11
CONCLUSIONS AND RECOMMENDATIONS

The committee was established to evaluate and summarize the peer-reviewed literature addressing the long-term health outcomes of traumatic brain injury (TBI). The previous chapters detailed the numerous health effects that are associated with penetrating TBI and mild, moderate, and severe closed TBI. This chapter summarizes what the literature tells us about the long-term outcomes in veterans and other populations. The committee also provides its recommendations for consideration by the Department of Defense (DoD) and the Department of Veterans Affairs (VA).

QUALITY OF THE STUDIES

The clinical literature on brain injury and its treatment is quite large, however, population-based studies of TBI are few, and the methods they have used are not uniform. One problem that arises in comparing findings of studies is the definitions or criteria used for classifying the severity of brain injury. Misclassification of the severity of brain injury can occur because it often depends on negative rather than positive clinical criteria.


A variety of problems are associated with longitudinal or prospective studies of TBI. Some of the most common are the selection of only some types of patients to follow at discharge from a primary-care facility, inclusion of only patients who have survived for a particular period, inconsistent followup periods for patients in a given study group, and failure to account for the disparate person-time calculation of outcome rates. Loss to followup can also be a serious problem and is common in all longitudinal studies, especially when they involve patients with less serious injuries. Even with the most aggressive attempts to track patients, there will be losses; but not comparing those lost with those followed can leave the validity of findings open to speculation.


Many of the US studies are cross-sectional, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset, and prognosis and makes it difficult to interpret the results of findings, particularly when several well-conducted studies produce inconsistent results. Furthermore, many studies rely on self-reports rather than objective measures of symptoms and exposure.


The studies of TBI patients are thus of varied quality, and it was difficult for the committee to determine outcomes across the severity levels of TBI. Although the studies have provided valuable information, many of them have limitations that hinder accurate assessment,



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11 CONCLUSIONS AND RECOMMENDATIONS The committee was established to evaluate and summarize the peer-reviewed literature addressing the long-term health outcomes of traumatic brain injury (TBI). The previous chapters detailed the numerous health effects that are associated with penetrating TBI and mild, moderate, and severe closed TBI. This chapter summarizes what the literature tells us about the long-term outcomes in veterans and other populations. The committee also provides its recommendations for consideration by the Department of Defense (DoD) and the Department of Veterans Affairs (VA). QUALITY OF THE STUDIES The clinical literature on brain injury and its treatment is quite large, however, population-based studies of TBI are few, and the methods they have used are not uniform. One problem that arises in comparing findings of studies is the definitions or criteria used for classifying the severity of brain injury. Misclassification of the severity of brain injury can occur because it often depends on negative rather than positive clinical criteria. A variety of problems are associated with longitudinal or prospective studies of TBI. Some of the most common are the selection of only some types of patients to follow at discharge from a primary-care facility, inclusion of only patients who have survived for a particular period, inconsistent followup periods for patients in a given study group, and failure to account for the disparate person-time calculation of outcome rates. Loss to followup can also be a serious problem and is common in all longitudinal studies, especially when they involve patients with less serious injuries. Even with the most aggressive attempts to track patients, there will be losses; but not comparing those lost with those followed can leave the validity of findings open to speculation. Many of the US studies are cross-sectional, and this limits the opportunity to learn about symptom duration and chronicity, latency of onset, and prognosis and makes it difficult to interpret the results of findings, particularly when several well-conducted studies produce inconsistent results. Furthermore, many studies rely on self-reports rather than objective measures of symptoms and exposure. The studies of TBI patients are thus of varied quality, and it was difficult for the committee to determine outcomes across the severity levels of TBI. Although the studies have provided valuable information, many of them have limitations that hinder accurate assessment, 367

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368 GULF WAR AND HEALTH including the lack of representativeness, low participation rates, and self-reporting of TBI exposure and outcomes. Some studies have inappropriate control groups or no control groups, and the definition of mild, moderate, and severe TBI differs from study to study, particularly in the moderate category. OVERVIEW OF HEALTH OUTCOMES It is clear that sustaining TBI can have detrimental effects on a person, whether the injury is mild, moderate, or severe. The committee found many instances of long-term outcomes that are associated with TBI; some acute outcomes resolved or lessened over time (such as some neurocognitive and psychosocial findings), and other sequelae became more apparent several years after injury (such as psychiatric conditions). 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 region of the brain affected and the volume of brain tissue lost. The evidence was consistent 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 TBI and unprovoked seizures. For example, there is a causal association between penetrating TBI or severe closed TBI and unprovoked seizures, whereas the evidence of risk of unprovoked seizures after mild TBI is limited and suggestive of an association. In general, the risk of seizure after all levels of TBI severity appears to be highest in the first year after trauma and to decline thereafter. Some of the literature reviewed supports an association between TBI and neurodegenerative diseases, for example, studies that yielded sufficient evidence of an association between moderate or severe TBI and dementia of the Alzheimer type or parkinsonism, although 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, a reaction to the person’s cognitive and social dysfunction after TBI, or a continuation of pre- existing conditions. The committee has chosen 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.

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CONCLUSIONS AND RECOMMENDATIONS 369 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 appears to be different between military and civilian populations. Studies of 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 of civilian populations led the committee to conclude that there is inadequate and insufficient evidence to determine whether an association between TBI and PTSD exists. The studies yielded sufficient evidence of an association between TBI and aggressive behaviors, but limited but suggestive evidence of an association between TBI and decreased alcohol and drug use. Finally, the studies yielded 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. Social function in those hospitalized with TBI is adversely affected, relative to those with no injury, for 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 employed 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. However, the committee concluded that there was inadequate and insufficient evidence of an association between mild TBI and 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, and severe TBI and premature death in people who survive TBI for 6 months or longer; 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, this 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. However, 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; this 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

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370 GULF WAR AND HEALTH closed question and that longer-term followup, especially in 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 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, 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.

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CONCLUSIONS AND RECOMMENDATIONS 371 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 with traumatic brain injury severity. It would be 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 amnesia are important for the accurate classification of service members into appropriate groups.

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372 GULF WAR AND HEALTH 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 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.