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1 INTRODUCTION 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. BACKGROUND 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), and to date several volumes have been published including Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines (IOM, 2000); Gulf War and Health, Volume 2: Insecticides and Solvents (IOM, 2003); Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants (IOM, 2005); Gulf War and Health: Updated Literature Review of Sarin (IOM, 2004); Gulf War and Health, Volume 5: Infectious Diseases (IOM, 2006c). 13

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14 GULF WAR AND HEALTH 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 lateral sclerosis in all veteran populations resulted in Amyotrophic Lateral Sclerosis in Veterans (IOM, 2006a), 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 (IOM, 2006b), 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 (IOM, 2007). 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). A TBI may be open (penetrating) or closed and is categorized as mild, moderate, or severe, depending on the clinical presentation (Gennarelli and Graham, 2005). The terms mild, moderate, and severe TBI are defined and discussed in Chapters 2 and 3. 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 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, a mild TBI is manifest as a brief change in mental status or unconsciousness, whereas a severe TBI results in an extended period of unconsciousness or amnesia (NCIPC, 2008). According to the World Health Organization Collaborating Task Force on Mild Traumatic Brain Injury, a mild TBI also might be referred to as a concussion, a minor brain injury, a mild head injury, or a minor head injury (von Holst and Cassidy, 2004). Furthermore, von Holst and Cassidy (2004) note that the term concussion is 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 and deceleration,” and can cover varied symptoms and severity (see Chapter 2). Assessment of injury severity is important in the clinical diagnosis and management of patients with TBI. The Glasgow Coma Scale has been the gold standard of neurologic assessment of trauma patients since its development by Teasdale and Jennett in 1974. Other TBI severity-classification systems grade single indicators, such as loss of consciousness and duration of posttraumatic amnesia. 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 and a lethal wound to the chest or abdomen (Okie, 2005). In the recent conflicts in Afghanistan and Iraq, however, TBI appears to account for a larger percentage of casualties, about 22%. Furthermore, 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 a TBI. Of those injuries, 56% were moderate or severe, and 44% were mild (Okie, 2005). However, for many

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INTRODUCTION 15 people who sustain a mild TBI, the effects might not be immediately evident and might not be evident with conventional neuroimaging (Gordon et al., 1998). That clearly presents a problem for VA with regard to preparation for the return of veterans from OEF and OIF with a TBI that might not be apparent. OPERATION ENDURING FREEDOM AND OPERATION IRAQI FREEDOM 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 (DMDC, 2008). As of January 2008, DoD reported that over 5,500 soldiers had suffered TBIs (CRS, 2008). As of July 30, 2008, there had been about 1.64 million US deployments as part of OEF and OIF and 4,128 US troop fatalities. The fatalities were due to improvised explosive devices (1,683, or 40.8%), car bombs (133, or 3.2%), mortars and rockets (126, or 3.1%), rocket- propelled grenades (102, or 2.5%), and helicopter losses and other hostile and nonhostile causes (2,082, or 50.5%) (O’Hanlon and Campbell, 2008). 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 (US Congress, House of Representatives, Committee on Veterans’ Affairs, 2007). Despite those improvements, military personnel continue to be critically wounded, and TBI continues to be a source of concern. CHARGE TO THE COMMITTEE The charge to this IOM committee was to examine the strength of the evidence of an association between TBI and potential long-term health effects. The committee also was to consider the different types of TBI and their possible long-term consequences. SCOPE OF THE REPORT The committee was charged with conducting a review of the scientific literature on the association between TBI and long-term health effects. The review included all relevant studies of human TBI in any population (occupational, clinical, and other) caused by any mechanism (for example, motor-vehicle collisions, falls, sports injuries, and gun shots) and long-term health outcomes. Thus, the committee reviewed all papers that provided information about TBI and long-term health outcomes. By examining the full array of evidence of health outcomes in different populations, the committee answered the question: Can sustaining a TBI be associated with a specific health outcome? It should be remembered that an association between a TBI and a health outcome does not mean that all cases of the outcome are related to the TBI; such direct correspondence is the exception rather than the rule in studies of health outcomes in large populations (IOM, 1994). The committee reviewed more than 30,000 titles and abstracts of scientific and medical articles related to TBI and health outcomes. The committee reviewed the full text of more than

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16 GULF WAR AND HEALTH 1,900 peer-reviewed journal articles, many of which are described in this report. Currently, there are no published studies from the Millennium Cohort Study that specifically assess TBI and subsequent health effects. The Millennium Cohort Study which began in 2001 is a DoD- sponsored project that was organized to follow the long-term health of service members for up to 20 years. As a long-term project, the Millennium Cohort Study will likely produce results for TBI-related outcomes in several years. The details of the committee’s approach to its charge, the literature-search strategy, the types of studies that were reviewed, the committee’s inclusion criteria, and categories of association are described in Chapter 4. The committee did not try to determine the costs associated with sustaining a TBI, with acute treatment for TBI, or likelihood of long-term rehabilitation of people with TBI. Nor did it draw conclusions about the long-term treatment of people with a TBI. Those issues were outside the boundaries of its charge. 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. ORGANIZATION OF THE REPORT Chapter 2 reviews the biology of TBI and provides information on the biomechanics and pathophysiology of TBI. Chapter 3 details the epidemiology of adult TBI and discusses the definitions of TBI, and scales and scoring systems used to describe TBI. Chapter 4 provides information regarding the committee’s approach to its charge and includes a discussion of how the committee identified and evaluated the literature. Chapter 5 provides an overview of the major cohort studies reviewed by the committee. Chapters 6–10 detail the health outcomes that might be associated with TBI and the committee’s conclusions regarding them. Finally, Chapter 11 summarizes the committee’s conclusions and provides recommendations.

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INTRODUCTION 17 REFERENCES CRS (Congressional Research Service). 2008. CRS Report for Congress: United States Military Casualty Statistics—Operation Iraqi Freedom and Operation Enduring Freedom. Washington, DC: Congressional Research Service. DMDC (Defense Manpower Data Center). 2008. Global War on Terrorism: Causalities by Reason. Washington, DC: Office of the Secretary of Defense. Gennarelli, T., and D. Graham. 2005. Neuropsychiatric disorders. In Textbook of Traumatic Brain Injury. Arlington, VA: American Psychiatric Publishing. Gordon, W. A., M. Brown, M. Sliwinski, M. R. Hibbard, N. Patti, M. J. Weiss, R. Kalinsky, and M. Sheerer. 1998. The enigma of “hidden” traumatic brain injury. Journal of Head Trauma Rehabilitation 13(6):39–56. IOM (Institute of Medicine). 1994. Veterans and Agent Orange: Health Effects of Herbicides Used in Vietnam. Washington, DC: National Academy Press. ———. 2000. Gulf War and Health, Volume 1: Depleted Uranium, Pyridostigmine Bromide, Sarin, Vaccines. Washington, DC: National Academy Press. ———. 2003. Gulf War and Health, Volume 2: Insecticides and Solvents. Washington, DC: The National Academies Press. ———. 2004. Gulf War and Health: Updated Literature Review of Sarin. Washington, DC: The National Academies Press. ———. 2005. Gulf War and Health, Volume 3: Fuels, Combustion Products, and Propellants. Washington, DC: The National Academies Press. ———. 2006a. Amyotrophic Lateral Sclerosis in Veterans. Washington, DC: The National Academies Press. ———. 2006b. Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press. ———. 2006c. Gulf War and Health, Volume 5: Infectious Diseases. Washington, DC: The National Academies Press. ———. 2007. Gulf War and Health, Volume 6: Health Effects of Deployment-Related Stress. Washington, DC: The National Academies Press. NCIPC (National Center for Injury Prevention and Control). 2008. Traumatic Brain Injury. (accessed July 31, 2008). O’Hanlon, M. E., and J. E. Campbell. 2008. Iraq Index Tracking Variables of Reconstruction and Security in Post-Saddam Iraq, June 16, 2008. Washington, DC: Brookings. Okie, S. 2005. Traumatic brain injury in the war zone. New England Journal of Medicine 352(20):2043–2047. Teasdale, G., and B. Jennett. 1974. Assessment of coma and impaired consciousness. A practical scale. Lancet 2(7872):81–84. US Congress, House of Representatives, Committee on Veterans’ Affairs. 2007. Matthew S. Goldberg, Deputy Assistant Director for National Security, Congressional Budget Office. October 17.

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18 GULF WAR AND HEALTH von Holst, H., and J. D. Cassidy. 2004. Mandate of the WHO collaborating centre task force on mild traumatic brain injury. Journal of Rehabilitation Medicine (43 Suppl):8–10.