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

Abou-Donia, M.B., et al., 1996. Neurotoxicity resulting from coexposure to
pyridostigmine bromide, DEET, and permethrin. Journal of Toxicology and
 Environmental Health 48:35-56.
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
 in the Gulf War. Journal of American Medical Association 277:231-236.
 et al., 1997a. Evaluation of neurologic function in Gulf War veterans. Journal of
 American Medical Association 277:223-230.
 et al., 1997b. Is there a Gulf War Syndrome? Journal of American Medical
 Association 277:215-222.
Jamal, G.A., et al., 1996. The "Gulf War syndrome". Is there evidence of dysfunction
 in the nervous system? Journal of Neurology, Neurosurgery, and Psychiatry
 60:449-451.