arms. We have a strong sham arm that is receiving two atmospheres of pressure, but adjusted oxygen to give them room air. Then, we have a group that has an equivalent of 1.5 atmospheres pressure, and another group that is an equivalent of two atmospheres pressure. So we’ve got...they all are feeling the same pressures. One is getting the equivalent of room air. One is getting one and a half times room air in terms of pressurized oxygen. The other is getting twice normal.

We’ve got a number of symptom inventories, a number of neuropsych batteries, as well as some physical measures we’ll be assessing. We have done this through five cohorts of 12 each, with four in each of the three groups. We currently have our last cohort of 12 there in chambers. We’ll be completed in about six and a half weeks and then we’ll rapidly move toward publication. We haven’t broken the blind on this one, so we don’t know the results. I will tell you that without knowing the blind, all the subjects appear to be improving in all three of the arms, both initially as well as at the three month. But, we have to do statistical analysis to confirm that. So, we’re not seeing obvious differences, but we will know the answers soon. 

The last group is a large N of 96. You can see the four different arms that we're looking at in this group. We do have a non-intervention control group. So, we’re just essentially at the base but aren’t getting intervention, not getting in a chamber, and we’ll see if the chamber itself is somehow magical or just being around it can demonstrate improvement. 

I’m going to move to the conclusion. Mild TBI is in the spotlight, as are the co-morbid conditions. There are a lot of rumors that mild TBI’s are much worse from a blast or from some sort of military exposure. My belief is that it’s a co-morbid and the co-existing conditions that are bringing that on. The story on that has yet to be looked at. And, similarly there’s belief that the interventions that are out there aren’t working. Again, I think it’s because we’re dealing with co-morbidities in a more holistic and integrated method – as the first researcher talked about. And finally, there are rumors out there that HBO - hyperbaric oxygen, not the television station – that the hyperbaric oxygen has a positive effect on outcome and preliminary analysis of double blind controlled trials. We don’t see that, but the definitive larger study is currently underway.

I’ll finish by indicating that my belief is that if hyperbaric oxygen does give us a boost in improvement in symptoms – whether it’s a strong placebo or some other effect – we need to capitalize on that by then intervening with the appropriate rehabilitative and restorative activities to enhance productivity – return to duty, return to work – so we’re taking advantage of that six, three month, or longer placebo effect. We will see the outcomes of that when these studies are finished. 

I’ll conclude now and turn it back over. Thank you.

Molly:  Thank you very much. Do you want to go ahead and leave your last slide up?

Dr. Cifu:  I would be happy to. Let me figure out how to do that.

Molly:  It’ll just give us something to look at. Okay, we do have... there we go. We do have a couple questions for each presenter. So, I’ll just go ahead with them one at a time and we’ll alternate through. The first one is for Regina. What about the co-occurrence of ADHD previous to Veteran deployment?

Dr. Cifu:   Is there someone you’d like specifically to answer that? Do you want Regina to touch on that or? 

Molly:  Yeah, that’s for Regina. Is your line unmuted Regina? Okay, we’ll wait and see if she can reconnect with us. Regina, you're line might be muted. We’ll move onto the question for Kris. Do you not consider suicide to be an obvious failure? How do you assess efficacy?

Dr. Siddharthan:   Well, mortality due to self-inflicted wounds is definitely a concern. We can’t include that either in the qualitative or quantitative sense in terms of modeling effort. Any life loss is of course a major tragedy. But, I can say very positively that on at least two occasions – one occasion a guy actually got a rope to hang himself and we were able to talk him out of it. So yes, we have failed maybe once. But, of these two occasions, we can say we have succeeded. It’s a very complex problem. 

Suicide is something we can never foresee. And one the one occasion, this person who took his life spoke to the nurse interventionist for almost half an hour and then she called him back a half an hour later to discuss something else and his brother said that he can’t talk anymore because he’s dying. So, what triggers this? We don’t know. And, our best effort is to try and give them the maximum intervention in terms of counseling. But, in terms of the outcome itself, no, I don’t consider that just because one person took his life it’s a failure because we look more at the positive aspects. 

I can say in terms of the depression field, a lot of them have considerably improved. So, that’s something positive that we can boast off in our study.

Molly:  Thank you for that reply. We’re going to go back to Regina now. What about the co-occurrence of ADHD previous to Veteran deployment?

Dr. McGlinchey:  Our study does not actually assess for the presence of ADHD, but it’s something we’re looking to do in the future. Our speculation is that ADHD is probably does pre-expose a lot of individuals to some of these other co-morbidities, including PTSD, due to some of the overlapping – again – brain areas that are involved in ADHD in terms of behavioral control, control of other kinds of executive functions that are going to be very important in theater. 

Molly:  Thank you for that reply. This next question is for David. Is there any evidence with statistical significance of HBOT? It appears the best only trended with P less than .08. Isn’t this evidence pretty thin?

Dr. Cifu:  Yeah, absolutely. That’s the point of it. There’s no control trials in this population that supports the use of hyperbaric oxygen for symptomatic mild TBI. But, despite the beginning signs, there’s still a very strong push at many levels to offer this service for our service members and our Veterans. We researchers are trying to advocate that until the research is in that it wouldn’t be an appropriate course to take. So, we’re trying to hurry these four studies through. We’ve got two and seven...2.75 of the studies done. We’re trying to finish all four so that we can strongly say there’s no evidence to support that. 

If anything, the folks who were in the sham did better on the impact – the lower score is better. So, they actually did better on the impact after their course than those who had the actual intervention.

Molly:  Thank you. I know we are a few minutes past the top of the hour but are our presenters able to stay on and answer the remaining five questions? 

Dr. Cifu:  I live for it. Yes. 

Molly:  Great. Thank you. Okay, this next one is for Regina. How can primary care providers limit medication induced worsening of MTBI functioning with co-occurring conditions and with time delayed access to polytrauma? Namely, how can we encourage busy PACTs to limit opioids and mental health to limit benzo’s? 

Dr. McGlinchey:  I actually feel like that question is a little out of my area of expertise. If anyone else could answer that, I’d appreciate it. 

Dr. Siddharthan:  Yeah, I think I can put in a word on that. This is a major problem because a lot of Veterans with pain present themselves in different clinics. If conditions are sought to frustrate the pain,  the problems associated with addiction and so on. And, the studies that we did and published about three years ago, we clearly showed that the level of opiates was very high, and narcotics was very high in the population. There is definitely a need to wean them away from that in the long run. But, on an immediate basis you always treat the pain. So, it’s a major challenge for the primary care provider who has to go by protocols in terms of pain management, yet at the same time has to be aware of the long-term consequences. 

The problem is many of these patients do not return to the clinics. In other words, they don’t provide an opportunity for a change in medication. Rather, they go ahead and refill their medications on My HealtheVet and don’t report symptoms that appear to improve. For example, if you have a lessoning of headaches they don’t necessarily go back and say I can do with less medication. That’s the major problem we’ve had. Through the staff coordination process that I spoke about, we’ve noticed some of that because each time the nurse calls them she asks them about the symptoms and wonders if indeed they’re getting better. If they are, then there’s no need for them to take that medication. But, to do that for this entire cohort of people who have come from Iraq and Afghanistan – close to 35,000 – that would be a major challenge.

Molly:  Thank you for that reply. We do just have three questions remaining. This one is for David. Does the natural history of MTBI show an improvement similar to the placebo effect seen in the HBO2 studies? For example, do patients tend to improve over time anyway regardless of the treatment?

Dr. Cifu:  Yeah, well I mean, there’s somewhat of a rhetorical question there. Obviously you know, traumatic brain injuries recover naturally for a period depending on the severity of the injury, from three months to – let’s say – two years. But, individuals with mild TBI are going to rarely see this level of symptom improvement in a two month period. These are individuals who on average were a year out from their injury, had had a stable level of symptoms – if not worsening symptoms, which may be suggestive of a different cause. So you know, if we had gotten these folks at two months out maybe we could suggest that. But folks that are a year out have pretty hardened and durable symptoms. 

Of course we don’t know that all these symptoms are, by definition, related to the TBI. We assume that. And, that’s what’s described by the patient and the clinicians try to confirm that. But, there could be other causes. And, those could be improving just by time. But, we’d expect to see that similar amount of improvement in both groups. So, in theory, that aspect of it would be controlled in this trial. The reason that the definitive study has got two arms that are essentially weightless or standard treatment, is just because of that. One of the groups is going to be TBI. One’s going to be combat exposed with no TBI. We’re just going to “be on the sidelines” while the other folks are getting time in the chamber. So, we’ll know that. I’m pretty certain these are not natural recovery findings. But, we won’t know that till the definitive. Good question.  

Molly:  Thank you. We have two remaining questions. How can we consult to get the sham HBO2?

Dr. Cifu:  So, you're asking to get a placebo? These are research trials and currently they’re specific for active duty service members through the logistics of them. However, the definitive trial, which is based out of Denver – both Ft. Carson in Colorado Springs and well as the Denver VA- may be opening it up to Veterans in the next six months. But right now, they’re just service members. But, you know if we believe that the placebo effect is having a significant role, while you can’t actually pressurize during treatment rooms or in the real world, you certainly can try to look at some of the other placebo aspects of it – which is obviously a nurturing environment, a positive outcome, folks that are directed towards some specific intervention whether that’s an intervention of exercise or intervention of debriefing. You know, they’re focused on an exercise.

In this case, they’re focused on the hyperbaric oxygen as passive. But, if you can get that level of engagement you may see a positive placebo effect. I mean again, we can’t enroll you in just a placebo arm at this point, and if you're a Veteran we can’t get you in even yet. But that’s our medium term goal. But certain, if we believe in the placebo effect or the effect of that engagement and that warm embrace, then we can create that outside of using a pressurized chamber.

The other choice is you can find a used telephone booth and put a hair dryer in it and blow it a lot. Maybe they’ll believe it’s pressurized.

Molly:  Alright. And, we do have one final question for you David and then we’ll rap up with some concluding comments. If the benefits of HBOT eventually prove to be from placebo effect, what are the major side-effects of the therapy and will the risks outweigh the benefit to justify using it?

Dr. Cifu:  Yeah, that’s a great question. But you know, obviously if we're finding that it’s a placebo effect or there’s an effect that’s not related specifically to the pressurized oxygen but to some other component, then the goal would be to – as I said – recreate that supportive placebo effect in a way that it’s zero risk and hopefully low cost.

One of the things we’ve been finding with the two and a half trials that have been completed is that really folks tolerate this extremely well and at the level that is recommended in the private sector for treatment, we’re seeing potentially no side-effects - certainly nothing of significance. It’s a low risk intervention when performed in a very controlled and regulated environment. The military has very, very tight controls in its chambers. That’s very important. Clearly the long-term goal is going to be to find out what does and doesn’t work and then figure out how to get the effect – if it’s hyperbaric or if it’s something else. So thanks. 

Molly:  Thank you. I’d like to give each of the presenters an opportunity to say a few concluding comments. So David, we’ll just go ahead and start with you.

Dr. Cifu:  Sure. A concluding comment is ...uh... I want to amplify what my other speakers have talked about because I don’t think hyperbaric oxygen is a reasonable intervention at this point. I would just strongly encourage you to manage patients in a very integrative fashion, in a single clinical setting, with a single set of clinicians who feel comfortable across the spectrum for taking care of the TBI and their co-morbidities. And, I think we’ll have the best outcomes.

Molly:  Thank you. Kris, would you like to make some concluding comments?

Dr. Siddharthan:   Yes, what our study has proven is it’s a very complex road ahead for many of these individuals. We are on the learning curve with this type of protocol – evidence based medicine – that we can apply on a wide basis. Unfortunately, we don’t have that as yet. We have many trials, but the sample sizes and the outcomes are clouded. This is something that’s going to go on for a long time. Hopefully we're getting a handle on it as we do it. And gradually, over the years, we will be able to address the problems that our Veterans face when they come back from combative duties. 

Molly:  Thank you. And, Regina?

 Dr. McGlinchey:  Yeah, I guess I would like to conclude by just suggesting that the way that we need to really treat these patients is in some ways the way that the VA has treated geriatric patients. That is to really put together a team approach and look at this from a multi-disciplinary problem and do everything that we can to try to get these patients into the VA at an early age as possible so we can try to influence the trajectory of some of these illnesses, so we don’t let too many years go by and let this chronicity develop. 

Molly:  Thank you. I would like to express my gratitude for all of our audience members for joining us today and also for our speakers lending their expertise. Just a couple quick notes as we wrap up: I would like to encourage all of our attendees to join us for the fourth and final session in this mini-series that will be taking place on November 13th. It will be on the management of TBI rehab and co-occurring mental health issues, post-traumatic stress disorder, suicide, depression, substance use disorders, and pain disorder. You can register for that by going to the HSR&D homepage, clicking on the cyber seminar link, and registering through our catalogue. 

Furthermore, as you exit today’s session you will be prompted to complete a short survey. Please do so. It helps us improve our program and make sure to offer sessions of interest to you. So, thank you once again to everyone and this does conclude today’s HSR&D cyber seminar.

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