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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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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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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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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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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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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.
Representative terms from entire chapter:
unexplained illnesses
