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Journal of Occupational & Environmental Medicine:
Original Articles

Gulf War Illnesses: Causation and Treatment

Hodgson, Michael J. MD, MPH; Kipen, Howard M. MD, MPH

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From the Division of Occupational and Environmental Medicine, Department of Medicine, University of Connecticut Health Center, Farmington, Conn. (Dr Hodgson); and the Division of Occupational Medicine, Environmental and Occupational Health Sciences Institute, Department of Environmental and Community Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ (Dr Kipen).

Address correspondence to: Howard M. Kipen, MD, MPH, EOHSI, UMDNJ-Robert Wood Johnson Medical School, 170 Frelinghuysen Road, Piscataway, NJ 08854.

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Abstract

Soldiers returning from the Gulf War in 1991 described a range of symptoms, including some consistent with the chronic fatigue syndrome, fibromyalgia, and multiple chemical sensitivity. Well-defined adverse health events attributable to service in the Gulf occurred. However, controlled epidemiological studies in Gulf War veterans and controls describe significant excesses of symptoms that were not clearly associated with pathologic disease. At least 12% of veterans currently receive some form of disability from the Department of Veterans Affairs. A number of reports outline theories proposed to explain the excess, but few are scientifically supported. Management guidelines for this spectrum of disorders resembles that of many of "emerging overlap syndromes," including multiple chemical sensitivity, chronic fatigue syndrome, and fibromyalgia. They include the establishment of a trusting doctor-patient relationship, negotiations around a common ground of scientific and etiologic beliefs, non-labeling of the disorder, and work toward recovery in the absence of clear etiologic answers.

Since late 1991, reports from repatriated units and individuals suggested that many soldiers returning from active service in the Persian Gulf attributed a broad range of symptoms and diseases to their service overseas. The scientific evidence and theories surrounding this problem have been summarized in a series of committee reports, including several from the Institute of Medicine,1-4 the Veterans' Administration Gulf War Expert Scientific Committee, and the Presidential Advisory Committee (PAC),5 after the initial Technical Assistance Panel at the National Institutes of Health.6 These reports do not provide definitive guidance as to the nature and cause of Gulf War Illness(es) (GWI), and the United States Department of Veterans Affairs' (VA) continuing education program provides no recommendations on clinical management of "non-specific" symptoms. Many physicians feel as poorly equipped to address patients in this situation as they do diseases related to environmental exposures in general.

Even within the VA system, veterans initially had difficulties obtaining either appropriate diagnostic testing or medical treatment. Now, with almost 12% of deployed veterans on some form of disability,7 many still feel ill and seek answers that will help them feel better. Among the wide range of etiologic theories for these symptoms, some have been discounted because the weight of evidence speaks against them, including adverse effects from exposure and contamination to and by depleted uranium munitions, exposure to biological warfare agents, and infections. Some theories remain at least plausible and subject to substantial investigative effort, including exposure to chemical warfare agents, adverse consequences of prophylactic pyridostigmine bromide exposure, and post-traumatic stress disorders (PTSDs), and these are considered in detail here. In this article, we review what is known about GWI and briefly review its potential causes, and we develop reasonable and practical interim recommendations for clinical management.

Management of any disease related to the environment usually involves at least four separate steps: documentation of the disease; documentation of exposure; linkage or exclusion of a relationship; and the formulation of management plans, using exposure control. Although a disease may sometimes be linked by clinical measures to a specific cause, absent precise knowledge of the nature of exposure (eg, asthma linked to a location, using clinical tests such as portable spirometry), most linkage strategies rely on epidemiologic or toxicologic analogies that involve duration of exposure and intensity estimation. Not infrequently, "low levels" of exposures can be documented for environmental health outcomes. These "low levels" are the same substance associated with effects at far higher levels but at levels well below those deemed necessary to cause disease. The problem is that often there are no good clinical markers for acute disease from the low exposures nor epidemiologic and toxicologic indicators of chronic disease at the doses encountered, leaving only records of exposures or measurements to support subsequent investigation. Therefore, documentation of exposures remains a key element in environmental toxicology in general. It is especially important for the Gulf War in particular, because records regarding exposures to many of the agents alleged to have caused clinical illness were not accurately or specifically kept. Few records were kept-whether for medications, pesticides, or environmental agents-in a fashion that allows useful definition of exposures to military personnel.

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Exposure

Exposure assessment in the clinical setting requires recognition of the exposure, some attempt at exposure quantification, and dose-estimation. Nevertheless, for many exposures, specific "safe" levels are, at best, poorly defined. Even formal guidelines such as threshold limit values do not claim to protect all workers, even at a specified level of exposure. The "industrial hygiene without limits" movement8,9 has suggested alternative approaches to exposure management, akin to the "As Low As Reasonably Achievable" (ALARA) guidelines known from radiation health, for which a fundamental assumption is that exposures even well below some set criterion are potentially related to disease. With the recognition of genetic heterogeneity,10 the influence of personal characteristics such as obesity and alcohol,11,12 and the interactions of various agents13-15 as contributors to the clinical appearance of disease after specific exposure levels, clinicians must consider such interactions in disease linkage and communication strategies.

The PAC Report5 details the limited state of knowledge as of late 1997 on exposures. Since that time, reports of further exposure incidents or new information concerning older exposure incidents have arisen. Such reports have been examined in detail and the results posted on a Department of Defense Web site as "incident analyses." In general, they have not supported exposures at levels likely to cause disease, and no clinical incidents of acute poisoning have been documented.

Three of the potential exposures are briefly described below.

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Depleted Uranium

Thirty-six US soldiers are known to have imbedded depleted uranium (DU) shrapnel from "friendly fire" incidents in which their vehicles were mistakenly attacked by other Americans with DU munitions. There are also "hundreds" of individuals who were exposed to DU particles through inhalation because they were on the vehicles that were accidentally attacked. These individuals may have rescued those on the vehicles after the attack, or they were assigned to the units that recovered these vehicles. The US General Accounting Office found that because few personnel were adequately informed about potential DU hazards, many may have been unnecessarily exposed.16 On the other hand, detailed assessments of the body burdens of DU-exposed veterans suggests that delivered doses are more than one order of magnitude below the levels associated with renal disease. The highest committed radiation dose from DU identified so far was less than 0.5 rem (M.A. McDiarmid, MD, MPH, unpublished data, 1998).

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Khamisiyah

An Iraqi arsenal was identified after the war, and, during demolition of the Khamisiyah ammunition bunker, a Sarin chemical plume fell over approximately 99,000 US troops over a 3-day period in March 1991. The amount of chemical agent in the plume was estimated to have been at least 0.01296 milligrams per minute per cubic meter.18 The amount of chemical agent in the plume is not likely to have caused ill health in anyone, according to current scientific knowledge. Preliminary epidemiological studies have not demonstrated higher symptom rates among soldiers located in the plume.

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Mustard Gas

On March 1, 1991, a soldier exploring a captured bunker in southern Iraq suffered a burn that the Department of Defense confirmed was caused by a mustard agent.1 That is the only confirmed exposure-related illness from any chemical warfare agent of a US service member in the Gulf Theater.

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Clinical Findings in Persian Gulf Veterans: Gulf War Illnesses

Several noncontroversial adverse health effects occurred in the Gulf. These include battlefield and non-battlefield injuries, a new form of viscerotropic Leishmaniasis, and excess respiratory symptoms.

Injuries were the leading cause of death. A majority occurred in non-battlefield settings.19 Even in battlefield settings, some of these were "preventable," such as the DU events.

Visceral Leishmaniasis has previously been described after infection with Leishmania donovani. Apparently the absence of a specific gene, which encodes for a Th2 response to L. tropica, allowed the development of viscerotropic Leishmaniasis in 35 soldiers. Despite investigators' energetic searching, no further cases have been found.20,21

A cross-sectional questionnaire survey identified differences in the rates of respiratory tract symptoms between servicemen and women sleeping in tents and barracks. An excess in chest symptoms was attributed to air-conditioning; an excess in nose and throat irritation was attributed to dust exposure in tents.22 Some attempt has been made to attribute infections to a combination of fine sand and viral disease.23

Such specific illnesses, including tuberculosis, malaria, and other infections not directly related to a specific military activity, were described after previous wars. More interestingly, prior wars have also led to chronic, delayed effects, such as excess lung cancer in survivors of mustard gas incidents in World War I or munitions manufacture in World War II.24 However, at the present time, the major point of controversy for Gulf War veterans is the excesses of poorly defined illnesses and symptoms without clear pathophysiologic explanation.

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Nonspecific Symptoms

Active-duty servicemen and women and veterans were given the opportunity to undergo standardized clinical examinations by the VA and the Department of Defense. A substantial proportion (10% to 20%) of these volunteers were asymptomatic individuals who wanted reassurance about their health.

A review of the data from the Department of Defense's registry, formally known as the Comprehensive Clinical Examination Program (CCEP), also does not support the presence of clinically diagnosable organic medical disorders as a common explanation for complaints among Gulf War veterans.21,22 On the basis of 20,000 self-selected volunteer medical examinations among active-duty Gulf War veterans, the most frequent symptoms were the following: joint pain (49%), fatigue (47%), headache (39%), memory loss (34%), sleep disturbance (32%), rash/dermatitis (31%), difficulty concentrating (27%), depression (23%), and muscle pain (21%). In contrast, the most common primary diagnoses were as follows: healthy (9.7%), tension headache (3.4%), fatigue, not chronic (3.3%), depressive disorder, not elsewhere classified (2.9%), PTSD (2.8%), headache (2.7%), migraine (2.7%), asthma (2.2%), and lumbago (2.0%). All of these diagnoses, except some cases of asthma, are largely based on symptoms without signs of organic pathology. A recent analysis was unable to document an association between symptoms and self-reported exposures.25

A similar registry was established in 1992 by the VA26 that shows a similar symptom profile, with 26.4% of subjects receiving no definitive medical diagnosis and another 12% with no health complaints.

Three retrospective population-based analyses provide data on the actual health experience of veterans, and none provides significant support for organic pathological causes of morbidity in Gulf War veterans. A morbidity analysis examined the hospitalization rates of long- and short-term veterans and compared utilization before and after deployment among individuals deployed to the theater of operations with those deployed elsewhere.27 Individuals with fewer than 2 years of service before the war had a relative increase in hospitalization rates for psychological causes and "ill-defined conditions" in the 2 years after the war. A second population-based morbidity study using self-report suggested a doubling of rates of symptoms of asthma, depression, fibromyalgia, PTSD, cognitive dysfunction, and anxiety in deployed veterans.28

The Centers for Disease Control and Prevention conducted a cross-sectional study of a highly symptomatic Air National Guard Unit that was unique for its exquisite attention to ruling out infectious etiologies for symptoms. Individuals defined by questionnaire to have a chronic multisymptom illness (cases) were no more likely than noncases to have positive findings upon physical examination, routine laboratory tests, or a battery of serologic tests. Cases did have diminished functioning and well-being and were more likely than noncases to meet Diagnostic Interview Survey criteria for depression and somatization disorder, as well as Mississippi Scale criteria for PTSD. This cross-sectional survey of veterans suggested that fatigue was the primary symptom.29

In general, various clinical programs and research studies have not found evidence of increased rates of organic pathological disease in Gulf War veterans. An initial mortality study suggested that US military personnel who had returned from the theater of operations were more likely to die of unintentional injuries than were those deployed elsewhere, with a statistically significant increase in motor vehicle accidents.30

Criticism has been leveled31 that such poorly defined diagnostic categories may hide an emerging syndrome, although other researchers have argued32 that the recognition and definition of "emerging syndromes" is a complex, time-consuming process. The conflicting opinions bear a striking similarity to the conflicts over symptom origin that characterize many instances of lower-level environmental exposures.33,34

These data suggest that diagnoses are largely determined on the basis of symptom reporting and that medical nomenclature is wanting for specificity. Psychiatric diagnosis may improve the descriptive capability, although, as is the case in the civilian population, psychological scales of distress, rather than categorical diagnostic thresholds, may be useful in accounting for a far greater proportion of variance.35 Although in general there is no comfortable and reassuring rubric for attributing the large numbers of symptoms in these populations to any underlying condition, whether physical or psychiatric, limited data from the CCEP confirms the importance of psychiatric diagnoses in terms of functional status. When disability was measured crudely as days lost from work in the previous 90 days, the mean for all diagnostic groups was 2.4 days. Individuals with neoplasms had the highest overall rate of days lost, but those with psychiatric diagnoses were next highest, with a mean of 3.7 days.36

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Questions of Etiology and Pathophysiology

Epidemiological studies in Gulf War veterans do suggest some consistent features. Women, subjects with combat experience, and subjects who describe higher rates of war-related stress describe higher rates of symptoms.29,31,37 However, individuals with self-reported exposure to nerve gas are also more symptomatic31,37 in population-based studies, although not in the CCEP.25 To date, such studies are clearly subject to recall bias or at least to response bias. Nevertheless, one of the major questions at present concerns this problem: Can we and how should we delineate whether the diffuse symptoms among veterans (both now and previously) are attributable to a neurotoxic exposure, to "stress," to psychological antecedents and vulnerabilities, or to a combination of the above?

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Neurotoxic Effects

A recent triad of articles38-40 documents factor-analytically-derived clusters of symptoms in a small group of Navy construction workers that had been deemed by the authors to be consistent with neurotoxic disorders, including a peripheral, a central, and an autonomic syndrome. This group was considered to have been potentially exposed to nerve gas from a SCUD missile attack. Although this group reported neuropsychological abnormalities, compared with those who lacked the symptom syndrome, results from clinical neurologic evaluations were negative and the positive interpretation of the neuropsychological findings has been challenged.3 Although one of these neuropsychological markers has been used previously as a marker of neurotoxicity from organophosphates41 and, more recently, as evidence of disease after a terrorist attack involving toxins,42 it is also reported to be a marker of anxiety (either of susceptibility or as a consequence of the anxious state).43

In addition, Jamal et al44 documented abnormalities in Gulf War veterans that they interpret as consistent with peripheral neuropathies. The general literature on organophosphates lends mixed support for a neuropathic or neurobehavioral effect in a chronic exposure setting. A clinical neurologic study of organophosphate-exposed sheep farmers suggested some evidence of peripheral neuropathy.45 Interestingly, an earlier neuropsychologic study of larger numbers from the same cohort found increased psychiatric vulnerability, as well as deficits in attention and information-processing speed in the farmers with chronic organophosphate exposure.46 However, in another heavily exposed but never-poisoned orchard farmer cohort, no neuropsychologic or psychiatric impairments were found.47 The difficulty of clearly separating symptoms and performance findings due to psychiatric disease from those due to subtle pathologic disease is apparent and is certainly difficult to interpret without some definition of exposure.

Gulf War veterans have described myalgias as a common symptom, with 21.8% reporting muscle pain, although only 0.8% report it as their chief complaint. Case series to some degree support the presence of some poorly defined but biologically measurable abnormalities, eg, those involving creatine phosphokinase and aldolase,48,49 although the appropriate interpretation of relatively minor abnormalities remains unclear.

Nerve gas exposures may cause poisoning episodes.50,51 However, an overriding major problem with a neurotoxic hypothesis is the lack of convincing and credible evidence for significant nerve gas or other neurotoxin exposure to large numbers of troops. Large numbers of veterans with symptoms were not at risk for exposure to known or conceivable areas of nerve gas release, and exposures to insecticide-impregnated uniforms and vector-control spraying of living areas is common in nonbelligerent deployments have not been reported to lead to significant levels of medically unexplained symptoms.

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Pyridostigmine Bromide

The Surgeons General of the US Armed Forces have developed a policy that suggests the prophylactic use of pyridostigmine bromide (PB) in situations where exposure to chemical warfare agents is likely. The recommended dosage is 30 mg every 8 hours. One study suggested that only 1% of soldiers52 had side effects from PB that required medical attention, and only 0.1% had symptoms that required discontinuation of PB prophylaxis. On the other hand, substantially greater percentages of Israeli soldiers described such side effects, and researchers have suggested an interaction between PB and wartime stress as a cause.53 It is apparent in the neuroendocrine literature that PB doses similar to those prescribed in the Gulf cause substantial short-term alteration in the hypothalamic-pituitary axis, particularly in the secretion of growth hormone, and that this effect is more substantial in subjects who are currently depressed.54 Implications of this alteration for soldiers have not been explored, but such large-scale administration of any drug is likely to cause unrecognized adverse reactions, possibly previously undescribed reactions.

Several recent studies examined the toxicology of PB. It appears to increase core temperature by itself and to cause some measurable muscle weakness at the recommended dosage,55 although it does not appear to cause noticeable symptoms and any such effects are unlikely to be of functional significance. Several studies suggest that at least in rats, fasciculations from PB overdosage predict the development of a chronic myopathy,56 and a chronic dose of 90 mg/kg causes myopathy in rats.57 These doses are substantially higher than those used in prophylactic administration. Nevertheless, given knowledge of PB interactions (see below) and the (albeit weak) evidence for muscle aches and abnormal muscle enzymes in the blood, this remains an interesting finding.

Controversy has arisen because of case reports that a genetic deficiency of serum (butyryl) cholinesterase is associated with some chronic disease that is as yet poorly characterized.58 Several cases in Haley's exposed cohort had cholinesterase deficiency, although there was no significant difference in mean levels of enzyme activity (R. W. Haley, personal communication, 1996). PB is a well-known drug used in the treatment of myasthenia, and is known to require individual dosage adjustment; some myasthenics are very "brittle" and may easily develop signs of cholinesterase poisoning, including weakness. Their management is at times very difficult.

PB was not given alone in the Persian Gulf; several other agents were present that could theoretically increase its toxicity, including diethyltoluamide (DEET) and permethrin, although these were unlikely to have been substantially present in January and February when PB was used. Recently published data59,60 suggest that these agents together, or in combination with heat,61 may have substantially more toxicity than any individual agent. Similarly, interactions between PB and caffeine62 may explain some worsening toxicity. Finally, Friedman et al63 demonstrated that central nervous system distribution of PB absorption may increase dramatically, with clearly documented consequences in neuroimaging and enzymatic activity, after rodent exposures in extreme stress situations. Additional animal studies suggest that PB exposure may lead to earlier development of hypertension in genetically hypertension-prone rats, as well as to a persistently abnormal startle response after PB treatment has ceased.64,65

These studies together suggest that some combination of drug interactions, coffee, and heat might lead to worsening toxicity. No data have been provided that supports this hypothesis for humans.

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Non-Organic Origins of Symptoms: Can Current Symptoms Be Readily Explained Through Psychological and Psychophysiological Disorders?

Hyams et al66 summarized the psychological consequences of war. For the aftermath of each war since 1860, they identified a syndrome that cannot be explained in terms of pathophysiology and disease as we currently view illness, notwithstanding depression and as yet undefined regulatory imbalances such as neuroendocrine and autonomic dysfunction. They argued that prior wars had caused similar syndromes, including a Vietnam War syndrome distinct from PTSD, and that most non-battle illness and injury could not be readily explained by either physiologically based or psychiatrically diagnosed conditions. Although there is little or no literature on such chronic symptom-syndromes in military veterans beyond the period of combat (exclusive of PTSD), there is a substantial military medical literature on the effective management of related battlefield complaints, such as acute combat stress reaction.67 Such reactions have long been recognized to cause long-term disability among veterans, and treatment and management guidelines have been developed.

Such non-specific symptoms often differ in appearance from PTSDs. Haley recently reviewed ten studies of PTSD among veterans.31 These studies used standard instruments (Mississippi Scale), although they required-in their final analysis-a lower symptom score to define individuals as having the outcome of concern than did older studies with the same instrument. The author therefore believes that these studies do not prove the presence of PTSD and that it is premature to conclude that a substantial degree of Gulf War veterans' morbidity can be attributed to this. On the other hand, Haley's reanalysis does not refute the excess depression and anxiety,28 the excess rates of psychological symptoms,28 and the clinical diagnoses of PTSD.21,29,68 An accompanying editorial31 argues that much work still needs to be done before the presence of a new syndrome arising out of the Gulf War is documented and proposes criteria by which one could recognize such a specific syndrome. Importantly, the authors argue that diseases are treated only after recognition of their pathophysiology, leaving veterans "untreatable."

Interestingly, the increases in accidental deaths for Gulf War veterans cited above are reminiscent of mortality patterns that emerged after service in the Vietnam War.69 A random assignment of birthday numbers ("the lottery") created two classes of subjects: eligible and not eligible for service in Vietnam. Those who returned from Vietnam experienced a significant 13% increase in suicide and an 8% increase in motor vehicle accidents. These data, in the view of those authors, were reminiscent of the data arising out of the Korean war. More remarkably, in a controlled study of the health of Vietnam veterans, compared with that of nondeployed troops, the Vietnam veterans had significantly higher rates of reporting poor/fair health as well as "somatic symptoms" (fatigue, nervousness, gastrointestinal ailments, dizziness, headaches) not explained by medical conditions diagnosed in special examinations done for the study.70 More recently, Elder et al71 examined the effects of combat among World War II veterans in a longitudinal study of "talented children" that began in the 1920s. They documented a 2.85-fold increase in death or other adverse health outcomes after combat exposure that was not explained by prior health or by habits such as alcohol consumption or cigarette smoking. Interestingly, there was also a suggestion that this same group suffered from a number of medically unexplained symptoms.

Shorter72 commented on the evolution of symptoms in parallel with the beliefs of the medical establishment for syndromes of poorly defined etiology. He reviewed the medical descriptions of patient complaints for syndromes that we do not understand, which resemble chronic fatigue, and argued that these could be best understood as a social process. The "help-seeking actions" of patients led to interpretations by physicians and categorization into syndromes consistent with prevailing medical paradigms. Another example of a help-seeking action is the use of alcohol and mood-altering drugs, and Keegan73 suggested that war is survivable by young men only with the help of substances such as alcohol and mood-altering drugs. These were apparently more conspicuously and effectively proscribed than usual in the Saudi Arabian deployment.

Spurgeon et al33 argued that all symptoms attributed to environmental exposures arise through one or both of two pathways: the typical one through the physical effects of organ pathology and exposure-induced alterations in function, and the second out of psychosocial constructs that accompany the exposure or psychological vulnerabilities of the individual. These include all of those factors so well studied in the epidemiology of syndromes attributed to toxins on hazardous waste sites, including personality structure, risk aversion, social amplification of risk, media influences, and more.

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The Arrogance of Etiology

The evidence reviewed above provides an increasingly clear picture of the manifestations of GWI. This allows placement of GWI on the map of human afflictions in the realm of medically unexplained symptoms with elevated rates of psychiatric comorbidity, with or without subclinical and borderline abnormalities on investigative tests of neurophysiologic and neuropsychologic function. The nature of lesions or toxicity from PB or nerve agents in Gulf War veterans is speculative at this time. With this in mind, we believe that it is critical to address the practical question of what to do for those Gulf War veterans and family members who suffer. The quest, which is perhaps ultimately futile, for etiology is critical in addressing preventive recommendations for future deployments, but it may also be seen as a diversion of attention and resources from the hard work of healing those with symptoms today.

Even if Gulf War veterans are finally shown to have neurotoxic illnesses, there is no specific treatment in present medical practice for the muscle aches, fatigue, headaches, and cognitive difficulty arising from cholinesterase intoxication, whether from sarin, PB, or agricultural chemicals. Whether in farm workers observed after acute organophosphate overdoses or in farmers with deficits after chronic exposure, specific or effective therapies for chronic after-effects are lacking. Although these therapies can be sought through research, one must seek viable approaches to treatment for those with symptoms today. Even though we know little about how such chronic, polysymptomatic illness arises, there are two effective therapeutic approaches that have evolved; both can be applied independent of etiology and both are essentially risk-free. If we use the symptom-reduction approaches developed in the CFS literature, the FM literature, the MCS literature, and what we have observed from veterans as guides, there is much that can be done to heal now.

The obvious core is to treat any psychiatric comorbidity assiduously. Whether it is depression or anxiety, we have powerful treatment tools. Whether the depression was caused by chemical exposures, eg, cholinergic agonists,74 by chronic physical illness due to war, or is of unclear etiology, there are demonstrated pharmacological and psychotherapeutic tools to apply. This can be done effectively and ethically without the cause being known, as long as we are clear that exposure to any possible cause has ceased. We can safely meet that requirement for all of the factors we have discussed because none are stored in body tissues and only those troops on active duty have a remote chance to receive PB in the future.

However, the unfortunate truth is that many of the symptoms encountered here will not yield to standard pharmacologic therapies for anxiety and depression, either because they have distinct, albeit unknown, etiologies or because available therapies are not completely effective.

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What Is the Appropriate Treatment?

Patients in primary care settings often seek help from their physicians for symptoms that are not easily explained,75 including musculoskeletal symptoms, cognitive symptoms, and fatigue. Some of these symptoms represent depression that is widely underdiagnosed.76 Some represent perceptions of illness77 that may reflect personality structures and health beliefs rather than organic disease. Spurgeon et al33 pointed out the relevance of this to environmental syndromes. In any case, primary care physicians have long spent much of their time addressing nonspecific symptoms while continuing to screen for more treatable diseases. The emotional work done with patients in the primary care setting has long been recognized as a source of both benefit to patients and satisfaction to physicians. As health care financing in the United States has changed, physicians have had less opportunity to spend time with their patients, to listen carefully and patiently, and to facilitate their self-healing. Ironically, at present, the treatment for "somatoform disorders" is just that-to refrain from ordering medical tests, to listen, and to help patients refocus on their next goal.78,79 In the setting of environmental disease, part of the obstacle to a patient's improvement may be the focus on the unknown cause of disease, the uncertainty of prognosis (with fear of progression), and the anger from perception of external, preventable causes, as has been recognized after work-related injuries.80

The authors consider two formal approaches to treatment worthwhile, one a well-established, scientifically valid (although expensive) approach, the other a practical, useful set of guidelines that has never been formally "tested" but remains good medical practice.

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Practical Guidelines

Patients with strong beliefs about environmental causes often seek help from physicians for treatment of diseases. For some diseases, such as asthma, clear linkage steps are available. For others, no clear diagnostic strategies are available. Physicians must then listen carefully and respectfully (often after describing time limitations), develop a relationship in which both parties are invested, negotiate with patients around scientific and lay models of illness for "plausible evidence," understand the existing problem, and develop a strategy for moving forward.

Trust and mutual respect are established through careful listening, recognition of the hazards of service in war, and acknowledgment of the very real diseases that were described, including Leishmaniasis, injuries, and respiratory tract disease.

A relationship is developed in the negotiation around a common set of beliefs. Etiologic hypotheses about disease-exposure relationships are formulated broadly enough to allow the patient to maintain some beliefs about his or her integrity and provide explanations that explain symptoms, without attributing them to "being crazy." The authors have found useful those communication strategies that help patients recognize the psychological contribution to all disorders, even those disorders with clear organic etiologies. These strategies include statements such as "All disease is in our head; the pain of heart attacks, the fear of dying with lung cancer, and the misery of the common cold are all in our head. Why should your... not be there?" Patients must be helped to the recognition (and they must discover it themselves) that there is no specific treatment for neurotoxic disease and that clinical improvement will involve learning to live with what they have, to increase endurance and strength, and to move past this phase of their lives.

For many chronic diseases, established linkage strategies rely on documentation of exposure. In the Gulf War case, although there are no good, externally accepted markers of exposure right now, they may become available in the future. Where no acute, reversible markers of effects are available, preventing the possibility of "n-of-one" clinical trials,80a or where no good measure of exposure is identified for epidemiologic purposes, physicians may simply be unable to provide an unambiguous answer on associations of disease and exposure. They may then outline the limitations of scientific knowledge and help patients attempt to move forward in their personal lives. This requires careful listening, and much time, with physicians remaining aware of the ambiguities of causal associations and reminding patients of this uncertainty when patients slip back into old beliefs.

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Scientifically Documented Treatment

Several groups of investigators have attempted to use cognitive behavioral therapy (CBT) as a formalized treatment to help patients return to productive states.81-85 For example, patients with CFS often feel disabled, although there are few biomedical data to explain their inability to work. Bonner and colleagues82 demonstrated mild benefits in a small trial, which was criticized because it was uncontrolled. Friedberg and Krupp83 showed some improvement in depression, but not in fatigue, in such patients. In 1995, a randomized trial from the Netherlands showed statistically significant improvement among subjects with unexplained symptoms, not specifically CFS.84 More recently, Deale et al85 demonstrated a parallel 70% return-to-work rate in CFS cases, using 17 sessions of CBT. Such sessions require approximately 1.5 hours of the physician-treater's time. Meanwhile, on the strength of these data, such treatment is covered by the National Health Service in the United Kingdom.

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Where Do We Go From Here?

At present, the cause of symptoms of fatigue or inability to perform in various activities among veterans remains unclear. These symptoms may reflect a psychological cause. On the other hand, they could, at least theoretically, reflect neurotoxicity from exposure to nerve gas, an effect of PB therapy, or an interaction of the two. Treatment guidelines on acute war syndromes recognize that long-term outcome may be better if soldiers are treated without labeling.86 Cognitive behavioral therapy and other management techniques for chronic and medically untreatable symptoms can be applied to individuals whether they have a chronic fatigue-like syndrome, a somatoform disorder, or a need to adjust to a chronic disability from nerve gas exposure. Especially for the latter, no other treatment is currently appropriate or available. The message needs to be that all of the common symptoms we have discussed are important and that psychologically oriented treatment does not exclude an organic lesion or imply a deficient state. It just admits that at this moment there is nothing more specific to be done.

Since the first meeting on Gulf War Illnesses,6 war-related stress has been under consideration as a potential cause for this problem. In fact, some of the key symptoms reported by Gulf War veterans have been equated with stress itself, rather than seen as an illness resulting from it (eg, fatigue, lack of energy, demoralization).87 Clinical experience and literature from this century have given rise to systematic approaches to war-related stress. Related to the increasing recognition of symptoms from stress-related syndromes, long an integral part of practiced military psychiatry, well-defined guidelines for their management at or near the front have been developed.67 These guidelines have included, since the first World War, "proximity, immediacy, and expectancy." That is, soldiers should be treated wherever they are identified with a psychological response, rather than referred on to specialists (psychiatrists) or other locations. They should be treated as soon as possible, rather than undergoing referrals. Finally, labeling the problem as a psychological disorder rather than as a normal response to an abnormal situation, even for soldiers, is associated with adverse long-term consequences and disability.

Many veterans appear to feel ill. They do appear to use the health care system more frequently for a broad range of problems, from asthma to "ill-defined conditions." Some of these conditions represent identifiable diseases commonly treated in primary care settings, such as asthma. Some are commonly seen but do not appear to be treated effectively by primary care physicians, who have little training in effective, often multidisciplinary approaches to these syndromes. Many veterans have applied for and received disability, although their VA records do not document how severely dysfunctional they claim to be.

It is likely that young, relatively healthy veterans will receive less aggressive screening for psychological aspects of symptoms in primary care settings than will older individuals, unless their primary care physicians are alerted to the need. Even then, review of the practices of primary care physicians suggests that physicians may benefit from efforts to help them optimally use all of the tools, both psychopharmacologic and psychotherapeutic, that are available for management of these challenging and chronic symptom states. Under the increasingly severe cost constraints of primary care practice, many physicians will avoid treating patients who need contact time during visits, because reimbursement for listening is increasingly difficult to justify. It may be unreasonable to expect veterans to acquire adequate services after repatriation unless these services are provided by the VA.

Symptoms among Gulf War veterans may represent a consequence of toxic exposure or reflect personal experience of a war zone. Either way, we believe that the VA is a logical choice to spearhead the development of insightful and responsive care delivery for this increasingly recognized and problematic type of disorder, in which the symptoms outweigh the clinical signs. We believe that this will require conduct of a randomized clinical trial of CBT, possibly in combination with the provision of educational materials for primary care providers. An alternative comparison arm that would simply allow ill veterans to speak with their attentive, supportive physicians for long periods of time would be a thought-provoking possibility.

While this manuscript was in review, the VA announced that it would conduct large-scale randomized controlled trials of treatments, including CBT, for symptoms of undiagnosed illnesses in Gulf War veterans.

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Acknowledgments

The authors wish to acknowledge the intellectual partnership of Matthew Puglisi, of the American Legion, who participated in the development of the ideas in this work but chose not to be listed as an author.

Dr Kipen's work was supported in part by National Institute of Environmental Health Science Center Grant ES-05022 and Academic Award ES00218, as well as the Department of Veterans Affairs' New Jersey Center for Environmental Hazards Research, and the Centers for Disease Control and Prevention Cooperative Agreement U50/CCU21463.

Dr Hodgson was supported in part by Academic Award 1 KO7-ES00305-01 and by a contract with the American Legion through the Association of Occupational and Environmental Clinics, Washington, DC.

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