SUMMARY

The first Persian Gulf War, an offensive led by US and coalition troops in January 1991, followed the August 1990 Iraqi invasion of Kuwait. The war was over on February 28, 1991; an official cease-fire was signed in April 1991, and the last US troops who participated in the ground war returned home on June 13, 1991. In all, about 697,000 US troops had been deployed to the Persian Gulf during the conflict. That war resulted in few injuries and deaths among coalition forces, but returning veterans soon began to report numerous health problems that they believed were associated with their service in the gulf. Those veterans were potentially exposed to numerous biologic and chemical agents, including vaccinations and other prophylactic medications, nerve agents, depleted uranium, pesticides, solvents, and combusted and uncombusted fuels.


On October 7, 2001, the United States began combat operations in Afghanistan in response to the September 11, 2001, terrorist attacks. The war in Afghanistan is often referred to as Operation Enduring Freedom (OEF). In March 2003, the United States became engaged in military operations in Iraq. The Iraq War, referred to as Operation Iraqi Freedom (OIF) or the second Iraq War, and OEF have been fundamentally different from the first Gulf War, not only in the number of troops deployed and in its duration but in the type of warfare and in the numbers of deaths and injuries, particularly brain injuries.


In 1998, in response to the growing concerns of ill Gulf War veterans, Congress passed two laws: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, and preventive medicines or vaccines associated with Gulf War service and to consider the NAS conclusions when making decisions about compensation. The study was assigned to the Institute of Medicine (IOM), which has published several volumes, including Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines; Gulf War and Health, Volume 2: Insecticides and Solvents; Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants; Gulf War and Health: Updated Literature Review of Sarin; and Gulf War and Health, Volume 5: Infectious Diseases.


The legislation did not preclude an IOM recommendation of or a Department of Veterans Affairs (VA) request for additional studies, particularly if a subject of concern arises. Consequently, a VA request that IOM consider whether there is an increased risk of amyotrophic



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SUMMARY The first Persian Gulf War, an offensive led by US and coalition troops in January 1991, followed the August 1990 Iraqi invasion of Kuwait. The war was over on February 28, 1991; an official cease-fire was signed in April 1991, and the last US troops who participated in the ground war returned home on June 13, 1991. In all, about 697,000 US troops had been deployed to the Persian Gulf during the conflict. That war resulted in few injuries and deaths among coalition forces, but returning veterans soon began to report numerous health problems that they believed were associated with their service in the gulf. Those veterans were potentially exposed to numerous biologic and chemical agents, including vaccinations and other prophylactic medications, nerve agents, depleted uranium, pesticides, solvents, and combusted and uncombusted fuels. On October 7, 2001, the United States began combat operations in Afghanistan in response to the September 11, 2001, terrorist attacks. The war in Afghanistan is often referred to as Operation Enduring Freedom (OEF). In March 2003, the United States became engaged in military operations in Iraq. The Iraq War, referred to as Operation Iraqi Freedom (OIF) or the second Iraq War, and OEF have been fundamentally different from the first Gulf War, not only in the number of troops deployed and in its duration but in the type of warfare and in the numbers of deaths and injuries, particularly brain injuries. In 1998, in response to the growing concerns of ill Gulf War veterans, Congress passed two laws: PL 105-277, the Persian Gulf War Veterans Act, and PL 105-368, the Veterans Programs Enhancement Act. Those laws directed the secretary of veterans affairs to enter into a contract with the National Academy of Sciences (NAS) to review and evaluate the scientific and medical literature regarding associations between illness and exposure to toxic agents, environmental or wartime hazards, and preventive medicines or vaccines associated with Gulf War service and to consider the NAS conclusions when making decisions about compensation. The study was assigned to the Institute of Medicine (IOM), which has published several volumes, including Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines; Gulf War and Health, Volume 2: Insecticides and Solvents; Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants; Gulf War and Health: Updated Literature Review of Sarin; and Gulf War and Health, Volume 5: Infectious Diseases. The legislation did not preclude an IOM recommendation of or a Department of Veterans Affairs (VA) request for additional studies, particularly if a subject of concern arises. Consequently, a VA request that IOM consider whether there is an increased risk of amyotrophic 1

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2 GULF WAR AND HEALTH lateral sclerosis in all veteran populations resulted in Amyotrophic Lateral Sclerosis in Veterans, a request for an examination of all health effects in veterans deployed to the Persian Gulf irrespective of specific exposures resulted in Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War, and a request for a review of long-term health effects that might be associated with deployment-related stress resulted in Gulf War and Health, Volume 6: Health Effects of Deployment-Related Stress. The present report is in response to a VA request regarding whether traumatic brain injury has long-term health effects. TRAUMATIC BRAIN INJURY Damage to the brain after trauma (for example, a blow or jolt to the head, a penetrating head injury, or exposure to an external energy source) is referred to as traumatic brain injury (TBI). TBI may be open (penetrating) or closed and is categorized as mild, moderate, or severe, depending on the clinical presentation. A brain injury that results from something passing through the skull, such as a bullet discharged from a gun or fragments from a missile, would be referred to as a penetrating or open head injury. A brain injury that results from something hitting the head or from the head hitting something forcefully, such as the dashboard of a car, is referred to as a nonpenetrating or closed head injury. According to the Centers for Disease Control and Prevention, mild TBI is manifested as a brief change in mental status or unconsciousness, whereas severe TBI results in an extended period of unconsciousness or amnesia. According to the World Health Organization Collaborating Task Force on Mild Traumatic Brain Injury, mild TBI might also be referred to as a concussion, a minor brain injury, a mild head injury, or a minor head injury. Furthermore, it has been noted that the term concussion, often used to indicate a mild or moderate brain injury, refers to a disturbance in neurologic function caused by the mechanical force of rapid acceleration or deceleration, and can include varied symptoms and severity. With regard to determining TBI severity, different methods have been used in the last three decades to measure the magnitude of brain damage and to predict its outcome. The most widely used tool for measuring severity is the Glasgow Coma Scale (GCS), which was developed in 1974 by Teasdale and Jennett as a measure of neurologic deficits after TBI and was an important contribution to the standardization of early assessment of TBI. It is based on a simple method of scoring three domains—eye opening, verbal response, and motor function— and yields a total score of 3 (comatose or nonresponsive) to 15 (no deficits in any of the three domains). The interpretation of scores at the ends of the scale is relatively straightforward, but scores like 8 or 9 or 11 or 12 might be subject to judgment error. Although the GCS is relatively straightforward, the classification of severity has been inconsistent. Many incidence studies have classified severity according to GCS scores of 3–8 as severe, 9–12 as moderate, and 13–15 as mild or minor. Other methods and instruments have been used to determine injury severity, such as the Abbreviated Injury Scale (AIS) and the International Classification of Diseases. Clinical measures—such as loss of consciousness (LOC), duration of posttraumatic amnesia (PTA), and computed tomography of brain lesions—have also been used to assess TBI severity. During peacetime, over 7,000 Americans with a TBI diagnosis are admitted to military and veterans hospitals each year. During the Vietnam War, 12–14% of all combat casualties had a TBI, and another 2–4% had a TBI plus a lethal wound of the chest or abdomen. In the recent

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SUMMARY 3 conflicts in Afghanistan and Iraq, however, TBI appears to account for about 22% of casualties. All patients admitted to Walter Reed Army Medical Center in the period January 2003–February 2005 who had been exposed to blasts were routinely evaluated for brain injury, and 59% of them were found to have TBI. Of those injuries, 56% were moderate or severe, and 44% were mild. In many people who sustain mild TBI, the effects might not be immediately evident and might not be evident with conventional neuroimaging. That clearly presents a problem for VA with regard to preparation for the return of veterans from OEF and OIF with TBI that might not be apparent. OPERATION ENDURING FREEDOM AND OPERATION IRAQI FREEDOM Throughout OEF and OIF, explosive devices have become more powerful, their detonation systems more creative, and their additives more devastating. According to the Department of Defense (DoD) Personnel and Procurement Statistics, 75% of all US military casualties in OEF and OIF are caused by explosive weaponry. As of January 2008, DOD reported that over 5,500 soldiers had suffered TBIs. As a continuing threat to our troops, blast injury, especially blast-induced neurotrauma (BINT), has been called the signature wound of the war in Iraq. In both civilian and military environments, exposure to a blast might cause instant death, injuries with immediate manifestation of symptoms, or injuries with delayed manifestation. BINT is a complex type of TBI that features closed (blunt) head injury that may be accompanied by polytrauma. The pathobiology of BINT parallels that seen in TBI, including secondary injury cascades that result in vasogenic and cytotoxic edema, emerging hemorrhagic lesions, metabolic disturbances, compromise of neural and glial structures that leads to cell death, and diffuse axonal injury in cases of sudden brain acceleration and deceleration. As of June 30, 2008, there had been about 1.64 million US deployments as part of OEF and OIF and 4,128 US troop fatalities. The ratio of wounded troops to troop fatalities, 7.37:1, is higher than that in previous military conflicts, probably because of the widespread use of body armor, improved battlefield medical response, and advances in aeromedical evacuation. Despite those improvements, military personnel continue to be critically wounded, and TBI continues to be a source of concern. Furthermore, there is an outdated dogma that neurologic impairments caused by primary blasts are rare because the skull provides excellent protection for the brain, that is, that brain injury is a consequence solely of air emboli in cerebral blood vessels. Despite recent clinical findings, experimental findings, and experience in contemporary military operations that suggest that substantial short-term and long-term neurologic deficits can be caused by blast exposure without a direct blow to the head, the old belief prevails in the professional literature and in civilian clinical practice. Indeed, information on blast injuries consists mainly of the consequences of secondary and tertiary blast mechanisms. Although BINT is one cause of in-theater injuries, it is often underdiagnosed. Its complex clinical syndrome is caused by the combination of all blast effects. It is noteworthy that blast injuries are usually manifested in a form of polytrauma, that is, injury involving multiple organs or organ systems. CHARGE TO THE COMMITTEE The charge to this IOM committee was to examine the strength of the evidence of an association between TBI and long-term health effects. The committee also was to consider the severity of TBI (that is, mild, moderate, and severe) and possible long-term consequences.

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4 GULF WAR AND HEALTH COMMITTEE’S APPROACH TO ITS CHARGE The committee began its work by overseeing extensive searches of the peer-reviewed medical and scientific literature, including published articles, other peer-reviewed reports, and dissertations. The searches retrieved over 30,000 potentially useful epidemiologic studies, and their titles and abstracts were reviewed. The committee focused its attention on clinical and epidemiologic studies of adults with long-term health effects that resulted from TBI by any mechanism, such as occupational injury, motor-vehicle collision, sports injury, gunshot wound, or other act of violence, including military combat. Studies of patients with TBI due to malignancy, stroke, infection, ischemia, other diseases or disorders of the brain, intoxication, or oxygen deprivation were not considered. The committee did not systematically review studies of young children, the elderly, or brain-injured patients in litigation for compensation claims. Its review excluded case reports, case series with few participants, and studies of acute outcomes that resolved within days to a few months (that is, less than 6 months). The committee did not review general studies of “disability” as a gross measure of morbidity but rather evaluated studies that associated TBI with specific health outcomes. After its assessment of the 30,000 titles and abstracts, the committee members identified about 1,900 studies for further review. Those studies were objectively evaluated without preconceived ideas about health outcomes or the existence or absence of associations. The committee adopted a policy of using only peer-reviewed published literature or unpublished reports that had undergone rigorous peer review, such as dissertations and some government reports, as the basis of its conclusions. The process of peer review by fellow professionals increases the likelihood of high quality but does not guarantee the validity of a study or the ability to generalize its findings. Accordingly, committee members read each study critically and considered its relevance and quality. They did not collect original data, nor did they perform any secondary data analysis. LIMITATIONS OF THE STUDIES OF TRAUMATIC BRAIN INJURY Many of the studies reviewed by the committee presented substantial obstacles to determining associations between TBI and long-term health outcomes in that they were beset by limitations that are commonly encountered in epidemiologic studies, including lack of a representative sample, selection bias, lack of control for potential confounding factors, self- reporting of exposure and health outcomes, premorbid status, and outcome misclassification. Some of the studies reviewed did not specify the time between injury and followup, so the committee could not determine whether the outcome lasted longer than 6 months. Many studies involved populations in rehabilitation centers where subjects might have had multiple injuries that included TBI but the initial TBI might have been due to a stroke or a brain tumor; these studies presented several problems, such as lack of representativeness of the younger veteran population and an inherent selection bias, for example, if they included only people who had health insurance. Most cohort studies rely on self-reporting of symptoms on questionnaires. Symptom self- reporting potentially introduces reporting or recall bias, which occurs when the group being studied reports what it remembers more frequently than a comparison group does. Reporting bias

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SUMMARY 5 can lead to overestimation of the prevalence of symptoms or diagnoses in the TBI population. Symptom self-reporting might sometimes introduce another type of bias known as outcome misclassification, which leads to errors in how symptoms are classified into outcomes and analyzed. Apart from some large population-based studies of mortality after TBI and a few others of neurologic outcomes, many of the studies evaluated by the committee had small samples. When a study sample is too small, it is possible to miss clinically important differences; this phenomenon is known in epidemiology as type II error. In such studies, attempts to examine even smaller subpopulations magnify the difficulties and reduce the likelihood of detecting meaningful differences. Of the studies examined by the committee, those with small samples were also sometimes hampered by other problems, including low participation rate, loss to followup, inadequate duration of followup, and self-reporting of symptoms. An additional limitation of the studies reviewed is the lack of uniformity in defining the severity of TBI. Studies typically note whether the injury was a penetrating or a closed head injury but often use different criteria to assess severity. The committee found it difficult to compare outcomes among studies, particularly in the “moderate” TBI category, because researchers used different durations of LOC and of PTA to define severity. Similarly, the range of scores on the GCS was not always uniformly applied in defining mild, moderate, and severe TBI. The committee focused on studies of people who had sustained TBI, followed the subjects to determine long-term sequelae, and generally asked whether a specific outcome was more likely in people with TBI than in controls without TBI. The committee discussed characteristics of the optimal control group for such studies because the type of controls could influence inferences drawn from the studies examined. When the outcome was a medical condition or a social outcome, the committee considered the best comparison group to be made up of people who had other traumatic injuries but without TBI (such as bone fractures) and were in the same facility as the subjects with TBI; such controls permit examination of the effects of TBI on outcome independently of the general effects of trauma and of the common risk factors that lead to trauma. When the outcome studied was death, the committee agreed that comparison with age- and sex-specific mortality in the general population provided the best comparison. The committee found many studies for inclusion in its review. However, many excellent studies were excluded because they were not designed to answer the question posed to the committee: What are the long-term outcomes associated with sustaining TBI? OVERVIEW OF HEALTH OUTCOMES It is clear that TBI can have detrimental effects on a person, whether it is mild, moderate, or severe. The committee found many instances of long-term outcomes of TBI, although some acute outcomes resolved or lessened over time (such as some neurocognitive and psychosocial dysfunction) whereas other sequelae became more apparent several years after injury (such as psychiatric outcomes). Many studies found a dose–response relationship with regard to TBI severity and outcome: generally, the more severe the TBI, the more severe the outcome. For example, with regard to neurocognitive outcomes, the committee found sufficient evidence of an association between penetrating TBI and decline in neurocognitive function associated with the

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6 GULF WAR AND HEALTH region of the brain affected and the volume of brain tissue lost. That evidence was consistently found in veterans of World War II and Vietnam. With regard to closed head injuries, the committee found sufficient evidence of an association between severe TBI and neurocognitive deficits, limited but suggestive evidence of an association between moderate TBI and neurocognitive deficits, and inadequate and insufficient evidence of an association between mild TBI and neurocognitive deficits. With regard to neurologic effects, the studies reviewed had numerous findings, including a strong association between brain injury and unprovoked seizures. For example, there is a causal association between penetrating TBI or severe closed TBI and unprovoked seizures, whereas the risk of unprovoked seizures after mild TBI is limited but suggestive of an association. In general, the risk of seizures after all types of TBI severity appears to be highest in the first year after trauma and declines thereafter. Some of the literature reviewed supports an association between TBI and neurodegenerative diseases—for example, studies that demonstrated a sufficient association between moderate or severe TBI and dementia of the Alzheimer type or parkinsonism, although sufficient evidence of an association with dementia pugilistica could be supported only in professional boxers. Other studies reviewed did not support a relationship between TBI and multiple sclerosis or amyotrophic lateral sclerosis and were categorized as inadequate and insufficient to determine whether an association exists. There were endocrine outcomes, such as sufficient evidence of an association between moderate to severe TBI and growth hormone insufficiency and hypopituitarism; however, the studies only supported a finding of limited and suggestive evidence of an association between moderate to severe TBI and diabetes insipidus. Psychiatric outcomes have been discussed by the committee, and there is some uncertainty regarding the mechanisms linking TBI and psychiatric diagnoses. For example, it is not clear whether psychopathologic conditions after TBI are biologic consequences of the injury, reactions to the person’s cognitive and social dysfunction after TBI, or a continuation of pre- existing conditions. The committee has chosen, however, to use the terminology of primary psychiatric disorders, as has been the custom in the TBI literature. The committee notes that the predominance of studies indicated that groups with TBI (mild, moderate, or severe) had higher rates of major depression 6 months or more after TBI than did appropriate comparison groups. The committee concluded that there is sufficient evidence of an association between TBI and depression and aggressive behaviors. The association between mild TBI and posttraumatic stress disorder (PTSD) appears to be different between military and civilian populations. Studies conducted in military personnel who served in the Gulf War led the committee to conclude that there is limited but suggestive evidence of an association between TBI and PTSD. In contrast, studies conducted in civilian populations led the committee to conclude that there is inadequate and insufficient evidence to determine whether an association exists between TBI and PTSD. With regard to aggressive behaviors, the studies support a conclusion of sufficient evidence of an association, but TBI is not associated with increased drug and alcohol use as there is limited but suggestive evidence of an association between TBI and decreased alcohol and drug use. Finally, the literature supported a finding of limited but suggestive evidence of an association between moderate to severe TBI and psychoses generally appearing in the second and third years after TBI. Social functioning is often severely hampered after TBI, especially if it is severe. Social function in those hospitalized with TBI is adversely affected, relative to those with no injury, for

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SUMMARY 7 at least 1 year. Results of some studies suggest that difficulties might continue up to 15 years after injury, depending on TBI severity. TBI decreases the probability of postinjury employment in people who were workers before they were injured, lengthens the time it takes them to return to work (if they do return), and decreases the likelihood that they will return to the same positions. Those adverse effects are related to the severity of injury as measured with neurologic severity indicators and are related even more strongly to post-TBI neuropsychologic impairment. Penetrating head injury sustained in wartime clearly is associated with unemployment. The probability of being employed 15 years after the Vietnam War was related to the number of residual neurologic deficits, brain-volume loss, and cognitive status. TBI also adversely affects leisure and recreation, social relationships, functional status, quality of life, and independent living. By 1 year after injury, psychosocial problems appear to be greater than problems in basic activities of daily living. The committee concluded that there was sufficient evidence of an association between penetrating TBI and long-term unemployment and between moderate to severe TBI and long-term adverse social-function outcomes, particularly unemployment and diminished social relationships. With regard to mild TBI, however, the committee concluded that the evidence was inadequate and insufficient with respect to long-term adverse social functioning, including unemployment, diminished social relationships, and decrease in the ability to live independently. There is sufficient evidence of a causal relationship between injury and premature death in people who survive penetrating head injury. There is inadequate and insufficient evidence to determine whether an association exists between mild, moderate, or severe TBI and premature death in people who survive 6 months or longer after TBI. That is largely because of the paucity of studies. Finally, in the subset of patients with moderate or severe TBI either admitted into or discharged from rehabilitation centers or those receiving disability support, there is sufficient evidence of an association between TBI and premature death; however, that finding is limited to patients who have sustained injuries severe enough to warrant inpatient rehabilitation or disability support. Large population-based registry studies of brain cancer found no association between TBI and brain tumors, but there is evidence from some other studies of a weak but significant association between TBI and meningioma and of an increase in risk of brain tumors 10 years or more after TBI; that suggests a long latent period before clinical presentation. The committee believes that the possibility of an association between TBI and brain tumors is not a closed question and that longer-term followup, especially with large registry-based studies, is warranted to determine whether there is a measurable increase in risk and, if so, when it is most likely to be observed. For now, the committee concludes that the inconsistent results among the studies are most supportive of a classification of inadequate and insufficient evidence to determine whether an association exists. RECOMMENDATIONS Scoring of Severity of Blast-Induced Neurotrauma BINT is a complex type of TBI that features closed (blunt) head injury that may be accompanied by a penetrating brain injury. The pathobiology of BINT parallels that of TBI. Because moderate, moderate to severe, and severe BINT is often part of complex polytrauma,

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8 GULF WAR AND HEALTH proper diagnosis of BINT should include both classification of blast injuries and scoring of the severity of head injury. The most recent version of the AIS incorporates blast injuries and is regularly used by the US Army; it can be used for global scoring of all injuries. In hospitals, the modified Pathology Scoring System can yield additional information that might be valuable in designing treatment strategies and predicting outcomes. A combination of the head AIS, as an anatomic measure, and the GCS, as a physiologic measure of brain-injury severity, is useful in initial estimation of brain damage. Nevertheless, use of additional TBI scoring systems is recommended, especially in the case of mild TBI or suspected concussion or when medical records provide less detailed information about the injury and its circumstances. In the military environment, use of the Brief Traumatic Brain Injury Screen and the Military Acute Concussion Evaluation is recommended for every soldier who has a history of blast exposure (even low- intensity blast exposure). The committee recommends that the Department of Defense use the Brief Traumatic Brain Injury Screen and the Military Acute Concussion Evaluation for every soldier who has a history of blast exposure (even of low-intensity blast exposure). Experimental and Clinical Studies of Blast-Induced Neurotrauma Blast injury, especially BINT, is a continuing threat to our troops. In both civilian and military environments, exposure to a blast might cause instant death, injuries with immediate manifestation of symptoms, or injuries with delayed manifestation. There is a paucity of information in the scientific literature regarding the sequelae of blast injury, and there is a need for prospective, longitudinal studies to confirm reports of long-term effects of exposure to blasts. Because of lack of information, adverse neurologic and behavioral changes in blast victims might be underestimated, and valuable time for preventive therapy or timely rehabilitation might be lost. The committee recommends that the Department of Defense and the Department of Veterans Affairs support prospective, longitudinal studies to confirm reports of long-term or latent effects of exposure to blasts. Those studies should examine the consequences of blast-induced neurotrauma, recovery timeline, and any factors that improve or worsen outcomes. Additionally, animal models provide the framework for predicting outcomes and developing optimal therapeutics for BINT; however, after reviewing the literature, the committee came to the conclusion that there is a need for more refined animal models of BINT. They should be aligned with emerging data on the human response to BINT. The accessibility to acute clinical data on human BINT from DoD and VA is essential for refining the animal models. The committee recommends that the Department of Defense and the Department of Veterans Affairs support research on animal models of blast-induced neurotrauma. Consideration should be given to developing models that would be relevant to human traumatic brain injury that encompass a more comprehensive experimental design. That could include studies that measure both behavior and pathology that might differ by traumatic brain injury severity. It would be

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SUMMARY 9 important for the Department of Defense and the Department of Veterans Affairs to work with the research community and provide acute clinical data on human blast-induced neurotrauma to enable refinement of the animal models. Registry Control Groups The studies of TBI evaluated by the committee had numerous limitations. A primary limitation results from the nature of the control or comparison group assembled by the investigator. In an attempt to improve the quality of future TBI studies, the committee has described what it considers to be appropriate control groups. Evaluating whether TBI in service members is associated with particular outcomes requires comparison groups of service members who have experienced injuries other than TBI and service members who have been deployed but not injured. Comparing outcomes of TBI with outcomes in those reference groups is the only means of identifying which outcomes are due solely to TBI and not to deployment or to injury in general. The committee recommends that the Department of Veterans Affairs include, in the development of the Traumatic Brain Injury Veterans Health Registry (hereafter referred to as “the registry”), other service members who could provide a valid comparison for the analysis of outcomes. Comparison groups should be made up of injured persons without traumatic brain injury or blast exposure, uninjured deployed veterans, and uninjured nondeployed but previously active- duty veterans. Those groups could be compared with persons who have received a diagnosis of traumatic brain injury and with those who have possible or probable traumatic brain injury. The three comparison groups should have samples large enough to provide reference rates of outcomes of interest. Furthermore, the registry needs to be representative of the traumatic brain injury population to be able to determine associations between such injury and various outcomes. There should be no exclusions on the basis of sex, race, geographic region, or rank. Access to medical records is essential to ensure the validity of a recommended research design. Neurologic status, computed tomographic or magnetic resonance imaging, electroencephalography, associated nonbrain injuries, and durations of impaired consciousness and PTA are important for the accurate classification of service members into appropriate groups. For the registry to have the greatest benefit, predeployment information on all groups mentioned above should be made available to the injury-research community. Complete medical information on outcomes of each person (stripped of personal identifiers) in the registry should be available whether or not care is sought at or covered by the VA system. Predeployment and Postdeployment Testing In considering the question of long-term outcomes of TBI, questions arise that are very seldom addressable in current studies: What was the predeployment cognitive ability of the person? How did the TBI affect the baseline functioning? The answers to those questions are important in isolating and understanding the effects of TBI itself on long-term outcome. Most

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10 GULF WAR AND HEALTH information about TBI effects comes from studies of World War I, World War II, and Vietnam veterans, but those studies are based on penetrating or severe closed head injuries. In the current conflict, many injuries are related to blast, and outcomes are unknown. In an effort to understand the long-term outcomes of traumatic brain injury, including consequences that might be related to blast, the committee recommends that all deployed military personnel undergo predeployment neurocognitive testing. The committee also recommends postdeployment neurocognitive testing of representative samples of military personnel (including those with traumatic brain injury, those with other non-TBI injuries, and uninjured service members without blast exposure). Among service members with predeployment and postdeployment testing, it should be possible to link the results for each person with DoD and VA records, and those should be made available for research and treatment. SUMMARY OF FINDINGS The committee attempted to express its judgment on the available data clearly and precisely. It agreed to use the categories of association (see below) that have been established and used by previous Committees on Gulf War and Health and other IOM committees that have evaluated vaccine safety, effects of herbicides used in Vietnam, and indoor pollutants related to asthma. The categories of association have gained wide acceptance over more than a decade by Congress, government agencies (particularly VA), researchers, and veterans groups. The five categories of association sound a recurring theme: the validity of an association is likely to vary to the extent to which common sources of spurious associations can be ruled out as reasons for the observed association. Accordingly, the criteria for each category express a degree of confidence based on the extent to which sources of error have been reduced. In each case below, findings are described for penetrating TBI or for closed TBI generally indicated as mild, moderate, or severe. Sufficient Evidence of a Causal Relationship Evidence is sufficient to conclude that there is a causal relationship between TBI and a specific health outcome in humans. The evidence fulfills the criteria of sufficient evidence of an association and satisfies several of the criteria used to assess causality, such as strength of association, dose–response relationship, consistency of association, temporal relationship, specificity of association, and biologic plausibility. Penetrating TBI and unprovoked seizures. Penetrating TBI and premature death. Severe or moderate TBI and unprovoked seizures. Sufficient Evidence of an Association Evidence is sufficient to conclude that there is a positive association; that is, a consistent association has been observed between TBI and a specific health outcome in human studies in

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SUMMARY 11 which chance and bias, including confounding, could be ruled out with reasonable confidence as an explanation for the observed association. Penetrating TBI and decline in neurocognitive function associated with the region of the brain affected and the volume of brain tissue lost. Penetrating TBI and long-term unemployment. Severe TBI and neurocognitive deficits. Moderate or severe TBI and dementia of the Alzheimer type. Moderate or severe TBI and parkinsonism. Moderate or severe TBI and endocrine dysfunction, particularly hypopituitarism. Moderate or severe TBI and growth hormone insufficiency. Moderate to severe TBI and long-term adverse social-function outcomes, particularly unemployment and diminished social relationships. Moderate or severe TBI, in the subset of patients who are either admitted into or discharged from rehabilitation centers or receive disability support, and premature death. TBI and depression. TBI and aggressive behaviors. TBI and postconcussion symptoms (such as memory problems, dizziness, and irritability). Professional boxing and dementia pugilistica. Limited/Suggestive Evidence of an Association Evidence is suggestive of an association between TBI and a specific health outcome in human studies but is limited because chance, bias, and confounding could not be ruled out with reasonable confidence. Moderate or severe TBI and diabetes insipidus. Moderate or severe TBI and psychosis. Moderate TBI and neurocognitive deficits. Mild TBI resulting in loss of consciousness or amnesia and unprovoked seizures. Mild TBI and ocular and visual motor deterioration. Mild TBI with loss of consciousness and dementia of the Alzheimer type. Mild TBI with loss of consciousness and parkinsonism. Mild TBI and posttraumatic stress disorder in Gulf War military populations. TBI and decreased alcohol and drug use in the 1–3 years after injury. TBI and completed suicide. Inadequate/Insufficient Evidence to Determine Whether an Association Exists Evidence is of insufficient quantity, quality, consistency, or statistical power to permit a conclusion regarding the existence of an association between TBI and a specific health outcome in humans. Moderate or severe TBI and brain tumor. Mild, moderate, or severe TBI that is survived for 6 months or more and premature death. Mild TBI and neurocognitive deficits. Mild TBI (without loss of consciousness) and dementia of the Alzheimer type. Mild TBI and posttraumatic stress disorder in civilian populations.

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12 GULF WAR AND HEALTH Mild TBI and long-term adverse social functioning, including unemployment, diminished social relationships, and decrease in the ability to live independently. TBI and mania or bipolar disorder. TBI and attempted suicide. TBI and multiple sclerosis. TBI and amyotrophic lateral sclerosis. Limited/Suggestive Evidence of No Association Evidence from several adequate studies, covering the full range of severity of TBI that humans are known to encounter, is consistent in not showing a positive association between TBI and a specific health outcome. A conclusion of no association is inevitably limited to the conditions, magnitudes of exposure (types of TBI—mild, moderate, and severe or penetrating), and length of observation in the available studies. The possibility of a very small increase in risk of the health outcome after TBI cannot be excluded. None.