Complications of mild traumatic brain injury in Veterans ：在老兵的轻度创伤性脑损伤的并发症

Complications of mild traumatic brain injury in Veterans ：在老兵的轻度创伤性脑损伤的并发症 Transcript of Cyberseminar Evidence-based Synthesis Program Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review Presenters: Maya O’Neil, PhD, MS; Kathleen Carlson, PhD, MS; Daniel Storzbach, PhD; David Cifu, MD; Robert Ruff, MD, PhD; Joel Scholten, MD March 26, 2013 This is an unedited transcript of this session. As such, it may contain omissions or errors due to sound quality or misinterpretation. For clarification or verification of any points in the transcript, please refer to the audio version posted at www.hsrd.research.va.gov/cyberseminars/catalog-archive.cfm or contact maya.oneil@va.gov. Moderator: I am going to do a quick introduction of our speakers and discussants for today’s session. Maya O’Neil is a psychologist and investigator at the Portland VA Medical Center and Assistant Professor at Oregon Health and Science University. She works with Evidenced-based Synthesis Program, HSR&D Research Enhancement Award Program, AHRQ Scientific Resource Center and Neuropsychology Service at the Portland VA. Her research focuses on consequences and treatment of polytrauma as well as systematic review methods. Kathleen Carlson is an epidemiologist and health services researcher at the Portland VA Medical Center. Her work focuses on unemployment and other functional outcomes among Veterans with TBI and comorbid mental health disorders. David Cifu is the Chief of PM&R Services at the VCU Health System, the Executive Director of the VCU Center for Rehabilitation Sciences in Engineering and National Director of PM&R Program Office and a member of the Senior Executive Staff to the Department of Veteran’s Affairs. Daniel Storzbach is a staff psychologist, Program Manager of Mood Disorders Research and Treatment Center and an Associated Professor of Psychology Department of Psychiatry at OHSU. Joel Scholten is the Washington, DC lead for the Joint Incentive Fund Project for Amputee Care in the National Capital region. He also works in the VA Central Office within the Physical Medicine and Rehabilitation Program Office as the National Director of Special Projects. Robert Ruff is the Neurology Service Chief at the Louis V. Stokes Cleveland Veteran’s Affair Medical Center and the National Director for Neurology Department of Veteran’s Affairs. With that Maya I am going to turn things over to you. Maya O’Neil: Okay, great. I will take myself off mute and we will get started. First of all thanks everyone for joining us this morning. It is TBI Awareness Month so an appropriate topic and thanks for coming. I am going to scroll through some of these introductory slides pretty quickly. Here we have a lot of just general introductory information. In case you do not know these slides are available online for people who cannot stay for the entire presentation and/or to view the presentation later, so we like to put a lot of information in there so you can read through them later at your convenience. Page 1 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 First of all acknowledgements, and this is something that I take pretty seriously. I think it is pretty important. For those of you who are not familiar with systematic reviews they are really, really intensive. They take a lot of work, a lot of effort from a lot of different people. Not only are the report authors very important, particularly our stakeholders. We have technical expert panel and then we have quite a few peer reviewers. So I want to make sure that we…hold on a second. We are getting a couple of questions that people cannot hear. So I am going to put the phone closer. Heidi can you hear me okay? Moderator: I can you hear you okay but if anyone in the audience is still having issues just send that in so we can see. Thank you. Maya O’Neil: Just so people know the process of this, I can see the questions that come in. Heidi is going to be doing a lot of the responding as I am talking but we still have some people who cannot hear. Is this significantly better for the folks that cannot hear because this way I am actually picking up the phone instead of talking to the speakerphone? Heidi does that sound better to you? Moderator: It sounds a little bit clearer. If anyone in the audience…I am hearing no that is not better. If you are on a computer and you are using your computer speakers you may need to dial in on the telephone. You will have a significantly better audio quality. The computer, the speakers that come on like a CPU unit are usually not great quality and you may need to dial in. Maya O’Neil: Okay. I am going to try putting again on speaker and we will try to move forward with that but if people still have problems hearing please do write in a question and let us know. Alright, hopefully people can still follow along with the slides even if they cannot hear everything perfectly at this point. Heidi I will let you handle the responses to questions of folks who are still having trouble if that is okay. Moderator: Sounds good, thanks. Maya O’Neil: Okay, so back to the acknowledgement side. I want to emphasize not only the focus that we have up here on the slide in front of us but like I said we had quite a few stakeholders for this report. A few of them are on the call today as our discussants. So Doctors Cifu, Hoffman, O’Maya, Ruff and Scholten were all stakeholders for this report. They were the people who initially request the report so I am going to have them talk a little bit about the process of why they requested the report, what information they were hoping to get from it at the end when we have more of a discussion from our stakeholders. It is great that they could be on the call with us today. We also had quite a few people on our technical expert panel and people who did pretty extensive peer review of our very lengthy report midway through. So those people in addition to the stakeholder panel were Doctors Belanger, Carrol, Eapen, Fann, Frank, Harris, Pogoda, Thayer, Vanderploeg and Vasterling. I just have to say they all provided really extensive comments and guidance as we were writing this report. It is a pretty complicated topic. It is a pretty hot topic in the VA and there are aspects of it that are controversial. So it was very helpful to have extensive guidance as we went through. Page 2 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 Okay, just some disclosure information that we have to put up there that you can read through. We also wanted to tell you for those of you particularly who are not familiar with the Evidence Synthesis Program we wanted to give you a little bit of information about the ESP and what we do. We are sponsored by QUERI. Basically what we do is provide evidence reviews or systematic reviews, Evidence Synthesis Reports to address healthcare topics that are really important to the VA in particular. So we are all affiliated with Evidence-based Practice Centers. There are four of us Evidence Synthesis Programs nationwide. So Evidenced-based Practice Centers are the United States’ way to address some of these important healthcare topics but then our role in the four ESPs are to address questions that are particularly important to Veterans and members of the military. There is a link there for the nomination process. We take nominations from anyone and everyone, clinicians, folks in central office, etcetera. We have a great coordinating center who are very responsive. If you are interested, if there are clinical questions of interest and you would like people to assist with investigating a topic they will kind of work up a topic for you, see if it warrants a full systematic review and help coordinate that process. So there is the link there if you are interested. We have an extensive steering committee like we talked about. We have a technical advisory panel; both for the overall ESP and for our individual reports. As I mentioned a lot of peer reviewers and policy partners and we will talk a bit more about that in the discussion portion. Here are a couple of examples of our recent reports. These are the reports that the Portland VA did in the past fiscal year. Most importantly we have a link. For those of you who are in the VA system you will be able to access the reports immediately. Some of the reports are released intranet only for about six months while they are in the publication process. That is the case with this particular report. So if you are not on a VA computer you will not be able to access the full report for this TBI report for another few months probably. But all of the reports are available there on that link. Just a bit of an overview of today’s presentation. We are going to keep the background really brief, talk a bit about the scope and methods. We are going to emphasize the results of the report, what we found for these different clinical topic areas and then we are going to have a pretty extensive discussion at the end. Like I said, we have our central office stakeholders on the call with us today. Especially because of some of the limited evidence that was found in our report, it is important to discuss ways to move forward and provide the best care to Veterans and members of the military regardless of some lower strength of evidence. So they are going to help us talk about that. So a little bit of background. Just very briefly, I am sure those of you who are familiar with the research that is out there on mild TBI, particularly as it relates to OEF, OIF, and OND members of the military and Veterans. A lot of different percentages are thrown about. Generally people talk about 10-23% of service members experiencing a TBI while deployed but those numbers do vary. There are also really differing accounts of mild TBI recovery. That is a lot of what we are going to be talking about in the report today. So existing research really differs in some of those estimates of the different postconcussive symptoms that people experience and how long they last. A couple of things to point out, one of the reasons that this specific report was requested for Veterans and members of the military is because recovery is likely pretty unique for our OEF, OIF and OND service members. This is because many of them experience multiple mild traumatic brain Page 3 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 injuries. The mechanism of injury differs from a lot of the folks in civilian populations who experience a TBI, so this is not your standard athletic event obviously; people who experienced blast exposures, sometimes multiple. And then other physical and mental health concerns. It is likely that PTSD is more common in military settings in people that experience traumatic brain injuries than in a lot of civilian settings. So these are all complicating factors and that is why this particular report was requested with a very specific focus on Veterans and members of the U.S. military. So here are key questions. Like I said specific to members and Veterans of the military. We were looking at the prevalence of health problems, cognitive deficits, functional limitations, mental health symptoms that develop or persist following an mTBI. Our key question two was really focused on anything that might moderate or mediate any of those mTBI outcomes. So what that means is that we looked at any article that reported on maybe demographic characteristics, comorbid mental health concerns, anything that might possibly affect those outcomes. We tried to take a look at those articles as well. We will talk about that a bit when we get to the results. Then we were also particularly interested in the resource utilization over time for Veterans and members of the military who have mild TBI. This was primarily for planning purposes. Again we will have our stakeholders talk about this at the latter portion of the talk today. So a couple of things about methods. I am not going to go into a whole bunch about systematic review methodology but I do want to talk for a bit about how we did this report. A systematic review for those of you who do not know it is very different from a traditional literature review. This is not like people sit down and come up with articles of interest to them or things that they might be familiar with from their colleagues that they know and things like that; that people normally do for a traditional literature review. But rather a very large scale systematic search. So in this case we searched multiple databases including Medline, PsychINFO and the Cochrane Register of Controlled Trials. All of that was searched until relatively recently. Our final search state as we were writing the report was October 3, 2012. So we know that there are articles published since then but for this report that is how far we searched and those are the articles that are included. Overall it means we searched over 2,600 titles and abstracts. Then 353 of those, after we went through those abstracts and titles, we pulled 353 full text articles to see which one of those met our specific inclusion and exclusion criteria, which I will get to in a second. Thirty-one of those met our inclusion criteria and were included in the report. So that is what we are mostly going to be talking about today, though we will highlight some of the groups of studies that we excluded for certain reasons. Once those studies were included, we did really extensive quality assessments of all of the primary studies and systematic reviews. We ended up not including any other systematic reviews in this report. So Kathleen Carlson, one of my co-presenters and co-authors on this report was the lead investigator on a recent systematic review talking about PTSD and TBI. So she is going to highlight some of those findings. It was a bit of a different research question but still relevant to the questions we were looking at here. Page 4 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 When we talk about quality assessment, it is pretty important to understand what that means. Quality assessment particularly of observational studies is relatively complicated and really specific to clinical topics. In this case we did not have any randomized controlled trials that met our inclusion criteria and this is not surprising. As you can imagine it would be difficult if not impossible to do ethical and diffusable randomized control trials on TBI. So we had a lot of observational studies. So we looked at a whole bunch of different quality criteria when we were examining the different observational studies and we will talk about that as we talk about the different results sections, because those quality criteria are very specific to the different studies. So when we talk about studies that are methodologically flawed, one thing I want to emphasize is that this is not an attempt to sort of bash the researchers or say they did not do a good job. In fact, all three of us sitting in the room with me today do TBI research and we know how hard it is to conduct really good quality studies. What I want to emphasize is that a lot of times you are really limited by the populations at hand, the different clinical topics, etcetera. So even if we cannot design a perfect study we still have to be able to look at the information gleaned from these less than perfect observational studies that are still well conducted by the researchers that are doing these studies. Sometimes we just cannot do those ideal studies that we want to see. Inclusion criteria: Like I said we were very specifically focused on Veterans and members of the military who have experienced a mild traumatic brain injury. One of the things we did early on was clarify how mTBI needed to be defined. In this case because of our population of interest we were specifically using the definition provided by the VA and DoD and their clinical process guidelines. So that is one thing that limited some of the studies that met our inclusion criteria. A lot of the studies that we saw talked about mild TBI in very different ways with a lot of different definitions and we do include a table of studies in our final report that referred to Veterans and members of the military with mild TBI but did not use the VA DoD criteria for mild TBI. There are about 60 of those studies that were excluded from this report. So you can take a look at those in the final report if you are interested in those. Anything that was not differentiating between like military and civilian populations or child and adult populations was excluded. Outcomes had to be things like health problems, cognitive deficits, functional limitations, mental health symptoms and cost and resource utilization. We looked at a variety of different study designs but as I said those ended up being pretty limited, basically due to what is feasible and ethical in this population. Another criteria that we implemented was that there had to be a minimum of 30 mild TBI cases reported in each of those studies. Primarily that was because we wanted to be able to generalize as much as possible based on these results so when you are looking in observational studies that just has two, three, five, participants that have mild TBI, you cannot really say a lot in terms of generalizability. We chose 30 as our minimum sample size but this did exclude a few sort of promising current research topics that are being expanded in the future. One of the things to highlight is some of the CTE studies and other imaging related studies are generally smaller sample size studies and they got excluded from this report just because the samples were too small. Page 5 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 So just overview of results and then I am going to talk a bit about what strength of evidence means for these outcomes. Like I said we had 31 studies that met our inclusion criteria. Again for those of you who are not familiar with systematic review methodology, one of the main points of an evidence report or systematic review is to rate the strength of evidence overall. So to say here is the evidence that meets our scoping and inclusion criteria and then we want to talk about how strong is that evidence. Basically meaning how much do we have really solid faith in those results that if other studies were to come along in the future would they pretty likely to change our opinions or not so much. In this case, because these studies are on a really complicated topic and it is really hard if not impossible to design more rigorous study designs like randomized control trials, then we rated the whole body of evidence as very low strength of evidence for all the outcomes being investigated in this report. Sometimes that was because there were only single studies that investigated certain outcomes. So when I was talking before about our key question two, which was looking at potential mediators or moderators of mTBI outcomes, so anything that might be a risk for protective factor, by and large there were very few studies that looked at any particular outcome. We could not even see a clear pattern for a lot of those results. Though there were some well conducted observational studies it is hard to put a ton of faith into any one single or few observational studies. So that is the main reason why the body of evidence is rated as very low strength. So basically, as we are talking about the results here, and our stakeholders as well will be discussing this at the end, I want to emphasize and I am going to emphasize this over and over again that our findings are very tentative. So we are going to be talking about what we found. There were 31 studies so we do have a bunch of findings to talk about. However, because of the observational nature of these studies the findings are very, very tentative and we are going to emphasize that over and over again. Please do not go back to your clinical practices and think, okay well I know the hard and fast answer and there are no differences between these two populations or something like that because it is just not the case. Let us see, in terms of overview of our results our cognitive, physical, mental health symptoms, we found that they were commonly reported by those with mTBI. However, one our very tentative findings, but findings that we found repeatedly, were that particularly for cognitive and mental health symptoms, they are not significantly more common in Veterans or members of the military with mTBI when you compare to a control group of very similar Veterans who have also been deployed but who do not have mild TBI. We are going to talk more about what that means in a specific results area. But again, very tentative results. This does not mean that mTBI does not exist. We are not saying anything like that. We are just saying that what the results of these studies show is that perhaps there are some Veteran and deployment specific factors that are really affecting folks when they come back from these conflicts recently. So we will talk about that in a bit. No consistent patterns of potential risk or protective factors were identified but we will highlight some of those results as we go. To get into the specifics of the results the first section we found 17 studies on cognitive functioning that met our inclusion criteria. So an important thing to note about this, this is somewhat specific to cognitive functioning results and somewhat generalizable to all our results. Studies by and large reported mean scores. Like I said I am also a primary researcher. This is something that I have Page 6 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 definitely done in the past and did not really think a lot about it until we were doing this report. When our stakeholders were saying, well we would like to know prevalence estimates. What are approximate percentages or proportions of Veterans with mTBI who are experiencing some of these difficulties? And when you have mean scores you cannot really tell that information. Particularly for cognitive functioning, mean scores are even more meaningless than in a lot of other areas. I say that because when you are defining cognitive functioning you are largely looking at change from baseline which is really hard to get a lot of times because it requires a longitudinal study design and so most of the studies were not able to look at change from baseline. In addition, mean scores should be reported… if you are reporting mean scores they should really be scores that are standardized scores. So at least some sort of estimates of impairment should be factored in if at all possible and by and large the studies did not do that. That is one thing for future research that would really be helpful to answer these kinds of questions. So for those of you doing research on mTBI looking at cognitive outcomes, that would be very helpful; reporting proportions of impaired scores and things like that. That said, mean scores were within normal limits for all of the reported domains. So that includes language abilities, general funds of verbal knowledge, visual spatial abilities, memory, attention/concentration and executive functioning. However, there is a caveat about that and that is that those are mean scores. So that means that though many of the folks who are tested might have been performing within normal limits there can always be exceptions. So for those of you doing neuro-psych testing then please keep in mind that there can always be some exceptions and these are never hard and fast rules based on these results here. Another thing to highlight from these results is that nonsignificant differences in cognitive performance compared to similar populations without mild traumatic brain injury was found in all reported domains again. So this is what I was talking about before that when you have a group of Veterans of members of the military who have mTBI and their scores on cognitive tests are compared to those very similar Veterans or members of the military who also experienced similar things like deployment. There were not statistically significant differences between those groups of Veterans with and without mTBI. These are on objective cognitive tests: a couple of things to point out is that there was significantly worse performance on some tests of memory, attention/concentration, and processing speed. But that was limited to… there were very few studies that believed… there were three studies authored by Cooper and Kennedy and Coldran. All three of those studies were using the ANAM and they were assessing active duty military members within 72 hours and then five days and then ten days following initial injury. Those statistically significant differences compared to a similar control group without mTBI disappeared after the first 72 hours to five days following injury. Another thing to point out in the cognitive functioning domain is that subjective cognitive complaints were common. For those of you who are familiar with working with Veterans or members of the military who have mTBI and very commonly comorbid PTSD, one of the things that we did see is that cognitive complaints were common in both of the mTBI and those with PTSD because of the symptom overlap. So it is something to consider. Page 7 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 We did not find any clear pattern of studies that looked at mediators or moderators, any potential risk or protective factors that could influence cognitive functioning. So that is sort of an overview of our cognitive functioning results. One thing I want to point out as I am talking about these different topics, please feel free to write in questions as we go and I will try to get at some of those at the end of the presentation. Our next topic area is physical health results; we have 17 studies that met inclusion criteria. You can see some of the specifics that we found there. We did not have a lot of studies that reported prevalence. There was one study that reported average scores in the mild to moderate range on the NSI. It brings up a good point about these physical health results. A lot of our results were based on single items from the NSI. So that is something to keep in mind. Another study, I believe this was a study actually by one of our co-presenters, Dr. Ruff, today, was reporting prevalence of neurology referrals for headaches in a population with mTBI and that prevalence was reported at 33.3%, about a third, of those with mTBI being referred to neurology for headaches. So something that seems, at least not one study, pretty common. Single studies were reporting significantly worse pain in vestibular symptoms for those with mTBI compared to those without mTBI. But again, those were single studies. They were often based on single items from the NSI but it is something to point out, that this was an instance when having a comparison group of very similar deployed Veterans there was still significantly worse scores on the NSI by those with mTBI. For our mental health results we found 20 studies meeting those inclusion criteria. We found that mean scores on measures of PTSD and anxiety measures suggested clinically significant impairment for those with mTBI. This is probably not surprising to those of you who work with our Veterans with mTBI. PTSD and anxiety disorders are pretty common. We did find some studies with some mixed results, both impaired and normal; normal range scores for depression. So PTSD and anxiety seem to be a bit more common for both mTBI and depression. But it was so commonly reported by folks with mTBI across the board. We found one study reporting 45% of those with mTBI experiencing clinically significant impairment from PTSD. Postdeployment Veterans with and without mTBI seemed to experience similar levels of PTSD and depression. So again, comparing those two populations, PTSD and depression was pretty common for both. Then you can see on the slides some prevalence estimates related to drug abuse and dependence, alcohol abuse and dependence; pretty common. Suicidal ideation, approximately one-quarter of Veterans with mTBI in one study reported suicidal ideations, so pretty high rates even though suicidal intent and past suicide attempts. Though that was not significantly different from controlled. And again, those controls were very similar groups of deployed Veterans and that is from just one study; so limited information. There are a couple of studies looking at overall Axis I disorders and that prevalence was about 50-78% in those two studies. One of the studies reported significantly higher rates of Axis I disorders for those with mTBI compared to controls. Page 8 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 Again let me just emphasize here, I know I said this before but these results really, really tentative based on few studies looking at very diverse outcomes. So we do not want to generalize a lot but this is the best available evidence that we have on this information. At this point I want to turn it over to Dr. Carlson to present a couple of other areas of our results and also just to talk very briefly about her PTSD and TBI systematic review. Dr. Kathleen Carlson: What do you think Maya if I give a brief background on that review while you look questions? Questions that are relevant to this section you just covered? Dr. Maya O’Neil: That would be great. Dr. Kathleen Carlson: Okay. So Maya is alluding to a similar review process that was commissioned by the VA back in 2009 and that was a review that I worked on in collaboration with my colleagues in Minneapolis and our stakeholders some of which are on the phone with us again today. It is a very similar process to this review and Maya is bringing it up because it was looking at the prevalence of comorbid PTSD in individuals with a history of traumatic brain injury. So we are trying to get at this overlap of comorbid PTSD with traumatic brain injury. Basically at that point in time we were providing the best evidence for purposes of a VA consensus conference on the diagnosis and management of mTBI and PTSD and also pain. But we were not nearly as restrictive on our traumatic brain injury definition. We did not rely on ACRM criteria for inclusion of studies that were on traumatic brain injuries. So basically if the authors or investigators said they were studying traumatic brain injury we took their word for it for a number of different reasons. We also were not restricted to just Veterans or military members. We wanted to see what was out there by way of comorbid TBI and PTSD. We also did not restrict to just mild TBI because one of our questions was whether the overlap of PTSD varied by severity of traumatic brain injury. As you can imagine just like in the review that we are representing today we had a handful of highly different studies with very different inclusion criteria and very different assessment methods and outcomes. I think we had 33 or 34 studies that we included in that review. We found that across all studies there was this enormously wide variation in the prevalence of PTSD across individuals with mild TBI history. That ranged all the way from 0% up to 89%. However, one of those striking outcomes was that there were three large studies involving Veterans and military members that were strikingly consistent in that 5% to 7% would screen positive for both history of traumatic brain injury and posttraumatic stress disorder. Then among those with the traumatic brain injury history consistently anywhere from 33% to 39% also screened positive for posttraumatic stress disorder. So those were relatively consistent findings in our experience in systematic reviews. So those were quite remarkable. We do know since then quite a few more studies have come out in the last three years and we know particularly in the VA when we are looking at VA users who are diagnosed with traumatic brain injury a much higher percent are also diagnosed with posttraumatic stress disorder. So some of the recent evidence that has come out from the polytrauma of blast related injuries QUERI and published last year by Taylor et al showed that Veterans in one fiscal year alone Veterans who were diagnosed with traumatic brain injury. Of those 73% were also diagnosed with posttraumatic stress Page 9 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 disorder. So we see that the comorbidity much more frequently in Veterans who are using VA services. Dr. Maya O’Neil: This is Maya again. One other thing to point out, a couple of people have asked about Kathleen’s slides and one thing I want to point out is that Kathleen was just talking about some of the results from her systematic review. I have asked her to highlight those because of the interest in comorbid PTSD and TBI. Her full slides and in fact whole cyberseminar presentation are available on the link to the ESP. If you look at the older ESP reports, those links are in my slides at the very beginning. So you can take a look at Kathleen’s whole cyberseminar and/or just her specific slides on that review and take a look at the full review as well. Dr. Kathleen Carlson: I do not have anything else to highlight on that. Did you want to respond to any other questions? Dr. Maya O’Neil: I think we had a couple of questions that I will just briefly respond to here since they relate to the cognitive and mental health results in particular. One question, a really good question about if we are talking about multiple or single mTBI events for these studies. It is a really good question and by and large if the study is even mentioned if they included that as a criteria in their studies, it was not factored into the analyses. So a lot of the researchers would say, well you know it is really common for multiple mTBIs to happen in this population so we just sort of included everyone. So it might be one, it might be multiple but it was pretty common for it to be multiple. But nothing looking specifically at the effects of multiple TBI events. So that is one thing to point out that relates to all of our results. We had another question about cognitive deficits typical for those with PTSD. Maybe Dan, are you comfortable addressing that. There was someone who wanted to know what kind of cognitive deficits are typical for those who present with PTSD. Dr. Daniel Storzbach: The research on PTSD is a little bit stronger but not a whole lot stronger than the research on mild traumatic brain injury. The findings mostly point to attention and memory difficulty of PTSD. Dr. Maya O’Neil: But a lot of overlap across those two disorders, a lot of overlapping symptoms. We had another question about possible feeling effects of the cognitive test use or is it possible that the tests used in these studies were designed to look at more severe deficits. That might be the case in some of the studies but by and large the tests that were used in these studies have a pretty broad range of possible scores and are used in a range of populations. In fact most commonly they are used to assess just normal populations in any kind of neuro-psych setting, etcetera. So I would not say that that is a serious concern. I am looking at Dan here, I do not think in these studies that is a serious concern, but definitely a possibility. Then we had another question about the cognitive results, if there were any studies that looked at symptom validity. That is a really good question. There were a few studies that looked at symptom validity or effort or motivation and not a lot of the studies took that into account. It is one of our Page 10 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 recommendations actually because of the few studies that did look at symptoms validity or adequate effort or motivation while doing cognitive tests, they did find that the scores were really influenced by effort or motivation. So for future research with cognitive tests we would strongly recommend also doing some validity tests or tests of effort and motivation. Another thing to point out is there is a review in civilian populations from 2004 that the World Health Organization did a review on the same topics that we were looking at but in civilian populations. One of their findings, there is obviously more research that they can include, one of their findings was that results were influenced by the setting of the testing. So that included if someone was being tested as part of a legal situation, some sort of litigation, or possible gain; that influenced their cognitive testing results. So something to consider in this population as well but it is sort of unclear. We did not have enough results to say anything really here or there. We will get to a couple of the other questions. There is a question about reviewing the VA DoD definition of mTBI. I think we put a link in our slides for folks to take a look at the VA DoD Clinical Practice Guidelines, which has that definition. Let me get that just so I read it totally accurately. So I will bring that up and read that in a second but let me have Kathleen go over a couple of more areas of the results and we will come back to that. Dr. Kathleen Carlson: So a lot of us are interested in the psychosocial functioning in Veterans who have a history of mild traumatic brain injury, particularly employment, unemployment, productivity and what is going on in that domain. We found only two studies that met our criteria and were included that mentioned anything about employment outcome. One was by Barnes et al published last year. This is a Cincinnati VA Group. Actually they were not focusing on employment outcomes. Their paper was about whether mTBI was associated with any increased risk in suicide in Veterans with PTSD. So there are two comparison groups where those with and without a history of mTBI and both groups had diagnoses of PTSD. So in the mTBI group there was a 20% proportion that reported that they were unemployed, disabled or retired. This was actually a smaller proportion than those without mTBI. This was not a significant difference. The other study by Toblin et al also published last year went into more detail on productivity and employment. This was a large study population of infantry soldiers six months postdeployment and they found that there was a significantly increased odds of those with a history of mild TBI reporting having missed more than two days of work in the last month. Also significantly increased odds of difficulty carrying a heavy load or performing physical training in the last month. This group also examined potential associations with the length of lack of consciousness and these outcomes and found none. So overall strength of evidence looking at employment outcomes of mild TBI. I do not know if we want to give the mild TBI definition now or…well I will carry on for now. There were 10 studies that we included that reported anything about sleep and measures of sleep outcomes range from F4 sleepiness scales to the NSI sleep and fatigue items, individual questions on sleep and sleep loss and so on. So wide variations. We had three studies that identified significantly worse sleep problems for patient with mild TBI compared to those without mild TBI history. Then three studies that found no difference. There was Page 11 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 one study that reported prevalence of sleep disturbance and the prevalence ranged from 13% who reported that they were getting less than four hours of sleep per night to 23% reporting that they had a greater than two hours loss of sleep per night. There was also some evidence in this domain of risk and protective factors for sleep problems and these included the etiology of the injury so whether it was blast related or not. Whether there were additional injuries, comorbid PTSD, neurological and neuropsychological findings, all being associated with an increased risk of sleep disorders. Also, on the flipside, we found one study looking at a headache intervention and in the group that was randomized to receive the headache intervention they indorsed decreased mean sleep disturbance after receiving the intervention. These improved sleep patterns were maintained six most postdeployment. Finally, we are really interested in the social outcomes of mTBI as well and we only found one study that met our inclusion criteria that reported anything in this realm and that was emotional support and also marital status. So again this was the Barnes et al study that was looking at suicide risk in those with PTSD. So they reported that the prevalence of lack of social support in the group, I think it was an n of 35 that had a history of mTBI was 26%. There was no association between mTBI and social support or marital status, so no difference, no significant differences between those PTSD groups with and without mTBI. They had no information on risk or protective factors for the lack of emotional support or marital status. Likely because the study was not designed to exam that issue. Moving on to service utilization and cost studies. This would be really helpful for service planning, resource planning and getting an understanding of the needs of VA and other healthcare systems that are treating Veterans with mild TBI over their lifetime. So we had seven studies that were included in this section and all had some kind of information on service utilization but zero had any information on the cost of treating Veterans with mild TBI. We found no differences in service utilization that were reported in four of our studies. One study showed an average of 18 medications in the mTBI group compared to only five in the non-TBI group. This is a quite a broad difference but no statistical significance test was recorded. Actually I do not know what the n was in that study. I cannot report that. In another study there was a report that the prevalence of counseling was 4-6% and the prevalence of medication used was 4-5% in the mTBI population. Again no studies on cost outcomes and this is likely, there is some information out there published by Taylor et al and this is the polytrauma and blast related injuries QUERI Group of out Minneapolis VA. They are doing some utilization reports and cost reports that report on Veterans that have been diagnosed with traumatic brain injury but those are based on ICD-9 diagnosis codes and in the VA it is virtually impossible to differentiate mild from moderate and severe TBI based on ICD-9 codes. So those reports and the Taylor study were excluded from our evidence review primarily because we could not differentiate mild TBI from anyone that may have had moderate to severe. Page 12 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 So that is probably the main barrier with studying costs of TBI in one healthcare system like the VA. But we did get a report from Meena [PH] Sayers, the director of the poly trauma QUERI that they are now, and Brent Taylor who is leading the key studies. They are looking at doing the same cost and healthcare utilization study but differentiating mild to moderate and severe TBI. So they are linking into a different data source to ascertain that severity information and then they are going to be looking longitudinally at patterns of service use and costs over time after the TBI diagnosis. So we should have more information in this realm over the next year or so. Dr. Maya O’Neil: This is probably a good time for me to jump in with the information on mild versus moderate and severe TBI and give a little bit of a rationale for why we limited studies to those only reporting mild TBI. Going by the VA DoD definition mild TBI is defined as those with some sort of TBI event but normal structural imaging, loss of consciousness 0 to 30 minutes, alteration of consciousness or mental state for a moment up to 24 hours, posttraumatic amnesia 0 to 1 days and Glasgow Coma Scale scores of 13-15. Moderate and severe are obviously much worse than that for all of these factors. The reason that an observational study in particular is so important to limit just to those that have mTBI by a very strict definition is because if you include even one, two, three Veterans that have moderate or severe TBI, mean scores can really get dragged up or down depending on just a few outliers. So in these observational studies we felt like it was really important to use these stringent criteria so only studies that very specifically describe their entire population as having mild TBI were included. One caveat was that though you can call that a definition that I just read structural imaging had to be normal. The vast majority of studies either did not report structural imaging results, did not have structural imaging results for their included populations or some of them said, well there were some positive imaging results but we included them as mild anyway. We went ahead and classified because of the variation. We would be excluding absolutely every study if we had stuck to that very hard and fast rule. So we did not use the imaging, the normal imaging criteria in this report. So that is an overview of our results. Like we said, overall very low strength of evidence for all of the outcomes. I am going to run through just a few discussion points and then I am going to turn it over to our discussants because I think they have a lot of important things to say. So just to highlight some of the findings. You can see there is an overview on the slides there. Little or no evidence for a lot of these areas. Findings are relatively consistent with civilian literature. The civilian literature says that cognitive impairment within a week of injury is common but these effects are no longer present after seven days in most cases. Most functional impairment resolves within a month. However, there are a lot of caveats. People have been asking questions as I have been looking here and as Kathleen was presenting about a lot of these specific factors related to OEF, OIF and OND populations. So multiple TBI events, combat exposure, all of those things that are really specific to this population. So they could definitely be a little bit different from civilian findings. There are a lot of limitations with this body of evidence. Like we talked about a lot of the methodologic flaws, the number and mechanisms of injuries is not often accounted for. Time since injury was frequently not accounted for and that makes any sort of longitudinal description of outcomes difficult if not impossible. We need more prevalence estimates. We talked about a lot of Page 13 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 these pieces as we went through but there is sort of a list. And a lot of just methodologic issues that some of the studies could better address. So when you have an assessor who is assessing different outcomes, if they are blinded to study hypothesis that could help increase our space in the results and things like that. Some specifics are listed there. There are also obviously limitations to this review. Limitations of using the various specific definition of mTBI, though we still think it was worth using that very stringent criteria. As I said we did not apply the imaging exclusion criteria. We also were not able to combine any of the results in Medi Analysis. That is because to do a medi analysis where you combine results of studies and increase statistical power you need to have very similar populations, which we did, that was a bonus. But we did not have very similar outcomes across studies. People used different tools to assess these different outcomes and they were just looking at a variety of different outcomes. So that is definitely a caveat. Future research needs: Highlight those last couple of points that I was making. There are common data elements and we have provided links to those in the presentation. So when you are doing this kind of research take a look at the common data element website. Make sure you are using the assessment tools that other people are using so that eventually we can combine these studies for medi-analytic purposes. Clear consistent reporting of mTBI definition and criteria including imaging results is needed. We definitely need people to be reporting and analyzing the impact of multiple TBI events, mechanism of injury, time since injury as well as other moderators. We need to adjust for known confounders in our research; things like PTSD and as people were pointing out in the questions effort and motivation. That testing can be pretty important to include. We want people to be reporting prevalence estimates. That could really help our stakeholders and our administrators as they are trying to set policy and figure out resource utilization estimates, cost estimates, etcetera. Then just some general study design recommendations there as well. We do have some implications for clinical care and I am going to turn it over to Dr. Dan Storzbach here. He is the Director of Neuropsychology here at the Portland VA; just to talk a little bit about clinical care in patients. Dr. Dan Storzbach: Thank you. I want to start first by clarifying this because I think I was introduced as the Depression Center Director and that should be corrected. I am the head of Neuropsychology at the Portland, Oregon VA Medical Center. I am also a DVA R&D funded principal investigator on mild traumatic brain injury studies. I think that context is important for why I was asked to comment on this particular part of the presentation. I span the two different spheres of professional activity as a clinician and it is very much right at the heart of the kind of work that I do to have the best possible understanding of mild traumatic brain injury. A very large number of the referrals that we get for assessment and some for treatment as well are persons for whom there are concerns of mild traumatic brain injury. But then also I am an investigator and I appreciate how difficult it is to do this kind of investigatory work and why looking at the limitations to the study as why it could be frustrating perhaps for both clinicians and investigators to have to deal with these limitations and coming up with recommendations to how to address treatment needs. Page 14 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 So to get to the point some of the symptoms that patients described to mTBI may be related to comorbid mental or physical health concerns or other factors such as combat stress with deployment and readjustment. Not so much in the outcome of the review studies was this clear as it is in actual clinical activity. The people that we do see for neuropsychological and psychological assessment in our clinic overwhelmingly there are multifactorial concerns that are related to things such as chronic pain and substance abuse and multiple comorbid mental health disorders are pervasive among the people that we see in our clinic. So I think that that should be from a clinician’s point of view and emphasis of future research. The next item is engagement in our services to identify potential health problems and appropriate evidenced-based treatment for those concerned with PTSD treatment etcetera. There is a large number of our referrals who are immediately referred to as postdeployment who have not yet received treatment. For instance, for PTSD and PTSD is the most common disorder apart from mild traumatic brain injury consistent with some of the statistic that you heard quoted earlier. Our policy is that it is not helpful to do a neuropsychological assessment of someone who has not yet been treated for PTSD or other comorbid mental health disorders. We think it is more likely to be useful to do that kind of assessment, that that assessment is deferred until at least some time has taken place for response to treatment. What we do instead, and I suggest this even though there is not an evidence-based directly to support it, is we provide psychoeducation on the expect effects of mild traumatic brain injury and the effects of the PTSD and other comorbid disorders. And suggest to providers that they defer referral for neuropsychological assessment until a later date if cognitive concerns continue. The next item, because of objective cognitive deficits are not common particularly after three months, individuals experiencing ongoing cognitive deficits following the first-line treatment of co-occurring symptoms need further testing. That speaks to the point that I just made. A separate and extremely important point is that clinically, and the research I think does support this to some extent not just in OEF, OIF and OND populations but prior Veterans and service member populations, subjective cognitive complaints are highly pervasive in these populations; not very often very highly correlated with objective cognitive or neuropsychological findings. Nonetheless, within the VA in particular, it is very common to find people who have been diagnosed with cognitive disorders on the basis of their cognitive complaints alone without any objective evaluation. Eeven to the extent that we recently, I saw a case that was diagnosed as dementia related to a mild traumatic brain injury with loss of consciousness of just a few seconds. There is a lot of room for harm to occur making diagnoses without an objective basis. It is a really important point to be addressed within clinical services that persons who have cognitive complaints that there not be a presumption that those complaints are necessarily evidence for there to be a cognitive deficit. Our time is, we have reached an hour and I think it would be useful for us to allow our commentators to weigh-in at this point in time. So I am going to stop right there. Dr. Maya O’Neil: That is a very good point. It would be useful and rude not to. I must say I apologize we ran over and we have really some outstanding stakeholders for this report who are on the call; David Cifu, Robert Ruff and Joel Scholten. So we have some discussions that we wanted to highlight. They are up there on the slides but maybe, Dr. Cifu, let me turn it over to you to start to Page 15 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 say just a little bit about why you requested the report and then some of the frustrations when a report comes back with very low strength of evidence. Where do we try to go from here? Dr. David Cifu: Thanks Maya, I appreciate it. Thanks for all the work and the overview and thanks for the speakers. I do agree. We have got a very impressive panel. I am very excited to hear what Bob and Joel are going to say because I do not know what I am going to say is that impressive. I think the reason we requested this is obviously this is not just an important political issue and hot issue but it is just a huge issue for the care of our Veterans. I think when we do not know the research that is out there we believe that there is some magical cure. There is some brain injury specific intervention. What we just heard is pretty common; headaches, some difficulty with memory disturbance and some emotional difficulties. We assume that we cannot just use the standard approach. There has got to be something specific for the dreaded blast injury or for concussion of other sort. The reality is that is probably not true. The reality from every study I have read and most of them you just reviewed is that there is nothing specifically unique about this population. They may have more issues if you look at it quantitatively but they really are presenting very similarly. So the reason we wanted the review done was to better understand what we felt we knew and fortunately we were actually right that there was not a huge body of literature that identified specific difficulties and specific interventions that would address those difficulties. But instead it showed that they look similar to other Veterans of age and of life experience. They have many of the same problems. Therefore, we can take the leap of faith that this same intervention that we feel very comfortable treating patients in a primary care setting will work for these patients. But I would also support what Dan said is that it is important that we diagnose them appropriately, we label them appropriately. We do not mislabel them. We do not just throw a name on them and if in doubt do not label them but rather understand what it is they are complaining of, what their symptom is and address that as you would any other patient. If you need a specialty service or a specialist or a polytrauma clinic to provide a label to help you with it that is fine but do not delay in treating them and educating them. The good news is that we are not exactly sure what is causing your headache or your memory dysfunction but we have got some wonderful treatments which will work the majority or the vast majority of times. That is important. That is why we asked for it; to better clarify because we think there is this belief that there is something magical happening in these peoples brains and that 20 years from now they are all going to be demented. There is really no evidence to support any of that. Maybe there is something magical happening in their brain in a good way but these folks are going to do well with the right kind of care. With care that is commonsensical, that is proactive, that gets these individuals back to doing activities they were doing beforehand quite well. It takes away some of the fear. So that overall is what we were looking for. It sounds like we found it. It was frustrating just because I think you always wish you could find that holy grail and you can find one study that really helps it to pop, but we were not able to do that. But let me turn it over to Joel and Bob. Actually speaking of the holy grail, I think Bob Ruff really has identified a number of really simple, I will not say commonsensical because that is an insult, but very simple straightforward approaches to care using medications specifically that have really had a wonderful result in things like headache and even some sleep disturbances. Let me ask Bob and Joel to comment further on what I said or just maybe introduce some other ideas. Page 16 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 Dr. Robert Ruff: This is Bob Ruff. I will just start to talk because Joel may be dumbfounded by the nice words you said about him. As a neurologist I came at this with a bias. And the bias was that if there is traumatic brain injury then obviously the problem is the brain. And I think the problem is related to the brain but the problem is, I do not feel, due to persistent structural damage to the brain. I think that the evidence that exists for persistent damage is really relatively minor damage. The deficits that I find on people in and of themselves are not what is causing them to have trouble reintegrating into society. I think that the pernicious aspect of TBI in the military and combat TBI is the co-association with PTSD in that the PTSD is causing a lot of the problems. We found that if we treated one aspect of the PTSD, treating sleep, using an agent that was discovered by another VA psychiatrist, Roy Raskin in Seattle, using a schedule of Prazosin if people were able to tolerate that agent. Prazosin is also Minipress, that people were able to reduce the frequency and in many cases eliminate their nightmares and get better sleep. And when they got better sleep their cognitive function improved. Their attention was better. Their irritability was better and they were able to have a dramatic improvement in their headaches. So I think, as David said, that it is important to sort of identify what the issues are with an individual and to treat those issues. I think there are a number of very effective behavioral treatments that can be used for people with posttraumatic stress disorder and other anxiety disorders that Dr. Storzbach sort of referred. I think that those need to be done as well. So I think that one of the wonderful things that David and Joel and Lucille Beck did in terms of establishing and developing the network of TBI care sites throughout VA is to emphasize that we need to approach the different issues that people have and try and treat them in the symptom by symptom; not to cripple the person. I think David is absolutely correct about that. You do not want to suddenly tell the person, you are never going to get better. You are going to be like this for the rest of your life. I think what I and the group I work with try to do is not to have patients, people with mild TBI, not to have them become professional patients. Not to have them become people who really need to come back to the VA because they are very much dependent on it. I think that, I agree basically with everything that David said. To emphasize what he said, that these people do not have severe disabling injury to the brain. By and large the residual deficits that they have are minimal but they may increase the likelihood that the experiences of war result are perpetuated through PTSD and similar types of anxiety disorders. That is what we need to focus on. There was a meeting of the American Headache Society held in California and there is some position papers coming out from that group and their position is basically that posttraumatic headaches do not have specific treatments. You treat the type of headache pain that the person has. Be it migraine like, tension like, a combination of them and that these are not a serious condition. They are treatable conditions if you approach them correctly. My own person bias is that probably the best thing for an individual is to get them back as a functional member of society, trying to get them working again. I think that having a person doing an activity that really occupies their mind is an excellent type of therapy that works better than any pills I can give them. Thank you. Dr. Maya O’Neil: Thank you so much Dr. Ruff. Page 17 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 Dr. David Cifu: Bob I just want to thank you and I agree 100%. I think you are right on. I hope the audience understands it is not just for headaches, it is for any of their conditions. I see they put up the slides for the future research, TBI research, and I do not know if Maya is taking that or someone else but I will stop talking so that we can go over that as well. Dr. Maya O’Neil: Thanks. This is actually Dr. Cifu’s idea to contact Stuart Hoffman who provided us with some slides on the current VA TBI research. So we have had quite a few questions come through about some, this is the exact question: What are the current studies being done in the VA and what is going on these days? So there are quite a few slides but just a very brief overview again provided by Dr. Hoffman on the funding of TBI conditions. You can see here. He breaks down the different research here into a bunch of epidemiology studies that are going on. There are studies on biological basis for mTBI that you can see here. Some biomarker studies, etcetera. There are quite a few assessment studies. Also quite a few imaging studies. Like we mentioned with this report we could not include a lot of the imaging studies because first of all there are not that many that exist at this point but also they tend to have very, very small sample sizes. So there are quite a few ongoing imaging studies that you can see here. So hopefully we will have better information on imaging in the near future. Then again quite a few treatment studies. There have been a lot of questions about what treatment studies are going on and what kinds of treatments are appropriate. Thank you Dr. Ruff for talking about that really practical suggestion of treating the different symptoms that are occurring with those with TBI. They are probably, based on our report, we can say with some degree of confidence, they are probably at least common for those with mTBI and also common for other Veterans, similar Veterans, who have been deployed and in similar situations. So treating those symptoms is pretty important. As you can see a lot of research going on in that area. Then I will leave Dr. Hoffman’s summary slide on the different research that is occurring on mTBI. Dr. Cifu let me have you end the presentation today. Anything that you think researchers and clinicians need to know going forward. What is some of that key information that folks should be taking from the presentation today. Dr. David Cifu: Sure Maya, I appreciate that. I will be as brief as I can. I think that the biggest area of research that folks need to focus on is; while it is lovely to do small studies and pilots with an n= of 12 or 40s, I think what we need is, if we are going to study something that is of a very high prevalence in the non-brain injury Veteran population, we are going to need to look at large samples across multiple centers. Because we do not necessarily know the natural history of this condition. Whether we are talking about the acute recovery, we are talking about the moderate term of effects or we truly believe that chronic traumatic encephalopathy is a topic of significant concern. Is it going to take 10 years, 20 years, we need to have a longitudinal design that looks over many years. So I would just recommend to researchers while lovely to do your small projects, if you are going to do small projects keep them very focused. Try to go certainly for a blinded strategy even a sham or placebo controlled strategy so we will really know what we are studying. We do not need any more bad or mediocre studies. Do not take it as an insult. We just need the best otherwise we are really not going to better understand this. What we really need is large multicenter longitudinal clinical trials, which we are trying to get up and running between the VA DoD and now the NFL and GE are kicking in some resources as well. So that is what we need to be approaching. Page 18 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 But until we do that let us use practical solutions. Let us treat the Veteran. Let us get them reactivated and get them back to life, back to the military if they are still active duty. But certainly get them back to volunteer work, a job, running their household, whatever they were doing. That is the best treatment you could ever come up with. Back to you Maya. Dr. Maya O’Neil: Thank you so much. Oh, Joel, you are on the line. Dr. Joel Scholten: Yes. I am sorry. I guess I was muted before by someone, a higher power other than myself. But I just wanted to emphasize one of the points that Dr. Ruff made that I think he made very well in the fact that the medications often when we are looking for treatment options we tend to default to meds. Certainly with in dealing with the scope of traumatic brain injuries, medications are rarely the answer. I do believe that mild TBI is a different beast than moderate and severe TBI but I think that the statement that medications are not the main answer for TBI holds across the entire severity spectrum. Often it is more important to emphasize things like exercise, therapeutic interventions, whether it be physical or occupational therapy or cognitive therapy or even counseling and diet. These are things that it is challenging for not only Veterans with ongoing symptoms but the overall American public to do. So these are, for compliance, it is really hard to get true compliance with some of these recommendations. I did want to remind everyone that education really is the best supported evidence for implementation or for managing mild TBI. So we need to take the time to speak to the Veterans that we are seeing in clinic. Also as Bob had mentioned prioritizing what symptoms they want to treat. We do not want to make professional patients by ordering 15 different consults and six different meds so they are coming to the medical center every day. But we need to work with them to prioritize and help them improve on their functional ability and independence. Now that I am off mute I have said my piece so back to you. Dr. Maya O’Neil: Thank you so much to the three of you for being willing and able to be on the call today. I think it is really helpful to get that clinical and research and administrative perspective. I know that is what a lot of people have questions about. For those of you I think we are over time, is that right Heidi? Moderator: I am sorry. What was that Maya? Dr. Maya O’Neil: Are we over time at this point? I think we were supposed to end at 10:15 Pacific. Moderator: We can go a little bit later. I do have another session starting in about 45 minutes but we do have about 15 minutes or so we can play with if you are able to stay on a little bit later. Dr. Maya O’Neil: We have, I do not know if my co-presenters are able to so we will try to wrap it up in just a second here. I just wanted to again thank your discussants for having those really practical strategies. I think part of the take-home message of this report is that even though there is not the best quality evidence out there, the best available evidence does support exactly what our Page 19 of 20 Complications of mild traumatic brain injury in Veterans and military personnel: A Systematic Review March 26, 2013 discussants were talking about. These really practical strategies; strategies with very low risk of harm. Getting education out there to Veterans and really it is quite a hopeful message. If anything, the information from this report and that our discussants provided is quite hopeful for our Veterans and members of the military who do have one or more mTBIs that there are these really practical strategies, very low risk of harm, things that they can do to treat these symptoms that they might be experiencing to help them feel better. So thank you very much for being on the call. We will address a lot of these other questions that came up. We have quite a few questions that I am looking through here and we will be addressing those over email. If there are questions for a specific presenter we will make sure to get them to them. I know Dr. Ruff there were quite a few questions that related when you were talking about the different treatments, about Prazosin and things like that. So for folks listening in we will get those to the appropriate presenters and discussants. Thanks so much. Please keep in mind there are still more cyberseminars coming up later on this month and even next month that are on TBI. In fact, Heidi you know this and Bob you know this better than I do but I think you have a presentation coming up in two days. Is that right Dr. Ruff? Dr. Robert Ruff: I guess. thDr. Maya O’Neil: Excellent. I think it is on the 28. I know I am signed up for it. So take a look at the other cyberseminars and if you missed any of this one it is going to be available online. So Heidi I will turn it over to you to end it now. Moderator: Fantastic. I was actually going to say, we actually have two TBI sessions this week. We have one this afternoon starting in about two and a half hours on DoD Measures in Deployed Settings. You can still register for that out on the HSR&D site. Or we do have a TBI session on Thursday at 2:00 p.m. Eastern (time) on Ongoing Pharmacologic Trials. So we do still have those available this week if you have some free time or we will be recording them and we will make them available in our archive. I do want to thank all of our attendees for joining us today. Those of you who stuck around for the whole thing we really appreciate it. As you leave today’s session could you, you will be prompted with a feedback survey. If you could take a few moments to fill that out we really do read through your feedback and we really do weigh that in our current and upcoming sessions. So please do take a few moments to fill that out. To our presenters and discussants today, thank you all very much for taking the time to prepare and present and discuss today. We really do appreciate the time that you all put into making these cyberseminars work. Thank you everyone for joining us for today’s spotlight on ESP cyberseminar and we hoped to see you at a future session. Thank you. [End of audio] Page 20 of 20