4

Evaluation of Health Conditions

Veterans who were deployed to the Persian Gulf region in 1990–1991 have consistently reported having poorer health and quality of life than veterans who served in the military during the war but were not deployed or were deployed elsewhere. This increase in adverse health effects has been seen not only in U.S. veterans, but also in veterans of the coalition forces, including Australia, Canada, Denmark, and the United Kingdom (UK). As noted in Chapter 1, these service members were exposed to a multitude of chemicals, vaccinations, and adverse environmental conditions that individually or in concert may be harmful to a few or many service members.

In this chapter, each health condition section starts with an overview of the condition, then a brief summary of Volumes 4 and 8 findings and conclusions, followed by a review of the new literature where available, and then a summary of the Volume 10 committee’s findings and conclusions. Each section ends with a summary table of the primary studies from Volumes 4 and 8 as well as any new primary studies. All health conditions addressed in Volume 8 are covered here; if new literature was not identified, this is indicated. In the last section of this chapter, the committee describes the only veteran studies that had objective exposure measures, that is, to depleted uranium (DU); no summary table is included for these primary studies, although they are described in the text.

Some health conditions discussed individually in Volume 8 were combined in this volume. The section on women’s health from Volume 8 is not mirrored in this volume; if information specific to women’s health conditions was identified it was included in the relevant health condition section. Fibromyalgia, chronic widespread pain, chronic fatigue syndrome (CFS), and conditions of the musculoskeletal system are all now discussed in the section on pain-related conditions. Although, the health conditions generally are presented in the same order as Volume 8, the names of some of the sections have been slightly modified and the terminology of the International Statistical Classification of Diseases and Related Health Problems (ICD), 9th or 10th edition, is no longer used. Finally the section on chronic multisymptom illness is now called Gulf War illness in keeping with the suggestion of prior Institute of Medicine (IOM) committees (IOM, 2010, 2014a). All cancers, regardless of the affected organ system, are discussed in the section on cancer rather than in the section on the organ system affected. Similarly,

all studies on mortality, whether from external causes or from disease, are now discussed in the section on causes of mortality.

Information on the committee’s process and criteria for identifying, reviewing, and categorizing the literature, as well as description of the categories of association the committee used, may be found in Chapter 2. It should be noted that not all studies were classified the same way for each health condition. A study may be classified as a primary study for one health condition because of the method used to obtain the data, but the same study may be classified as secondary for another health condition if less rigorous methods were used to assess that condition. The committee indicates in each section why a particular study was classified as primary, secondary, or was best described in the subsection “Other Related Studies.”

The Volume 10 committee relied on human epidemiologic studies to draw its conclusions about the strength of evidence regarding associations between deployment to the Gulf War and health conditions seen in Gulf War veterans. A major problem with comparing rates of health conditions in deployed cohorts vs nondeployed cohorts or versus the general public is the so-called healthy-warrior effect (see Chapter 2 for a description), which may underestimate effects on veterans. Inasmuch as military personnel must meet physical-health criteria when they enter the military and while they are on active duty, particularly when deployed, the group’s health status is usually better than that of their nondeployed counterparts or the general population of the same age and sex.

Further complicating the assessment of Gulf War veterans’ health is that in recent years, the diagnostic criteria or definitions for several of the health conditions discussed in this volume have been revised to reflect the evolving understanding of these conditions brought on by scientific and other advances. These types of changes are normal in medical science, and it is likely that the diagnostic criteria for these conditions will further change in the future as knowledge about them grows.

Among those health outcomes with recently changed criteria are mental health disorders, fibromyalgia, CFS, and Gulf War illness. Although none of the studies discussed in this report have used the revised diagnostic criteria for mental health disorders, fibromyalgia, and CFS, there are research implications as the new criteria are adopted and implemented. As future bodies review and compare studies using the old criteria and new diagnostic criteria, there may be differences in the incidence or prevalence of a condition that may result from the use of the revised criteria. For example, the new diagnostic criteria for autism resulted in a lower prevalence estimate of the condition than the old criteria (Maenner et al., 2014). The revised criteria for these conditions are briefly discussed in the relevant sections below.

GULF WAR ILLNESS

Shortly after Gulf War veterans returned from their deployments to the Persian Gulf region, many of them began complaining of a broad range of symptoms that did not have an obvious, documentable etiology and pathophysiology. This reporting of symptoms was seen not only in U.S. veterans who had been exposed to many chemicals, including possibly nerve agents from the demolition at Khamisiyah, but Gulf War veterans from coalition countries, including Australia, Canada, Denmark, and the United Kingdom, also reported an increase in numerous symptoms. Many of the coalition forces were in the Persian Gulf region after Khamisiyah or were otherwise unlikely to have been exposed to nerve agents. Since the mid-1990s, numerous studies have documented that deployment to the Gulf War in 1990–1991 entailed an increased risk of developing a multitude of symptoms that veterans themselves called “Gulf War illness” or “Gulf War syndrome.” Although exact numbers are not available, it has been estimated that as many as one-third of the Gulf War deployed veterans may have Gulf War illness (RAC, 2014) and in the recent survey of the National Cohort of Gulf War and Gulf Era Veterans, Dursa et al. (2016) esti-

mated that as of 2013 approximately 44% of deployed veterans reported having chronic multisymptom illness compared with 20% of the era veterans (weighted estimates). Studies have consistently shown that deployed Gulf War veterans have a higher number and greater severity of symptoms compared with nondeployed and era veterans (IOM, 2010). The cause of and treatment interventions for Gulf War illness have been addressed by several previous IOM committees (IOM, 2000, 2006b, 2010, 2014b), by the Department of Veterans Affairs (VA) Research Advisory Committee on Gulf War Veterans’ Illnesses (RAC), and by numerous researchers. Several difficulties persist in studying this illness, including the many different methods used for identifying cases and the variable presentations and complex manifestations. All primary studies of Gulf War illness are summarized in Table 4-1 at the end of this section.

Definitions of Gulf War Illness

The proper term to use when describing the complex set of symptoms experienced by Gulf War veterans has been the subject of considerable discussion. This conglomeration of symptom clusters linked to various organ systems has been called chronic multisymptom illness by VA (Kang et al., 2009). However, several alternate definitions and suggestions for classifying these syndromes have been proposed, including those of the Centers for Disease Control and Prevention (CDC) (Fukuda et al., 1998) and a definition proposed by Lea Steele on the basis of her work with Gulf War veterans in Kansas (Steele, 2000) (see Table 4-2). Other definitions include the Gulf War illness syndromes proposed by Robert Haley and colleagues based on factor analysis and clinical assessments (Haley et al., 1997b); three categories of symptoms identified in veterans living near Portland, Oregon (Bourdette et al., 2001; Spencer et al., 1998); and symptom reporting by veterans in the National Health Survey of Gulf War Veterans and Their Families begun by VA in 1995 (Kang et al., 2000, 2009). This multiplicity of definitions makes it difficult to compare results across studies of Gulf War illness.

Prior IOM committees and other organizations have struggled with choosing a name or label to exactly delineate the complex set of symptoms that Gulf War veterans present with. A variety of terms have been used to refer to what was initially labelled “Gulf War illness,” and this proliferation of definitions has resulted in a lack of clarity and inconsistency in the research literature as to what symptoms or conditions are actually being studied. VA has traditionally used the term “unexplained illnesses” for the symptoms experienced by Gulf War veterans. “Gulf War syndrome” was used shortly after the war, but in general most groups, including the RAC, have used the term “Gulf War illness,” although there is no ICD code for such an array of symptoms. The Volume 4 committee approached the issue of multisymptom illnesses from the perspective of “unexplained illness,” focusing on symptoms reported by Gulf War deployed veterans in efforts to determine whether the presenting symptoms defined a unique illness complex. The Volume 8 committee did not attempt to make such a determination, but rather accepted that “multisymptom illness” was in itself a diagnostic entity and assessed the literature regarding the association between symptom reporting indicative of “multisymptom illness” and deployment to the Gulf War.

Recently, the IOM report Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined (IOM, 2014a) reconsidered chronic multisymptom illness in Gulf War veterans. After carefully examining the existing definitions (Bourdette et al., 2001; Fukuda et al., 1998; Haley et al., 1997b; Kang et al., 2009; Spencer et al., 1998; Steele, 2000) that committee concluded that two of those definitions—the CDC and the Kansas definitions—appeared to capture the most salient and commonly identified arrays of symptoms presented by deployed veterans, although neither definition captured all aspects of a case definition. All of the studies reviewed by that committee included reports of fatigue, pain, and neurocognitive symptoms. The committee recommended that VA use those two case definitions,

TABLE 4-2 Case Definitions of Gulf War Illness* Used in Gulf War Veteran Studies

*Gulf War illness is called chronic multisymptom illness in the IOM report.

SOURCE: Adapted from IOM, 2014a.

pointing out that each of the definitions could serve specific needs. The CDC definition was considered to be less suitable for research that would require a more narrowly defined study population; whereas, the Kansas definition, which is more rigorous, might identify too few cases, thus, compromising the needed statistical power for studying various outcomes of interest. From a practical perspective, adapting the definitions for use in clinical settings was another priority. Besides recommending that VA use both definitions, the committee also recommended that VA systematically monitor data to identify and further refine additional features of chronic multisymptom illness, such as onset, duration, severity, frequency of symptoms, and exclusionary criteria in order to produce a more robust case definition. The committee also recommended that VA use the term “Gulf War illness” rather than “chronic multisymptom illness” for symptomatic Gulf War veterans. The Volume 10 committee uses the term “Gulf War illness” in its discussion of this constellation of symptoms but uses the terms cited by a study’s authors in summaries of the studies.

Summary of Volumes 4 and 8

The Volume 4 committee noted that findings from factor and cluster analyses for symptoms of Gulf War illness (the committee used the term “unexplained illness”) seem quite similar despite methodologic differences. Similar symptom clusters include neurocognitive symptoms, musculoskeletal symptoms, and peripheral nervous system symptoms. Less commonly reported are symptom clusters involving gastrointestinal and respiratory symptoms. Among the five primary studies of veterans from Iowa (Doebbeling et al., 2000), Australia (Forbes et al., 2004), two UK cohorts (Cherry et al., 2001a; Ismail et al., 1999), and a large national cohort studied by VA (Kang et al., 2002), factor analysis started with representative, generalizable populations and high participation rates. These primary studies found that in general deployed veterans reported more symptoms or more severe symptoms than their nondeployed counterparts. There were seven secondary studies (Bourdette et al., 2001; Fukuda et al., 1998; Haley et al., 1997b, 2001; Hallman et al., 2003; Knoke et al., 2000; Shapiro et al., 2002) that fell short on either the criteria of having high participation rates or having representative samples, that is, the studies included members of only one branch of the service, had small samples of veterans, or used only symptomatic groups of veterans, thus lacking a nonsymptomatic comparison group. Nevertheless, the results of the secondary studies are valuable and add detail to the epidemiologic literature on Gulf War veterans. Although the committee did not find a unique syndrome, illness, or symptom complex in deployed Gulf War veterans, it did report that Gulf War veterans had higher rates of nearly all symptoms or sets of symptoms than their nondeployed counterparts.

The Volume 8 committee considered new information on factor analyses and cluster analyses. That committee found no new studies using factor or cluster analyses on veterans with symptoms of Gulf War illness and discussed only one new primary study focused on prevalence of chronic multisymptom illness (Blanchard et al., 2006). The large and nationally representative National Health Survey of Gulf War Era Veterans and Their Families conducted by VA in 1993–1995, found that nearly 30% of deployed veterans met the CDC case definition of “multisymptom illness” compared with 16% of nondeployed veterans. The Volume 8 committee agreed with the Volume 4 committee in that there was increased reporting of symptoms indicative of multisymptom illness among those deployed to the Gulf War. Furthermore, this increased symptom reporting was also found for deployed veterans from several coalition countries, including Australia, Canada, Denmark, and the United Kingdom, thus adding credence to the findings. The findings across all the studies considered in Volume 8 were similar, broadly describing neurologic, psychologic, cognitive, fatigue, and musculoskeletal symptoms. Even though some studies that compared the most representative samples found symptom patterns that were similar between the deployed and nondeployed groups, symptoms were more severe or more frequent in the deployed than in the nondeployed groups. The Volume 8 committee concluded that there was sufficient evidence of association between deployment to Gulf War and chronic multisymptom illness.

New Literature

This committee reviewed epidemiologic, clinical, and physiologic studies related to Gulf War illness. A major limitation with many of these studies, in particular the epidemiologic ones, is the use of retrospective information (recalled exposures) not clearly verifiable as well as the length of time that has elapsed since the original exposure—that is, deployment to the Persian Gulf region—and the numerous voluntary and involuntary exposures to environmental and other agents that the veterans may have experienced since deployment. In a comparison of symptoms reported by U.S. and UK troops in earlier surveys, Ismail et al. (2011) found that deployed troops from both countries reported more symptoms

than nondeployed troops from either country. The most frequently reported symptoms were similar across all four groups (that is, unrefreshed sleep, headaches, irritability, fatigue, and pain).

The Volume 10 committee identified two primary studies and one secondary study that provided new information on Gulf War illness published after the Volume 8 report.

Primary Study

In 2000–2002, Kelsall et al. (2009) conducted a longitudinal assessment of 1,381 of the 1,871 eligible Australian male veterans who had deployed to the Gulf War and a comparison group of 1,085 veterans who had been on active service during the war but had not deployed, as well as 292 veterans who had deployed elsewhere during the war. All the veterans completed a 63-item symptom questionnaire, as well as the 12-item General Health Questionnaire (a measure of psychological distress), the 12-item Short-Form Health Survey (a measure of health-related quality of life), and the Alcohol Use Disorders Identification Test (AUDIT). Veterans also received an in-person health assessment that included a full physical examination, with lung function and fitness tests, and a mental health assessment using the psychologist-administered, computer-assisted Composite International Diagnostic Interview (CIDI). Multisymptom illness was defined using a modification of the CDC operational definition that required one or more symptoms in the past month rated as at least of moderate severity from at least three of four categories (fatigue, “psycho-physiological,” cognitive, and arthroneuromuscular).

The prevalence of multisymptom illness was 25.6% in the Gulf War veterans and 16.0% in the total comparison group. The odds ratio (OR) of having multisymptom illness in the deployed veterans was statistically significant (OR = 1.80, 95% CI 1.48–2.19); models were adjusted for age, military service, rank, education, marital status, other medical conditions, AUDIT score, smoking, health, weight, atopy, and history of diabetes. The odds ratio of multisymptom illness was greatest when deployed veterans were compared with veterans who had not deployed at all (OR = 1.91, 95% CI 1.55–2.36) vs veterans who had deployed elsewhere (OR = 1.45, 95% CI 1.03–2.04). Multisymptom illness was associated with functional and occupational impairment, increased health care utilization, unexplained chronic fatigue, slightly elevated neuropathy score, and increased waist circumference, but not with reduced spirometry performance, lung function, or elevated blood pressure. In particular, multisymptom illness was strongly associated with affective disorder, major depression, any anxiety disorder (but not posttraumatic stress disorder [PTSD]), somatoform disorder, and alcohol use or dependence disorder, in the Gulf War deployed and nondeployed veterans but not in the deployed elsewhere comparison group (Kelsall et al., 2009).

Laboratory values for Gulf War veterans with multisymptom illness were significantly elevated for inflammation (erythrocyte sedimentation rate > 10 mm/hour or > 15 mm/hour if > 50 years of age; C-reactive protein > 10 mg/L or leukocyte count > 11.0 × 10⁹/L) and elevated random plasma glucose compared with deployed veterans who did not have multisymptom illness. Deployed elsewhere veterans with multisymptom illness also showed an elevated plasma glucose compared with their healthy counterparts; these veterans also had more markers of liver disease as determined by alanine aminotransferase > 55 U/L and aspartate aminotransferase > 45 U/L (OR = 6.20, 95% CI 1.61– 23.93; adjusted for military service, age, rank, education, and marital status). Nondeployed veterans with multisymptom illness had more markers of obstructive liver disease than their counterparts without multisymptom illness. There were no other significant differences in laboratory values between veteran groups with multisymptom illness and those without it (Kelsall et al., 2009).

In a follow-up to Kelsall et al. (2009), Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013. This study is an assessment

of the entire 1,871 Australian Gulf War cohort, 10 years after the 2000–2002 baseline study (Kelsall et al., 2006) and 20 years after the war. Because only about 2% of the participants were women, only results pertaining to males were reported. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. As with the earlier study, veterans completed a 63-item general health symptom questionnaire (sent via mail) and an over-the-phone CIDI, and gave consent for their Department of Defence health records and Medicare claims to be accessed. In-person health assessment or physical examinations were not performed. Gulf War deployed veterans reported a greater prevalence of all 63 symptoms and the difference was statistically significant for 47 of them. Results showed a greater increase in the number of symptoms reported for deployed vs nondeployed veteran. Among the 20 most prevalent symptoms, half were significantly more persistent and/or more incident in the deployed group. The follow-up survey used the same criteria for multisymptom illness as the 2000–2002 baseline study. The prevalence in Gulf War veterans was 29% in veterans who met the criteria for multisymptom illness compared with 18% in nondeployed veterans (these percentages dropped to 26% and 16%, respectively when cases with explanatory conditions were excluded). Gulf War veterans were significantly more likely to have multisymptom illness at follow-up (OR = 1.60, 95% CI 1.31–1.95) than their nondeployed counterparts.

Secondary Study

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans (discussed in greater detail in Chapter 3), conducted in 2012–2013 via mail, website, or a computer-assisted telephone interview, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether they had experienced a number of physical and mental health symptoms (Dursa et al., 2016). The survey also asked veterans about the presence and occurrence of any unexplained multisymptom illnesses. The weighted prevalence of reporting of multisymptom illness increased from just over 36% in 2005 to 43.9% in 2013 for deployed veterans and from about 12% in 2005 to 20.3% in 2013 for era veterans (Dursa et al., 2016; Kang et al., 2009). There was a significant difference in the prevalence of chronic multisymptom illness between deployed and era veterans (OR = 3.06, 95% CI 2.78–3.83); adjusted for age, race, sex, body mass index (BMI), smoking status, service branch, and unit component. The presentation by VA on the preliminary results of this survey noted that among deployed and era veterans with self-reported lifetime chronic multisymptom illness, there was a statistically significant difference in symptom reporting in the past 12 months only for unrefreshing sleep, headaches, and trouble finding words (Bossarte, 2014).

Other Related Studies

Since publication of Volume 8, there have been several new studies focusing on the association of Gulf War illness symptoms with potential exposures and biological mechanisms that may be responsible for the symptoms. During its review of the published literature, the committee identified studies on Gulf War illness that, while they did not meet the criteria for being considered as primary or secondary studies, provided information that the committee believes may be useful in addressing future research questions related to Gulf War illness. The studies focus on three main areas: the effect of Gulf War illness on other health conditions and vice versa; new efforts to link Gulf War illness with particular exposures prior to or during deployment, and neuroimaging and brain metabolism studies that attempt to identify biomarkers of Gulf War illness in brain or other tissues. Investigators for these studies used a variety of

definitions of Gulf War illness (or chronic multisymptom illness), including the CDC definition (Fukuda et al., 1998), the Kansas definition (Steele, 2000), and Haley’s Gulf War illness syndromes (defined by 3–6 symptom clusters) (Haley et al., 1997b).

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories; no statistical testing was performed. A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period. These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans. Of these users, 176,541 (61.5%) of the deployed Gulf War veterans and 157,051 (58.2%) of the nondeployed veterans presented with symptoms, signs, and ill-defined conditions (ICD-9-CM 780-799). The most commonly reported of these were general symptoms (> 50% of veterans in both groups reported having them), respiratory (> 39%), and skin (> 26%) (VA, 2014a,b).

Comorbidities

Gulf War illness is not only characterized by a broad range of symptoms, but it has also been associated with other more clearly defined health conditions. Several researchers have attempted to determine whether having Gulf War illness puts a veteran at risk for developing another disease or whether having any particular medical diagnosis or symptoms makes a veteran more susceptible to having Gulf War illness. In this section, the committee considers some of the recent literature on Gulf War illness and its possible comorbidities.

Wallin et al. (2009) assessed neuropsychologic performance in Gulf War deployed veterans with Gulf War illness (n = 25) and without (n = 16), obtained from the 1995 population-based National Health Survey of Gulf War Era Veterans and Their Families. Cases were defined as meeting the CDC criteria for Gulf War illness. The neuropsychological testing battery included assessment of verbal abilities, attention, memory and learning, problem solving, and motor skills. There were no significant differences between cases and controls for any of the cognitive domains, and the composite test scores for both groups were within normal limits. However, there were statistically significant differences in Personality Assessment Inventory scores used to assess psychiatric symptoms; cases were significantly more impaired than controls on 8 of 11 clinical scales such as somatic complaints, anxiety, depression, mania, and paranoia. Responses to the 36-Item Short Form Health Survey indicated that cases also had poorer self-reported general physical and mental health.

Two new studies have assessed autonomic dysfunction in veterans who have Gulf War illness. In a nested case-control study, Haley et al. (2013) used the Autonomic Symptom Profile questionnaire (a self-administered questionnaire), the Composite Autonomic Severity score, and high-frequency heart rate variability data from a 24-hour electrocardiogram to assess whether some of the symptoms of Gulf War illness are due to autonomic dysfunction. Veterans were selected from the U.S. Military Health Survey (Iannacchione et al., 2011). Sixty-six veterans met Haley’s definitions for one of three syndromes of Gulf War illness (21 with syndrome 1, 24 with syndrome 2, and 21 with syndrome 3), 16 veterans were not ill and had deployed to the Kuwaiti theater during the war, and 15 veterans were in the military but did not deploy. All veterans with Gulf War illness reported significantly more autonomic symptoms (p < 0.001) and had elevated Composite Autonomic Symptom Scale scores (scores were most elevated for syndrome 2 primarily due to a reduction in sudomotor function in the foot), compared with controls.

Ill veterans also lacked the normal increase in high-frequency heart rate variability at night compared with controls.

In the second study, Li et al. (2014) also studied autonomic dysfunction in 16 veterans with Gulf War illness and 12 era controls. Ill veterans were those who self-reported CFS-like multisymptoms in the 2005 survey titled Health of U.S. Veterans of 1991 Gulf War: A Follow-up Survey in 10 Years. Veterans responded to autonomic nervous system questionnaires and received physical examinations, including large fiber nerve conduction studies, quantitative sensory testing, autonomic testing, a quantitative sudomotor axon reflex test, and a diagnostic tilt-table test. Five veterans in the ill group had impaired cardiovascular function, whereas none of the control group had any impairment. The ill group also had significantly higher baseline heart rate and higher scores on a compound autonomic scoring scale compared with controls. The authors suggest that objective autonomic testing should be carried out on veterans with Gulf War illness who complain of unexplained postexertional fatigue.

In a 2003–2005 follow-up to the 1995 National Health Survey of Gulf War Veterans and Their Families, Coughlin et al. (2011b) assessed alcohol consumption in 9,970 respondents and found that veterans who were problem drinkers (defined as answering yes to any of five questions about problem drinking or hazardous driving in the past 6 months) were more likely to have unexplained multisymptom illness (defined as having unexplained physical symptoms and illnesses that persisted for 6 months or longer and were not explained by other diagnoses) with an odds ratio of 1.56 (95% CI 1.37–1.77, p < 0.001), adjusted for age, sex, race/ethnicity, branch of service, rank, and deployment status. These authors used the same survey results to assess the association between BMI and various health conditions. Multisymptom illness was more prevalent in Gulf War deployed veterans who were obese than in normal weight deployed veterans, but this increase was not evident in a multivariate analysis (Coughlin, 2011a).

Many veterans with Gulf War illness report problems with sleep. In a small study of 18 male veterans with Gulf War illness and 11 asymptomatic control veterans, Amin et al. (2011) found that veterans with the illness had a statistically significant increase in the frequency of sleep arousals from apneas or hypoapneas (p = 0.006), and flow-limited breaths (p < 0.0001); differences in other sleep parameters were not significant between the two groups. The samples were matched for age and BMI. Compared with 36% of control veterans, 96% of veterans with Gulf War illness had their breathing flow limited.

Many veterans with Gulf War illness complain of having headaches. Rayhan et al. (2013b) examined the presence of headache that accompanied Gulf War illness in a small study of 50 veterans with the illness based on the CDC definition (Fukuda et al., 1998), 39 subjects with CFS based on the 1994 CDC criteria, and 45 control subjects (veteran status was not reported for the latter two groups). Compared with 13% of controls, migraines were endorsed in 64% of the veterans with Gulf War illness (OR = 22.5, 95% CI 7.8–64.8). Migraines were frequently comorbid with tension headaches (20 of 32 veterans: OR not reported); tension headaches without migraines occurred in about 20% of the veterans with Gulf War illness and 26% of the controls. Most of the migraines associated with Gulf War illness were with aura (24 of 32); only 8 of 32 did not have aura.

Deployment Exposures and Gulf War Illness

Steele et al. (2012) conducted a case-control study in 2000 that compared Gulf War veterans’ exposures in a population-based sample of 304 deployed veterans, 144 with Gulf War illness and 160 healthy controls. Case status was determined based on screening using the CDC definition, and subsequent inclusion in the study was based on the Kansas definition for Gulf War illness. Study participants were asked about their deployment locations and duration and whether they had any of 19 specific exposures or experiences during deployment. Among veterans in Iraq or Kuwait, Gulf War illness was most

strongly associated with the use of pyridostigmine bromide (PB) tablets (OR = 3.5, 95% CI 1.7–7.4), being within 1 mile of an exploding Scud missile (OR = 3.1, 95% CI 1.5–6.1), using pesticides on the skin (OR = 2.07, 95% CI 1.06–4.05, and being exposed to smoke from oil-well fires (OR = 2.78, 95% CI 1.01–7.66). For veterans who were in support areas, Gulf War illness was most closely associated with wearing pesticide-treated uniforms (OR = 12.7, 95% CI 2.6–61.5). For all veterans combined, Gulf War illness was also significantly associated with frequently getting less than 4 hours sleep in 24 hours (OR = 2.91, 95% CI 1.41–6.01).

Haley and colleagues have published a number of studies looking at the epidemiology of the syndromes they have elicited from veterans, as well as using purposive subsamples of subjects meeting criteria for the various syndromes, and performing mechanistic and etiologic experiments in efforts to identify the underlying pathophysiology for each of the three primary Gulf War illness syndrome variants Haley et al. have defined. The publications of this research group have been criticized for restricting their subjects to a pool of 249 out of 606 original veterans of the Twenty-Fourth Reserve Naval Mobile Construction Battalion (Seabees), thus making it difficult to generalize the findings to the entire Gulf War veteran cohort. In a recent publication, Iannacchione et al. (2011) conducted a validation study among a stratified random sample of more than 8,000 deployed and deployable-but-nondeployed veterans selected from all Gulf War active duty and ready reserve veterans. Termed the U.S. Military Health Survey, this study was conducted by telephone between May 2007 and April 2009; the response rate was 60%. Iannacchione et al. report validating, through factor analysis and related techniques, their original three major and three minor Gulf War illness syndromes. The authors also collected information on whether veterans in the validation study met the CDC’s criteria for multisymptom illness, but these data were not reported. Results from the survey indicated that the overall case definition of Gulf War illness was more prevalent in the deployed than nondeployed veterans (OR = 3.87, 95% CI 2.61–5.74); veterans were considered to have met the overall factor case definition if they met any of the six dichotomized component definitions. Each of the Gulf War illness variants was also more prevalent in the deployed veterans than the nondeployed veterans (OR = 3.33, 95% CI 1.10–10.10, for syndrome variant 1; OR = 5.11, 95% CI 2.43–10.75, for variant 2; and OR = 4.25, 95% CI 2.33–7.74, for variant 3).

Haley and Tuite (2013) examined the relationship between the cohort identified in Iannacchione et al. (2011), the prevalence of Gulf War illness (based on both the CDC and the factor analysis case definitions), and the two dependent variables of chemical alarm awareness and unit location with respect to the Khamisiyah explosions. They estimated that 13.6% of the veterans deployed to the Kuwaiti theater of operations had Gulf War illness using the factor-analysis case definition, whereas 41.7% had it on the basis of the CDC definition (95% of veterans classified as having Gulf War illness by the factor analysis met the CDC case definition as well). It was further estimated that 39% of veterans in the theater had exposure to low levels of nerve agents based on responses to the survey question about hearing chemical alarms, and 16% may have been located in the plume of nerve agent from the Khamisiyah demolition based on Department of Defense (DoD) exposure models. The risk of having Gulf War illness (Haley overall factor case definition) was strongly associated with hearing chemical alarms (OR = 4.13, 95% CI 2.51–6.80), and the authors found a dose–response relationship between the relative risk of having Gulf War illness and the number of alarms heard. The risk of Gulf War illness and being in the nerve agent plume was not statistically significant (OR = 1.21, 95% CI 0.86–1.69). The authors suggest that factor analysis syndrome 1 is less likely to be related to nerve agent exposure than the other two major syndromes. A strong role for recall bias to produce the relationships with recalled chemical alarms cannot be excluded (the survey was conducted from 2007 to 2010). The two epidemiologic studies by Haley and colleagues do not appear to shed much light on the etiology or mechanism of Gulf War illness,

however, they do advance the stature of the factor analysis case definitions of the illness into apparently representative national samples.

The committee recognizes that association is not causation, but felt it was important to look for consistency of associations across studies. One study reports that exposures for which there were significant associations with Gulf War illness include self-reported PB use, proximity to Scud missile explosions, pesticides on skin, wearing permethrin-treated uniforms, and smoke from oil-well fires (Steele et al., 2015), whereas the studies by Haley and Tuite (2013) and Iannacchione et al. (2011) indicated that hearing chemical alarms—but not the nerve agent plume—was associated with the development of Gulf War illness. Together these studies suggest the possibility that chemical exposures—PB, pesticides, insecticide treatment, and alarms—may play a role in Gulf War illness. Nevertheless, the committee cautions that a substantial limitation to this potential association is the lack of any measure that clearly documents the actual chemicals or doses to which the veterans were exposed. Gulf War veterans from the coalition forces also reported increased symptoms indicative of Gulf War illness, but their exposures may have differed from those of U.S. service members. For example, Danish troops were in the Persian Gulf region after the war as peacekeepers and were not exposed to sarin (Ishoy et al., 1999b). There are no reliable or validated biomarkers to indicate that a particular veteran with or without Gulf War illness had a specific chemical exposure during deployment. Also, there is little biologic plausibility for the concept that exposure to PB concentrations that did not cause acute effects would result in long-term effects (IOM, 2004). The committee concludes that, on the basis of the studies of deployment exposures and Gulf War illness (e.g., Haley and Tuite, 2013; Iannacchione et al., 2011; Steele et al., 2015), there is little new information that sheds light on the etiology of or mechanisms for Gulf War illness.

Genetic Factors and Gulf War Illness

There is considerable evidence that a set of genes that is important in metabolizing toxicants is involved in the development of some diseases such as amyotrophic lateral sclerosis (ALS). To explore the etiology of Gulf War illness, several researchers have sought to identify genetic mutations that would affect the body’s ability to metabolize certain toxicants associated with Gulf War deployment, with a particular focus on genes that encode proteins that metabolize cholinesterase inhibitors. PB, some pesticides, and sarin and cyclosarin are potentially toxic exposures that are known to inhibit cholinesterase. Without cholinesterase to inactivate acetylcholine (a neurotransmitter), overstimulation of organs and muscles controlled by acetylcholine may occur.

The most relevant proteins are paraoxonases¹ (PON) 1, 2, and 3; butyrylcholinesterase² (BChE); acetylcholinesterase (AChE); and cytochrome P450-2D6 (CYP2D6). PON and BChE have received the most study in Gulf War illness and so are reviewed here briefly.

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¹ The paraoxonases (PON) 1, 2, and 3 are esterases, encoded by genes on chromosome 7, which metabolize oxidized lipids as well as a range of cholinesterase inhibitors (sarin, soman, diazinon, chlorphyrifos). They also oxidize some clinically approved compounds, such as the statins. PON1 has upward of 200 genetic variants in normal individuals. The most common are the variants glutamine-192-arginine and leucine-55-methionine. Also of interest are two regulatory polymorphisms within the PON1 promoter. The impact of these variants on PON1 hydrolase activity varies with the substrate. For example, at codon 192, variant Q has higher activity for sarin, soman, and diazinon, while variant R has higher activity for parathion and paraxon. Studies of the C-108T promoter polymorphism show that the C allele has higher promoter activity (Brophy et al., 2001; Costa et al., 2005; Davies et al., 1996).

² BChE (pseudocholinesterase, plasma cholinesterase, chromosome 3q) hydrolyzes many choline esters, including butyrylcholine, a synthetic substance. BChE inactivates organophosphates by both binding and hydrolyzing them. BChE has been studied extensively because of its role in metabolizing succinylcholine. There are several allelic variants in the BChE gene, identified as BChE-U, which has high enzyme activity, and allelic vairants K, A, and F, which are less common and have less activity. The lower activity alleles are sometimes lumped in one category (Jensen et al., 1995).

The Volume 10 committee reviewed studies described in Volume 8 as well as new studies of genetic associations to interpret the evidence as a whole. The Volume 8 committee reviewed several studies that sought to positively link PON1 genotype (Haley et al., 1999; Hotopf et al., 2003b; Mackness et al., 2000) or BChE genotypes (Lockridge, 1999; Sastre and Cook, 2004) to Gulf War illness; these were generally underpowered and inconsistent. The Volume 8 committee recommended that well-designed studies be undertaken and replicated to robustly test the hypothesis that variants in genes that code for detoxifying enzymes for cholinesterase inhibitors may be a susceptibility factor for development of Gulf War illness.

As described in Volume 8, a genetic association between cholinesterase inhibitors and PON1 was first proposed by Haley et al. (1999) who studied 25 symptomatic Gulf War veterans. The authors suggested that PON1 variants are overrepresented in Gulf War illness; however, this study did not reach statistical significance (p = 0.08 before correction for multiple comparisons). Mackness et al. (2000) initially reported an association of Gulf War illness with reduced PON1 enzyme activity; however, Hotopf et al. (2003b) reported that PON1 levels are low in both symptomatic and asymptomatic Gulf War veterans.

Lockridge et al. (1999) reported that rare, low-activity variants of BChE are overrepresented in symptomatic Gulf War veterans, but Sastre and Cook (2004) could not replicate this. They found an association between multisymptom illness and carriers of rare BChE genotypes who also self-reported PB exposure. A caveat is that the numbers of carriers of rare genotype were small in these studies (11/226 in Lockridge; 28/304 in Sastre and Cook).

Four new studies investigating the role of certain genes in Gulf War illness were identified and reviewed by the Volume 10 committee (Craddock et al., 2015; Georgopoulos et al., 2015; Haley et al., 2010; Steele et al., 2015). Steele et al. (2015) examined Gulf War illness (using Kansas and CDC definitions) in relation to BChE activity and genotype, and examined deployment exposures to pesticides and PB use in 144 Gulf War veterans with symptoms of the illness and 160 asymptomatic veterans. While cases and controls did not differ by BChE activity or genotype, BChE activity did differ by genotype. The 276 veterans with the more common genotypes (designated BChE-U; including U/U and U/K genotypes) had significantly higher BChE activity than the 28 veterans with the less common variants (designated BChE-LCV; including K/K, U/AK, U/A, A/F, and AK/F genotypes). There were no differences between veterans with and without Gulf War illness in regard to associations between BChE activity (low vs high activity measured by benzocholine in serum) and self-reported exposures to PB and pesticides. However, when the veterans were stratified by BChE genotype (BChE-U vs BChE-LCV), those who reported taking PB pills were more likely to have Gulf War illness than those who did not (OR = 40.00, p = 0.0005). The same association existed for the BChE-U group, but the magnitude of the association was less (OR = 2.68, p = 0.0001). The difference between those two associations was significant (p = 0.019), thus the authors suggest an interaction between BChE genotype and PB that affects the risk of Gulf War illness such that Gulf War veterans who have BChE-LCV genotypes and took PB are at greatest risk comparatively in this study. The committee notes that the number of cases in these groups was small; there were only 28 veterans in the BChE-LCV group—14 with Gulf War illness (of whom 13 had PB exposure) and 14 without (of whom only 3 had PB exposure). By contrast, members of the BCHE-LCV group did not have a higher risk of Gulf War illness if they reported chemical weapons exposure. Lastly, when the authors re-sorted the cases not using the CDC case definition for Gulf War illness (a broader definition than the Kansas definition), the result was the same but less pronounced.

Another analysis suggests that in veterans with Gulf War illness, altered immune function may be related to human leukocyte antigen (HLA) genes (Georgopoulos et al., 2015). Like Steele et al. (2015), this investigation used a sample of Gulf War veterans (66 with Gulf War illness, using either the CDC criteria or the Kansas case definition, and 16 without the illness) who had participated in the earlier study described in Steele (2000). Nine HLA genes were compared between the two groups and 144 unique al-

leles of Class I and II HLA genes were found. Six Class II alleles were found to correctly classify veterans as either cases or controls 84% of the time (sensitivity = 84.8%; specificity = 81.2%) and results were statistically significant. The frequency of the six alleles appeared to be protective in the control group such that allele frequencies were significantly lower among cases (p < 0.002) and there was a negative correlation between overall symptom severity and frequency of the six alleles (p < 0.0001). Two of the six alleles were completely absent among veterans with Gulf War illness. The authors interpret their findings as indicating that veterans with Gulf War illness might have a genetic susceptibility by which certain exposures (possibly vaccination or chemical exposures) result in immune dysfunction and the symptoms of Gulf War illness.

In a subset of Gulf War veterans, Haley et al. (2010) further analyzed levels of Q192 vs R192 serum PON1 activities and investigated the relationship between enzyme activity, the PON1 Q192R genotype, and exposure to nerve agents. Using a history of an alarm sounding as a marker for early exposure to these agents, the authors concluded that early exposure was strongly associated with Gulf War illness and the risk was highest in individuals with the lowest quartile of Q isozyme activity.

Craddock et al. (2015) examined the association between gene expression patterns in male veterans with Gulf War illness to gene expression patterns associated with some human conditions and to genes targeted by known pharmaceuticals. The study collected data and specimens from 17 veterans with Gulf War illness (using the CDC case definition) and 22 healthy but sedentary Gulf War era veterans between 2006 and 2008. Nineteen gene expression patterns were significantly associated with Gulf War illness; these patterns were correlated to 18 conditions that share features of Gulf War illness.³ Eight of the 19 modules of genes associated with Gulf War illness had known drug targets. Rheumatoid arthritis was found to be correlated with the same eight modules. The authors interpreted their work to support previous studies that suggested that Gulf War illness is associated with dysregulation in some genetic pathway and to hypothesize potentially useful drug treatments.

Immune Function and Cytokines in Gulf War Illness

Eight studies examined immune function and cytokines in veterans with Gulf War illness. Five are from one group that tested the hypothesis that Gulf War illness involves a dysfunction in the immune system. One looked for abnormal patterns of pro-inflammatory immune markers, one study reported a comparison of cytokine expression in patients with either Gulf War illness or myalgic encephalomyelitis, and the final study looked at immune function in veterans with Gulf War illness. Each is discussed below.

Five papers on the immune system (Broderick et al., 2011, 2012, 2013; Smylie et al., 2013; Whistler et al., 2009) all used a similar exercise protocol to stimulate the immune system and tested responses. The initial pilot study (Whistler et al., 2009) tested the hypothesis that physiological responses to stress might differ in veterans with Gulf War illness. Nine veterans with Gulf War illness and 11 sedentary, nondeployed veterans were tested for stress-related biomarkers before, during, and after a standard bicycle ergometer exercise test. Endpoints measured included blood cell counts, natural killer (NK)-cell cytotoxicity, cytokines, expression levels of 20,000 genes, and salivary cortisol. As expected, exercise increased blood lymphocyte levels in the controls, but this response was muted in veterans with Gulf War illness. Compared with control veterans, Gulf War illness veterans had the following: decreased

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³ In order from most correlated to least correlated: Frontotemporal lobar degeneration (FTLD) sporadic frontal; cerebral palsy semitendinous muscle; schizophrenia; FTLD progranulin mutation frontal; benzene exposure; autism; bipolar disorder; chronic stress; adenocarcinoma of the esophagus; acute quadriplegic myopathy; spastic paraplegia; mixed hyperlipidemia; glaucoma; nonsevere asthma CD8 T cells; multiple sclerosis; Crohn’s disease; Becker muscular dystrophy; and sickle cell disease.

NK cell cytotoxicity, altered gene expression associated with NK-cell function, decreased blood concentrations of pro-inflammatory cytokines, T-cell ratios (CD4/CD8), and mediators of the stress response, including decreased salivary cortisol. The authors concluded that Gulf War illness involved impaired immune function. The authors suggested an overlap in symptomology and clinical findings with persons who have CFS.

A later study published by the same group (Broderick et al., 2011) appears to be from the same cohort and with similar samples as reported by Whistler et al. (2009), but the samples are analyzed in a different way. Instead of making comparisons between individual cytokines, the authors used multivariate statistical models to determine patterns of change shared by various cytokines, cortisol, and neuropeptide Y, to analyze the “fight or flight” response to exercise. The method used a form of graph theoretical methods and complex mathematical systems to identify significant trends shared by pairs of biomarkers and then constructed association networks linking immune and endocrine biomarkers in each study group (Broderick et al., 2011). The results reported differ from those reported by Whistler et al. (2009), but the authors mention several times that their method of analysis can detect altered patterns in the immune system that would not be detected by standard analyses. The authors concluded that the study showed that “the potential heightened lymphocyte and hypothalamic-pituitary-adrenal axis (HPA) responsiveness to IL-1 stimulation in the context of a mixed Th1:Th2 immune signature supports an autoimmune component to Gulf War illness.”

In Broderick et al. (2012), the authors sought to determine if the expression of immune biomarkers can be used to diagnose Gulf War illness. The results indicate that such biomarkers are not adequate for the diagnosis of Gulf War illness in individuals, but they could offer insight into the physiological basis for the disease. In a later paper (Broderick et al., 2013), the same protocol was used to test the difference in immune response to exercise in patients with Gulf War illness (n = 20) compared with those with CFS/myalgic encephalomyelitis (CFS/ME) (n = 7) and with healthy veterans (n = 22). Earlier studies (Barbier et al., 2009) had indicated that gene expression in stressed mice exposed to PB showed increases in hippocampal expression of three genes involved in memory development: brain-derived neurotrophic factor, tropomyosin-related kinase B, and calcium/calmodulin protein kinase II alpha. These studies could not be conducted in humans, but the investigators used circulating lymphocytes to reflect changes in the brains of veterans. The hypothesis was the NF-kappa beta activity was altered in circulating lymphocytes of Gulf War illness subjects as a lasting result of exposure to acetylcholinesterase inhibitors in the field. The authors performed an analysis of gene expression using a novel methodology (Efroni et al., 2007, 2008) for estimating the activity level of more than 400 pathways described in the National Cancer Institute databases. The authors point out that this is a significant departure from conventional analysis, where no estimate of pathway activation is produced. Using the alternative approach, pathway activation from gene expression in peripheral blood monocytes before, during, and after exercise in Gulf War illness and in healthy veterans was estimated. A statistical association of baseline Gulf War illness symptom burden with increased activation at peak exercise time in pathways was found, supporting neuronal development along with down regulation of apoptotic signaling. This was accompanied by prolactin-mediated increases in NF-kappa beta activation, a shift in T- and NK-cell populations, and the expression of IL-10 and IL-1 alpha.

Finally, the same group (Smylie et al., 2013) compared cytokines in peripheral blood of 20 male and 10 female Gulf War illness veterans with 12 male and 10 female CFS patients and 21 male and 9 female healthy veterans before, during, and after exercise. Analysis was performed as in the earlier studies. Linear classification models were constructed using stepwise variable selection to identify cytokine coexpression patterns characteristic of each group. Common to the signature of both Gulf War illness and CFS were IL-10 and IL-23 accompanied by NK and Th1 markers in males and Th2 markers in fe-

males. Exercise response differed between sexes. Male Gulf War illness veterans presented characteristic signatures at rest, but not at peak exercise effort. The opposite was true for females.

The data analyses that were used in the last four of the above five studies testing the immune network response in veterans groups before, during, and following exercise stress, were nonconventional and hard to interpret. Even the authors discuss the limitations of their approach saying, “it must be emphasized that our analysis was constrained to a specific set of documented pathways and was by no means comprehensive” (Broderick et al., 2013). In addition to the limited scope of pathways examined, the authors point out that they found the mathematical method of Efroni et al. (2007, 2008), which they used, was conservative and unable to detect the loss of more subtle signaling mechanisms. Also, the number of subjects is small, and the panel of cellular and molecular markers used is relatively narrow and does not represent a complete survey of immune response (Broderick et al., 2011). Therefore the data from these researchers must be considered preliminary until more information is obtained.

In a small study, Parkitny et al. (2015) tested to see if Gulf War illness was associated either with abnormal concentrations or abnormal fluctuations in pro-inflammatory immune markers in sera. Three hypotheses were tested: First, that serum pro-inflammatory cytokines would be higher in Gulf War illness veterans than in healthy veterans; second, that daily cytokine fluctuations would be greater in Gulf War illness veterans than in healthy veterans; and third, that daily self-reported fatigue in Gulf War illness veterans would covary with the concentrations of pro-inflammatory cytokines. Seven Gulf War illness veterans and eight healthy veterans had daily blood draws and gave daily self-reports on fatigue symptoms for 25 consecutive days. Among the 21 pro-inflammatory cytokines measured, only eotaixn-1 was found to be elevated in the blood of Gulf War illness veterans compared with healthy veterans. Higher self-reported fatigue days were associated with greater concentrations of IL-1b and IL-15. The small size of the study plus the fact that fatigue was self-reported diminished the potential significance of the study.

One study compared cytokines in sera in veterans with Gulf War illness and CFS/ME. Khaiboullina et al. (2015) tested the hypothesis that Gulf War illness resembles CFS/ME and might be a subset of that disease. For the study, 77 cytokines were measured in sera from Gulf War illness veterans (37), patients with CFS/ME (67) and healthy controls (42). The profile of cytokines could be used to delineate Gulf War illness and ME from controls, but the Gulf War illness values resembled control values more than the CFS/ME values. The authors concluded that the two conditions have distinct immune profiles despite their overlapping symptomology.

British physicians have tested the hypothesis that Gulf War illness results from an imbalance in the Th1/Th2 immune system (Skowera et al., 2004). Their subjects consisted of 80 nonsymptomatic Gulf War veterans, 40 symptomatic veterans, 20 symptomatic veterans of peacekeeping duties in Bosnia, and 39 symptomatic veterans in service at the time of the Gulf War but not deployed. The latter two groups were combined (total = 59) to form a control group who had multisymptom illness but had not been in the Gulf War. Peripheral blood CD4+ lymphocytes were stained using appropriate PE-conjugated anti-cytokines and were analyzed by flow cytometry for IL-2, IFN-gamma, IL-4 and IL-10 in the absence of activators. There was considerable overlap in the data but symptomatic Gulf War veterans had significantly higher mean levels of non-stimulated IL-4+ and IL-2+ cells compared to well Gulf War veterans and the control group. After short-term polyclonal stimulation, the cultured cells were found to secrete more IL-10 in the symptomatic Gulf War group than in the nonsymptomatic group. The IL-10 levels were also higher in the control group compared with the nonsymptomatic group. Again, there was considerable overlap in the data. The authors conclude that, even several years after the Gulf War, symptomatic veterans showed evidence of ongoing immune activation which is predominately Th1 and an expansion of IL-10 producing memory cells. The considerable overlap of the data in all three groups

indicates that these immune markers could not be used as biomarkers in diagnosis of Gulf War illness. While significant differences were observed, the biological significance is uncertain. Earlier reviews did not find that immunological responses were abnormal in symptomatic Gulf War veterans (Everson et al., 2002).

While several investigators have attempted to define a cytokine profile unique to Gulf War illness, their studies have not been successful. The committee notes that the findings of Broderick et al. (2013) are intriguing but preliminary and their significance is uncertain. Nonetheless, the committee observes that there is potential merit in the methodology. It would likely be productive to repeat these transcriptomic studies with several protocol enhancements including expansion of the study cohorts for sufficient power; use of appropriately chosen controls; use of distinct discovery and replication cohorts, each appropriately powered; use of RNAseq methods to analyze the sequences and numbers of all coding and noncoding RNA transcripts in an unbiased manner; and appropriate use of bioinformatics tools to discern specific disease pathways.

Other Studies of Possible Relevance

In a search for persistent enteroviruses, Urnovitz and colleagues (1999) compared levels of circulating RNA in sera from 24 deployed Gulf War veterans and 50 nonmilitary controls. RNA was isolated and amplified with primers from untranslated domains of the enterovirus, longer species of circulating RNAs in sera of Gulf War veterans were detected. Two of these were sequenced and found to map to human chromosome 2q11; they were not enteroviral sequences.

In a series of genes proposed to be relevant to susceptibility to chronic fatigue, Vladutiu and Natelson (2004) studied CFS/idiopathic chronic fatigue in two case-control sets: 49 veterans with CFS and 30 veterans without CFS, and in 61 nonveterans with CFS and 45 nonveterans without CFS. They examined the frequency of gene variants for three proteins: angiotensin converting enzyme, myoadenylate deaminase, and carnitine palmitoyltransferase II. The authors reported that an insertion allele (“I”) in intron 16 of the gene encoding angiotensin-converting enzyme (otherwise designated DCP1) is reduced in frequency in Gulf War veterans (0.15) with CFS compared with asymptomatic vets (0.48). Reciprocally, the alternate deletion “D” allele was overrepresented in symptomatic Gulf War veterans (0.85), as was the DD allele (0.78). However, the frequency of the I-allele in symptomatic and asymptomatic nonveterans was the same as the asymptomatic veterans (0.48–0.50). The reduced I-allele was predicted to enhance angiotensin-converting enzyme activity and promote higher angiotensin II levels, a profile that has been associated with adverse outcomes (more coronary artery disease).

Conclusions

Gulf War illness continues to be the signature health concern of veterans who served in the Persian Gulf region in 1990–1991. A variety of studies in U.S. and the coalition forces veterans who served during and even after the conflict continue to show that veterans who were deployed to the Gulf War experience more symptoms, signs, and ill-defined conditions and that their symptoms are more severe than their nondeployed counterparts; furthermore, these symptoms have persisted for more than 25 years after the war. In spite of concerted efforts to identify a cause or physiologic mechanism for Gulf War illness, no clear answer has been established, and the committee finds that Gulf War illness is not a mental health condition. Several new studies report associations between several exposures, particularly to chemicals, and the presence of Gulf War illness, but to date, there are no reliable or validated biomarkers of exposure or symptoms to substantiate the etiology or mechanisms of the illness. Animal

toxicology studies of Gulf War illness are discussed in Chapter 5. As noted earlier in this section, one of the difficulties in studying Gulf War illness is the several case definitions and the variable presentations of this condition.

Studies looking for biomarkers of Gulf War illness or other health conditions face many methodological problems irrespective of the approach or technology used (neuroimaging, genetics, cytokines). In general, such studies are small and often not adequately powered, suffer from multiple comparisons, and focus on nonspecific pathology that may indicate, or be involved in, many different disease pathways, known and unknown. Furthermore, researchers interpret their results as demonstrating positive findings without consideration of the high possibility of type I errors (false positive). Biomarkers, in general, are indicators of current pathology and are not useful or reliable measures of an exposure or an effect occurring many years earlier. They are, however, good for discovering clinically latent or subclinical disease.

Therefore, the Volume 10 committee concludes that there is sufficient evidence of association between deployment to the Gulf War and the constellation of chronic symptoms (including fatigue, musculoskeletal pain, sleep disturbances, cognitive dysfunction, alterations of mood) known as Gulf War illness.

TABLE 4-1 Primary Studies of Gulf War Illness

NOTE: CCEP = Comprehensive Clinical Evaluation Program; CDC = Centers for Disease Control and Prevention; CI = confidence interval; CIDI = Composite International Diagnostic Interview; CMI = chronic multisymptom illness; CMV = cytomegalovirus; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; DU = depleted uranium; EBV = Epstein-Barr virus; GHQ = General Health Questionnaire; GW = Gulf War; GWV = Gulf War veteran; ICD = International Classification of Diseases; NDV = nondeployed veteran; OR = odds ratio; PB = pyridostigmine bromide; PMR = proportional morbidity ratio; PTSD = posttraumatic stress disorder; RR = risk ratio; SF-12 = 12-item short form health survey; UK = United Kingdom; U.S. = United States; VA = Department of Veterans Affairs.

CANCER

Cancer can develop at any age, but the median age for any type of cancer diagnosis is 65 years (National Cancer Institute, 2015). The National Cancer Institute’s Surveillance, Epidemiology, and End Results Program estimates incidence, prevalence, and deaths from all cancers and site-specific cancers using age-adjusted rates and actual cases and deaths from 2008–2012. The overall incidence rate for all cancer sites in 2015 was estimated to be 454.8 per 100,000 people per year, or a total of 1,658,370 new cases that year (National Cancer Institute, 2015). Based on 2010–2012 data, approximately 40% of U.S. men and women will be diagnosed with cancer (that is, a malignant neoplasm) at some point during their lifetime (National Cancer Institute, 2015). As of January 1, 2014, approximately 14.5 million people in the United States had a history of a cancer diagnosis (American Cancer Society, 2015). Cancer usually has a long latency period (≥ 20 years) (Cogliano et al., 2004), and, therefore, many Gulf War veterans are still young for cancer diagnoses (the mean age of military personnel during the Gulf War in 1991 was 28 years). However, some forms of cancers—such as testicular cancer, skin cancer, leukemia, lymphoma, and brain cancer—may also develop in younger people or may have shorter latency periods.

Relatively few studies of Gulf War veterans have focused on cancer incidence or prevalence; rather, the majority of studies on the association between overall or cause-specific cancers and Gulf War deployment are mortality studies, which are discussed in the section on causes of mortality. All primary studies of cancer morbidity are summarized in Table 4-3 at the end of this section.

Summary of Volumes 4 and 8

The Volume 4 committee reviewed four cancer studies and found no consistent evidence of a higher overall incidence of cancer in Gulf War veterans than in nondeployed veterans. However, the committee also noted that many veterans were young for a cancer diagnosis and, for most cancers, the follow-up period after the Gulf War was probably too short to expect the onset of most cancers. The incidence of cancer in general, and testicular cancer in particular, have been assessed in cohort studies. Two studies focused on the risk of developing testicular cancer, but results were inconsistent: one study concluded that there was no evidence of an excess risk (Knoke et al., 1998), and the other, a small registry-based study, suggested there may be an increased risk but no definitive conclusions could be made because few cases were identified (Levine et al., 2005). One study examined cancer of all sites. The first study examined incident cases of all cancer in UK Gulf War deployed and nondeployed veterans in the 10 years following the conflict, but after adjusting for sex, age group, service branch, and rank found no evidence of an association between deployment to the gulf and development of cancer (Macfarlane et al., 2003). The Volume 4 committee concluded that additional follow-up time was needed to assess the association between deployment and development of site-specific cancers.

The Volume 8 committee reviewed three primary studies and 10 secondary studies. No consistent evidence of a higher overall incidence of cancer was found in veterans who were deployed to the Gulf War vs nondeployed veterans. Two primary studies found no statistically significant increase in hospitalizations from neoplasms in Gulf War veterans compared with their nondeployed counterparts. A third primary study found no association between deployment and any cancer, including brain, testicular, and digestive tract, among Canadian Gulf War veterans. The Volume 8 committee concluded that there was insufficient/inadequate evidence of an association between Gulf War exposures and brain cancer. Mixed results for testicular cancer were reported by the Volume 4 committee, and the Volume 8 committee did not identify any new studies of this cancer site. The Volume 8 committee agreed with the Volume 4 committee in that many veterans were still too young for cancer diagnoses, and the follow-up period

was too short for most cancers. Therefore, the Volume 8 committee found that further follow-up was necessary to be able to make a conclusion about whether there is an association between deployment during the Gulf War and any cancer outcomes. The Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and any cancer. The committee also recommended that due to the long latency period for cancer, there needed to be continued follow-up of Gulf War veterans and an appropriate comparison group to adequately determine any association.

New Literature

The Volume 10 committee identified three new studies of cancer in Gulf War veterans; two were deemed primary studies, one was considered a secondary study.

Primary Studies

The first primary study was the Australian Gulf War Veterans’ Follow Up Health Study (Sim et al., 2015) that examined cancer incidence rates through 2008 in the entire cohort of 1,871 Australian Gulf War veterans and a comparison group of 2,922 veterans frequency matched based on age, sex, rank category, and service branch. Incident cancers were identified and linked to the cohort using the Australian Cancer Database, which collects data on all primary, malignant cancers diagnosed in Australia since 1982, but does not include basal cell or squamous cell carcinomas of the skin, cancer recurrences, or metastases. Data includes date of cancer diagnosis, site, histology, the Austrialian state in which the cancer was diagnosed, date of death (if applicable), and the ICD-10 codes for the type of cancer. Cancer diagnoses were presented as all malignant neoplasms; lip cancer; colorectal; other digestive organs; lung, trachea, and bronchus; melanoma; prostate; testis; kidney; brain and other central nervous system cancers; thyroid; all lymphomas; and leukemia. Hazard ratios (HRs) were used to make comparisons between the two veteran groups and standardized incidence ratios were used to make comparisons between each veteran group and the Australian population.

Because women veterans composed only 2% of the Australian deployed cohort, and no deployed women developed cancer in the 18-year follow-up, women were excluded from the cancer incidence analyses. A total of 115 cancers were observed among the male veterans, affecting about 2.5% of the total male cohort. No significant differences between the deployed and the comparison group were found for all malignant cancers (adjusted HR = 1.20, 95% CI 0.83–1.73) or any type of cancer. For site-specific cancers, there were fewer than five cases observed for deployed or comparison groups for several sites including colorectal; brain and other parts of the central nervous system; testis; lung, trachea, and bronchus; kidney; thyroid; lip; and leukemia. No significant differences were observed between deployed veterans and the Australian male population for site-specific cancers; however, few incident cancers were available for analysis and the power of this study to identify rare cancers was low. There was a statistically significant risk for thyroid cancer calculated on the basis of standardized incidence ratios (SIR = 2.89, 95% CI 1.20–6.93), although this estimate was based on only five cases of thyroid cancer observed in the comparison veterans, which limits the conclusions that can be drawn. The number of brain cancer cases, while not statistically significant and based on less than five cases, was higher than expected among Gulf War veterans compared to the general Australian population (SIR = 2.38, 95% CI 0.89–6.35). The authors concluded “In the 18 year period since the Gulf War, there have been no statistically significant differences in cancer incidence of any type between the male Gulf War veterans, the male comparison group members, and the same-aged Australian male population.”

The committee notes that while the Australian study adjusted for some factors—such as age, service branch, and rank—the study did not adjust for other important potential confounders such as smoking, body mass index, and alcohol use.

The second primary study examined proportional cancer incidence among all 621,902 U.S. veterans deployed to the Gulf War and 746,248 era veterans (Young et al., 2010). Era veterans were a stratified random sample of veterans from all military personnel who served during the conflict but were not deployed to the Persian Gulf region. Veterans diagnosed with cancer between 1991 and 2006 were identified using data from the Defense Manpower Data Center (DMDC), which was linked to central cancer registries in 28 states and the VA Central Cancer Registry. The 28 state registries captured 84% of the U.S. population, based on the 2000 Census; cancer cases were grouped into 30 categories. Logistic regression models that controlled for age, race, and sex were used to determine whether the proportion of veterans with a diagnosed cancer differed between deployed and era veterans. Crude and adjusted proportional incidence ratios (PIRs) were calculated to determine differences by specific cancer type; adjustment was made for sex, diagnosis age, diagnosis age squared, diagnosis year, race, branch of service, unit type, and registry group. For cancer types with statistically significant adjusted PIRs, SIRs were calculated. The SIRs compared the Gulf War veterans and era veterans with the general population, adjusted for sex, race, and age.

A total of 21,075 incident cancer diagnoses were identified—8,211 among the deployed veterans and 12,864 among the era veterans—of these, 2,796 were identified from the VA Central Cancer Registry. No statistically significant association was found between deployment status and the proportion of veterans diagnosed with cancer (OR = 0.99, 95% CI 0.96–1.02). No difference in proportional incidence between deployed and era veterans was found for brain cancer (PIR = 0.86, 95% CI 0.73–1.01), melanoma (PIR = 0.98, 95% CI 0.89–1.09), other skin cancers (PIR = 0.82, 95% CI 0.53–1.28), digestive system cancers (PIR = 1.07, 95% CI 0.97–1.18), or leukemia (PIR = 0.93, 95% CI 0.78–1.12). Lung cancer was the only site-specific cancer found to have a significantly higher proportion among deployed veterans compared with era veterans (PIR = 1.15, 95% CI 1.03–1.29). It remained significant when further analysis compared proportional incidence of lung cancer in Army and Marine veterans with era veterans (PIR = 1.21, 95% CI 1.07–1.38). Two types of cancers had statistically significant decreased proportional incidence ratios in deployed veterans compared with nondeployed veterans: testicular cancer (PIR = 0.85, 95% CI 0.75–0.98) and Kaposi sarcoma (PIR = 0.54, 95% CI 0.37–0.79). SIRs comparing deployed and era veterans with the general U.S. population were calculated for lung cancer, testicular cancer, and Kaposi sarcoma. Neither deployed nor era veterans showed significantly increased risks of lung or testicular cancer compared to the general population. Both of these veteran groups had significantly decreased risks of Kaposi sarcoma when compared with the general population (SIR deployed = 0.08, 95% CI 0.05–0.12; SIR era = 0.18, 95% CI 0.13–0.24).

The committee notes that as with the Australian cohort study, Young and colleagues (2010) were able to adjust for some demographic, diagnostic, or military factors, but no data on smoking status were available, and therefore, this factor was not included in the adjusted effect models. The length of follow-up was, at most, 15 years, which may not be enough time for certain cancers such as lung cancer to develop if there were a Gulf War etiologic factor. Additionally, the numbers of incident cancer diagnoses are likely to be underestimated because 22 states were not represented, which may alter the PIR as it is affected by the relative frequencies of other cancer types. Also, of the 28 state registries that were included, not all covered the full time period. Major strengths of the study are that it used the entire population of deployed Gulf War veterans and a large and representative sample of era veterans, and that it used cancer registry data—as opposed to mortality, hospitalization, or self-reported diagnoses—to assess cancer incidence outcomes. For more frequently occurring cancers such as lung, prostate, and melanoma, the sample sizes were large enough to provide adequate statistical power to

detect relatively small differences between veteran groups and between each veteran cohort and the general U.S. population.

Secondary Studies

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans four questions pertaining to cancer: whether a doctor ever told the veteran that they had skin cancer (other than melanoma), melanoma, brain cancer, or any other cancer, with space to write in what that cancer was (Dursa et al., 2016). If the veteran responded yes, they were asked whether the condition had been present in the past 4 weeks.

Weighted prevalence and adjusted odds ratios (models were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component) were presented for the four self-reported cancer questions among deployed and era veterans. No statistically significant differences between deployed and era veterans were observed for weighted reports (cases) of skin cancer (4.4% [488 cases] vs 5.4% [418 cases]; OR = 1.06, 95% CI 0.88–1.29), melanoma (2.5% [230 cases] vs 2.7% [183 cases]; OR = 1.15, 95% CI 0.87–1.52), or other cancers (5.2% [505 cases] vs 5.6% [399 cases]; OR = 1.12, 95% CI 0.91–1.37). The number of brain cancer cases was small: 30 among the deployed and 19 among the era veterans (0.3% each; OR = 1.02, 95% CI 0.47–2.21) (Dursa et al., 2016). Bossarte (2014) presented additional results to the committee on weighted cases of self-reported brain cancer among deployed and era veterans by service branch, but no significance testing was performed.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including the top 10 malignant cancers (ICD-9-CM 140–209) (see Table 4-4); no statistical testing was performed. A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans. In addition to the malignant neoplasms in Table 4-4, a total of 43,337 benign neoplasms were diagnosed among deployed veterans, and 43,757 benign neoplasms were diagnosed among nondeployed veterans.

Conclusions

Given the lack of new evidence on the effect of deployment to the Gulf War and incidence of overall or site-specific cancers from two primary studies, the committee concurs with the conclusions of the Volume 8 committee that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and the incidence or prevalence of any cancer. (Cancer mortality is discussed in the section on causes of mortality.) However, the committee also concurs with the Volume 8 committee’s recommendation that because many cancers have long latency periods, follow-up of deployed Gulf War veterans and an appropriate comparison group of era veterans should be continued to adequately determine whether there is an association.

TABLE 4-4 10 Most Frequent Malignant Neoplasm Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

Brain and lung cancer have been of particular concern to Gulf War veterans (see statement of task in Chapter 1). Both of the new primary studies reported on these cancers, but neither provided evidence of an increased risk for these cancers among Gulf War veterans. Young et al. (2010) found a higher proportion of lung cancer in Gulf War veterans compared with era veterans, but there was no difference when compared to the general population. Moreover, Young et al. (2010) made no adjustment for smoking status in their analyses. CDC (2014) estimates that cigarette smoking is linked to 90% of lung cancers. No statistically significant differences for brain cancer were identified in either of the primary studies. Volumes 4 and 8 described studies (Barth et al., 2009; Bullman et al., 2005) that reported an increased risk of brain cancer mortality potentially associated with demolition of chemical munitions at Khamisiyah, however these authors based exposure on a plume model for which there is considerable uncertainty (GAO, 2004). The committee thus concurs with the Volume 4 and 8 committees that there is insufficient/inadequate evidence of an association between demolitions at Khamisiyah and an increased risk of brain cancer. The committee finds that follow-up of cancer prevalence and incidence has only been conducted through 2006 (15 years since the Gulf War), which may not account for latency periods of 25 years or longer. Because cancer incidence in the past 10 years has not been reported, additional follow-up is needed.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and any form of cancer, including lung cancer and brain cancer.

TABLE 4-3 Cancer

NOTE: BIRLS = Beneficiary Identification Records Locator System; CCD = Canadian Cancer Database; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DC = District of Columbia; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GW = Gulf War; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; NDI = National Death Index; NDV = nondeployed veteran; NJ = New Jersey; PIR = proportional incidence ratio; PMR = proportional morbidity ratio; RR = risk ratio; SEER = Surveillance, Epidemiology, and End Results; SIR = standardized incidence ratio; SMR = standardized mortality ratio; SRR = standardized rate ratio; UK = United Kingdom; U.S. = United States; VA = Department of Veterans Affairs.

BLOOD AND CIRCULATORY SYSTEM CONDITIONS

Cardiovascular disease is a broad term for any disorder of the heart or the blood vessels, such as atherosclerosis and hypertension. Cardiovascular disease, which includes coronary heart disease and stroke, is the leading cause of death for both women and men in the United States.

Conditions of the blood and blood-forming organs include conditions affecting blood cells (erythrocytes, leukocytes, platelets) as well as the organs where these cells are produced (bone marrow, lymph nodes, spleen). The etiology of these disorders is varied, and can include genetic conditions, exposure to toxins and medications, infections, and nutritional deficiencies. All primary studies of conditions of the blood and circulatory system are summarized in Table 4-5 at the end of this section.

Summary of Volumes 4 and 8

As reported in Volume 4, two primary studies (Eisen et al., 2005; Smith et al., 2003) found no statistically significant differences in the prevalence of cardiovascular disease between deployed and nondeployed Gulf War veterans. In the secondary studies, which included hospitalization studies, deployed veterans were generally more likely to self-report hypertension and palpitations, but those reports were not confirmed by medical evaluations. Thus, the Volume 4 committee concluded that there was no difference in the prevalence of cardiovascular disease between deployed and nondeployed Gulf War veterans.

Primary studies of hospitalizations for cardiovascular conditions reviewed in Volume 8 (Gray et al., 1996, 2000; Smith et al., 2002, 2006) did not find an increased risk in deployed vs nondeployed veterans during the first 10–15 years after the Gulf War. The few studies measuring blood pressure in deployed and nondeployed veterans also found no differences between the two groups (Ishoy et al., 1999b; Kelsall et al., 2004a). The only study that found an increase in cardiovascular disease assessed cardiac dysrhythmia in deployed veterans who were possibly exposed to the Khamisiyah plume compared with those who were not exposed (Smith et al., 2003). No studies confirmed this association in other populations, nor was there an increase in hospitalizations for cardiac disease in veterans exposed to smoke from oil-well fires (Smith et al., 2002).

Seven secondary studies provided self-reported prevalence of different cardiovascular conditions, including high blood pressure, palpitations, stroke, heart attacks, and unspecified heart problems by deployment status (Goss Gilroy Inc., 1998; Kang et al., 2000, 2009; Kelsall et al., 2004a; Page et al., 2005a; Proctor et al., 1998; Simmons et al., 2004; Steele, 2000; Stretch et al., 1995). In these studies, deployed veterans were generally more likely to self-report hypertension, palpitations, and other cardiovascular disease, but those reports were not confirmed by clinical evaluations.

Conditions of the blood were not considered as distinct health conditions in Volume 4; however, the Volume 8 committee identified five primary studies that examined hospitalization rates for blood disorders in deployed and nondeployed veterans (Gray et al., 1996, 2000; Smith et al., 2002, 2003, 2006). Overall, these studies did not show that the prevalence of blood disorders was different in deployed Gulf War veterans vs nondeployed veterans. However, these studies precluded any firm conclusions being drawn because hospitalizations were mostly restricted to DoD hospitals, the studies lacked information on outpatient visits where patients with mild disorders are most likely to be seen, most studies lacked information on potential confounders, and none of them differentiated between specific hematologic disorders. Two other primary studies measured hematologic parameters in Danish and Australian Gulf War veterans compared with nondeployed veterans, but neither showed any major difference by deployment status (Ishoy et al., 1999b; Sim et al., 2003). The two studies were limited by different participation rates for deployed and nondeployed veterans—suggesting a bias—and lacked adjustment for confounding

variables. Additionally, studies of blood disorders are limited by the nature of the disease; some blood disorders typically have a long latency, and hospitalization and mortality studies are poor approaches to detect their prevalence and incidence. The Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and cardiovascular disorders or disorders of the blood and blood-forming organs.

New Literature

The Volume 10 committee did not identify any new primary studies on the risk of Gulf War veterans having conditions of the cardiovascular system.

Secondary Studies

Three secondary studies were identified. One study assessed cardiovascular outcomes in deployed and nondeployed Australian veterans and two studies assessed them in U.S. Gulf War veterans.

The Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013, assessed the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war (Sim et al., 2015). This study was a follow-up to the Kelsall et al. (2004b) baseline study discussed in Volumes 4 and 8. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Health outcomes were based on self-reports and on self-reports of doctor-diagnosed conditions. Deployed veterans were slightly but not significantly more likely to report high blood pressure (RR = 1.14, 95% CI 0.95–1.37) and angina (RR = 1.26, 95% CI 0.51–3.10) but less likely to report having had a heart attack or myocardial infarction (RR = 0.91, 95% CI 0.51–1.63). High cholesterol was the most prevalent medical condition reported by both groups; 35.4% of deployed veterans and 33.2% of nondeployed veterans reported having this diagnosis, but no statistically significant difference between groups was found (RR = 1.13, 95% CI 0.98–1.32).

In 2005, Li et al. (2011a) reported on findings from the 10-year follow-up survey of U.S. Gulf War deployed (n = 5,469) and nondeployed veterans (n = 3,353) who had also participated in the 1995 National Health Survey of Gulf War Veterans and Their Families. Compared with nondeployed veterans, deployed veterans were less likely to report having hypertension (RR = 0.85, 95% CI 0.76–0.96), although they were more likely to report a new incidence of it (RR = 1.15, 95% CI 1.02–1.29). Deployed veterans were also more likely to report the persistence of coronary heart disease, but not significantly so (RR = 1.14, 95% CI 0.70–1.86), and they had a statistically significantly increased risk of new onset of coronary heart disease (RR = 1.61, 95% CI 1.17–2.23). The risk ratios were adjusted in 2005 for age, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. There was a significant difference between the deployed and era veterans in self-reports of tachycardia (8.1% vs 5.9%; OR = 1.47, 95% CI 1.20–1.79), coronary heart disease (5.6% vs 5.3%; OR = 1.32, 95% CI 1.09–1.59), and hypertension (43.0% vs 40.0%; OR = 1.22, 95% CI 1.10–1.35); the prevalence of stroke was not significantly different between the two groups (2.2% vs 2.4%; OR = 0.99, 95% CI 0.75–1.32) (Dursa et al., 2016). The ORs were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

Other Related Studies

VA provided a health care utilization report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the blood and blood-forming organs (ICD-9-CM 280–289) and diseases of the circulatory system (ICD-9-CM 390–459) (see Table 4-6). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Other studies have assessed the effect of a co-occurring health condition on the prevalence of coronary heart disease, hypertension, and tachycardia. Based on responses to the Patient Health Questionnaire component of the second wave of the VA National Health Survey of Gulf War Era Veterans, Coughlin and colleagues (2011a) found that among 6,111 Gulf War deployed and 3,859 era veterans, deployed veterans, regardless of their weight status (underweight, normal weight, overweight, or obese), self-reported more coronary heart disease and hypertension than nondeployed veterans. No information on diet or physical activity was provided. Further assessment of these veterans found that self-reported

TABLE 4-6 10 Most Frequent Diagnoses of Diseases of the Circulatory and Blood and Blood-Forming Organ Systems for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

hypertension was more prevalent in both deployed and nondeployed veterans with problem drinking (33.4% vs 33.5%) than in deployed and nondeployed veterans without problem drinking (29.4% vs 27.5%). Similar results were also seen for self-reported tachycardia, where deployed veterans with and without problem drinking had an increased prevalence compared with nondeployed veterans (16.6% vs 11.4% and 13.7% vs 9.9%, respectively) (Coughlin et al., 2011b). Heavy drinking was defined as ≥ 15 drinks/week.

Abouzeid et al. (2012) assessed the co-occurrence of PTSD and hypertension in Australian veterans who had deployed to the Gulf War. They found that in 2000–2002, among the 1,381 veterans for whom medical information and results of the CIDI for diagnosing PTSD were available, 100 veterans were considered to have probable hypertension. The ORs for hypertension were 2.90 (95% CI 1.19–7.09) for veterans with PTSD in the past 12 months (n = 71) and 2.27 (95% CI 1.01–5.10) for lifetime prevalence (n = 91), compared with veterans without PTSD (n = 1,290 and 1,310, respectively). The ORs were adjusted for age, occupation, education, marital status, service branch, military service experience, questionnaire score, military rank, BMI, waist circumference, pack-years of smoking, AUDIT case status, and the presence of affective disorders or anxiety disorders other than PTSD.

Conclusions

The new secondary studies of Gulf War veterans that compared cardiovascular disease in deployed veterans vs nondeployed veterans had mixed results. One study found that U.S. deployed veterans had a significantly increased risk of having tachycardia but a second study, using the same cohort, found no significant increase in the risk of having hypertension or of having coronary heart disease, although there was a moderate increase in the risk of developing both conditions. A study of Australian Gulf War veterans found no significantly increased risk of having high cholesterol, high blood pressure, heart attacks or myocardial infarction, or angina in deployed vs nondeployed veterans.

The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new blood and circulatory conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and cardiovascular conditions or conditions of the blood organs.

TABLE 4-5 Conditions of the Blood and Circulatory System

NOTE: CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GW = Gulf War; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; mmHg = millimeters of mercury; mmol = millimoles; NDV = nondeployed veteran; OR = odds ratio; pg = picogram; PMR = proportional morbidity ratio; RR = risk ratio; sd = standard deviation; VA = Department of Veterans Affairs.

ENDOCRINE AND METABOLIC CONDITIONS

Among the general U.S. population, the most frequent conditions in this category are diabetes, thyroid disease, and obesity. It is estimated that 29 million people in the United States (9.3%) have diabetes; 1.7 million people aged 20 years or older were newly diagnosed with diabetes in 2012, and another 86 million adults—more than one in three U.S. adults—have prediabetes, where their blood sugar levels are higher than normal but not high enough to be classified as type 2 diabetes (CDC, 2015a). The CDC also estimates that more than one-third (34.9% or 78.6 million) of U.S. adults are obese (CDC, 2015b), a risk factor for diabetes. Although the Volume 10 committee attempted to identify other specific endocrine or metabolic conditions in Gulf War veterans, no new literature on those outcomes was found to have been published since Volume 8. Primary studies for Volumes 4 and 8 are detailed in Table 4-7 at the end of this section.

Summary of Volumes 4 and 8

Volume 4 included diabetes under diseases of the circulatory system. Two primary studies were identified; one study (Eisen et al., 2005) included medical evaluations for diabetes, and the other (Smith et al., 2003), a hospitalization study, used a dispersion model to determine exposure status to nerve agents at the Khamisiyah demolition site. Neither study found a statistically significant increase in the prevalence of diabetes in deployed veterans or in hospital diagnoses for endocrine, nutritional, and metabolic diseases. None of the four secondary studies found a statistically significant increase in diabetes in any of the Gulf War veteran populations they studied; however, most of the studies relied on self-reported diagnoses.

Two primary studies reviewed by the Volume 8 committee reported on risk factors of diabetes, insulin levels, and blood glucose in Gulf War veterans from Denmark (Ishoy et al., 1999b) and Australia (Sim et al., 2003), but neither reported differences between deployed and nondeployed veterans. The five secondary studies of self-reported outcomes in four military cohorts indicated comparable risks of diabetes between deployed and nondeployed veterans (Kang et al., 2009; Page et al., 2005a; Proctor et al., 2001a; Simmons et al., 2004; Smith et al., 2006).

Thyroid disease was not specifically described in Volume 4. The Volume 8 committee reviewed one primary study (Eisen et al., 2005) that reported elevated but not statistically significant risks for hyperthyroidism and for hypothyroidism in deployed veterans compared with nondeployed veterans based on medical examinations.

Obesity was also not studied separately in Volume 4. Studies reviewed by the Volume 8 committee used measures of BMI, weight, and waist circumference to measure obesity in veterans. One primary study, conducted in 1997, found a slightly higher weight and waist circumference in Danish deployed veterans compared with nondeployed veterans (Ishoy et al., 1999b), whereas an Australian study found that BMI and waist circumference measures were comparable between deployed and nondeployed male and female veterans in 2002 (Sim et al., 2003). A secondary study found no differences in BMI, glycemia, or blood levels of thyroxine-stimulating hormone between deployed and nondeployed UK veterans (Ismail et al., 2008).

The Volume 8 committee reported that primary studies showed no clinically relevant differences between deployed and nondeployed veterans in prevalence of different endocrine and metabolic conditions, including diabetes, thyroid disease, and obesity. Five of the eight primary studies relied on hospital discharge data; thus, conditions that did not require hospitalization were not evaluated. The existing studies, however, did not indicate any increased risk of these conditions among deployed veterans. Results

from secondary studies were similarly inconclusive: deployment status was unrelated to self-reported diabetes but observed findings were less consistent for “other endocrine disorders.” The Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and endocrine, nutritional, and metabolic conditions.

New Literature

No new primary studies were identified by the Volume 10 committee.

Secondary Studies

The Volume 10 committee identified three studies that met its criteria for secondary studies. These studies assessed the prevalence of diabetes on the basis of self-reports.

Li et al. (2011a) conducted a 10-year follow-up survey of U.S. Gulf War deployed (n = 5,469) and nondeployed veterans (n = 3,353) who had participated in the 1995 VA National Health Survey. Compared with nondeployed veterans, deployed veterans in 2005 were at decreased risk of having diabetes (RR = 0.8, 95% CI 0.7–1.0) or having new onset of the disease (RR = 0.9, 95% CI 0.8–1.2). The risk ratios were adjusted for age in 2005, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

Sim et al. (2015) conducted the Australian Gulf War Veterans’ Follow Up Health Study between 2011 and 2013 to assess the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Health outcomes were based on self-reports and on self-reports of doctor-diagnosed diseases. Deployed veterans had a nonsignificant decreased risk of having diabetes compared with nondeployed veterans (RR = 0.76, 95% CI 0.51–1.14).

Dursa et al. (2016) reported results from the third wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had diabetes or some other endocrine disorder. The weighted prevalence for diabetes was the same in deployed and era veterans—13.2%, but the OR was not statistically significant. Era veterans had a slightly higher weighted prevalence (8.0%) of other endocrine disorders compared with deployed veterans (7.4%), but the OR of 1.09 was not statistically significant (95% CI 0.87–1.33).

Other Related Studies

Other studies have assessed the effect of a co-occurring health condition on the prevalence of diabetes and other endocrine and metabolic conditions. In a 2003–2005 follow-up to the 1995 National Health Survey of Gulf War Veterans and Their Families, Coughlin and colleagues (2011a) investigated self-reported health outcomes among 6,111 Gulf War deployed and 3,859 era veterans stratified by weight. The percentage of normal weight, overweight, and obese deployed veterans who reported a diagnosis of diabetes was 9%, 10.8%, and17.5%, respectively. The corresponding percentages for nondeployed veterans were 7.8%, 10.1%, and 15.6%, respectively. Underweight deployed and nondeployed veterans had a greater percentage of diabetes than normal weight veterans (15.4% and 16.7%, respectively). These data were not adjusted for age and no information on diet or physical activity was provided in this study.

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including for diseases of the endocrine, nutritional, and metabolic systems (ICD-9-CM 240-279) (see Table 4-8); no statistical analyses were performed. A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the veteran is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

The Volumes 4 and 8 committees found no evidence of an increase in the prevalence of endocrine disorders such as diabetes and thyroid disease or disorders such as obesity in veterans who were deployed to the Gulf War. The several hospitalization studies also found no increased risk of these conditions, although the Volume 8 committee noted that most of these conditions do not require hospitalization and therefore, the prevalence may be underreported.

The new literature reviewed by the Volume 10 committee, much of which was follow-up of previously discussed Gulf War veteran cohorts, also found no evidence of an increased risk of having or developing diabetes or other endocrine or metabolic conditions.

The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new endocrine and metabolic conditions will develop 25 years after the Gulf War that are attributable to their Gulf War service, it is doubtful that further assessments will show an increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and endocrine and metabolic conditions.

TABLE 4-8 10 Most Frequent Diagnoses of Diseases of the Endocrine, Nutritional, and Metabolic Systems for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

TABLE 4-7 Conditions of the Endocrine and Metabolic Systems

NOTE: BMI = body mass index; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; NDV = nondeployed veterans; OR = odds ratio; pmol = picomoles; PMR = proportional morbidity ratio; RR = risk ratio; VA = Department of Veterans Affairs.

MENTAL AND BEHAVIORAL HEALTH CONDITIONS

Mental health disorders are among the most disabling and costly health conditions globally. Notwithstanding their high prevalence and their impact on cost and disability, appropriate interventions for mental health conditions remain one of the most neglected areas in health care worldwide, a reality that may be related to stigma as well as diagnostic issues. The latter may result in ambiguous definitions that may affect the proper characterization of those in need of services.

Mental health conditions are well-known sequelae of war (Pizarro et al., 2006; Wessely, 2005). These conditions have been an important focus of studies of military populations, and each large cohort study of Gulf War veterans has included at least some psychological assessments. Mental health conditions most commonly studied in the Gulf War veteran population include major depressive disorder (MDD), PTSD, and substance use disorders. In general, for most of the studies discussed in this section, the American Psychiatric Association’s (APA’s) Diagnostic and Statistical Manual of Mental Health Disorders, fourth edition (DSM-IV), was the basis for the assessment of mental health disorders in veterans and others (APA, 2000). In 2013, the APA released a revised fifth edition of the DSM, which substantially changed many of the criteria that are used to diagnose mental health disorders.

For example, the DSM-5 diagnostic criteria for PTSD may affect the incidence and prevalence of PTSD in both military and civilian populations. Part of the difficulty in assessing and treating for PTSD is the inherent heterogeneity in presentation. For example, Galatzer-Levy and Bryant (2013) found that the DSM-5 criteria could result in 636,120 PTSD symptom combinations. The new criteria for PTSD are summarized in Box 4-1. None of the studies considered in this report used the new criteria.

General population estimates of prevalence of mental health conditions show that in general, about one-third of the U.S. adult population may, at some time in their lives, meet criteria for a mental health disorder. The National Comorbidity Survey–Replication, a large epidemiologic study in the United States, found a 12-month prevalence estimate of 3.1% for alcohol abuse, 2.4% for bipolar disorder, 1.4% for drug abuse, 2.7% for generalized anxiety disorder, 3.6% for PTSD, 8.9% for MDD, 3.7% for panic disorder, 7.2% for social phobia, and 9.2% for specific phobia (Gadermann et al., 2012). Lifetime prevalence for the same mental health disorders in the general U.S. population tends to be higher (Kessler et al., 2005). The rates of mental disorders in the general population based on the above estimates tend to be higher than those reported in deployed veterans and much higher than in the nondeployed veteran populations (IOM, 2010), a finding that has been interpreted as due to a “healthy-warrior effect,” but these rates may not be comparable as they have been obtained through different research strategies. It is likely that both military screening and self-selection contribute to the belief that individuals entering the military, and being eligible for deployment, may have a better mental and physical health status than similar individuals in the general population. However, it is well recognized that deployment and exposure to combat result in an increased incidence of certain mental health disorders such as PTSD.

The proper examination of mental health conditions among veterans serving in the Gulf War has been complicated by the passage of time, the stigma that mental health disorders may convey on veterans and their families, and the rejection of these diagnoses by many veterans who vigorously advocate against their symptoms and disorders being called “mental” or “psychiatric.” Indeed, many Gulf War veterans fear that discussion of the psychological aspects of their symptoms would question the legitimacy of their health problems.

All primary studies of mental and behavioral health conditions are summarized in Table 4-9 at the end of this section.

Summary of Volumes 4 and 8

In Volume 4, eight primary studies were reviewed that used direct interviews of large Gulf War cohorts. Across those studies, publications from three U.S. cohorts, one Australian cohort, and one Canadian cohort reported a two- to three-fold increased prevalence of mental health conditions including generalized anxiety disorder, panic disorder, PTSD, any anxiety disorder, and substance abuse in deployed vs nondeployed veterans (Barrett et al., 2002; Black et al., 2004a,b; Brailey et al., 1998; Kang et al., 2003; Proctor et al., 1998; Wolfe et al., 1999a,b). Analyses also indicated reduced functioning and quality of life in deployed veterans with mental health conditions. Two of those studies indicated that symptoms of depression and PTSD could worsen over time (Brailey et al., 1998; Wolfe et al., 1999a). The primary studies and most of the secondary studies, regardless of their techniques of ascertainment or their target population, reported almost identical conclusions regarding the psychiatric outcomes of Gulf War deployment for veterans. Depression, substance abuse or dependence, and anxiety disorders, especially PTSD, were increased in Gulf War deployed veterans compared with nondeployed veterans. Symptom severity was associated with the perceived level of deployment stress, even if veterans did not have direct combat exposure.

The Volume 8 committee identified four new primary studies (Fiedler et al., 2006; Ismail et al., 2002; Kang et al., 2009; Toomey et al., 2007) and five new secondary studies (Al-Turkait and Ohaeri, 2008; Axelrod et al., 2005; Black et al., 2006; Kang et al., 2005; Rona et al., 2007) that further supported the Volume 4 committee conclusions on the relationship between deployment to the Gulf War and mental health disorders. First, that committee found that combat exposure in the Gulf War was causally related to PTSD. The primary studies were in Kuwaiti, UK, and U.S. veterans. The available evidence from

these studies is sufficient to support the conclusion that the causal relationship of combat exposure to PTSD shown for other wars, such as Vietnam and the conflicts in Iraq and Afghanistan, also pertains to combat exposure and the development of PTSD in the 1990–1991 Gulf War. Second, there is sufficient evidence of an association between deployment to the Gulf War and several other psychiatric disorders. These include generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. Third, the associations between Gulf War deployment and psychiatric disorders were still evident 10 years after deployment. For many of the psychiatric disorders that were measured in long-term followup studies, their prevalence even 10 years after the war was more than two-fold higher in veterans who had been deployed compared with nondeployed veterans.

In particular, the Volume 8 committee found that the high prevalence of medically unexplained disability in Gulf War veterans could not be completely explained by specific psychiatric causes or disorders. Somatization disorder, which is rare, requires eight symptoms that are not caused by a medical illness. Somatoform disorders in DSM-IV included separate diagnoses such as somatization disorder, hypochondriasis, pain disorder, and undifferentiated somatoform disorder. The latter is a disorder with little specificity and is by far the most commonly found; it requires only one symptom that cannot be attributed to known medical causes. In the study by Ismail et al. (2002), “undifferentiated somatoform disorder” was more commonly seen in deployed than in nondeployed Gulf War veterans and in disabled Gulf War veterans compared with disabled veterans from other wars, but the diagnosis was present in only a small minority of disabled Gulf War veterans, and medical evaluations were not sufficiently comprehensive to rule out medical explanations for the symptoms in those given the undifferentiated somatoform disorder diagnosis. Fiedler et al. (2006) and Toomey et al. (2007) found almost no cases of somatization disorder among Gulf War veterans, nor was there a significant elevation in somatization disorder among deployed vs nondeployed veterans. They and other researchers (Al-Turkait and Ohaeri, 2008; Toomey et al., 2007) found a statistically significant increase in the prevalence of psychiatric disorders, notably PTSD, MDD, and substance dependence, in deployed vs nondeployed Gulf War veterans. Thus, based on available evidence that used the DSM-IV for diagnoses, the high prevalence of medically unexplained disability in Gulf War veterans cannot be explained by DSM-IV somatoform disorders.

On the basis of available evidence, the Volume 8 committee concluded that there was sufficient evidence of a causal relationship between traumatic war exposures experienced during deployment to the Gulf War and PTSD. The committee also concluded that there was sufficient evidence of an association between deployment to the Gulf War and other psychiatric disorders, including generalized anxiety disorder, depression, and substance abuse, particularly alcohol abuse. Furthermore, these disorders persist for at least 10 years after deployment. Finally, the excess of unexplained medical symptoms reported by deployed Gulf War veterans cannot be fully explained by any DSM-IV psychiatric disorder.

New Literature

Primary Studies

During its review of the scientific literature on mental health disorders in Gulf War veterans published since 2008, the committee identified only one new study that met its criteria for a primary study (Sim et al., 2015). The Australian-based Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013, is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war (Sim et al., 2015). Because only about 2% of the participants were women, only males were recruited for the study. Results were adjusted for age, rank category, and service branch. Of the deployed cohort of 1,456 eligible veterans, 715 participated in

the study and 675 of the 1,449 nondeployed veterans provided the comparison group. There were four survey components (see Chapter 3), one of which—the CIDI administered via telephone—was used to assess the presence of mental health disorders. Based on the CIDI interviews, as well as responses to the PTSD Checklist (PCL) and self-reports of doctor-diagnosed and treated PTSD in the past 12 months, 7.3% (PCL) and 8.2% (CIDI) of the deployed veterans met the criteria for PTSD compared with 2.7% (PCL) and 4.8% (CIDI) of the nondeployed veterans. Compared with the prevalence of PTSD in the baseline study, deployed veterans were more likely to have PTSD in the follow-up (RR = 1.96, 95% CI 1.29–2.97). Furthermore, Gulf War veterans were more likely to develop incident PTSD than nondeployed veterans (RR = 2.29, 95% CI 1.24–4.24). The authors report that excess PTSD in Gulf War veterans appears to persist even 20 years after the war, and it appears to be increasing with time compared with the nondeployed veterans.

Sim et al. (2015) also used the CIDI to assess for other mental health disorders in the Australian veterans between 2011 and 2013. Compared with nondeployed veterans, deployed veterans had a greater risk for 12-month alcohol use disorder at follow-up (RR = 1.93, 95% CI 1.10–3.38) or the AUDIT (RR = 1.26, 95% CI 1.05–1.52), but not self-reported doctor diagnosis and treatment (RR = 1.55, 95% CI 0.64–2.81). The prevalence of alcohol use disorder had about doubled in deployed veterans since the baseline study (RR = 2.0, 95% CI 1.25–3.20); a similar increase in nondeployed veterans was not statistically significant (RR = 1.78, 95% CI 0.84–3.76). The number of substance use disorders was too small to allow for statistical analysis and was not assessed. There were no statistically significant differences between the Gulf War and era veterans in the prevalence of other 12-month mental health disorders (as measured by the CIDI) including dysthymia, bipolar disorder, generalized anxiety disorder, obsessive compulsive disorder, social phobia, specific phobia, panic disorder, drug dependence or abuse, and any somatic disorder (i.e., somatization, conversion disorder, pain disorder, and hypochondriasis).

Compared with PTSD and alcohol use disorders, the prevalence of MDD did not differ between the two groups at follow-up (RR = 1.2, 95% CI 0.8–1.7), although it had increased by about 2% in each group since the baseline assessment (from 7.8% to 9.6% in deployed and from 5.0% to 7.2% in nondeployed veterans) (Sim et al., 2015). In a separate analysis of the depression data, it was noted that deployed veterans reported slightly more severe symptoms and were more likely to have been prescribed antidepressants (RR = 1.56, 95% CI 1.05–2.32). There was also a dose–response relationship between depression and self-reports of war-related stressors (Ikin et al., 2015).

Sim et al. (2015) also reported that one out of four Gulf War veterans and one out of six comparison group participants met the criteria for at least one CIDI-defined 12-month psychiatric disorder at followup. This difference between groups was statistically significant.

Secondary Studies

The committee identified only two studies published in the peer-reviewed literature that met its criteria for a secondary study. In 1997, Ishoy et al. (2004) examined psychological symptoms in 686 Danish Gulf War veterans and 231 nondeployed military controls who were matched to the deployed veterans on age, gender, and profession. Subjects completed the Symptom Checklist, revised edition (SCL-90-R), that measures self-reports of symptoms of psychological distress in nine dimensions: somatization, obsessive-compulsive symptoms, interpersonal sensitivity, depression, anxiety, hostility, phobia, paranoid ideation, and psychoticism. Being a Gulf War veteran was statistically significantly associated with six of the nine dimensions—somatization, interpersonal sensitivity, anxiety, hostility; the strongest associations were with obsessive-compulsive and depression. The associations with phobia, paranoid ideation, and psychoticism were not significant.

In addition to the published study by Ishoy et al. (2004), Dursa et al. (2016) published on the most recent results of the third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans. The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. Depression and alcohol use are included in the survey, and participants were also asked about the effect of a variety of emotional problems on their daily lives. The 17-question PCL was used to screen for PTSD. After adjustment for age, race, sex, service branch, and unit component, the adjusted OR for a positive screen for a mental health condition for deployed vs era veterans was 1.93 (95% CI 1.67–2.24) for PTSD, 1.56 (95% CI 1.41–1.73) for MDD, 1.24 (95% CI 1.08–1.38) for other depressive disorders, and 1.34 (95% CI 1.17–1.54) for other anxiety disorders.

Other Related Studies

Blore et al. (2015) reviewed 14 studies that compared the presence of depression and dysthymia or chronic dysphoria in Gulf War veterans with nondeployed veterans (11 of the studies were discussed in Volumes 4 or 8). The authors concluded that although PTSD has been the focus of attention in past studies, depression and dysthymia were twice as common among Gulf War veterans compared to nondeployed military personnel (OR = 2.28, 95% CI 1.88–2.76 and OR = 2.39, 95% CI 2.0–2.86, respectively), regardless of the method used to screen for or diagnose the disorders.

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including mental health diagnoses (ICD-9-CM 290–319) (see Table 4-10). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the veteran is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

The prevalence of PTSD specifically in U.S. Gulf War veterans has been the subject of a systematic review and meta-analysis by Magruder and Yeager (2009). Using quality adjusted Forrest plots of 12

TABLE 4-10 10 Most Frequent Mental Health Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

NOTE: NEC = not elsewhere classified.

SOURCES: VA, 2014a,b.

papers published between 1993 and 2003 that assessed PTSD in deployed and nondeployed veterans (one paper was on women veterans only), the authors found that deployed veterans were twice as likely to develop PTSD as were nondeployed veterans (overall OR = 2.03, 95% CI 1.32–3.15; OR range for the 12 papers was 0.74–5.98). Studies were adjusted for sampling methods, sampling frame and study population, PTSD diagnostic criteria, time since exposure, survey methods, exposure assessment, participation rate, analytic strategy, and interviewer training. A similar meta-analysis was done by Kelsall et al. (2015) looking at literature published on Gulf War veterans between 1990 and 2014. They found seven studies that looked at alcohol use disorders in deployed and nondeployed Gulf War veterans and determined a summary OR of 1.33 (95% CI 1.22–1.46). The three studies that assessed substance use disorders in Gulf War veterans yielded an OR of 2.13 (95% CI 1.11–1.66). Kelsall et al. derived ORs for any studies that did not include them. All of the studies in these meta-analyses had been reviewed by the Volume 8 committee.

Although there were few papers that provided any evidence on which to reconsider the conclusions of the Volume 8 committee, this committee did identify several papers that contained findings that may inform future research efforts. For example, in a study of 1,197 male Royal Australian Navy veterans who had served in Gulf War, McKenzie et al. (2010) found that in veterans with no prewar history of mental health diagnoses, postdeployment diagnoses of alcohol abuse or dependence, anxiety disorders, and affective disorders peaked in the first 2 years after deployment, but then decreased in subsequent years. Alcohol abuse and dependence was the most prevalent diagnosis, and was greatest in veterans reporting the most psychological stressors, but anxiety disorders were the first to be evident. Although the onset of affective disorders also peaked at 1–2 years after the war, the effect of time phase was not significant.

In a 2003–2005 follow-up to the 1995 National Health Survey of Gulf War Veterans and Their Families, Coughlin et al. (2011a) found that PTSD was more prevalent in both deployed and era Gulf War veterans who were obese or overweight compared with Gulf War veterans who were of normal weight (OR = 1.5, 95% CI 1.2–1.8 and OR = 1.2, 95% CI 1.0–1.5, respectively). These same researchers also found that when deployed veterans who had drinking problems were compared with deployed veterans who did not have drinking problems, the former were more likely to have PTSD (OR = 2.72, 95% CI 2.33–3.16) and MDD (OR = 2.32, 95% CI 1.99–2.70). PTSD and MDD were also more prevalent in nondeployed veterans with drinking problems (Coughlin et al., 2011b). Heavy drinking was defined as ≥ 15 drinks per week.

Previous IOM Gulf War and Health committees have found that veterans exposed to traumatic war experiences show higher rates of mental health disorders, particularly of PTSD, than those with low or no exposure or nondeployed veterans (IOM, 2008b). The Gulf War and Health, Volume 6 report on deployment-related stress (IOM, 2008b) found a dose–response relationship between the degree of traumatic war exposure and PTSD, but deployment to a war zone even without direct combat exposure could be considered to be a risk factor for the development of PTSD and other mental health disorders such as anxiety and depressive disorders (Ikin et al., 2004). Recent studies of Gulf War veterans continue to show that being in combat and exposed to dead, wounded, and dying people adversely affects mental health (Gade and Wenger, 2011); increases the likelihood of developing PTSD but not depression (Maguen et al., 2011); and leads to a higher level of postdeployment substance abuse, particularly alcohol use (Kelsall et al., 2015; Maguen et al., 2011). One large study that assessed Gulf War veterans over time found that between 1995 and 2005, the number of deployed veterans with PTSD increased significantly (p < 0.05) from 12.01% to 14.4%, and this rate was three times that of nondeployed veterans (3.9% and 4.0%, respectively) (Li et al., 2011a).

Other studies have found that the presence of PTSD increases the risk of having other psychiatric and physical conditions (IOM, 2012).

Conclusions

A well-accepted reality in today’s medical practice is the frequent co-occurrence of chronic physical conditions such as diabetes, hypertension, and cancer, with mental health conditions such as depression, anxiety, and PTSD. This co-occurrence of health conditions can make it difficult to disentangle the physical from the psychological components of these conditions.

The Volume 10 committee identified only one new primary study and two secondary studies that provided new information on the mental health status of Gulf War veterans. The primary study found that even 20 years after the war, deployed Australian veterans continued to have a greater prevalence of PTSD and were more likely to develop PTSD than nondeployed veterans. Two secondary studies also supported the finding that even many years after the war, U.S. and Danish Gulf War veterans experience more PTSD, depression, and other mental health conditions than nondeployed veterans.

The committee finds that associations between Gulf War service and PTSD, generalized anxiety disorder, substance abuse, and depressive disorders are well established. Furthermore, the committee finds that monitoring and treating these issues and the mental and physical problems that may have caused them deserves greater attention than additional studies that seek to examine their relationship to Gulf War deployment.

The committee recognizes that comparing combat-related PTSD in deployed and nondeployed veterans is not necessarily the best approach for determining the risk of PTSD in either group. Nondeployed veterans cannot have PTSD related to non-existent combat experiences. However, as noted in the Summary of Volumes 4 and 8 section, some of the studies reviewed in the earlier volumes reported that increased levels of combat exposure may result in an increase in PTSD among the deployed veterans, that is, the greater the exposure the more likely the development of PTSD and the more severe its symptoms. Interestingly, even years after the war, deployed veterans continue to show a greater prevalence of PTSD (combat related or otherwise was not specified) and a greater risk for new incidence of it than nondeployed veterans (Sim et al., 2015). Whether the cause of the PTSD in later years is deployment or a post-war exposure was not stated in the study of Australian veterans. As noted in the IOM reports on PTSD (IOM, 2012, 2014c), although delayed onset PTSD can occur it is not common. Furthermore, some veterans may have many of the symptoms of PTSD for years, but initially may not have met the full criteria for such a diagnosis. Future long-term studies of PTSD in Gulf War veterans or other veteran groups would be enhanced by providing information on the traumatic event that precipitated the development of PTSD in both deployed and nondeployed veterans. For the most part, the studies reviewed by Gulf War and Health committees, including this one, have not adequately determined the cause of PTSD in any of the veterans. The use of screening measures, without subsequent diagnostic assessments, is inadequate to make this determination.

Therefore, the Volume 10 committee concludes that there is sufficient evidence of a causal relationship between traumatic experiences during deployment to the Gulf War and PTSD. The committee also concludes that there is sufficient evidence of an association between deployment to the Gulf War and generalized anxiety disorder, depression, and substance abuse (particularly alcohol abuse).

TABLE 4-9 Mental and Behavioral Health Conditions

NOTE: AUDIT = Alcohol Use Disorders Identification Test; BAI = Beck Anxiety Inventory; BDI-II = Beck Depression Inventory; BSI = Brief Symptom Inventory; CAPS = Clinician Administered PTSD Scale; CES = Combat Exposure Scale; CI = confidence interval; CIDI = Composite International Diagnostic Interview; DSM-IV = Diagnostic and Statistical Manual of Mental Health Disorders, fourth edition; GAD = generalized anxiety disorder; GHQ-12 = 12-Item General Health Questionnaire; GWV = Gulf War veteran; ICD = International Classification of Diseases; MDD = major depressive disorder; NDV = nondeployed veteran; NS = not significant; OR = odds ratio; PCL = PTSD Checklist; PCL-M = PTSD Checklist–Military Version; POW = prisoner of war; PRIME-MD = Primary Care Evaluation of Mental Disorders; PTSD = posttraumatic stress disorder; QoLI = Quality of Life Inventory; RR = risk ratio; SCID = Structured Clinical Interview for DSM Disorders; SF-12 = 12-Item Short Form Health Survey; SF-36 = 36-Item Short Form Health Survey; SNAP = Special Needs Assessment Profile; UK = United Kingdom; U.S. = United States.

NEUROLOGIC CONDITIONS

Neurologic conditions have been associated with a variety of environmental exposures, such as those experienced by Gulf War veterans while deployed. In addition to exposures to nerve agents, organophosphate pesticides, and prophylactic agents such as pyridostigmine bromide, exposure to combat with its inherent and immediate risk of traumatic brain injury (TBI) and traumatic peripheral nerve injury can also result in the subsequent development of posttraumatic neurologic conditions including localization-related epilepsy and cognitive disorders related to focal and diffuse TBI. Other risk factors for the development of specific neurologic disorders include age and family history. Among the neurologic problems that have been studied following deployment to the Gulf War are peripheral nerve pain, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), immune-mediated neuropathies (including Guillain Barré syndrome), and migraines. In this section, the committee considers previous Gulf War and Health reports and new literature on neurologic conditions, specifically peripheral neuropathy, MS, ALS, and other neurodegenerative conditions in Gulf War veterans. In each section, the committee summarizes the findings and conclusions from Gulf War and Health Volume 4 and Volume 8, reviews the new literature published since Volume 8, and discusses any other studies that do not meet the criteria of a primary or secondary study but that nonetheless provide further information to assess neurological conditions in Gulf War veterans. All primary studies of neurologic conditions are summarized in Table 4-11 at the end of this section.

Peripheral Neurologic Disorders

Peripheral neuropathy may be defined as weakness, numbness, and pain in the nerves, typically, but not exclusively, in the hands and feet. Peripheral neuropathy can result from traumatic injuries, diabetes, alcohol abuse, infections, metabolic problems, inherited factors, and exposure to toxicants, including chemotherapeutic agents. This section reviews studies of peripheral mononeuropathy, polyneuropathy, or neuromuscular symptoms, as identified by the investigators conducting the studies.

Types of peripheral neurologic conditions and their diagnoses were characterized in Volumes 4 and 8 of the Gulf War and Health series and are not repeated here. This committee agreed with prior Gulf War and Health committees in that neurophysiologic studies with objective measures are especially helpful in determining the presence of neuropathy and are used in conjunction with clinical evaluations including diminished or absent distal deep tendon reflexes, distal or symmetric leg and foot weakness and atrophy, and change in sensation in toes and feet. Studies that include objective and quantitative measures, such as nerve conduction tests or more sophisticated neurophysiological tests, and even nerve biopsies, are optimal and considered to be primary studies. Studies that relied solely on self-reports of neuropathic symptoms (including numbness, neuropathic pain, weakness, among other related symptoms) were considered to be secondary.

Summary of Volumes 4 and 8

In Volume 4, two primary studies were identified. One was a large, well-designed population-based study of a VA cohort that looked at the presence of distal symmetric polyneuropathy in 1,047 deployed and 1,121 nondeployed Gulf War veterans (Davis et al., 2004). The neuropathy was evaluated based on history, physical examination, and standardized electrophysiological assessment of motor and sensory nerves. Spouses of each group of veterans and 240 Khamisiyah-exposed veterans were also studied. That committee found that the distal symmetric polyneuropathy identified by nerve conduction was the

best, most reliable measure of peripheral neuropathy. There were no significant differences between the deployed and nondeployed veterans in term of distal symmetric neuropathy, nor were there differences upon physical examination or self-reported peripheral neuropathy, although more deployed veterans reported numbness and tingling. The other primary study was a smaller evaluation of UK troops deployed to the Gulf War who handled pesticides and nerve agent prophylaxis (Rose et al., 2004; Sharief et al., 2002). Objective neurologic and myopathic testing showed no significant differences between deployed and nondeployed veterans who had neuromuscular symptoms of Gulf War illness with the exception of greater effort on the bicycle exercise test.

The four secondary studies reviewed in Volume 4 also showed a lack of association between deployment and peripheral neuropathy on the basis of objective measures or were inconclusive. Some studies reported higher rates of peripheral neuropathy, but they used self-reports, which the committee did not accept as a reliable measure of peripheral neuropathy. The different case definitions of peripheral neuropathies used by researchers led to problems with ascertainment, and thus, it was difficult to make comparisons among studies.

The Volume 8 committee identified one additional primary study of Australian Gulf War veterans (Kelsall et al., 2005). On the basis of self-report, the deployed veterans had more lower-extremity symptoms that were considered to be possibly indicative of neuropathy but they did not differ from nondeployed veterans on the basis of neurologic examinations. The increased self-reports of neurological symptoms were associated with self-reports of immunizations and exposure to chemical agents including PB and pesticides. The authors found no clinical evidence of an increased risk of myopathy or muscle weakness across the entire cohort. Therefore, the Volume 8 committee concluded that there was limited/suggestive evidence of no association between deployment to the Gulf War and peripheral neuropathy.

New Literature

The Volume 10 committee did not identify any new primary studies that assessed the association between deployment to the Gulf War and peripheral neurologic disorders.

Secondary Studies

The committee found two studies that met its criteria for secondary studies because they were based on self-reports of health conditions. Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013. This study is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Neuropathic symptoms were based on self-reports for 17 symptoms. Deployed veterans were significantly more likely to report at least one neuropathic symptom in the previous month than nondeployed veterans (60% vs 52%; RR = 1.13, 95% CI 1.03–1.25) and more likely to report at least four neuropathic symptoms (24% vs 18%; RR = 1.32, 95% CI 1.07–1.64). Among the symptoms of muscle weakness, the most significant differences were found for difficulty lifting object above head (RR = 1.42, 95% CI 1.13–1.79), difficulty getting up from sitting in a chair (RR = 1.25, 95% CI 1.06–1.48), and problems with tripping or feet slapping while walking (RR = 1.54, 95% CI 1.07–2.22); the symptoms of sensory disturbance with the greatest differences were difficulty feeling pain, cuts, or injuries (RR = 3.25, 95% CI 1.45–7.30), and unusual sensitivity or tenderness of skin when clothes or bedclothes rub against the

person (RR = 2.07 95% CI 1.23–3.46); the difference in the one symptom of autonomic dysfunction (feeling faint when standing up from lying or sitting) was not significant.

The wave 3 survey of the cross-sectional National Health Study of Persian Gulf War Era Veterans was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks (Dursa et al., 2016). There was a significant difference in the self-reports of neuralgia between the deployed and era veterans (9.4% vs 6.3%; OR = 1.65, 95% CI 1.40–1.95). The OR was adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the nervous system and sense organs (ICD-9 codes 320–389). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans. Of these veterans, 166,396 (58.0%) deployed veterans and 156,772 (58.1%) nondeployed veterans had any diagnosis for ICD-9 codes 320–389. Of these, 11.9% of deployed veterans and 11.8% of nondeployed veterans had a diagnosis of mononeuritis of the upper limb or mononeuritis multiplex (VA, 2014a,b).

Conclusions

The primary studies that assessed peripheral neuropathy used objective measures, clinical examinations, or both to diagnose the damage. These studies uniformly found no association between deployment to the Gulf War and peripheral neuropathy in the veterans. However, several of the secondary studies that relied on self-reports of neurological problems did find increased reporting of those problems among veterans who had deployed to the Gulf War when compared with nondeployed veterans. The committee believes that objective measures are a more reliable diagnostic tool than self-reports.

It is reasonable to consider polyneuropathy to have two phases of expression. The first is related to proximate exposure in the field due to some hypothesized toxic factor (e.g., pesticide exposure), and the second is late in life with deployment to the Gulf War serving as a modifying factor. That is, perhaps some exposure experienced during the Gulf War would make a veteran more likely to express polyneuropathy in later life, whether as an idiopathic entity or even in a veteran with a known causal factor, such as a nutritional or diabetic neuropathy, or even Charcot-Marie-Tooth disease (one of the most common genetic neurologic conditions). Although the committee recognizes that these phases are speculative, they do argue for peripheral neuropathy as a continuing area of study in aging Gulf War veterans; however, the committee also emphasizes that age itself is one of the stronger factors associated with symmetric loss of ankle jerk reflexes, which is often asymptomatic, but is nonetheless an objective evidence of polyneuropathy.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and objective measures of peripheral neurologic conditions.

Multiple Sclerosis and Related Neuroinflammatory Conditions

MS is a chronic inflammatory disease of the brain and spinal cord caused by an immune-mediated attack primarily on the myelin membrane that surrounds and insulates nerve fibers (axons) that are responsible for normal transmission of electrical and chemical information in the nervous system. MS can vary from a relatively benign illness to a rapidly evolving and incapacitating disease. Symptoms of MS—such as weakness of the limbs, numbness, vision loss or blurring, pain, imbalance, fatigue, slowed thinking, and bladder/bowel/sexual dysfunction—reflect the loss of neural connections required for normal function.

MS affects about 400,000 people in the United States and is approximately three times more common in women than men (Multiple Sclerosis Association of America, 2015). The age of onset is typically between 18 and 40 years of age, but the disease can present across the life span. MS also appears to be increasing in frequency in multiple populations, especially in women. The environmental factors that influence MS are not known; however, several risk factors have been implicated in the development of MS, including infection with Epstein-Barr virus, ultraviolet light exposure and vitamin D status, and cigarette smoking (Wingerchuk, 2011).

Summary of Volumes 4 and 8

No literature on MS was available for review in Volume 4, but one secondary study was reviewed in Volume 8 (a primary study on mortality from MS is discussed in the section “Causes of Mortality”). The small secondary study (Kelsall et al., 2005) did not show any increased risk for MS in the deployed Australian Gulf War cohort. Therefore, the Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and MS. The Volume 8 committee recommended that additional well-designed, adequately powered studies of MS incidence following deployment are needed.

New Literature

Primary Study

The committee identified one new primary study that assessed the association between deployment to the Gulf War and MS. Wallin et al. (2014) assembled an incident cohort of veterans of the Gulf War who had been on active-duty military service during the 1990–1991 war. Cases of MS were identified based on VA Compensation and Pension files for service connection for MS for 17 years after the war. Service connection for MS requires definitive evidence of clinical signs of MS upon examination during or within 7 years after military service. The authors found 330 cases of MS among the 696,118 deployed veterans (250 in males and 80 in females) and 1,230 cases among the 1,780,215 nondeployed veterans (837 in males and 393 in females), resulting in a total relative risk of 0.69 (95% CI 0.61–0.78) for MS in deployed vs nondeployed. The RR for men was 0.72 (95% CI 0.62–0.83) and 0.96 for women (95% CI 0.75–1.22).

Wallin et al. (2014) also assessed the association between deployment to the Gulf War and neuromyelitis optica and other neurologic conditions that the authors grouped under the term “other demyelinating disease” (ODD), that is demyelinating conditions other than MS. ODD also included possible MS (compared with definite MS), transverse myelitis, optic neuritis, and other clinically isolated syndromes. An incident cohort of 57 deployed veterans of the Gulf War who had an ODD diagnosis was compared with 224 nondeployed ODD-diagnosed veterans of the same era. Possible MS was the most common ODD, followed by optic neuritis. The absolute risk (17-year cumulative risk) for any ODD was 8.19 for deployed personnel (57 cases in 696,118 service members) and 12.54 for nondeployed personnel (224 cases in 1,786,215 service members). Further analysis comparing deployed with nondeployed veterans was not conducted.

Secondary Studies

The committee found two studies that met its criteria for secondary studies. In the Sim et al. (2015) Australian Gulf War Veterans’ Follow Up Health Study discussed in the previous section on peripheral neurologic disorders, only 1 of the 697 deployed male Australian Gulf War veterans and 1 of the 659 nondeployed veterans reported a doctor-diagnosed case of MS.

Dursa et al. (2016) reported results from the third wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had multiple sclerosis. The adjusted OR for self-reported MS in the deployed vs nondeployed veterans was 1.35 (95% CI 0.72–2.51) and the prevalence was 0.6% and 0.5%, respectively.

Conclusions

Together the new primary study and the two additional secondary studies, combined with the study in Volume 8, indicate that Gulf War veterans do not have an increased risk of developing MS.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and multiple sclerosis.

Amyotrophic Lateral Sclerosis

ALS, often referred to as Lou Gehrig’s disease, motor neuron disease, or Charcot’s disease, is a neuromuscular disease that affects approximately 20,000 to 30,000 people in the United States (ALS Association, 2008; National Institute of Neurological Disorders and Stroke, 2006, 2009). ALS affects all races and ethnic backgrounds, and the risk is higher in men than women of the same age (Annegers et al., 1991). The disease is almost always fatal, although the rate of progression varies from patient to patient.

ALS causes degeneration of the motor neurons in the cerebral motor cortex, the brain stem, and the spinal cord (Rowland, 2000). The motor neurons are nerve cells that provide communication between the highest levels of the nervous system and the voluntary muscles of the body (National Institute of Neurological Disorders and Stroke, 2006). When the upper motor neurons degenerate, their connections to the lower motor neurons and spinal interneurons are disrupted, leading to muscle weakness and spasticity. Lower motor neuron degeneration disrupts nerve contact to the muscles resulting in muscle atrophy. Eventually, affected people are unable to move their arms and legs and cannot speak or swallow. When the connection between the neurons and the muscles responsible for breathing is disrupted,

patients either die from respiratory failure or require mechanical ventilation to continue to breathe. The majority of persons with ALS die from respiratory failure within 5 years from the onset of symptoms. To be diagnosed with ALS, patients must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes.

While most cases of ALS are sporadic, about 10% of cases are transmitted through families as a dominant trait (Sreedharan and Brown, 2013). These inherited forms of ALS have provided a powerful opportunity to dissect pathological events that trigger motor neuron disease. The gene most commonly mutated in ALS (about 40–45% of familial cases and 5–8% of sporadic cases in the United States) is also implicated in frontotemporal dementia; it is designated C9orf72 (DeJesus-Hernandez et al., 2011; Gijselnck et al., 2012; Renton et al., 2011). Some variability in C9orf72 prevalence by race/ethnicity and country of origin exists in both sporadic and familial ALS (Majounie et al., 2012). The defect is expansion of intronic hexanucleotide repeats. The second most common ALS gene is superoxide dismutase, whose mutations (usually missense changes) account for approximately 20% of ALS cases. Mutations in the RNA binding proteins FUS/TLS and TDP43 each account for approximately 5% of cases. All told, there are upward of 50 ALS genes with clear Mendelian inheritance and more than 120 that may bear on the genetic risk of ALS.

Several hypotheses purport to explain why these mutations are pathogenic (Ling et al., 2013; Peters et al., 2015). Many mutations, like SOD1, lead to protein instability and aggregation with multiple adverse effects on cellular metabolism. Others, like FUS/TLS (Kwiatkowski et al., 2009) and TDP43 (Sreedharan et al., 2008), perturb RNA metabolism both within the cell body and in dendrites and axons. Toxicity of the C9orf72 expansions probably arises in part from deposition of RNA foci in cell nuclei, which sequesters intranuclear proteins, disturbances of nuclear membrane transport, and in part via expression of toxic dipeptides through atypical protein translation.

The causes of sporadic ALS are not well defined, but may include complex interactions of multiple gene variants, exposure to environmental toxins, and activation of endogenous retroviruses, as well as occupational, socioeconomic, demographic, and life style risk factors (Li et al., 2015; Mayo Clinic, 2014). Despite a number of epidemiologic studies examining environmental, occupational, socioeconomic, demographic, and life style risk factors for ALS, to date no consistently identified nongenetic risk factors have been reported (Armon, 2003, 2004; Armon et al., 1991; Cermelli et al., 2003; Chio et al., 2005; Kamel et al., 2002; McGuire et al., 1996, 1997; Nicolson et al., 2002; Rowland, 2000; Valenti et al., 2005).

Summary of Volumes 4 and 8

In Volume 4, two primary studies (Coffman et al., 2005; Horner et al., 2003) and one secondary study (Haley, 2003) found that deployed veterans appear to be at increased risk for ALS. In the nationwide epidemiologic case ascertainment study, Horner et al. (2003) found an almost two-fold increase in the risk of ALS for the deployed Gulf War veterans compared with nondeployed (RR = 1.92, 95% CI 1.29–2.84). In a further study of the same data using capture–recapture analysis, Coffman et al. (2005) confirmed the nearly doubled risk. A secondary study found a slightly higher relative risk but within the same overall range when Gulf War veterans were compared to the general U.S. population. Other U.S. and UK mortality studies and a hospitalization study have not found an excess risk of ALS in Gulf War veterans (see the section on causes of mortality in this chapter). The Volume 4 committee concluded that further follow-up was warranted.

In Volume 8, one new primary study (Horner et al., 2008) extended the follow-up of the author’s earlier study through 2001 and described a short-term increase in ALS risk in the deployed Gulf War

veterans during the decade after the war. These analyses together support an estimate of a near doubling in risk among deployed veterans compared with nondeployed veterans. The Volume 8 committee concluded that there was limited/suggestive evidence of an association between deployment to the Gulf War and ALS; however, further follow-up was warranted.

New Literature

Primary Study

The committee identified one new primary study of ALS in Gulf War veterans by Kasarskis et al. (2009). This extension of the earlier epidemiologic studies by Horner et al. (2003, 2008) included an additional 28 veterans identified during the 2001–2002 follow-up surveillance period for a total of 43 deployed and 66 nondeployed veterans with ALS (deployment status was based on designation by the Defense Manpower Data Center [DMDC]). Median ventilator-free survival time for deployed veterans was significantly less than that of nondeployed veterans (40.2 vs 57.0 months, HR = 0.62, 95% CI 0.40–0.96, p = 0.03) when adjusted for age and neuroanatomical region of onset of clinical disease.

Secondary Studies

Only two studies met the committee’s criteria for a secondary study. In the Australian Gulf War Veterans’ Follow Up Health Study discussed in the previous sections, Sim et al. (2015) found that only 2 of the 697 deployed male Australian Gulf War veterans had ALS and none of the 659 nondeployed veterans reported having ALS. Given the few cases of ALS, statistical analyses could not be conducted.

The committee also considered the results from Dursa et al. (2016) on the third wave of the National Health Study of Persian Gulf War Era Veterans (discussed in the previous section). The adjusted OR for self-reported ALS in the deployed (0.1% of 8,104) vs era (0.05% of 6,148) veterans was 4.32 (95% CI 0.82–21.74; adjusted for age, race, sex, BMI, smoking status, service branch, and unit component).

Other Related Studies

Miranda et al. (2008) attempted to link the risk of developing ALS in deployed military personnel to specific geographic areas in the Gulf War region using geographic information system modeling. They found that the estimated ALS risk was greatest, although not statistically significant, for troop units with a potential exposure to nerve agents resulting from the munitions destruction at Khamisiyah (RR = 1.7, 95% credible interval⁴ 0.7–3.7). The authors cautioned, however, that there may have been other unknown exposures in the plume that may account for the increased risk.

Conclusions

The one new primary study and the two new secondary studies provided further information on the association between ALS and deployment to the Gulf War. Only one of the studies indicated an increase in ALS among the deployed veterans compared with nondeployed veterans. One study suggested that deployed veterans had a more rapid decline than nondeployed veterans although no explanation for

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⁴ “Essentially a Bayesian version of a confidence interval” (Miranda et al., 2008).

this outcome was suggested. Thus, the new literature does not substantially alter the Volume 8 conclusion, including the need for further follow-up of veterans with and without ALS and both deployed and nondeployed. Since the publication of Volume 8, a substantial growth of knowledge has occurred regarding genetic risk alleles as well as highly penetrant genes associated with ALS. The absence of this information in prior studies is an important limitation in fully understanding the scope of risk of ALS and Gulf War deployment.

Therefore, the Volume 10 committee concludes that there is limited/suggestive evidence of an association between deployment to the Gulf War and amyotrophic lateral sclerosis; however, further follow-up continues to be warranted.

Other Neurodegenerative Conditions

Alzheimer’s disease is the most common neurodegenerative disorder and a cause of dementia in elderly populations. Parkinson’s disease—primarily considered a movement disorder—is the second most common neurodegenerative disorder. Both have progressive courses and no known cure. The neurodegeneration in Parkinson’s disease has been associated with a combination of repeated, prolonged, or chronic exposures to toxicants (particularly pesticides), genetic factors, gene–toxicants interactions, and aging-related effects. In contrast with the Parkinson’s disease literature, the associations, if any, between Alzheimer’s disease and related disorders and environmental toxicants, or their interactions with age or genetic factors, are not as well established.

Summary of Volumes 4 and 8

The committee was unable to identify any studies of dementia or Alzheimer’s disease in Gulf War veterans for Volumes 4 and 8, or for the current study. This committee did not identify any new literature on Parkinson’s disease in Gulf War veterans. The Volume 8 committee noted that Parkinson’s and Alzheimer’s diseases generally present later in life (usually after age 60) and thus, it is unlikely that Gulf War veterans would manifest symptoms or signs of these neurodegenerative disorders until they reach at least the sixth decade of life. Therefore, the Volume 8 committee concluded that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurodegenerative conditions.

New Literature

The committee only identified one new study that met the criteria for a secondary study of other neurodegenerative conditions in Gulf War veterans. Dursa et al. (2016) reported results from the third wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had Parkinson’s disease. The weighted prevalence was 0.5% in both deployed and era veterans and the OR was not statistically significant (OR = 1.15, 95% CI 0.59–2.24). However, the committee noted that given the long latency of Alzheimer’s disease, Parkinson’s disease, and related disorders, associations may not be evident without longitudinal prospective monitoring of an aging Gulf War veteran population.

Conclusions

This committee concurs with the determination of the Volume 8 committee that a very long latency period for these health outcomes is a possibility, and that current studies have inadequate follow-up time to assess whether risk for these disorders is increased among Gulf War veterans. Given the lack of new information on the prevalence or incidence of neurodegenerative disease among Gulf War veterans, the Volume 10 committee had no evidence on which to modify the Volume 8 conclusions.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurodegenerative conditions; further follow-up is warranted.

Neurocognitive and Neurobehavioral Outcomes

This section contains an overview and update on neurocognitive and neurobehavioral performance in Gulf War deployed veterans compared with nondeployed veterans.

Summary of Volumes 4 and 8

In Volumes 4 and 8, the committees defined primary studies as those “studies that used neurobehavioral tests that had previously been used to detect adverse effects in population-based research on occupational groups.” In Volume 4, two primary studies found significant differences in neurobehavioral performance—specifically the Purdue Pegboard Test, the California Verbal Learning Test, and the Wisconsin Card Sorting Test—when deployed Gulf War veterans were compared with nondeployed veterans or those deployed elsewhere (David et al., 2002; Proctor et al., 2003). Only one of the three secondary studies found a difference in neurocognition between the two groups. The Volume 8 committee identified two additional secondary studies. One study (Proctor et al., 2006) did not compare deployed with nondeployed veterans but rather looked at neurocognition with respect to putative level of exposure to sarin during deployment. The second study of participants from the National Health Study of Gulf War Era Veterans and Their Families Study, assessed veterans 10 years after the war. Deployed veterans scored poorly compared with nondeployed veterans on two of eight factors (Toomey et al., 2009). The study authors and the committee found that the results did not suggest overall impaired neuropsychological functioning.

In conclusion, primary studies of Gulf War deployed vs nondeployed veterans failed to demonstrate differences in cognitive and motor measures as determined through neurobehavioral testing. Therefore, the Volume 8 committee concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and neurocognitive and neurobehavioral performance.

New Literature

Primary Study

The committee identified one new study that met its criteria for a primary study. The committee did not identify any new secondary studies of neurocognitive or neurobehavioral performance in Gulf War veterans.

In 1997, Ishoy et al. (2004) examined neurobehavioral symptoms in 686 Danish Gulf War veterans and 231 nondeployed military controls that were matched to the deployed veterans on age, gender, and profession. Subjects performed the Coordination Ability Test System (CATSYS) tests including its extensions, the tremor test and the sway test. Physicians administered a questionnaire on cognitive and psychological symptoms the veteran had experienced in the prior 12 months. Results indicated that compared with nondeployed veterans, deployed veterans reported statistically significant increases (p ≤ 0.001) in concentration or memory problems, repeated fits of headache, balance disturbances or fits of dizziness, abnormal fatigue (not caused by physical activity), and problems sleeping all night. However, the CATSYS tests showed that for 23 of the 26 tests results there were no significant differences between the two groups; for the 3 tests for which the difference was significant (p = 0.05: hand supination/pronation test standard deviation, reaction time test standard deviation, and mean sway velocity), the differences between the two groups were small.

Other Related Studies

Wallin et al. (2009) assessed neuropsychologic performance in a sample of 41 veterans from the National Health Survey of Gulf War Era Veterans conducted in 1995. Twenty-five of the participants met the CDC definition of Gulf War illness, and the 16 controls did not. There were no statistically significant differences between the two groups for composite scores on the traditional and computerized neuropsychologic testing battery, which included verbal abilities, vigilance, processing speed, reading level, memory and learning, problem solving and reasoning, motor coordination, speed, and strength, and effort on testing (all p ≥ 0.1). The veterans with Gulf War illness, however, did have significantly more impairment on the Personality Assessment Inventory for somatic complaints, anxiety, anxiety-related disorders, depression, mania, paranoia, and borderline personality disorders (all p < 0.01) but not for schizophrenia, antisocial features, or alcohol or drug problems.

Chao et al. (2010) studied the cognitive effects of possible exposure to sarin and cyclosarin on 40 exposed and 40 unexposed Gulf War veterans who were participating in a study of Gulf War illness at the San Francisco Veterans Affairs Medical Center between 2002–2007. Fifty-four percent of the exposed veterans and 59% of the unexposed veterans met the Fukuda et al. (1998) definition for chronic multisymptom illness. Study participants underwent a neuropsychological test battery. Test results showed no significant differences between the exposed and unexposed groups on measures of general verbal intelligence, attention, executive function, manual dexterity, visuospatial abilities, or memory. When subjects who failed the Test of Memory Malingering were removed from the analysis, there were no statistical differences between the groups for neurobehavioral functioning.

In a cross-sectional, follow-up study of 64 exposed and 64 “matched” unexposed veterans who underwent neuropsychological and magnetic resonance imaging (MRI) assessment, Chao et al. (2011) found exposed veterans committed more errors of omission and had slower responses on the Continuous Performance Test than unexposed veterans, but these were reported without correction for multiple comparisons. Regression analysis found that exposure to the nerve agents predicted the number of continuous performance test omission errors (β = 0.22, p = 0.02).

Conclusions

The one new primary study found only a very small association between deployment to the Gulf War and a few adverse neurobehavioral outcomes in Danish veterans. There were no new secondary studies. These results echo those of the Volume 8 committee.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and neurocognitive and neurobehavioral performance.

Migraines

This section contains an overview and update on migraines in Gulf War veterans compared with nondeployed veterans. Many studies have included headaches as part of multiple item, self-reported symptom checklists or clustered them with other symptoms related to a specific condition, such as CFS and Gulf War illness. For both CFS and Gulf War illness, as well as in general, more headaches are reported among deployed vs nondeployed veterans (Doebbeling et al., 2000; Haley et al., 1997b; Ishoy et al., 1999b; Kang et al., 2000, 2009; Kelsall et al., 2004a; Pierce, 1997; Proctor et al., 1998; Stretch et al., 1995; Unwin et al., 1999). Fewer studies have focused on migraine among Gulf War deployed and era veterans or looked at sex differences in prevalence. The latter point is important as three out of four people with migraines are women.

Summary of Volumes 4 and 8

Volumes 4 and 8 did not include any studies of migraine, and headaches were only considered within the symptom complex of Gulf War illness and CFS. The Volume 8 report also included one study under a section on female veterans’ health that assessed the health of 525 women who had been on active duty or in the reserve or National Guard during the Gulf War, of whom 160 served in the Persian Gulf region (Pierce, 1997). The women were asked about their physical and emotional health 2 years after the war (time 1) and 4 years after the war (time 2). At time 2, deployed women were more likely than nondeployed women to report headaches (p = 0.001), regardless of the length of their deployment. Reported health problems were not related to whether the woman was on active duty, in the reserves, or a member of the National Guard. The Volume 8 committee did not make any conclusions regarding an association between deployment to the Gulf War and migraines or headaches.

New Literature

The Volume 10 committee did not identify any new literature that met its criteria for a primary study, but two secondary studies and one other related study were identified for migraine and other headache disorders in Gulf War veterans.

Secondary Studies

The Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013, assessed the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war (Sim et al., 2015). This study was a follow-up to the Kelsall et al. (2004b), baseline study discussed in Volumes 4 and 8. Results were adjusted for age, rank category, and service branch, but not

for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group; women were not included in the analysis. Health outcomes were based on self-reports and on self-reports of doctor-diagnosed conditions. Deployed veterans were slightly but not statistically significantly more likely to report doctor-diagnosed migraines (RR = 1.06, 95% CI 0.66–1.70). Using a 63-item symptom checklist, 60.2% of deployed veterans and 49.2% of era veterans reported headaches in the last month. Deployed veterans were statistically significantly more likely to report headaches compared with era veterans (RR = 1.19, 95% CI 1.08–1.31). The change in the prevalence of headaches reported between deployed and era veterans was not statistically different. The incidence of headaches (not reported at baseline but reported 10 years later at follow-up)—43% of deployed and 29% of comparison veterans—was statistically significantly higher among deployed than era veterans (RR = 1.43, 95% CI 1.14–1.78).

The second study reviewed by the committee was results from the third wave of the National Health Study of Persian Gulf War Era Veterans, conducted in 2012–2013 (Dursa et al., 2016). The wave 3 survey asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had migraine headaches. If the person answered yes, the next question was whether it had been present in the past 4 weeks. Further in the survey, the same two headache questions that were asked in wave 2 of the survey were repeated. The first asked whether the person had “persistent or recurring problems with” any headaches in the past 12 months. If yes, the person was to indicate whether the headaches were mild or severe (defined at the beginning of the survey section) and whether they had been present for 6 months or longer. Survey respondents were asked to indicate how much they had been bothered by headaches in the past 4 weeks. Questions elucidating potential confounders and risk factors such as experiencing head injury or TBI were not included. The weighted prevalence of migraine headache was 20.3% in the deployed and 16.1% in the era veterans. The odds of migraine headache were statistically significantly increased for self-reported migraine headaches among the deployed compared with the era veterans (OR = 1.30, 95% CI 1.15–1.47; adjusted for age, race, sex, BMI, smoking status, service branch, and unit component). Weighted prevalence of headache was limited to study participants who self-reported having lifetime chronic multisymptom illness.

Other Related Studies

In the VA utilization reports discussed in the section on peripheral neuropathy earlier, 166,396 (58.0%) deployed veterans and 156,772 (58.1%) nondeployed veterans received any diagnosis for ICD-9 codes 320–389. Of these 20,473 (12.3%) deployed veterans and 17,599 (11.2%) nondeployed veterans had a diagnosis of migraine (VA, 2014a,b).

Conclusions

Migraines were not considered independently of symptom complexes of other conditions in Volumes 4 and 8. Two secondary studies were reviewed, but findings were not consistent. Among Australian veterans, the odds of migraine headache were statistically significantly increased for self-reported migraine for deployed compared with era veterans. Among U.S. veterans, deployed veterans did not report statistically significantly more doctor-diagnosed migraines compared with era veterans, but deployed veterans were statistically significantly more likely to report headaches compared with era veterans; over 13 years of follow-up, incident headaches were statistically significantly higher among deployed than comparison veterans.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and migraines and related headache conditions.

Other Neurologic Outcomes

Haley and colleagues performed detailed neurologic assessments in several case-control studies of Seabee reservists to investigate any possible neurologic underpinning of Gulf War illness. The cases were veterans who had met criteria for factor-derived syndromes defined by Haley et al. (see Chapter 3). Under the hypothesis that those veterans were ill from neurotoxic exposures, especially to organophosphates, the assessments covered broad neurologic function (Haley et al., 1997b), autonomic function (Haley et al., 2004), vestibular function (Roland et al., 2000), basal ganglia injury (Haley et al., 2000a,b), normalized regional cerebral blood flow (Haley et al., 2009), and paraoxonase (PON) genotype and serum concentrations (Haley et al., 1999). Separate groups of investigators also studied PON genotype or activity (Hotopf et al., 2003b; Mackness et al., 1997) and neuropsychologic functioning (Hom et al., 1997).

Summary of Volumes 4 and 8

The Volume 8 committee regarded the Seabee case-control studies as secondary studies primarily because of their lack of generalizability, strong potential for selection bias, and small sample sizes. Although their study design was characterized as nested case-control, the studies of Haley et al. are not true nested case-control studies. Cases were, appropriately, selected from the original cohort, but controls were not. With regard to the lack of generalizability, the authors selected as cases the most severely affected veterans—that is, those who scored highest on factor analysis-derived syndromes—whereas the Volume 8 committee thought that a random sample of those who met a particular case definition would be more appropriate.

The Volume 8 committee concluded that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurologic outcomes.

New Literature

The committee did not identify any new literature that met the criteria for a primary or a secondary study of other neurological outcomes in Gulf War veterans.

Conclusions

There was no new literature to supplement or contradict the conclusions of the Volume 8 committee.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and other neurologic outcomes.

Neuroimaging Studies of Gulf War Veterans

Overview of Studies

A number of studies using MRI of the brain have been published on veterans who have Gulf War illness. Veterans who participate in these studies usually have a diagnosis that meets the definition of Gulf War illness as established by Haley et al. (1997b) or by the CDC (Fukuda et al., 1998). These studies span the gamut of different MRI modalities—structural MRI, task activation functional MRI (fMRI), 1H MR spectroscopy, diffusion MRI, and perfusion MRI. Many of these studies attempt to identify correlations between imaging and clinical or psychological findings, while others seek to identify a unique imaging biomarker for Gulf War illness. In this section, the committee considers the limitations of using MRI technology to identify, distinguish, and characterize neurologic conditions in veterans who have or do not have Gulf War illness.

The first limitation is that none of the MRI modalities themselves are specific for any disease or disorder. The small brain volume or reduced cortical thickness (i.e., atrophy) seen on structural MRI, response patterns on task fMRI, spectroscopic metabolite levels, spin diffusion metrics, and tissue perfusion of Gulf War veterans may also be seen in many other disease conditions (Fotuhi et al., 2012). For example, decreased brain volume—especially hippocampal atrophy—figures prominently in many structural MRI studies of Gulf War veterans. However, atrophy of various brain regions, particularly the hippocampus, is seen in many other conditions such as epilepsy; neurodegenerative disorders such as frontotemporal lobar degeneration syndromes and Alzheimer’s disease; sleep disorders; developmental disorders; chronic stress; mental health disorders such as depression, anorexia and PTSD; head trauma; and ischemic cerebrovascular disease. Apfel et al. (2011) and Chao et al. (2014a) both found reduced hippocampal volume to be associated with PTSD in Gulf War veterans, but Chao (2014b) also found reduced brain volume to be associated with disturbed sleep efficiency in Gulf War veterans. Thus, brain atrophy, especially hippocampal atrophy, is not specific for, nor predictive of, Gulf War illness or Gulf War deployment, and any reported imaging findings are potentially attributable to other factors such as PTSD.

Other studies have analyzed N-acetyl aspartate (NAA), a brain metabolite visible on 1H MR spectroscopy, which reflects neuron number and health; it is often referenced as a ratio to creatinine (Cr). Decreased NAA/Cr levels in basal ganglia have been reported in veterans with Gulf War illness compared with veterans without Gulf War illness (Haley et al., 2000a; Menon et al., 2004), but as with atrophy, decreased NAA/Cr is seen in a variety of other conditions and a direct relationship with Gulf War illness cannot be inferred.

Decreased NAA/Cr levels in basal ganglia have been reported in veterans who have Gulf War illness compared with veterans who do not have Gulf War illness (Haley et al., 2000b; Menon et al., 2004). In contrast, Weiner et al. (2011) found no evidence of reduced NAA/Cr in Gulf War veterans with Gulf War illness compared with veterans without Gulf War illness using both the CDC and Haley syndrome 2 definitions of Gulf War illness.

Task fMRI activation is a complex measure that reflects changes from the resting (control) state for both local blood flow and brain oxygen extraction in response to mental tasks. Differences in task activation patterns were found in various groups of veterans with Gulf War illness (Calley et al., 2010; Gopinath et al., 2012; Moffet et al., 2015; Rayhan et al., 2013d; Tillman et al., 2010), but altered task fMRI activation properties have been reported in many neurodegenerative, developmental, psychiatric, and other conditions.

Diffusion MRI is a measure of the magnitude and directionality of the diffusion of water in tissue. Intact tissue microstructure (e.g., white matter tracts, cell membranes, cell processes) impedes the ran-

dom motion (diffusion) of water to a greater extent than tissue with disrupted microstructure. Diffusion MRI uses two common measures, mean diffusivity (MD) and fractional anisotropy (FA), to determine the integrity of tissue microstructure. MD is a scalar quantity, and the lower the MD value the more intact the tissue microstructure. FA is a vector quantity and the greater the FA value the more intact is the white matter tract myelination. The component measures that contribute to FA (radial vs axial diffusivity) are sometimes analyzed separately; however, detailed modeling studies have called into question the validity of this approach (Wheeler-Kingshott and Cercignani, 2009). Perfusion MRI measures tissue perfusion—that is, the delivery of blood via the microvascular system to tissue. Abnormalities in both diffusion and perfusion MRI are seen in many different neurodegenerative and psychiatric conditions such as those mentioned above. In summary the committee recognizes that some of the imaging findings described could mediate symptoms associated with combat exposure (e.g., medical temporal lobe atrophy and PTSD). However, these MRI modalities are not disease-specific biomarkers in contrast to an imaging modality such as amyloid PET imaging (Clark et al., 2011; Ikonomovic et al., 2008; Klunk et al., 2004), which is specific for β-amyloid deposition in Alzheimer’s disease.

The second limitation to attempting to identify imaging biomarkers for Gulf War illness is that specific environmental exposures were not habitually or reliably documented for every unit or for every veteran while deployed to the Persian Gulf region. To date, no imaging studies have identified a specific neuroimaging finding that might serve as a biomarker of exposure for a particular toxicant relevant to Gulf War illness (e.g., sarin, PB, or N,N-diethyl-meta-toluamide [DEET]). Some imaging studies have sought to identify an imaging signature of stress or of other mental health conditions such as PTSD. Although much work is being done in this area, it would be difficult many years after deployment to be sure that any neuroimaging anomalies were the result of deployment-related or combat-related stress rather than a subsequent stressful situation More importantly, exposure to the stress of combat and putative exposure to environmental toxins are often comingled within study cohorts. This makes cause-and-effect inferences between environmental toxin exposure and specific imaging findings suspect.

The third limitation concerns methodological features of many imaging studies in this area. While structural MRI results are highly reproducible over time, derived MRI metrics (perfusion, diffusion, functional activation) are less so. Furthermore, voxel-based or multiple regions of interest-based analyses using atlases for anatomic labeling of brain regions can result in numerous comparisons in a given analysis. Large samples are needed to avoid statistical errors. Unfortunately, the sample sizes in many studies are small, which undermines the reliability of the results, particularly those for the more “noisy” imaging modalities. Another methodological issue is that participants in imaging studies are selected from larger cohorts. The criteria used to select participants for the imaging studies are rarely mentioned, which raises the question of participation bias. Moreover, participant selection biases likely differ from imaging study to study, thus contributing to interstudy inconsistencies. Because of these limitations, results within and across the neuroimaging studies are often conflicting and not reproducible, thereby calling into question any specific imaging signature or consequence of Gulf War illness.

Bierer et al. (2015) found decreased MD and increased FA in the right (but not left) cingulum bundle in Gulf War veterans with PTSD (n = 12) compared to those without PTSD (n = 8). Decreased MD and increased FA imply greater myelination and thus increased anatomic connectivity between brain areas served by these tracts. Bierer et al. also found that the presence of Gulf War illness in those with PTSD diminished these effects. The authors concluded that Gulf War illness is a distinct entity from PTSD, but unlike PTSD, Gulf War illness is associated with decreased central nervous system plasticity. The difficulty with this interpretation is that the inference about a specific effect of Gulf War illness on diffusion measures was based on comparing nine PTSD subjects with Gulf War illness against three PTSD subjects without Gulf War illness. Much larger samples and evidence of independent replication of results

would be needed to draw firm conclusions about pathophysiology. Rayhan and colleagues published a series of papers in 2013 comparing subsets of the same groups of Gulf War veterans with and without Gulf War illness (determined by the Haley criteria). The groups were compared across many regions of interest on measures of diffusion MRI (Rayhan et al., 2013a) and task fMRI (Rayhan et al., 2013c,d). Various associations were found among the different Gulf War illness syndrome groups, but group sizes in some cases were less than 10 subjects. Small sample sizes coupled with failure to correct for multiple comparisons make it difficult to draw any conclusions.

Chao et al. (2015) compared diffusion MRI measures in 59 Gulf War veterans with predicted exposure to sarin/cyclosarin with 59 nonexposed veterans. Although prior research has linked FA changes to documented sarin exposure from the Tokyo subway sarin attack (Yamasue et al., 2007), the authors did not find FA changes in white matter in their predicted sarin-exposed group. They did report increased axial diffusivity among veterans with predicted exposure, but the interpretability of axial/radial diffusivity measures has been called into question (Wheeler-Kingshott and Cercignani, 2009), and Chao et al. (2015) did not correct for multiple comparisons.

Moffet et al. (2015) found fMRI activation differences between Gulf War veterans who met criteria for Haley’s Gulf War illness syndrome 2 compared with controls during a verbal fluency task. The authors infer that the fMRI data provides support for the hypothesis that Gulf War illness syndrome is attributable to unique toxicant exposures during the Gulf War. However, the subjects performed worse on verbal fluency than the controls when the testing occurred outside the scanner. The fMRI findings are not a biomarker for a particular syndrome attributable to toxin exposure but are simply a manifestation of the fact that the control group performed better on verbal fluency tasks than the subject group. The same fMRI result would be expected when any two groups of subjects are compared where one group outperforms the other on the cognitive task of interest. Hubbard et al. (2014) found fMRI activation differences between Gulf War veterans with and without Gulf War illness (Gulf War illness was determined using the Haley criteria). It is noteworthy though that the same research group (Odegard et al., 2013) using a similar functional activation paradigm did not find fMRI differences among the three Gulf War illness syndrome groups.

Chao et al. (2010, 2011) examined brain volume and cognitive performance measures in a group of Gulf War veterans who may have been exposed to sarin or cyclosarin in comparison to matched Gulf War veterans who were not exposed. They found that grey and white matter brain volumes were reduced in the exposed group; however, there was no dose–response relationship between exposure and brain volume (which would be expected if the association were reliable). The exposed group performed worse on some psychometric tests but performed better on other tests. The results overall were inconsistent and do not conclusively support a relationship between exposure and either cognitive performance or reduced brain volumes. Li et al. (2011b) and Liu et al. (2011) published results of cerebral perfusion measured with arterial spin labeling MRI in response to physostigmine challenge in Gulf War veterans who met Haley’s criteria for Gulf War illness syndromes 1, 2, or 3 and controls. Syndrome 2 and 3 subjects displayed reduced physostigmine effect on perfusion compared to controls, but syndrome 1 exhibited an increased physostigmine effect. The results were thus inconsistent among those who met the criteria for Gulf War illness. Moreover, it might be expected that syndromes 1 (impaired cognition) and 2 (confusion-ataxia) would be more similar than 2 and 3 (central neuropathic pain) because 1 and 2 both include impaired mental function, but the opposite was seen.

Other functional modalities in addition to imaging have been used. Tillman et al. (2010, 2012, 2013) assessed functional response by event-related potentials in groups of Gulf War illness syndromes. Various findings were reported, but sample sizes in some of the Gulf War illness syndrome groups were less than 10 subjects.

Summary

The imaging literature generally supports the established concept that MRI findings, such as evidence of brain atrophy, may be associated with chronic stress. But, the literature does not support the conclusion that any type of imaging signature is consistently associated with Gulf War illness, deployment to the Gulf War, or any specific Gulf War exposure. Thus, the committee does not find MRI abnormalities to be a valid biomarker of Gulf War illness.

The committee emphasizes that environmental exposures at the individual veteran level cannot be determined and therefore finds that conducting studies that seek or propose a cause-and-effect relationship between environmental exposures unique to Gulf War veterans (sarin, cyclosarin) and neuroimaging results is not advisable. Any studies of Gulf War veterans that use neuroimaging techniques should be adequately powered and should contain independent replication samples that are also adequately powered. This would help address the current state of the imaging literature, which is characterized by conflicting and nonreplicable results that make it difficult to draw coherent conclusions.

TABLE 4-11 Neurologic Conditions

NOTE: AFQT = Armed Forces Qualifying Test; ALS = amyotrophic lateral sclerosis; ANCOVA = analysis of covariance; BARS = Behavioral Assessment and Research System; BDI = Beck Depression Inventory; CATSYS = Coordination Ability Test System; CI = confidence interval; CVLT = California Verbal Learning Test; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; MANCOVA = multivariate analysis of variance; MS = multiple sclerosis; NART = National Adult Reading Test; NDV = nondeployed veteran; NIS = Neuropathy Impairment Score (Mayo Clinic version); ODTP = Oregon Dual Task Procedure; OR = odds ratio; PASAT = Paced Auditory Serial Addition Test; PB = pyridostigmine bromide; PCA = principal components analysis; RR = risk ratio; sd = standard deviation; SF-12 = 12-item Short Form Health Survey; SF-36 = 36-Item Short Form Health Survey; SIR = standardized incidence ratio; TOMM = Test of Memory Malingering; UK = United Kingdom; VA = Department of Veterans Affairs; WAIS-R = Wechsler Adult Intelligence Scale-Revised; WCST = Wisconsin Card Sorting Test; WMS = Wechsler Memory Scale.

^aAlthough the study defined distal symmetric polyneuropathy as distal sensory or motor neuropathy identified on basis of neurologic examination, nerve conduction study, or both, the committee defined it by nerve-conduction study alone.

^bAlcohol dependence, diabetes mellitus, renal insufficiency, hypothyroidism, AIDS/HIV, collagen vascular disease, and neurotoxic medications.

RESPIRATORY SYSTEM CONDITIONS

As noted in previous Gulf War and Health reports (IOM 2006b, 2010), respiratory conditions such as asthma, bronchitis, chronic obstructive pulmonary disease (COPD), and various symptoms consistent with respiratory disease, such as wheezing and shortness of breath, have consistently been self-reported more frequently by deployed Gulf War veterans than era veterans. Exposures of concern during deployment include smoke from oil-well fires, high levels of ambient dust, pesticide sprays, and nerve gas exposure. Lung cancer is discussed in the section on cancer. All primary studies of conditions of the respiratory system are summarized in Table 4-12 at the end of this section.

Summary of Volumes 4 and 8

Volume 4 presented five primary studies (Eisen et al., 2005; Gray et al., 1999a; Ishoy et al., 1999b; Karlinsky et al., 2004; Kelsall et al., 2004b) that represented four cohorts from three countries. Those studies examined associations of respiratory outcomes with deployment to the Gulf War region. Outcomes were, in part, determined on the basis of pulmonary function measures or respiratory disease diagnoses. None of those studies reported any positive associations with Gulf War Service. Numerous secondary studies were reviewed that relied on self-reported respiratory symptoms, and the overwhelming majority of these studies found that deployed veterans report higher levels of respiratory symptoms and respiratory illnesses than nondeployed veterans.

The Volume 4 committee also reviewed objective measures of respiratory conditions associated with specific exposures experienced by Gulf war veterans during their deployment. Three studies used the same objective exposure measure and methods to estimate exposure to smoke from oil-well fires, but no associations were detected for doctor-assigned diagnoses of asthma, respiratory health outcomes, and hospitalization for asthma, acute bronchitis, chronic bronchitis, or emphysema. One study (Gray et al., 1999b) found an association between modeled exposure to nerve agents at Khamisiyah and a small increase in postwar hospitalization for respiratory system disease. However, that study had several limitations, including likely exposure misclassification, failure to control for tobacco smoking, lack of a clear dose–response pattern, and there appeared to be little biologic plausibility for effects on the respiratory system. A second study of nerve agent exposure and pulmonary function measures found no association between the two (Karlinsky et al., 2004). The Volume 4 committee noted that, with respect to nerve agents at Khamisiyah, no study that used valid objective estimates of exposure found statistically significant associations with pulmonary function measures or physician-diagnosed respiratory disease.

Based on one additional primary (Smith et al., 2006) and four secondary studies (including one study that assessed Khamisiyah-exposed veterans specifically), the Volume 8 committee also found that studies of Gulf War veterans based on self-reported symptoms and self-reported diagnoses have frequently, but inconsistently, shown an excess of respiratory conditions. However, there appears to be no increase in respiratory disease among Gulf War veterans when examined with objective measures of disease. Pulmonary function studies have shown no significant excess of lung function abnormalities among Gulf War veterans. Therefore, the Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and respiratory disease. The committee also concluded that there was limited/suggestive evidence of no association between deployment to the Gulf War and decreased lung function in the first 10 years after the war.

New Literature

The Volume 10 committee did not identify any new primary studies of Gulf War veterans that assessed respiratory conditions.

Secondary Studies

The Volume 10 committee identified three secondary studies. Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the Kelsall et al., 2004b, baseline study discussed in Volumes 4 and 8). This study assessed the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans formed the comparison group. Respiratory symptoms were based on self-reports and on self-reports of doctor-diagnosed respiratory symptoms. Deployed veterans were significantly more likely to report morning cough (RR = 1.67, 95% CI 1.26–2.23), wheeze (RR = 1.44, 95% CI 1.15–1.80), morning sputum (RR = 1.38, 95% CI 1.10–1.74), and daytime or nighttime cough (RR = 1.36, 95% CI 1.09–1.70). They were also more likely to report a doctor-diagnosis or treatment for sinus problems (RR = 1.51, 95% CI 1.07–2.15) and pneumonia (RR = 1.87, 95% CI 1.03–3.39). Deployed veterans were also more likely to report, although not significantly so, a doctor-confirmed diagnosis of asthma, chronic bronchitis, emphysema, or COPD.

Li et al. (2011a) conducted a 10-year follow-up survey of U.S. Gulf War deployed (n = 5,469) and nondeployed veterans (n = 3,353) who had also participated in a 1995 VA National Health Survey. Compared with nondeployed veterans, deployed veterans in 2005 were less likely to report the persistence of chronic asthma (RR = 0.76, 95% CI 0.59–0.97), although they did have a nonstatistically significant increased risk of a new onset of it (RR = 1.26, 95% CI 0.94–1.68). The risk ratios were adjusted for age in 2005, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

Dursa et al. (2016) reported results of the third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans. The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013 via mail, website, or a computer-assisted telephone interview, asked 8,104 Gulf War deployed and 6,148 era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. There was a statistically significant difference between the deployed and era veterans in self-reports of asthma (10.2% vs 9.0%; OR = 1.22, 95% CI 1.04–1.44) and COPD (8.4% vs 6.3%; OR = 1.48, 95% CI 1.23–1.78). The OR was adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the respiratory system (ICD-9 categories 460–519) (see Table 4-13). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single

TABLE 4-13 10 Most Frequent Respiratory Disease Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

The three new secondary studies provide mixed results. In the Australian study, there was a significant increase in self-reported respiratory symptoms such as cough in deployed compared with nondeployed Gulf War veterans. However, two of the three studies showed no increase in the risk of asthma or COPD (Li et al., 2011a; Sim et al., 2015); whereas, the VA survey found a slight increase in the risk of asthma and a slightly greater risk of having COPD (Dursa et al., 2016). All of these studies relied on self-reports of diagnoses.

Because the respiratory system is a common portal for exposure, the committee finds that should surveillance of respiratory conditions in Gulf War veterans continue to be conducted, the studies need to adjust for smoking status if the data are to be informative.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and respiratory disease. The committee concludes that there is limited/suggestive evidence of no association between deployment to the Gulf War and decreased lung function.

TABLE 4-12 Conditions of the Respiratory System

NOTE: CI = confidence interval; DMDC = Defense Manpower Data Center; DoD = Department of Defense; FEV₁ = forced expiratory volume in 1 second; FVC = forced vital capacity; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; MRR = mortality rate ratio; NS = not significant; OR = odds ratio; PFT = pulmonary function test; UK = United Kingdom; U.S. = United States.

GASTROINTESTINAL SYSTEM CONDITIONS

Digestive disorders may be functional, structural, or in some cases combinations of both (see Gulf War and Health, Volume 6, for a description of functional and structural digestive disorders). The functional gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) or functional dyspepsia, are conditions without pathology or clear structural change—that is, recurrent or prolonged clusters of symptoms that occur together. GI conditions, sometimes called “organic” or structural conditions, such as peptic ulcer and inflammatory bowel disease (that is, ulcerative colitis and Crohn’s disease), are characterized by morphological abnormalities seen on X-ray, endoscopy, or through laboratory tests. All primary studies for conditions of the gastrointestinal system are summarized in Table 4-14 at the end of this section.

Summary of Volumes 4 and 8

The Volume 4 committee reviewed three primary studies of digestive system disorders, two of which analyzed hospitalization data. In one report (Eisen et al., 2005), dyspepsia was diagnosed on the basis of in-person interviews and was statistically significantly associated with deployment; however, the Volume 8 committee noted that some cases of dyspepsia may have been misdiagnosed given the terminology used by the authors. One study by Gray et al. (1996) found no excess hospitalizations for conditions of the digestive system for deployed or nondeployed veterans, although in a later study they found an increase in hospitalizations for digestive system conditions at VA hospitals but not in other hospital systems for deployed vs nondeployed veterans (Gray et al., 2000). Two secondary studies showed that deployed veterans more frequently reported gastrointestinal symptoms than nondeployed veterans (Ishoy et al., 1999a,b; Sostek et al., 1996). The Volume 4 committee noted that gastrointestinal disturbances in Gulf War deployed veterans seem to be linked to contaminated water and burning of animal waste.

The Volume 8 committee found in numerous studies that Gulf War veterans self-reported more GI symptoms than nondeployed veterans (Kang et al., 2000; Kelsall et al., 2004a; Proctor et al., 1998; Simmons et al., 2004; Sostek et al., 1996; Unwin et al., 1999). The primary study by Sostek et al. (1996) used survey questions that were highly specific for functional GI disorders and that met the Rome III criteria for IBS. The study found statistically significant increases in the reporting of symptoms consistent with IBS and other functional GI disorders in deployed veterans compared with nondeployed veterans. All of the secondary studies identified by the committee found that deployed veterans reported more GI symptoms than their nondeployed counterparts, but the studies were limited because their methods are insufficient to determine a clear association between deployment and the onset of a functional disorder—diagnosed by standard Rome criteria—or of a structural disorder. The committee noted that the diagnosis of structural GI conditions should be validated by medical records because physicians may place an organic label on a patient’s symptoms (e.g., gastritis or peptic ulcer) without performing the necessary diagnostic studies.

The Volume 8 committee found limitations in the epidemiologic body of evidence for GI disorders, mostly related to methods of effect assessment. These limitations included self-reporting of GI symptoms that did not fulfill the criteria for diagnosing a functional GI disorder; inability to determine the degree to which the gastrointestinal symptoms are specific to IBS and other functional GI disorders, or are part of a larger spectrum of illness (specifically, Gulf War illness); lack of determination of the presence of medical and psychosocial comorbidities; and a lack of adequate medical diagnostic testing to identify a GI structural disease. Nevertheless, taken together, the Volume 8 committee found that the overall pattern of symptoms reported in the few primary and numerous secondary studies confirmed

an association between deployment to the Gulf War and functional GI symptoms, including abdominal pain, diarrhea, nausea, and vomiting, and a few studies exist that provide presumptive data to allow standardized diagnosis of functional GI disorders. These studies were strengthened by physiologic and mechanistic data for veterans with IBS, with particular reference to new evidence for preexisting acute gastroenteritis as a predictive factor in postinfectious IBS and dyspepsia. The Volume 8 committee recommended that further studies be conducted to determine the role of prior acute gastroenteritis among deployed service members in the development of functional GI disorders. Therefore, the Volume 8 committee concluded that there was sufficient evidence for an association between deployment to the Gulf War and GI symptoms consistent with functional GI disorders such as IBS and functional dyspepsia. The committee also concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to a war zone and the development of structural GI conditions.

New Literature

The Volume 10 committee did not identify any new studies that met its criteria for a primary study. One study of Australian veterans and preliminary results on VA’s follow-up survey of U.S. Gulf War veterans were considered to be secondary studies.

Secondary Studies

Sim et al. (2015) conducted the Australian Gulf War Veterans’ Follow Up Health Study between 2011 and 2013 to assess the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans made up the comparison group. The prevalence of GI conditions was based on self-reports and on self-reports of doctor-diagnosed conditions. There were no statistically significant differences in reporting of doctor-diagnosed GI conditions. More deployed than nondeployed veterans reported having polyps in the bowel (RR = 1.34, 95% CI 0.96–1.88). There were statistically significantly more deployed veterans who met the Rome III criteria for IBS based on self-reported symptoms than nondeployed veterans (13% vs 8%; RR = 1.64, 95% CI 1.18–2.27).

The committee also considered the results from Dursa et al. (2016) on the third wave of the National Health Study of Persian Gulf War Era Veterans The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013 via mail, website, or a computer-assisted telephone interview, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. There were statistically significant differences between the deployed and era veterans in the weighted prevalence of self-reports of IBS (24.4% vs 14.3%; OR = 2.1, 95% CI 1.79–2.45), gastritis (20.2% vs 14.3%; OR = 1.59, 95% CI 1.35–1.73), and functional dyspepsia based on the ROME criteria (27.7% vs 15.9%; OR = 1.94, 95% CI 1.75–2.17). The ORs were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component. Self-reports of hepatitis and cirrhosis were also included in the survey, but the odds of either condition were not statistically different between deployed and era veterans (Dursa et al., 2016).

TABLE 4-15 10 Most Frequent Diagnoses of Diseases of the Digestive System for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the digestive system (ICD-9 categories 520–579) (see Table 4-15). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

In another analysis of the second wave of VA’s National Health Survey of Gulf War Veterans, Coughlin and colleagues (2011a) found that among 6,111 Gulf War deployed and 3,859 era veterans, deployed veterans, regardless of their weight status (underweight, normal weight, overweight, or obese), self-reported more physician-diagnosed cirrhosis of the liver, hepatitis, and gastritis than nondeployed veterans. No information was provided on diet or physical activity. Further assessment of these veterans found that self-reported GI outcomes were more prevalent in both deployed and nondeployed veterans with problem drinking. Unadjusted percentages of veterans reporting cirrhosis, hepatitis, and gastritis are presented in Table 4-16 (Coughlin et al., 2011b). Problem drinking was determined based on affirmative answers to questions about problem or hazardous drinking in the previous 6 months. No modeling or statistical testing was reported pertaining to these outcomes.

TABLE 4-16 Unadjusted Percentages of Self-Reported Physician-Diagnosed Outcomes Reported in Deployed vs Nondeployed Gulf War Veterans

SOURCE: Coughlin et al., 2011b.

Conclusions

The Volume 8 committee found there was sufficient evidence for an association between deployment to the Gulf War and gastrointestinal symptoms consistent with functional GI disorders such as IBS and functional dyspepsia. Two new secondary studies provide additional support for this conclusion by reporting increased rates of IBS among deployed veterans; however, they are based on self-reported information.

The Volume 8 committee also concluded that there was inadequate/insufficient evidence to determine whether an association exists between deployment to a war zone and the development of structural gastrointestinal conditions. Little new literature was available to assess the risks of structural gastrointestinal disease, but the literature did not suggest increased risks among deployed veterans. The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new gastrointestinal conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is sufficient evidence for an association between deployment to the Gulf War and gastrointestinal symptoms consistent with functional gastrointestinal disorders such as IBS and functional dyspepsia.

The committee also concludes that there is inadequate/insufficient evidence to determine whether an association exists between deployment to the Gulf War and the development of structural gastrointestinal conditions.

TABLE 4-14 Conditions of the Gastrointestinal System

NOTE: CFS = chronic fatigue syndrome; CI = confidence interval, COSHPD = California Office of Statewide Health Planning and Development; DoD = Department of Defense; GI = gastrointestinal; GWV = Gulf War veteran; IBS = irritable bowel syndrome; MCS = multiple chemical sensitivity; NDV = nondeployed veteran; OR = odds ratio; PMR = proportional morbidity ratio; PTSD = posttraumatic stress disorder; U.S. = United States.

CHRONIC SKIN CONDITIONS

Skin conditions are among the most frequent health problems reported by Gulf War veterans. Rash usually refers to dermatitis, an umbrella term covering several subtypes, including atopic dermatitis, contact dermatitis, seborrheic dermatitis, and psoriasis. All primary studies for chronic skin conditions are summarized in Table 4-17 at the end of this section.

Summary of Volumes 4 and 8

On the basis of two primary (Eisen et al., 2005; Higgins et al., 2002) and two secondary studies (Kang et al., 2000; Proctor et al., 1998) of dermatologic conditions, the Volume 4 committee determined that unrelated skin conditions occur more frequently among Gulf War deployed veterans compared with nondeployed veterans, but the findings were not consistent among studies. The Volume 4 committee noted that there is some evidence in deployed veterans of a higher prevalence of two distinct dermatologic conditions—atopic dermatitis and warts.

The Volume 8 committee identified an additional primary study (Ishoy et al., 1999b) that reported significantly greater rates of eczema; retarded wound healing; other skin problems; hair loss or hair disease; and sweaty, clammy, or damp hands in deployed Danish veterans than nondeployed veterans based on medical examination. However, there were no significant differences in the prevalence of psoriasis or nettle rash between deployed and nondeployed troops. Although the examination process used to verify the veteran’s actual skin conditions at the time of the interview by the physician is somewhat unclear in the report, the use of a physician to discuss the veterans’ responses to the questionnaire provided added validity to the study.

Secondary studies were largely consistent with the primary studies, but they lacked specificity regarding dermatologic outcomes or relied only on self-reported symptoms or self-reports of physician-diagnosed dermatologic conditions. Several large cohort studies reported similar findings in Gulf War veterans based on self-reported data collected by questionnaires. These results reflect higher rates of rash and skin irritation; dermatitis; and skin conditions other than dermatitis, skin cancer, eczema, or psoriasis among Gulf War veterans than control groups (Kelsall et al., 2004a; Proctor et al., 1998; Unwin et al., 1999). Additional secondary studies that relied on long lists of self-reported symptoms indicated that the prevalence of generally nonspecified skin conditions or conditions in deployed Gulf War veterans was greater than in nondeployed veterans including skin allergies or other skin conditions, sweating, itching skin, hair loss, boils, or abscesses; physician-diagnosed or treated skin conditions other than skin cancer; moderate or multiple skin symptoms; eczema; skin allergies; and dermatitis (Cherry et al., 2001a; Goss Gilroy Inc., 1998; Gray et al., 1999a; Kang et al., 2000; Proctor et al., 2001a; Simmons et al., 2004; Steele, 2000; Wolfe et al., 1998).

In summary, the Volume 8 committee found a high frequency of self-reports of various types of rash and other skin conditions among deployed vs nondeployed veterans, and, in general, these reports were confirmed by dermatologic examination. Overall, very few studies rigorously assessed the prevalence of skin conditions in Gulf War veterans, and results are mixed, with increases for some skin conditions but not for others. Furthermore, there was no consistency across these studies, which suggests that the findings could have occurred by chance. Finally, most of the studies are weak in design and limited by self-selection and possible reporting bias. The Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and skin disorders.

New Literature

New literature pertaining to skin conditions in Gulf War veterans includes two secondary studies, and one other related study. The committee did not identify any new primary studies.

Secondary Study

Sim et al. (2015) conducted the Australian Gulf War Veterans’ Follow Up Health Study between 2011 and 2013 to assess the entire Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch, but not for smoking. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans made up the comparison group. Skin conditions were based on self-reports and on self-reports of doctor diagnoses. Statistically significantly more deployed veterans reported having dermatitis (RR = 2.21, 95% CI 1.35–3.59) and eczema (RR = 2.84, 95% CI 1.43–5.65) than nondeployed veterans. There was no significant difference in reporting of doctor-diagnosed psoriasis (RR = 1.11, 95% CI 0.66–1.85).

Dursa et al. (2016) published on the most recent results of the third survey wave of the cross-sectional National Health Study of Persian Gulf War Era Veterans. The wave 3 survey (discussed in greater detail in Chapter 3), conducted in 2012–2013, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had dermatitis. The weighted prevalence was 27.4% and 21.1% in the deployed and era veterans, respectively, and the odds of dermatitis were statistically significantly increased in the deployed compared with the era veterans (OR = 1.44, 95% CI 1.27–1.63).

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of skin (ICD-9 categories 680–709) (see Table 4-18). A veteran can have multiple diagnoses with each health care encounter, and therefore, may

TABLE 4-18 10 Most Frequent Diagnosed Skin Diseases for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

Both the Volume 4 and Volume 8 committees noted a high frequency of self-reports of various types of skin conditions among deployed vs nondeployed veterans, but the specific skin conditions found were not consistent across the studies. For the most part, the studies, while occasionally using a dermatologic examination to confirm the skin conditions, did not include adequate assessment of the skin conditions. In Volume 10, the one new secondary study further suggested that while self-reports of some skin conditions such as dermatitis and eczema are more prevalent in deployed Gulf War veterans, others such as psoriasis are not. The committee finds that given the aging of the population of Gulf War veterans and the unlikelihood that new chronic skin conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes that there is insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and skin conditions.

TABLE 4-17 Chronic Skin Conditions

NOTE: CI = confidence interval; GWV = Gulf War veteran; NDV = nondeployed veteran; OR = odds ratio; UK = United Kingdom; U.S. = United States.

PAIN-RELATED CONDITIONS

This section discusses health conditions that are hard to diagnose and that are typically manifest with multiple symptoms including chronic fatigue, headaches, and muscle and joint pain. These conditions are also associated with impairment of function and increased use of health care. Diagnostic criteria for CFS, fibromyalgia, and rheumatic disorders such as rheumatoid arthritis and osteoarthritis are distinct, but the conditions have overlapping symptoms and in some cases may be difficult to distinguish from each other and from related conditions such as chronic widespread pain (CWP) and Gulf War illness, which are seen in many Gulf War veterans.

In 2010, the American College of Rheumatology (ACR) published new diagnostic criteria for fibromyalgia that updated the 1990 criteria to revise the distribution and intensity of symptoms as essential elements of the diagnosis. The new criteria removed the requirement for a clinician rating and rely solely on subjective information from the patient. The result may be that more people will be diagnosed with fibromyalgia. The new criteria may also shift the demographic profile of people with fibromyalgia to include more men (Bennet et al., 2014), which would significantly affect the rate of fibromyalgia observed in a population of mostly men, such as Gulf War veterans. While all the studies in this report that assessed fibromyalgia used the 1990 criteria, new studies may show different trends or associations based on the new criteria. Additionally, exclusive reliance on self-report in the most recently revised criteria for fibromyalgia contrasts with the importance that this committee assigned to studies based on objective outcomes. It will be important to consider the two sets of criteria if the prevalence of fibromyalgia using the new criteria is compared with studies using the old criteria.

CFS, also known as myalgic encephalomyelitis, was recently assessed by another IOM committee (IOM, 2015). That committee proposed new diagnostic criteria and a new name for the condition, systemic exertion intolerance disease (SEID). The new criteria were based on a systematic review of the evidence. It is not clear what effect the new definition will have on future epidemiologic studies; the studies reviewed in this chapter did not adopt the new name nor use the new diagnostic criteria. In Volumes 4 and 8, pain-related conditions were considered as separate entities as there was considerable literature on each in Gulf War veterans. However, for this volume, there is little new scientific information on the prevalence of these conditions in Gulf War veterans. Many of the studies look at more than one condition. Therefore, this committee has chosen to assess the literature on these conditions in one section to highlight the differences and overlap in the new data. All primary studies of pain-related conditions are summarized in Table 4-19 at the end of this section.

Summary of Volumes 4 and 8

In Volume 4, CFS and fibromyalgia were considered in separate sections as were conditions of the musculoskeletal system such as arthritis and arthralgia. Chronic pain was considered in the section on symptoms, signs, and abnormal laboratory findings (ICD-10 R00–R99). In volume 8, CFS was discussed in the section on multisymptom illnesses and there were separate sections on fibromyalgia and CWP, and on musculoskeletal conditions.

Chronic Fatigue Syndrome

The CDC case definition for CFS requires fatigue and related impairment in function, and the occurrence of four of eight other defining symptoms for at least 6 months (Fukuda et al., 1994). Of the eight symptoms, the most commonly reported are headaches, postexertional malaise, impaired cognition, and

muscle pain (Buchwald and Garrity, 1994). This definition is widely used by researchers, although some studies describe a “CFS-like” syndrome. The Volume 4 and Volume 8 committees considered a primary study for CFS to be one in which CFS had been diagnosed according to the CDC criteria and a secondary study to be one in which a CFS-like condition was documented. Self-reports of CFS or self-reports of a physician’s diagnosis of CFS were not included among the primary studies because such self-reports are frequently inaccurate. Neither committee included studies that lacked a control group; estimated the prevalence of symptoms of “chronic fatigue” or multisymptom illness; or used scalar measures of disability and poor quality of life related to health as surrogates for the CDC criteria.

The Volume 4 committee reviewed one primary and four secondary studies and noted that because the diagnosis of CFS depends entirely on symptoms, not on physical or laboratory findings, the prevalence was variable from study to study. The one primary study (Eisen et al., 2005) demonstrated a higher prevalence of CFS in deployed vs nondeployed veterans (1.6% vs 0.1%; OR = 40.6, 95% CI 10.2–161.15). All the secondary studies (Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997; Kang et al., 2003; Proctor et al., 2001b) also showed a higher prevalence of CFS or CFS-like illnesses among veterans deployed to the Persian Gulf than among their nondeployed or deployed elsewhere counterparts.

The Volume 8 committee identified two new primary studies (Ismail et al., 2008; Kelsall et al., 2006) and one new secondary study (Lucas et al., 2007). One study in Australian Gulf War veterans showed that CFS and complaints of unexplained chronic fatigue were increased in deployed vs nondeployed veterans (CFS OR = 1.2, 95% CI 0.5–2.9; chronic fatigue lasting more than 6 months OR = 1.9, 95% CI 1.4–2.7) (Kelsall et al., 2006). CFS was also more prevalent in disabled Gulf War veterans from the United Kingdom compared with either nondeployed or deployed elsewhere veterans who had similar levels of disability (OR 7.8, 95% CI 2.5–24.5) (Ismail et al., 2008).

CFS and complaints of unexplained chronic fatigue appear to be increased in deployed Gulf War veterans compared to contemporaneous cohorts (either nondeployed or deployed elsewhere). Those results were also observed in several cross-sectional population-based studies that used self-reports to define CFS or chronic fatigue. However, the absolute prevalence of these symptoms varied considerably from study to study. Associations between fatigue, subjective neurological symptoms, and exposures were also based entirely on retrospective self-reports. Therefore, the Volume 8 committee concluded that there was sufficient evidence for an association between deployment to the Gulf War and CFS.

Fibromyalgia and Chronic Widespread Pain

Fibromyalgia is characterized by widespread muscle and skeletal pain in combination with point tenderness at numerous soft tissue sites. Although a diagnosis of fibromyalgia cannot be confirmed through pathologic or laboratory tests, the ACR (Wolfe et al., 1990) established diagnostic criteria for clinical examinations.⁵ The case definition requires both widespread pain (pain on both sides of the body, above and below the waist, and including axial skeletal pain) lasting for at least 3 months and pain (not just tenderness) in at least 11 of 18 tender point sites on palpation with an approximate force of 4 kg. Other symptoms of fibromyalgia include fatigue, sleep disturbance, morning stiffness, and cognitive impairment, but those are not sensitive and specific enough to use for classification; fibromyalgia may be considered to be a subset of CWP (Wolfe et al., 1990). The disorder is chronic and varies in intensity (Wolfe et al., 1997). It has been estimated that the prevalence of fibromyalgia in the general U.S. population is about 3% in women and about 0.5% in men, and its prevalence increases with age (Wolfe et al., 1995).

___________________

⁵ In 2013, the ACR revised the criteria for fibromyalgia. However, no studies reviewed in this section use the revised criteria.

Among the pain-related disorders, none of the studies reviewed by the current and past Gulf War and Health committees have used the recently changed diagnostic criteria of fibromyalgia that base diagnosis on self-report (Bennett, 2014). These new criteria would likely have the effect of changing the inclusion criteria for fibromyalgia. This change in diagnostic criteria may also increase the diagnosis in males and therefore may increase the proportion of Gulf War veterans meeting criteria for fibromyalgia. Despite the recent change in the diagnostic criteria for fibromyalgia, the complete reliance on self-report may change the results and interpretive value of investigative studies, thus future researchers will have to weigh this in their planning.

The ACR defines CWP as “the presence of pain above and below the waist, or on both the left and right sides of the body, for 3 months or longer.” Prior studies have reported CWP prevalence rates between 11% and 13% in Germany, Sweden, the United Kingdom, and the United States. Several studies have reviewed the presence of chronic pain in Gulf War veterans, but its definition varies by study. Many studies of Gulf War veterans reported increased pain symptoms that could be clustered into CWP, but the terminology used in the studies is not consistent and includes joint pain and general aches and pain; these pain clusters may or may not meet the ACR criteria for CWP. The committee required that primary studies include a physical examination and not rely solely on symptom reporting by patients.

In Volume 4, only one study used the full ACR case definition of fibromyalgia (Eisen et al., 2005), including criteria based on physical examination and found significantly more deployed Gulf War veterans than nondeployed veterans diagnosed with fibromyalgia (OR = 2.32, 95% CI 1.02–5.27). However, another study based on hospitalizations for fibromyalgia assessment found no association between Gulf War deployment and hospitalization for fibromyalgia in active-duty service members. These findings are consistent with other study findings because few cases of fibromyalgia are severe enough to warrant hospitalization. In two large, but secondary, cohort studies, deployed veterans reported significantly increased fibromyalgia symptoms compared with nondeployed veterans but those findings are of limited value as the studies did not include physical examinations. The Volume 4 committee concluded that there was a higher prevalence of fibromyalgia among deployed than nondeployed Gulf War veterans.

The Volume 8 committee reviewed one primary study (Ang et al., 2006) and three secondary studies on Gulf War deployment and CWP. Although each of the studies found a higher prevalence of CWP in deployed than in nondeployed veterans, all of them had considerable limitations. The primary study that looked specifically at CWP was a large random sample of veterans who reported significantly more bodily pain than did nondeployed veterans; a 10-year follow-up study of a subset of these veterans who had not met the classification criteria for CWP at 5 years after the war, found that the prevalence of CWP at 10 years after the war had increased both with combat exposure and with perception of life stress at the time of deployment. Three secondary studies indicated that pain symptoms were reported more frequently in deployed than nondeployed veterans. The Volume 8 committee concluded that there was limited but suggestive evidence of an association between deployment to the Gulf War and both fibromyalgia and chronic widespread pain.

Conditions of the Musculoskeletal System

Arthritis is the most common form of joint disease and is generally related to major trauma, repetitive joint use, heavy manual material handling, and age. Arthralgia, which is a self-reported symptom of arthritis, refers to painful joints. In the absence of other clinical features and radiographic findings, arthralgias are not necessarily diagnostic of arthritis.

The Volume 4 committee found that in the one primary and two secondary studies that examined these outcomes, there was no statistically significant difference in arthralgias for the deployed vs nondeployed Gulf War veterans who underwent a medical examination. The primary study by Eisen

et al. (2005) found a nonsignificant increased risk arthralgias in deployed veterans (OR = 1.5, 95% CI 0.70–1.89). The secondary studies also indicated that self-reports of arthritis was more common among those deployed to the gulf.

The Volume 8 committee identified five new primary studies that looked at hospitalization discharge diagnoses of some form of musculoskeletal disease in Gulf War veterans, but specific diagnoses were not provided in any of the studies. Those studies showed no increased risk of hospitalization for musculoskeletal system conditions among Gulf War deployed veterans compared with their nondeployed counterparts. Possible exposure to smoke from oil-well fires and nerve agents from the Khamisiyah demolition also failed to result in increased hospitalizations. The committee notes, however, that many musculoskeletal conditions, such as arthritis, do not typically require hospitalization and are more likely to be treated on an outpatient basis. The Volume 8 committee concluded that there was insufficient/inadequate evidence to determine whether an association exists between deployment to the Gulf War and musculoskeletal system conditions.

New Literature

The committee did not identify any new primary studies for any pain-related disorders in Gulf War veterans. The committee did review four studies that met its criteria for a secondary study (Dursa et al., 2016; Kelsall et al., 2014; Li et al., 2011a; Sim et al., 2015).

Secondary Studies

Li et al. (2011a) conducted a 10-year follow-up survey of 5,469 U.S. Gulf War deployed and 3,353 nondeployed veterans who had also participated in the 1995 VA National Health Survey. Compared with nondeployed veterans, the authors found that in 2005 deployed veterans were no more likely to report the persistence of the most prevalent chronic conditions in the past year including arthritis (RR = 1.10, 95% CI 0.93–1.10) and CFS-like illness (RR = 1.63, 95% CI 0.72–3.72) than nondeployed veterans. However, deployed veterans had a statistically significant increased risk of reporting a new onset of both arthritis (RR = 1.24, 95% CI 1.11–1.39) and CFS-like illness (RR = 2.36, 95% CI 1.90–2.93) since 2005 than nondeployed veterans. The risk ratios were adjusted for age in 2005, gender, race, rank, service branch, service type, BMI, and current cigarette smoking.

In a cross-sectional study, Kelsall et al. (2014) compared 1,381 Australian veterans of the Gulf War with 1,377 veterans who were serving in the military at the time or had previously deployed. The assessment, conducted in 2000–2002, queried veterans about doctor-diagnosed arthritis or rheumatism, back or neck problems, joint problems, and soft tissue disorders. Medical practitioners then rated the self-reported diagnoses as nonmedical, unlikely, possible, or probable; only probable diagnoses were analyzed. This approach, which added a level of medical judgment to the self-reported conditions but did not verify the self-reported diagnoses with a clinical evaluation, showed that the odds of having any musculoskeletal disorder was increased for the deployed veterans (OR = 1.19, 95% CI 1.00–1.43), but the odds of having any specific disorder was not. Depression was significantly associated with having any musculoskeletal disorder (OR = 1.81, 95% CI 1.21–2.69), arthritis or rheumatism (OR = 3.42, 95% CI 1.64–7.14), and back or neck problems (OR = 2.32, 95% CI 1.49–3.60), but not joint problems (OR = 1.51, 95% CI 0.88–2.58) in deployed veterans. However, depression was also significantly associated with the same disorders, including joint problems, in the comparison group. PTSD was significantly associated with arthritis or rheumatism (OR = 2.89, 95% 1.21–6.86) and joint problems (OR = 1.97,

95% CI 1.05–3.70) in the deployed veterans and significantly associated with all the musculoskeletal disorders except arthritis or rheumatism in the comparison group.

Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the baseline study discussed in Volume 8). This study is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Because only about 2% of the participants were women, only males were recruited for the study. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Fatigue and musculoskeletal symptoms were based on responses to questions about the veterans’ experience with fatigue, prolonged fatigue (at least 1 month duration), and chronic fatigue (at least 6 months duration). Deployed veterans (n = 697) were significantly more likely than nondeployed veterans (n = 659) to report extreme tiredness or fatigue (RR = 1.38, 95% CI 1.15–1.65), prolonged fatigue (RR = 1.37, 95% CI 1.04–1.80), or chronic fatigue (RR = 1.41, 95% CI 1.02–1.96). The Chalder Fatigue Scale⁶ was used to assess fatigue severity, and results indicated that deployed veterans met the standardized diagnostic criteria more frequently than nondeployed veterans (RR = 1.23, 95% CI 1.04–1.45). Furthermore, the prevalence of prolonged fatigue and chronic fatigue more than doubled from baseline to follow-up in both the deployed and nondeployed groups, and these increases were statistically significant.

Veterans were also categorized into one of five chronic pain grades. Although deployed veterans were more likely to report both greater intensity pain and more disability from it than nondeployed veterans, the differences were not statistically significant. Compared with nondeployed veterans, deployed veterans had pain in more body areas in the previous 7 days (based on categories of four to six body areas, OR = 1.47, 95% CI 1.12–1.93, and 11 or more body areas of pain, OR = 2.89, 95% CI 1.01–8.28, but not in 7 to 10 body areas). Gulf War veterans also reported more pain-related health symptoms in the past month, general muscle aches or pains, headaches, and low back pain. More than half of both deployed and nondeployed veterans reported those symptoms. Finally, with regard to musculoskeletal disorders, the follow-up study asked more specific questions than the baseline study, so longitudinal comparisons were not made. In the follow-up study, veterans were asked whether they had a doctor diagnosis of or had been treated for osteoarthritis, rheumatoid arthritis, other inflammatory arthritis, or gout since 2001. There were no statistically significant differences between the deployed and nondeployed groups for any of the musculoskeletal disorders; osteoarthritis was the most common ailment in both groups (Sim et al., 2015).

The third wave of VA’s National Health Study of Persian Gulf War Era Veterans conducted about 20 years after the war, asked 8,104 deployed and 6,148 Gulf War era veterans to indicate whether a doctor had ever told them they had a medical condition and then whether the condition had been present in the previous 4 weeks. Dursa et al. (2016) found a statistically significant difference between the deployed and era veterans in the prevalence of self-reported CFS (11.8% vs 5.3%; OR = 2.36, 95% CI 1.94–2.86), fibromyalgia (3.7% vs 2.9%; OR = 1.48, 95% CI 1.15–1.91), rheumatoid arthritis (9.9% vs 7.9%; OR = 1.40, 95% CI 1.17–1.67), and arthritis not specified (33.9% vs 31.8%; OR = 1.16, 95% CI 1.05–1.29). Self-reported osteoarthritis was not statistically significantly different between deployed and era veterans (OR = 1.06, 95% CI 0.92–1.23). The ORs were adjusted for age, race, sex, BMI, smoking status, service branch, and unit component.

___________________

⁶ The Chalder fatigue scale is widely used to measure physical and mental fatigue in CFS patients (Chalder et al., 1993).

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the musculoskeletal systems and connective tissue (ICD-9 categories 710–739) (see Table 4-20). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Other studies have assessed the effect of a co-occurring health disorder (e.g., musculoskeletal disorders) on the prevalence of PTSD. Using data from the Patient Health Questionnaire component of the second wave of the VA National Health Survey of Gulf War Era Veterans, Coughlin and colleagues (2011a) found that among 6,111 Gulf War deployed and 3,859 era veterans, CFS, fibromyalgia, or arthritis was more commonly reported by obese veterans compared with normal weight veterans. This was also true for having a CFS-like illness in the past 12 months for obese nondeployed veterans but not for obese deployed veterans. Further assessment of these veterans found that having a self-reported CFS-like illness was also more prevalent among deployed and era Gulf War veterans with problem drinking than those without problem drinking. Gulf war veterans, deployed or era, were at significantly increased risk of having a CFS-like illness if they had problem drinking (OR = 1.48, 95% CI 1.22–1.78, adjusted for age, sex, race/ethnicity, branch of service, rank, and deployment status) (Coughlin et al., 2011b). Heavy drinking was defined as ≥ 15 drinks per week.

Individuals with fibromyalgia typically experience an exacerbation of their symptoms following acute exercise. In an effort to determine whether Gulf War veterans with chronic widespread pain had a similar reaction to exercise, Cook et al. (2010) assessed 27 Gulf War veterans from a VA medical center, 11 of whom had chronic muscle pain and 16 healthy controls. There was no difference between the two groups with regard to heat and pressure pain thresholds either before or after exercise; however, after exercise (submaximal cycling) veterans with chronic muscle pain rated the heat-pain stimuli after exercise as more intense and reported greater leg-muscle pain intensity during exercise compared with the healthy controls.

TABLE 4-20 10 Most Frequent Diagnosed Diseases of the Musculoskeletal System and Connective Tissue for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

Two studies tested for differences in synovial fluid in veterans with Gulf War illness complaining of joint pain compared to patients with either osteoarthritis or rheumatoid arthritis (Diaz-Torne et al., 2007; Pessler et al., 2008). Neither found evidence of synovitis in veterans with Gulf War illness using tests that easily detected synovitis in the arthritis patients.

Conclusions

There were no new studies that were of sufficient quality to be considered primary studies for Volume 10. Four secondary studies described inconsistent results for pain-related disorders among deployed veterans.

CFS was assessed in two new secondary studies that reported increased CFS (Dursa et al., 2016) and new onset CFS (Li et al., 2011a). Sim et al. (2015) found increased chronic fatigue and greater severity of it in deployed veterans. These results lend further support to the conclusion reached by the Volume 8 committee. Furthermore, the Volume 10 committee believes that the changes to the CFS case definition discussed at the beginning of this section will not significantly affect its conclusions with regard to the association between CFS and deployment to the Gulf War.

Reports for fibromyalgia and chronic pain are described in two studies. Sim et al. (2015) found that deployed veterans reported greater pain intensity and more disability than nondeployed veterans, but the differences were not statistically significant; however, deployed veterans reported statistically significant more pain in more body areas, and Dursa et al. (2016) reported a statistically significant greater rate of fibromyalgia in deployed veterans compared with era veterans. While these results are suggestive of an association between chronic pain and fibromyalgia and deployment, their reliance on self-reports limits the committee’s confidence in the association.

Evidence for musculoskeletal disorders was less consistent in the three studies that reported this outcome, which supports the Volume 8 conclusion of insufficient/inadequate evidence. Sim et al. (2015) found no statistically significant differences between the deployed and nondeployed groups for any of the musculoskeletal disorders, but deployed veterans reported more general muscle aches or pains and low back pain. Li et al. (2011a) found that rates of arthritis were similar in both groups, but deployed veterans were more likely to report new onset arthritis. Kelsall et al. (2014) found increased rates of any self-reported musculoskeletal disorder in deployed veterans but not for specific conditions, such as arthritis.

Despite the limited number of musculoskeletal disorders studies in this cohort, the aging Gulf War veteran cohort is likely to experience an increase in musculoskeletal disorders studies over time, consistent with the prevalence of musculoskeletal disorders documented in other occupational groups and the general population.

Thus, the committee finds that given the effects of aging and the unlikelihood that new pain-related conditions that are attributable to service in the Gulf War will develop 25 years later, it is doubtful that further assessments will show an increased risk of these conditions. Should these conditions be followed in this cohort, differences in musculoskeletal disorders by gender and race/ethnicity should be reported when data are available.

Therefore, the Volume 10 committee concludes that that there is sufficient evidence for an association between deployment to the Gulf War and CFS; that there is limited/suggestive evidence of an association between deployment and both fibromyalgia and chronic widespread pain; and that there is insufficient/inadequate evidence to determine whether an association exists between deployment and musculoskeletal system conditions.

TABLE 4-19 Pain-Related Conditions

NOTE: CCEP = Comprehensive Clinical Evaluation Program; CDC = Centers for Disease Control and Prevention; CFS = chronic fatigue syndrome; CI = confidence interval; COSHPD = California Office of Statewide Health Planning and Development; CWP = chronic widespread pain; DMDC = Defense Manpower Data Center; DoD = Department of Defense; GWV = Gulf War veteran; HR = hazard ratio; ICD = International Classification of Diseases; IPGWSG = Iowa Persian Gulf War Study Group; NDV = nondeployed veteran; OR = odds ratio; PB = pyridostigmine bromide; PMR = proportional morbidity ratio; RR = risk ratio; UK = United Kingdom; U.S. = United States.

GENITOURINARY SYSTEM CONDITIONS

Major conditions evaluated in this section include kidney disease, urolithiasis (kidney stones), urinary tract infections, prostatitis, and sexual difficulties. Gynecologic outcomes including abnormal cervical pathology and inflammatory disease of the ovary are also assessed. Cancers of the genitourinary system such as testicular cancer are discussed in the section on cancer. All primary studies of conditions of the genitourinary system are summarized in Table 4-21 at the end of this section.

Summary of Volumes 4 and 8

Genitourinary outcomes were not addressed separately in Volume 4 of the Gulf War and Health series. The Volume 8 committee identified five primary studies of hospitalization for genitourinary system conditions, one other primary study that was not on hospitalization (Frommelt et al., 2000), and 10 secondary studies (mostly large surveys of self-reported outcomes). Frommelt et al. (2000) found that the evidence did not support an association between Gulf War deployment and cervical pathology using clinical confirmation of Pap smear results among female veterans in all age groups except women aged 26–30 who had a slight increase in “other than within normal limits,” but the authors concluded that there was no biologically plausible evidence to support an age-specific association between deployment and abnormal cervical pathology.

In the 10 secondary studies, the prevalence of various self-reported genitourinary conditions was greater among Gulf War deployed veterans compared with nondeployed veterans (Gray et al., 2002; Kang et al., 2000, 2009; Page et al., 2005a; Pierce, 2005; Proctor et al., 1998; Simmons et al., 2004; Steele, 2000; Unwin et al., 1999). In one study of the effects of exposure to nerve agents released by the Khamisiyah demolition, reporting of genitourinary conditions was similar in exposed and unexposed veterans (Page et al., 2005b).

Five hospitalization studies, mostly in DoD hospitals, assessed conditions of the genitourinary system. Gray et al. (1996, 2000) and Smith et al. (2006) assessed the difference between deployed and nondeployed veterans, and two other studies examined the effects of environmental exposures to nerve agents or oil-well fires among Gulf War veterans (Smith et al., 2002, 2003). These studies suggest that excess hospitalization due to conditions of the genitourinary system did not occur among active-duty Gulf War veterans within the 10 years following the war. There is some suggestion that postwar hospitalizations for genitourinary conditions were similar among Gulf War deployed veterans who were and were not exposed to nerve agents or smoke from oil-well fires, but the results are not generalizable to the entire cohort of Gulf War veterans. Furthermore, by limiting such studies of genitourinary outcomes to hospitalizations, conditions that are not severe enough to require inpatient care were not assessed. Combining all genitourinary conditions into a single broad diagnostic category of “diseases of the genitourinary system” would also have limited the ability to detect associations with more specific, but etiologically distinct, outcomes.

The specific conditions being evaluated in surveys of Gulf War veterans have varied across studies, generally addressing frequency of urination, urinary tract infections, sexual problems, or broadly defined “disease of the genital organs.” Secondary studies addressing deployment and genitourinary conditions are limited by self-reported outcomes, lack of clinical confirmation, potential recall bias, and generally poor response rates. The discrepancies between hospitalization studies and survey studies of genitourinary outcomes may reflect variation in the severity and types of genitourinary outcomes ascertained by the different approaches; differences in active-duty, reserve, and former military personnel; the influence of reporting and selection biases; or the role of chance.

Studies of self-reported sexual dysfunction have included reports of decreased libido, erectile dysfunction, discomfort or pain during intercourse, and a burning sensation after sex. One primary study was discussed in Volume 4 that indicated deployed veterans reported more sexual problems than controls and problems were associated with traumatic events (having seen killed or wounded people, watched a friend or colleague being threatened or shot at, or having been threatened themselves) (Ishoy et al., 2001b).

The Volume 8 committee identified no new primary studies of sexual dysfunction in Gulf War veterans but did consider seven secondary studies (Gray et al., 2002; Iowa Persian Gulf Study Group, 1997; Page et al., 2005a; Proctor et al., 1998; Simmons et al., 2004; Steele, 2000; Unwin et al., 1999). Gulf War veterans consistently reported an increased prevalence of sexual problems when compared with nondeployed veterans. The one study assessing exposures specific to Gulf War service reported no association between nerve agent exposure, and reported sexual problems among veterans deployed to the Gulf War (Page et al., 2005b). With the exception of a single study that incorporated physician interviews to verify symptom reporting, studies of sexual problems have relied exclusively on self-reports. The Volume 8 committee concluded there was inadequate/insufficient evidence to determine whether an association exists between Gulf War deployment and other specific conditions of the genitourinary system. The Volume 8 committee also concluded there was limited/suggestive evidence of an increased prevalence of self-reported sexual difficulties among Gulf War veterans.

New Literature

The committee did not identify any new primary studies on the genitourinary system, including sexual dysfunction. However, Ishoy et al. (2001b) which assessed sexual difficulties in Danish Gulf War veterans, and was included in Volume 4 as a primary study in the section on male fertility problems, has been added to the table in this section.

Secondary Studies

The committee found two studies that met its criteria for a secondary study. Sim et al. (2015) reported on the Australian Gulf War Veterans’ Follow Up Health Study, conducted between 2011 and 2013 (this study was a follow-up to the baseline study discussed in Volume 8). This study is an assessment of the entire 1,871 Australian Gulf War cohort 10 years after the 2000–2002 baseline study and 20 years after the war. Results were adjusted for age, rank category, and service branch. Of the 1,456 eligible deployed male veterans, 715 participated in the study and 675 of the 1,449 nondeployed veterans provided the comparison group. Deployed veterans were more likely to report physician-diagnosed kidney disease (RR = 1.83, 95% CI 0.95–3.35) and bladder disease (RR = 1.65, 95% CI 0.74–3.67), but the differences were not statistically significant.

Dursa et al. (2016) reported results from the third wave of VA’s cross-sectional National Health Study of Persian Gulf War Era Veterans that was conducted in 2012–2013 and asked 8,104 deployed and 6,148 Gulf War era veterans whether a doctor ever told the veteran that they had “any disease of the genital organs” or “repeated bladder infections.” The weighted prevalence of genital organ disease was 5.1% in the deployed and 4.6% in the era veterans (OR = 1.17, 95% CI 0.93–1.47); the weighted prevalence of repeated bladder infections was 2.4% and 2.8% in deployed and era veterans, respectively (OR = 1.00, 95% CI 0.76–1.33). ORs were adjusted for age, sex, race, service branch, unit, BMI, and smoking status.

Other Related Studies

VA provided a health care use report for Gulf War deployed and era veterans who sought care in VA facilities from October 2001 to December 2013. The report presented the prevalence of diagnoses of diseases by ICD-9 code categories, including diseases of the genitourinary systems (ICD-9 categories 580–629) (see Table 4-22). A veteran can have multiple diagnoses with each health care encounter, and therefore, may be counted in multiple categories, but the person is counted only once in any single diagnostic category. A total of 286,995 Gulf War deployed and 296,635 era veterans received treatment at VA over the approximately 11-year period (VA, 2014a,b). These VA health care users represent 46% of all deployed Gulf War veterans and 36% of all nondeployed era veterans.

Conclusions

The studies cited in Volume 8, particularly the secondary studies, found that Gulf War veterans reported more conditions and symptoms of the genitourinary system. The one secondary study identified by the Volume 10 committee indicated that deployed veterans were slightly but not significantly more likely to report having had a disease of the kidney or bladder.

Therefore, the Volume 10 committee concludes that there is inadequate/insufficient evidence to determine whether an association exists between Gulf War deployment and genitourinary conditions.

There was no new evidence to support or refute the association between self-reported sexual dysfunction and deployment in Gulf War veterans. The committee finds that given the aging of the Gulf War veterans and the unlikelihood that new genitourinary conditions will develop 25 years after the Gulf war that are attributable to their Gulf War service, it is doubtful that further assessments will show increased risk of these conditions.

Therefore, the Volume 10 committee concludes there is limited/suggestive evidence of an increased prevalence of self-reported sexual difficulties among Gulf War veterans.

TABLE 4-22 10 Most Frequent Genitourinary Diagnoses for Deployed and Nondeployed Gulf War Veterans Seeking Health Care in VA Between 2002 and 2013

SOURCES: VA, 2014a,b.

TABLE 4-21 Conditions of the Genitourinary System