In August of 1990, the Iraqi
army invaded Kuwait and annexed it as one of its territories. Despite
repeated attempts to resolve this diplomatically, Iraq remained defiant
and approximately 700,000 American servicemen and women were deployed to
the Persian Gulf for Operation Desert Shield/Storm. They performed
valiantly in one of the most decisive battles in modern military history,
ending the war in early 1991. For some, the war didn't end there
as many returning Gulf War veterans began describing a wide variety of
debilitating health problems. These symptoms became known as Gulf
War Syndrome and at first, were not taken seriously. After much pressure,
the Pentagon began to investigate possible causes of these symptoms and,
in 1995, a presidential committee was appointed to study gulf war illnesses.
Several independent researchers also conducted studies to try and determine
the causes of Gulf War Syndrome. Their results seemed to indicate
an exposure to chemicals or a combination of chemicals, resulting in damage
to the nervous system.
An estimated 5,000 to 80,000
Gulf War veterans remain ill with vague symptoms that resemble chronic
fatigue syndrome, but defy diagnosis (Haley, et al., 1997b). Some veterans
appear to be neurologically impaired but the variance of symptoms appear
too broad to fit any single syndrome. This has led many to believe
that these are due to illnesses that would have occurred without taking
part in the war or are psychologically based (Haley, et al., 1997b).
These include a variety of nonspecific symptoms such as numbness, paraesthesiae,
loss of muscle strength, loss of control of bowel or bladder, muscle pain,
weakness, arthralgias, headache, memory loss, sleep disorders, dyspnea
and gastrointestinal problems (Amato, et al., 1997).
Research technicians administered
neuropsychological tests to affected Gulf War veterans and veterans of
the same battalion who were matched for age, sex, and education who did
not develop symptoms (Table 1) (Haley, et al., 1997a). Tests were
performed by six separate research teams, each unaware of the other teams
results until the completion of the study. Tests given were the Halstead-Reitan
Neuropsychological Test Battery for Adults, including the Trail Making
Test part B and the General Neuropsychological Deficit Scale. The
Halstead-Reitan Battery has been extensively validated to identify brain
damage and distinguish it from other conditions, including psychological
disorders (Haley, et al., 1997a). Results showed that mean
scores were significantly higher (more abnormal) in the cases than the
controls on the two tests. This suggested slowed sensory transmission
up the posterior columns of the spinal cord to the brain, indicating
abnormalities of the cranial nerve VIII, the cochlear nucleus, or the brainstem,
indicating dysfunction of the nervous system (Haley, et al., 1997a). The
mean scores of the controls were consistent with scores found in normal
(non-brain-damaged) individuals given these tests.
Soldiers deployed to the Persian Gulf region were exposed to or given
a variety of chemicals and vaccines.
These different agents may
have acted alone or in combinations to cause the symptoms veterans are
now experiencing. Deployed military personnel are routinely vaccinated
against tetanus, diphtheria, yellow fever, typhoid, poliovirus, influenza,
and meningococcus (Amato, et al., 1997). Veterans were also issued
insect repellent that was 75% N, N-diethyl-m-toluamide (DEET) and provided
with tablets known as NAPTS and BATS, an added preventative against potential
chemical and biological weapons use during the war. These tablets
contained pyridostigmine bromide (PB) and pentavalent botulinum toxoid
and were to be self administered, one tablet every 8 hours (Jamal, et al.,
1996). Many soldiers also wore flea collars that contained pesticides
such as permethrin or pyrethrin that inhibit acetylcholinesterase (AChE),
plasma butyrylcholinesterase (BuChE), and neuropathy target esterase (NTE)
(Haley and Thomas, 1997).
Exposure to combinations
of these organophosphates (OPs) and other cholinesterase-inhibiting chemicals
may be producing the symptoms experienced by Gulf War veterans. In
studies using chickens, researchers found that two pesticides, DEET and
permethrin, and the anti-nerve agent PB were harmless when used alone,
even at three times the doses soldiers received. When used in combinations,
however, they caused neurological symptoms similar to those reported by
Gulf War veterans (Abou-Donia, et al., 1996). A flea collar
on the market at the time of the Gulf War contained DEET and the pesticide
pyrethrin. It was later removed from the market when the combination
was found to cause fatal neurotoxicity in cats (Haley and Thomas, 1997).
The chemical mix is dangerous
because test results indicate the anti-nerve gas agent PB reduces the body's
normal ability to inactivate the two pesticides, which can then travel
to the brain and cause damage to the brain and nervous system (Abou-Donia,
et al., 1996). The body normally removes foreign chemicals with the
help of enzymes such as BuChE. This enzyme inactivates the foreign
chemicals by scavenging and inactivating absorbed OPs, but there is a finite
number of these enzymes in the bloodstream, and they can neutralize only
one chemical at a time. When multiple chemicals are present, the
enzyme is unable to neutralize them all, resulting in a toxic accumulation
in the bloodstream (Abou-Donia, et al., 1996).
In addition to this, the anti-nerve gas agent PB inhibits the action
of the enzyme AChE from nerve gas damage but does not distinguish between
BuChE and AChE, binding reversibily to both. This prevents permanent
binding by OPs and with postexposure atropine and oxime therapy reduces
mortality from some nerve agents (Haley and Thomas, 1997). This makes
even less BuChE available to neutralize pesticides and ends up magnifying
the effects of the other chemicals by tying up the available BuChE (Abou-Donia,
et al., 1996).
With BuChE already tied
up and the body's natural protection gone, OPs in the bloodstream bind
with the enzyme NTE, which is attached to neural membranes throughout the
nervous system. The resulting organophosphorylated-NTE complex undergoes
molecular reorganization over a one to six week aging period and forms
a byproduct that is axonotoxic (Haley and Thomas, 1997). This time-dependent
process which accounts for the delay between exposure and symptoms is called
"aging" and OPs in which it occurs are called aging OPs. The anti-nerve
gas agent PB does not cross the blood-brain barrier and therefore does
not protect NTE from being bound by aging Ops (Haley and Thomas, 1997).
If more than 70% of NTE is inhibited, distal axonopathy with dying back
of the axon from its distal end and secondary demyelination result in both
the central and peripheral nervous system (Haley and Thomas, 1997).
With exposure to OPs and
related compounds, either of two syndromes may be produced: immediate cholinergic
symptoms, which are not fatal or a variant of the syndrome of the central-peripheral,
distal, sensory-motor axonopathy known as organophosphate-induced delayed
polyneuropathy (OPIDP), which can be fatal (Haley and Thomas, 1997).
Laboratory studies in chickens confirm that repetitive administration of
an OP, carbamates (DEET and PB), and related compounds, such as pesticides,
in sub-OPIDP doses act synergistically to produce OPIDP. Other research
indicates that giving an NTE-inhibitor before exposure to an OP prevents
OPIDP, and giving after exposure to an aging OP can markedly exacerbate
the severity of OPIDP (Haley and Kurt, 1997).
After comparing the types
of neurologic symptoms and the many hypothesized causes, it was then believed
that the best explanation for the symptoms veterans were now experiencing
was due to variants of OPIDP resulting from exposures to combinations of
OPs and other cholinesterase-inhibiting chemicals (Haley and Kurt, 1997).
To test this hypothesis, a cross-sectional survey of ill and well veterans
in a single battalion was designed. After a 2-stage factor analysis
of symptoms, three strongly clustered symptoms and three weaker clustered
ones were identified. This may represent injuries from separate agents
to which the veterans were exposed or partial syndrome overlap (Haley,
et al., 1997b). Differences among the syndromes may also be due to
differences in "brain reserve capacity" of the groups at the time of the
war, possibly interacting with differences in combinations of cholinesterase-inhibiting
chemicals to which they were exposed. This suggests dysfunction of
the central, peripheral, and autonomic components of the nervous system
(Haley, et al., 1997a). The three strong syndromes were focused on,
each with strongly homogeneous symptoms. Veterans from these groups consistently
scored more in the abnormal direction on objective tests of neurologic
function than the control veterans
Differences in the combinations of abnormal test results suggest that
these three syndromes represent variants of a single pathologic process
distinguished by severity of impairment by predominant involvement of different
components of the nervous system (Haley, et al., 1997a). Syndrome
1 ("impaired cognition") is characterized by distractibility, difficulty
remembering, depression, middle and terminal insomnia, fatigue, slurring
of speech, confused thought process, and migrainelike headaches.
Syndrome 2 ("confused-ataxia") is characterized by problems with thinking,
reasoning and getting confused or disorientated and problems with impotence
and a high frequency of occupational disability. This is associated
with testing abnormalities characteristic of brain and spinal cord damage
and possibly peripheral neuropathy (Haley, et al., 1997a). Syndrome
3 ("neuro-myo-arthropathy") is characterized by generalized joint and muscle
pains, muscle weakness and fatigability, and stocking-glove paresthesias.
This is different from the other two in that it has definite neurologic
abnormalities that could be from dysfunction of either the central of peripheral
nervous system (Haley, et al., 1997a).
The results of these studies
give a strong argument that the cause of Gulf War Syndrome is actually
variants of OPDIP resulting from exposure to combinations of organophosphates.
There is still a lot of research to be conducted and experiments to specifically
narrow down the cause of the syndrome. There may be other causes
as well, some think that low concentrations of nerve gas did come into
contact with coalition forces and is what's causing Gulf War Syndrome.
Whether this is true or not has not yet been proven. If it is, it
would probably only support the theory that Gulf War Syndrome is actually
variants of OPIDP because nerve agents are organophosphates.
Other speculations to the
cause of the symptoms Gulf War veterans are experiencing include parasites,
inoculations, burning oil well fires, depleted uranium shells and a host
of other causes. These are all valid, but they each need to be tested
to determine if they are actually connected to Gulf War Syndrome or possibly
all of them contribute to the problem as well, but that remains to be tested
and proven.
Literature Cited
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to
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Amato, A.A., A. McVey and C. Cha, 1997. Evaluation of neuromuscular
symptoms in
veterans of the Persian Gulf War. Neurology 48:4-11.
Haley, R.W., and K.L. Thomas, 1997. Self-reported exposure to neurotoxic
chemical
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et al., 1997a. Evaluation of neurologic function in Gulf War
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et al., 1997b. Is there a Gulf War Syndrome? Journal of American
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Jamal, G.A., et al., 1996. The "Gulf War syndrome". Is there evidence
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