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J Some Hypotheses Regarding Illnesses in Persian Gulf War Veterans OVERVIEW In our attempt to investigate comprehensively the health-related consequences of service in the Persian Gulf (PG), we have encountered numerous hypotheses, often provided by independent investigators, that have suggested a wide variety of associations among agents and exposures, circumstances that existed in the Gulf, and adverse clinical outcomes. These hypotheses have had various degrees of plausibility and supporting research. Some investigators brought their work to the attention of the committee. In each case, the material presented by individuals and groups, in person or in documents, was evaluated by the entire committee and considered as we formed our overall impression of the health consequences of service in the Gulf. The many investigations (both federal and private) and the putative causal associations that we evaluated demonstrate the vexing nature of the medical problem presented by what some have referred to as a "Gulf War Syndrome" (GWS), and we refer to as unexplained illnesses (UI). A precis of many of the hypotheses and much of the supporting evidence that the committee received is provided herein. Most of this material was not solicited. Thus, this list is not intended to be exhaustive or complete, but rather to illustrate the issues that faced both the investigators and the committee. The number and variety of hypotheses call attention to the variety of different types of abnormalities that have been reported and the strong likelihood that no single hypothesis could account for all of these, whether or not the illnesses result from service in the Persian Gulf War (PGW). 117

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118 HEALTH CONSEQUENCES OF THE PERSIAN GULF WAR The committee has been troubled by news stories about activities to promote the treatment of clinically evident manifestations of UI. These raise ethically troublesome questions about the lack of documented efficacy, and some of these interventions could even prove harmful to individual patients. Finally, since placebo treatment of patients with almost any ailment (psychological or otherwise) will often result in marked improvement in symptoms or even physical signs of disease, well-designed clinical studies must be employed to understand the efficacy of any medical intervention. CHRONIC FATIGUE SYNDROME The complaints and signs reported by POW veterans suggested to some observers the possibility of chronic fatigue syndrome (CFS) as a common diagnostic label. The syndrome is of unknown etiology, occurs worldwide, and is reported to result in significant disability for the patient. Early doubts have not been fully reversed, but there is a growing consensus that CFS may be a valid diagnosis. This syndrome has been reported in the medical literature for several hundred years (Straus, 1991~. Numerous names have been attached to the many symptoms, signs, and laboratory findings identified in investigations of clusters of patients. In 1987 a definition of the syndrome was reached by a consensus development process under the sponsorship of the Centers for Disease Control and Prevention (CDC) (Holmes et al., 1988~. Subsequently, similar definitions were published by British (Sharpe et al., 1991) and Australian (Lloyd et al., 1990) epidemiologists. These efforts culminated in 1994 in a combined international case definition that maintained the major components of the 1988 document but reduced the required number of minor symptoms and eliminated all physical findings as a necessary part of the definition (Fukuda et al., 1994~. The group settled on the definition given below to facilitate "a more systematic collection of data internationally." An interesting aspect of this syndrome is the reporting by numerous investigators of objective necrologic (Rowe et al., 1995), muscular (Kuratsune et al., 1994), and immunological (Barker et al., 1994) findings. Despite these observations, no common etiology has been identified and not all manifestations are found in each patient. Therefore, such objective evidence is not included in the definition. This definition (Fukuda et al., 1994) attempts to clarify what fatigue is and includes eight of the most common symptoms of the syndrome. Fatigue, the main CFS symptom, is defined as "self-reported persistent or relapsing fatigue lasting six or more consecutive months," and all other possible medical and psychiatric causes are eliminated. The classification of chronic fatigue syndrome is made when the criteria for severity of fatigue are met and four or more of the following eight symptoms are concurrently present or recurring for 6 or more months of illness not predating fatigue: (1) impaired memory or

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SOME HYPOTHESES REGARDING ILLNESSES INPGW VETERANS 119 concentration, (2) sore throat, (3) tender cervical or axillary lymph nodes, (4) muscle pain, (5) multijoint pain without joint swelling or redness, (6) new headaches, (7) nonrefreshing sleep, and (8) postexertion malaise lasting more than 24 hours. Patients who have chronic fatigue but do not meet these criteria are classified as having idiopathic chronic fatigue. MULTIPLE CHEMICAL SENSITIVITY As concern over UI has emerged, a condition known as multiple chemical sensitivity (MCS) syndrome has been suggested by several investigators and clinicians as the link between PG veterans' unexplained illness and environmental exposures (Miller, 1994, 1996; Ziem, 1992, 1994~. Certain investigators have suggested that PGW veterans who are experiencing multiple symptoms, consistent with the constellation described for MCS, had their disease "induced" by one or more exposure in the Gulf, including pesticides, solvents, drugs, or virtually any of the other agents encountered there. These investigators hypothesize that the subsequent "triggering" of disease occurs after low-level exposures to similar noxious substances, likely becoming manifest after the return home of the affected troops. This process would constitute the "loss of tolerance" as described by Miller (1996~. MCS syndrome has become a diagnosis increasingly assigned to patients with a variety of commonly experienced symptoms attributed to exposure to various environmental chemicals at very low levels (Sparks et al., 1994~. Consequently, a working definition of MCS relies on the individual's subjective symptoms of distress, attributed to environmental exposure, rather than on measurable objective evidence. Patients labeled with MCS are clearly distressed and many are functionally disabled. Cullen (1987) defined MCS as "an acquired disorder characterized by recurrent symptoms, referable to multiple organ systems, occurring in response to demonstrable exposure to many chemically unrelated compounds at doses far below those established in the general population to cause harmful effects." He stated that there was no single widely accepted test of physiological function shown to correlate with symptoms. This definition remains the most widely used clinical definition but does not apply to all patients currently diagnosed with MCS. There are four major views about the etiology of MCS. One view is that MCS is a physical or psychophysiologic reaction to multiple chemicals. A second view is that MCS symptoms may be precipitated by low-level environmental exposures, but the underlying increased sensitivity is initiated primarily by psychologic stress. A third view is that MCS is a misdiagnosis and chemical exposure is not the cause of the symptoms. In this case the symptoms may be due to misdiagnosed physical or psychiatric illness. The fourth view is that MCS is simply a belief system instilled by certain practitioners, the media, or others in society; MCS is, therefore, the manifestation of culturally shaped

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120 HEALTH CONSEQUENCES OF THE PERSIAN GULF WAR illness behavior (Sparks et al., 19949. Although there is often a willingness to attribute these symptoms to a primary anxiety disorder, it has been noted that few patients diagnosed as having MCS meet the established criteria for this psychiatric diagnosis. OXIDATIVE PHOSPHORYLATION DISORDER McGill (1993, 1995) has suggested that unexplained illnesses are caused by a disorder of the mitochondrial metabolism leading to encephalomyopathy. In this construct, veterans are afflicted with a multisystem, multiorgan disease that has a vast array of secondary complications and can present in a variety of forms and severities. It is presumed to be linked Biologically with poor nutrition combined with increased metabolic demand. Definitive diagnosis clef this condition is not straightforward, and there is no current medical consensus concerning the validity of this proposed entity. A series of questionnaires and laboratory tests that focus on neurological and metabolic abnormalities have been proposed as a means of identifying individuals with variations of this syndrome. DENTAL AMALGAMS Summers (1994) has proposed that a set of unexplained symptoms in POW veterans (skin rashes, chronic fatigue, headaches, sore joints, hair loss, irritability, insomnia, diarrhea, and depression) may be related to mercury toxicity occurring as a result of the installation of dental amalgams just prior to or immediately after service in the POW. This hypothesis asserts that installation of these amalgams resulted in clinically evident elemental mercury toxicity that continues as patients have ongoing exposure to mercury. Mercury-based dental amalgams have been employed for more than 150 years, and the amalgams used in service personnel are similar to those used in civilian dental practices. It is clear that the placement of dental amalgams results in systemic exposure to mercury (Gross and Harrison, 1989; Summers et al., 19939. It is also clear that significant exposure (e.g., occupational exposure by inhalation) to elemental mercury results in a toxic syndrome with a complex clinical presentation (Wyngaarden et al., 1992~. However, the reports of elemental mercury-induced disease available in the literature are associated primarily with inhalation exposures that are very much higher that those associated with amalgam placement (Parkinson, 1992~. At the same time, relatively few human studies of adverse effects of amalgams have been done. Interest in diminishing elemental mercury exposure has resulted in proposals in Sweden, Denmark, and Germany for restrictions on the use of mercury-containing dental amalgams. The U.S. Public Health Service reviewed this issue and concluded that it was inappropriate at that time (1993) to

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SOME HYPOTHESES REGARDING ILLNESSES INPGW VETERANS 121 recommend restriction of the use of dental amalgams (DHHS, 1993~. Thus, there appears to be consensus in this country that mercury from dental amalgams is unlikely to be the source of significant morbidity. To date, the hypothesis of unexplained symptoms in POW veterans associated with the recent installation of dental amalgams has not been directly investigated to the best of our knowledge. BACTERIAL ILLNESS Persistent streptococcal or other bacteremia has been suggested (Hymen, 1996) as a cause of UI related to service in the Gulf. The suspected bacteremia is proposed to resemble that encountered after dental procedures and is claimed to be diagnosable by using unique microscopic evaluation of the urine, which streptococci enter from the blood via the kidney. No specific exposure in the PG has been suggested to have resulted in infection with the bacterium. This purported bacteremia has been treated with intravenous and oral antibiotics (primarily clindamycin) for extended periods, with undocumented reports of "curing" veterans having unexplained symptoms. To our knowledge, no reports of any study of the risk that this treatment increases the risk of infection by antibiotic-resistant bacteria have been made available. Of note, clindamycin is considered inappropriate for treatment of almost all forms of urinary tract infection. In addition, this antibiotic can produce significant gastrointestinal side effects when used for prolonged periods. The proposer of this hypothesis indicates that he has seen streptococci in urine in civilians for more than 30 years. Although there have been attempts to initiate a formal study of this putative bacterial syndrome, federal funding for the research has been withheld after review by several groups found the researcher's proposals to be of poor quality. The prevalence of this disorder in otherwise unexposed asymptomatic individuals is unexplored. 1\4YCOPLASMA AND CHRONIC FATIGUE Some investigators have hypothesized that a subset of soldiers with unexplained illnesses of a type considered similar to CFS have mycoplasma infections that can be diagnosed if appropriate laboratory tests are available. Nicolson and Nicolson (1995a) have reported on a group of 73 individuals composed primarily of veterans but including some family members (the group is referred to as a nonscientific sample) since mycoplasma infections can be spread by close contact. These individuals with unexplained CFS-like illness were studied for mycoplasma-related DNA detectable in peripheral blood cells, and 55% were found to have evidence of such DNA. These individuals, who were not found to have mycoplasma in the peripheral blood by standard

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122 HEALTH CONSEQUENCES OF THE PERSIAN GULF WAR methods, were found to be positive by using a polymerase chain-reaction method targeting DNA in their white blood cells (Nicolson and Nicolson, 1995b). The polymerase chain-reaction method used has not been directly related to pathologic potential or outcome, nor have the results been independently confirmed. No source of mycoplasma infection has been documented, although mention has been made of the potential immunosuppressive effects of inhaled fine sand particulates present in the Gulf region. Nicolson has stated that the preliminary study of this hypothesis did not utilize "a scientific sample" (Nicolson, 1996) and has briefly described studies that have been proposed in collaboration with CDC to further examine this hypothesis. To date the relevance of this finding is unclear. SKELETAL MUSCLE BIOENERGETICS This putatively GWS-related clinical entity may share some similarity with disorders of oxidative phosphorylation, also proposed to be causally related to UI (see above). Fishman (1995) examined three veterans with undefined chronic fatigue. Two patients were evaluated by using magnetic resonance imaging, and an additional seven patients are being examined with magnetic resonance spectroscopy for metabolic evaluation of skeletal muscle. The data presented suggest that some sort of abnormalities may be present in muscle oxidative capacity in these veterans, but it is unclear if the abnormalities are related to each other. A brief letter provided to the committee explains that the individuals were referred for evaluation of GWS. The letter did not include demographic or other data on the individuals, such as their age, gender, life- style habits, whether they were taking other medications or had other illness, what branch of the military they were serving in, the sorts of exposure they might have encountered, or how "normal" comparison values were generated for the tests on muscle function. The investigative findings were suggested to potentially contribute to understanding the pathophysiology of fatigue, and no cause for this fatigue was suggested. SARCOIDOSIS AND LINGUAL ABNORMALITIES Milner (unpublished) has studied the occurrence of sarcoidosis in PGW veterans self-referred to the Veterans Administration Medical Center (VAMC) in Allen Park, Michigan. This study compared the occurrence of a diagnosis of sarcoidosis in 626 male PGW veterans who were self-referred from 1991 through 1994 with the occurrence of the condition in 9,567 self-referred male veterans who were not deployed to the PG. A total of ten cases of sarcoidosis were diagnosed (all in African Americans): five cases were found in the PGW veterans and five in the non-PGW veterans, resulting in a fifteenfold difference in prevalence. This led to the conclusion that the crude (nonage-adjusted)

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SOME HYPOTHESES REGAR~INGILLNESSESINPGW VETERANS 123 incidence of sarcoidosis among PGW veterans could be estimated as approximately 800 per 100,000 compared with an estimated 136 per 100,000 in the control group. The etiology of sarcoidosis is unknown, and this study suggests that further work might be indicated, particularly since there has been some suggestion that sarcoidosis is exposure related. At the same time, the prevalence reported in this study seems unlikely to account for a significant portion of illness in PGW veterans. Other studies at the same VAMC have suggested that there is a "toxic exposure sign" associated with ill health related to service in the Gulf. Milner and Plezia (1995) have reported that 33% ofthe PG veterans they examined had lingual papillitis as well as lingual and buccal hairy striae. The lingual findings are reported as painless multiple erythematous papular elevations along the anterodorsal aspect of the tongue, which appeared to be inflamed hypertrophic filiform papillae. These veterans were noted to have multiple linear inflamed areas along the cheek and occasionally along the dorsolateral surface of the tongue. The authors suggest that the findings may serve as an initial sign that the patient is suffering multisystem effects of toxic exposure. As a biological model, Milner and colleagues (unpublished) have suggested that the unexplained illness associated with PGW service is the result of an immunopathologic picture of immunosuppression. The immunosuppression has, in this model, resulted in type 1, type 2, type 3, and type 4 hypersensitivity reactions. These reactions, again in this model, are putatively related to low- dose, repetitive exposure to "extracellular antigens"; exposure to intracellular antigens presented at high dose; and finally, exposure to "reactivated viral infections." In this fashion, multiple-system disease with many secondary manifestations can be seen as the natural outcome of a single pathologic entity. To date, no confirmatory studies of these hypotheses have been investigated. Information on sarcoidosis diagnoses in other geographic locations is lacking, and as yet, the "toxic exposure sign" has not been noted by other investigators. BR\INSTEM DYSREGULATION SYNDROME One investigator has undertaken a case investigation of 10 PGW veterans who reported heat Intolerance or photophobia, autonomic instability with headaches, and the presence of motor abnormalities, exaggerated startle response to noise, or decreased sense of taste (Baumzweiger, 1996~. Based on detailed investigation of these 10 cases and his general observations of similar symptoms in nonveterans, the investigator has developed a hypothesis of a syndrome experienced by PGW veterans that is called the "Two-Hit Brainstem Syndrome." The hypothesis suggests that two "insults" to the brainstem, one early in life and one later (e.g., while in the Gulf region), could produce a

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124 HEALTH CONSEQUENCES OF THE PERSIAN GULF WAR polysymptomatic illness. The combined result is loss of control over the T-cell lymphocyte receptor, with resulting confrontation between the attentional and immune systems. The consequence is increasingly poor response to brainstem- related adaptive mechanisms No testable specification of this hypothesis has been presented and no study protocol has been reviewed by the committee. MICROSPORIDIA INFECTION One VAMC investigator examined the stool of PGW veterans to search for protozoa! infections using histochemical staining techniques (Blanck, 1996~. Based on the results of these tests and the size characteristics of bodies noted in the stools from 133 of the 143 individuals tested, the investigator suggested that microsporidia infection might be related to service in the PGW. Similar bodies were reported in individuals at the same location who were diagnosed with AIDS, cancer, or chronic steroid therapy. Intensive follow-up investigation of these findings was undertaken by using specimens from these individuals and from PGW veterans at other locations. The specimens were examined by experts in protozoa! disease using electron microscopy, immunofluorescence, and special staining techniques. No microsporidia were identified. One expert consulted suggested that the bodies originally noted had been yeast. An investigation of stool specimens collected in one case-control study of PGW veterans revealed no positive stool specimens. ORGANOPHOSPHATE-INDUCED DELAYED NEUROTOXICITY The multiplicity of symptoms involved in the PGW-related unexplained illnesses have led a group of investigators to survey the 24th Reserve Naval Seabee Battalion (Haley, 1995~. Seven hundred and twenty individuals were mailed the survey and approximately one-third participated. Of this one-third, there was a cluster of individuals who reported symptoms consistent with damage of the central and peripheral nervous systems. Based on this information, the investigators have proposed that the unexplained illnesses are related to delayed toxicity, such as has been described with organophosphate exposure. Unpublished reports of the results of this study have indicated that there may be some evidence of delayed neurotoxicity associated with symptoms in veterans. As of May 1996, no peer-reviewed report of this small study was available for the committee. While it may serve as an example for hypothesis generation, the study has significant problems, including small sample size, response, possible selection bias, and recall bias. There are no definite exposure measurements in the study group, and multiple hypotheses have been tested in conducting the study.

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SOME HYPOTHESES REGARDING ILLNESSES IN PGW VETERANS 125 CHEMICALLY INDUCED PORPHYRIA It has been suggested that some of the unexplained symptoms reported by PGW veterans are similar to those present in individuals with chemically induced porphyrins (Donnay, 1994~. Those proposing this hypothesis indicate a concern that pesticide exposures in the Gulf region may have caused such symptoms, which include photosensitivity to sunlight and occasional dark- brown to red-colored urine. These findings are suggested to be similar to those in individuals who are reported to have MCS syndrome. No formal proposal of a study of this hypothesis was received by the committee. FIBROMYALGIA Unexplained illnesses that have been seen in veterans have been said to be strikingly similar to the condition known as fibromyalgia. The diagnosis of fibromyalgia is based on symptoms presented by the patient and one symptom- related physical finding: namely, at any of multiple sites of the body, pinching or pressure by a probing finger induces unexpected withdrawal or exclamations of pain. This discriminating criterion is a major diagnostic finding that, along with widespread musculoskeletal pain, is part of the classification proposed in 1990 by the American College of Rheumatology (Wolfe et al., 1990~. The nature and etiology of fibromyalgia remain elusive. Patients diagnosed with fibromyalgia often also have symptoms that overlap those described for MCS and CFS. Fatigue can be the presenting complaint, as can weakness, sleep disturbance, cognitive complaints, arthralgia, or myalgia. There has been speculation that central nervous system hyperactivity, associated with an increase in excitatory neuropeptides or a decrease in inhibitory neurotransmitters (e.g., serotonin), leads to many of these symptoms. Thus, this cascade is associated with increased sensitivity to pain, autonomic dysregulation, and neuroendocrine disturbances. Although there has been little systematic study of fibromyalgia in veterans, the symptom complex has been noted in some veterans to parallel that reported for UI. This has led to speculation that some of the unexplained illnesses may have an fibromyalgia-like character. However, no definite exposure or experience has yet been linked to this entity; thus, its possible relationship to PGW service remains unclear. SOMATIZATION DISORDER Unexplained illnesses have also been compared with a polysymptomatic condition termed somatization disorder. This entity has its clinical onset prior to age 30, extends over a period of years, and is characterized by a combination of pain with gastrointestinal, sexual, and pseudoneurological symptoms (APA,

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126 HEALTH CONSEQUENCES OF THE PERSIAN GULF WAR 19949. The symptoms cause clinically significant distress or impairment in social, occupational, or other areas of functioning. In contrast to factitious disorders or "malingering," the physical symptoms in this disorder are not under voluntary control. An essential feature of somatization disorder is a pattern of recurring multiple somatic complaints that cannot be fully explained by any known general condition or by the result of exposure to any known substance. Somatization associated with a companion general medical condition results in physical complaints in excess of those expected from evaluation of the patient. Individuals with this disorder usually describe their complaints in colorful, exaggerated terms, but factual information is often lacking. In a presentation to the committee, Barsky (1995) discussed four major influences in the reporting of symptoms. Cognition influences are the first important factor in symptom reporting; that is, when people notice symptoms, they try to attribute or make hypotheses that might explain their symptoms. Symptoms attributed to disease are generally perceived as more intense than symptoms that are dismissed. Another important factor in reporting symptoms is the context of what is being perceived. The occurrence of the symptom and people's experiences of a symptom will influence how it is reported. A third factor is attention as an amplifier of a symptom. Paying attention to a symptom will intensify it, and to some extent, the symptom can be "infectious." The fourth factor influencing symptom reporting is mood, with anxiety and depression being important influences and amplifiers of symptoms. SUMMARY The committee found these descriptions of ongoing work interesting for a variety of reasons. First, their diverse nature provides additional compelling evidence that no one disease entity will likely be adequate to resolve the understanding of all unexplained illnesses in PG veterans. Second, these ideas, hypotheses, and investigations also serve as testimony to the efforts of many health professionals who strive to find avenues, overlooked by others, that might lead to new understanding of these illnesses and result in amelioration of the suffering that has occurred and continues to be reported. Third, although these approaches have varying merit and the investigators are dedicated to solving the problem, we are not optimistic that any are sufficiently well substantiated to offer much hope of important answers or relief for significant numbers of ailing American veterans. Hypotheses can be tested in research that has undergone scientific review by one's peers and been submitted for publication in a peer- reviewed journal for the scientific community as a whole to evaluate. Finally, although the committee has not identified an explanation for the unexplained illnesses in PG veterans, we do not doubt that many individuals reporting such illness are seriously affected. We also recognize that many

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SOME HYPOTHESES REGARDINGILLNESSESINPGW VETERANS 127 illnesses in the population at large lack explanation according to current medical understanding and also require an open mind. Continuing efforts to explore all possible avenues to increase our knowledge of such illnesses, and to reduce suffering and disability, are certainly indicated. The fact that work of the tentative nature summarized here continues 6 years after cessation of the POW underscores the importance of taking seriously the reports of ill health among active and returning troops. Those involved in future conflicts must anticipate the need to integrate into Defense Depa~l~ent and Department of Veterans Affairs planning at all stages high-quality research on the health consequences of combat and of deployments to hostile environments.