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Gulf War Illness

One-fourth of the veterans of the 1990-91 Gulf War complain of persistent memory and concentration problems, chronic headaches, widespread pain, gastrointestinal problems, and other chronic abnormalities not explained by well-established diagnoses. Treatments are ineffective and symptoms do not improve over time. Gulf War Syndrome or Gulf War Illness is a controversial diagnosis, and some have questioned whether it really exists. Now a new report from the Research Advisory Committee on Gulf War Veterans’ Illnesses has concluded that Gulf War Illness is real and that it is probably attributable to pyridostigmine bromide (PB) and pesticide exposures.

Its major conclusions:

  • Gulf War illness is a serious condition that affects at least one fourth of the 697,000 U.S. veterans who served in the 1990-1991 Gulf War.
  • Gulf War illness fundamentally differs from trauma and stress-related syndromes described after other wars.
  • Evidence strongly and consistently indicates that two Gulf War neurotoxic exposures are causally associated with Gulf War illness: 1) use of pyridostigmine bromide (PB) pills, given to protect troops from effects of nerve agents, and 2) pesticide use during deployment.

The Research Advisory Committee on Gulf War Veterans’ Illnesses was mandated by Congress and appointed in 2002. The report, published November 17, 2008, is an exhaustive review of all available data, including some that is unpublished. It runs to 454 pages, has multiple authors and consultants, lists 1840 references and has multiple appendices. I can’t pretend to have mastered all the information, but I have read enough to understand the basis of their conclusions. They are based on good evidence and logic, but they leave me with some doubts.

Evidence Suggesting GWI Isn’t Real

Skeptics have pointed out that ill-defined syndromes have been reported after every conflict, attributed to everything from shell shock to Agent Orange. Two 1996 articles in the New England Journal of Medicine found no difference in hospitalizations or in death rates from illness in Gulf War veterans. A 1998 study found that Gulf War veterans were less likely to be hospitalized for unexplained illnesses and were healthier overall than veterans who were not deployed. In a 2000 study, factor analysis did not identify a unique Gulf War syndrome. A 2006 report by the The US Institute of Medicine found that although veterans of the first Gulf War report significantly more symptoms of illness than soldiers of the same period who were not deployed, studies have found no cluster of symptoms that constitute a syndrome unique to Gulf War veterans. The Committee’s report addresses these and other arguments and rejects them.

GWI Is Real, But What Is It?

The Committee says “there is no question that Gulf War illness is a real condition with real causes and serious consequences for affected veterans.” I don’t think anyone questions that these people are really impaired and are suffering, but that doesn’t say anything about diagnosis or cause.

GWI is a “complex of multiple symptoms not explained by familiar medical or psychiatric diagnoses.” It “does not fit neatly into our current concepts of disease.” We don’t really even have an acceptable case definition. Diagnosis depends on subjective self-reports of symptoms. There are no objective findings on routine clinical tests. Objective findings on non-routine and experimental tests have generally been of small magnitude, uncertain significance, and have not resulted in anything useful for diagnosis.

…neuropsychological studies in Gulf War veterans consistently indicate that symptomatic veterans are affected by persistent, but subtle, “subclinical” central nervous system damage. Symptomatic veterans exhibit decrements in attention and executive system functioning, memory, visuospatial skills, psychomotor functioning, and mood. In some instances, study results reflected slowed response latencies across several cognitive domains. Measured deficits are generally modest and are not identified in all Gulf War veterans with cognitive symptoms. Characterizing Gulf war illness-related cognitive effects requires careful testing and analytic methods…

And I would add, it requires considering that many of these tests are effort-dependent: individuals who report symptoms may not try as hard to succeed.

There is some overlap with other multisystem illnesses like chronic fatigue syndrome (CFS), fibromyalgia, and multiple chemical sensitivity (MCS); but the Committee believes they are distinct entities. “The illness appears not to be the result of a single cause producing a well-known effect” and a synergistic effect of multiple causes may be implicated.

“Studies consistently indicate that Gulf War illness is not the result of combat or other stressors and that Gulf War veterans have lower rates of posttraumatic stress disorder than veterans of other wars.” “No similar widespread, unexplained symptomatic illness has been identified in veterans who have served in war zones since the Gulf War, including current Middle East deployments.”

In various studies of different populations with different diagnostic criteria, the prevalence of unexplained multisystem illness ranged from 8-36% in those who were not deployed and 29-65% in those who served in the Gulf.

Other Factors Not Ruled Out

The Committee looked at a large number of suspects including psychological stress, Kuwaiti oil fires, depleted uranium (DU), vaccines, nerve agents, infectious disease, fine sand and airborne particulates, exhaust from tent heaters, other fuel exposures, solvents, and freshly-applied CARC (chemical agent resistant coating) paint. The evidence was not sufficient to either implicate or rule out most of these.

They found a consistent association of Gulf War illness with exposure to PB and pesticides across studies of Gulf War veterans, with a convincing dose/response relationship. Those exposed to one suspected cause were usually exposed to several. Rates of GWI and exposures were higher among Army and Marines than Navy and Air Force, higher among enlisted than officers, and higher among forward troops than rear troops.

The other suspects that couldn’t be entirely ruled out could be involved via multiple exposures and synergism.

Other Gulf War Illnesses

Brain cancer? Veterans who were downwind from the Khamisiyah munitions demolitions in March 1991 have died from brain cancer at twice the rate of other Gulf War veterans. It is suspected, but not proven, that low levels of the chemical warfare nerve agents sarin and cyclosarin were released into the air during that operation.

Birth defects? There was a significant, but modest, excess of birth defects in children of Gulf War veterans compared to non-deployed veterans. But information on specific types of birth defects was inconsistent, and overall rates were within the normal range found in the general population.

Effects on spouses? There didn’t seem to be any consistent effects on spouses. A mysterious “burning semen” phenomenon was reported by wives but was never explained. On the other hand, Gulf veterans’ spouses had significantly fewer skin anomalies, such as moles, skin tags, and scars. (This is a good example of the “noise” that plagues studies like this.)

ALS? A cluster of cases of amyotrophic lateral sclerosis (Lou Gehrig’s disease) was found, mainly in the Air Force. In September, 2008, VA Secretary James Peake announced that all U.S. veterans, of all eras, would be given presumptive service connection for ALS.

Disability Claims

There was a similar controversy about illness due to Agent Orange after the Viet Nam war. Eventually, the VA agreed to presumptively recognize a series of health conditions related to Agent Orange. Vietnam veterans with one or more of these conditions do not have to show that their illness(es) is (are) related to their military service to get disability compensation.

  1. Chloracne occurring within 1 year of exposure to Agent Orange.
  2. Non-Hodgkin’s lymphoma.
  3. Soft tissue sarcoma (other than osteosarcoma, chondrosarcoma, Kaposi’s sarcoma, or mesothelioma).
  4. Hodgkin’s disease
  5. Porphyria cutanea tarda (must occur within 1 year of exposure).
  6. Multiple myeloma
  7. Respiratory cancers, including cancers of the lung, larynx, trachea, and bronchus.
  8. Prostate cancer.
  9. Acute and subacute transient peripheral neuropathy (must appear within 1 year of exposure and resolve within 2 years of date of onset).
  10. Type 2 diabetes.
  11. Chronic lymphocytic leukemia

In addition, veterans’ children with spina bifida are covered.

Think about this for a minute. How many of those veterans would have developed diseases like diabetes and prostate cancer if they had never gone to Viet Nam? Compensating victims of Agent Orange means we have to compensate a lot of other people who are not victims.

The same thing is true for GWI. If 8-36% of the nondeployed have the same symptoms, diagnosing the 29-65% of the deployed who have those symptoms means we will be labeling far too many. Incidentally, I find the 65% figure hard to swallow, and so did the Committee – they estimated ¼ to 1/3.

There are special provisions that allow Gulf War veterans disabled by chronic symptoms that are not explained by a specific diagnosis to receive disability compensation for “undiagnosed illnesses.” You’d think everyone who served in the Gulf would be reporting difficult-to-diagnose symptoms for purposes of financial gain, but as of February, 2008, just two percent of Gulf War veterans had applied. Despite all the reports of bothersome symptoms, most patients with GWI are employed and functioning reasonably well.

Effects of PB and Pesticides

Only about 62% of ground troops reported using pesticides and only about half of them took PB for varying periods (sometimes very brief). Some of them used higher-than-recommended amounts of pesticides: these exposures were reduced by stricter guidelines in Iraq, but that resulted in more cases of leishmaniasis.

According to the FDA website,

Pyridostigmine bromide was first approved in 1955, and has been prescribed by doctors to treat patients with myasthenia gravis for over 40 years. To date, no long-term health problems thought to be associated with pyridostigmine bromide have been reported by these patients.

The reported side effects and the signs of overdose of PB overlap but do not match the GWI syndrome. Symptoms reported for acute pesticide toxicity and for long-term low-dose exposure to pesticides in peacetime are not a good match for GWI either.

Both PB and pesticides are acetylcholinesterase inhibitors. It’s been speculated that the combination and the concomitant exposure to other risk factors may have caused unexpected synergisms. There is also some evidence that people with certain genetic polymorphisms might be uniquely susceptible.

Paradoxically, PB has been tried as a TREATMENT for multisystem illnesses like CFS and fibromyalgia.

Suspicions Roused

Anthrax shots were suspicious because they caused a high incidence of mild reactions and because they were given in a hush-hush setting and often weren’t even identified. They had not been extensively tested but military authorities decided the military risk outweighed the risk of the vaccine and justified omitting informed consent. They imposed secrecy for security reasons – we didn’t want the enemy to know we thought they had biological weapons and were protecting our troops.

The military does a lot of things for military reasons that would not be acceptable in a civilian setting. They couldn’t afford to have a flu epidemic depleting their troops, so everyone was required to get annual flu shots back when the package inserts said “Not intended for children or healthy adults.”

The troops didn’t like the idea of taking PB tablets. Some people got side effects from them; these individuals were more likely to report symptoms of GWI later on. I remember when I was a flight surgeon we required our flyers to take a test dose to make sure they wouldn’t have any bad reactions that would interfere with flying skills. Some of them objected strenuously to taking a medicine when they weren’t sick, but they would have faced a court-martial for disobeying orders if they didn’t comply. Anecdotally, I don’t remember any of them complaining of side effects from the test dose.

There were frequent false alarms of chemical warfare. Initial alarms could be triggered by factors such as fuel vapors and engine exhaust, oily smoke, blowing sand, and low batteries on the units. Initial alarms had to be verified by further, more accurate tests. Verification was often not possible in battlefield situations. Logs went missing. The most likely exposure to chemical agents, at Khamisiyah, was never actually verified. It was rated “likely” but not certain.

Things like these led to a lot of suspicion and resentment. It contributed to a mindset that the government was lying and was knowingly endangering personnel. Some people were on the lookout for any symptom that might corroborate their suspicions.

Recommendations

Hundreds of studies have been done; millions have been spent. The report recommends spending much more to study GWI further, to do long-term followup, and to find effective treatment. I have mixed feelings about this. Research money is short. It’s hard to quantify exposures this long after the fact; it’s hard to decide what treatments to test when you don’t know the cause. There have already been some poorly conceived attempts to treat GWI with long courses of antibiotics and with various alternative therapies. On the other hand, we might learn something that we could apply to other illnesses and to future wars.

Conclusion

When a subject is as highly charged as this one, I despair of ever knowing the truth. We all want to support our troops. We want to give their symptoms a name. We want to find a cause. With all the emotions and the political concerns, it is practically impossible to maintain true scientific objectivity. The very choice of what to study and how to study it embodies some degree of bias. The Committee’s report was a noble effort, but I’m not entirely convinced. It bothers me that the symptoms are subjective and poorly defined. It bothers me that the known effects of PB/pesticides are not a good match for the symptoms of GWI. If you look at enough factors, you are guaranteed to find significant correlations that are not causal. Before I read this study I didn’t know what to think about GWI. Now, after reading it, I still don’t know.

Posted in: Politics and Regulation

Leave a Comment (9) ↓

9 thoughts on “Gulf War Illness

  1. w_nightshade says:

    Once again I am deeply impressed with the quality of the posts here as SBM. It questions the underlying assumptions of GWI without being dismissive or disrespectful, and it is not afraid to conclude with “I don’t know” (I am coming to the point where I find that the most trustworthy response to any question). I learned some new information along the way.

    Thanks for this article, Dr. Hall.

  2. MedsVsTherapy says:

    i have the same opinion: gosh, tough to put all of the data in perspective and confidently come to some conclusion.

    i had acrobat do a search for “vasterling,” and nothing came up. so, all of the neuropsych research done by jennifer vasterling and colleagues with gulf war-experienced tropps is apparently not incorporated. maybe acrobat search did not work right.

    one major study from vasterling and colleagues notes neuropsych diffs between two army cohorts: similarly composed -all from Stryker Brigade, I believe – but some with Gulf war exposure and some not; extensive neuropsych battery conducted BEFORE and after on all. what more could you ask for? DK why this 2006 study not included:

    Ref, and brief results:
    Vasterling JJ, Proctor SP, Amoroso P, Kane R, Heeren T, White RF. Neuropsychological outcomes of army personnel following deployment to the Iraq war. JAMA. 2006 Aug 2;296(5):519-29.
    “Iraq deployment, compared with nondeployment, was associated with neuropsychological compromise on tasks of sustained attention (beta = 0.11; P<.001), verbal learning (beta = -1.51; P = .003), and visual-spatial memory (beta = -3.82; P<.001). Iraq deployment was also associated with increased negative state affect on measures of confusion (beta = 1.40; P<.001) and tension (beta = 1.24; P<.001). In contrast, deployment was associated with improved simple reaction time (beta = 4.30; P = .003). Deployment effects remained statistically significant after taking into account deployment-related head injury and stress and depression symptoms. CONCLUSIONS: Deployment to Iraq is associated with increased risk of neuropsychological compromise.”

  3. Karl Withakay says:

    Thanks for the excellent post Harriet. This is exactly the kind of analysis I was looking for when I suggested a post on Gulf War Illness and the new report. I knew you would do top notch job on the subject.

    How can anyone who has looked at the subject objectively and critically be 100% sure they know whether GWI is real or not?

    The study seems pretty sure that GWI exists, even though they don’t know what it is, and, presumably, can’t even be sure it is a single condition.

    I suspect that:

    If GWI is real, it is smaller than is popularly reported.
    If GWI is real, it is possibly not a single distinct syndrome, but is several distinct conditions with different causes that are getting lumped together under the GWI label.

    I wonder if, in the end, how much more it would cost to not expend any more time and money and resources on further study and instead provide blanket disability claim coverage for Gulf War vets similar to what was done with Vietnam vets for Agent Orange exposure. It may be easier to officially say “We don’t know, so we’ll cover it just in case.”

  4. Harriet Hall says:

    A comment on this post was accidentally deleted. I’ll try to give the gist of what it said. The commenter responded to my statement that we all want to support the troops by saying “No, not all of us do.” Then he criticized me for not discussing compensation for civilian victims of Agent Orange in Viet Nam. I thought the comment was inappropriate, but its deletion was not an attempt at censorship, it was purely accidental.

  5. David Gorski says:

    Maybe it had something to do with this post having accidentally being published on Sunday long enough for someone to have commented, then my depublishing it when I realized that it shouldn’t be up yet (its original date was December 2), and then Harriet setting the date to today and republishing.

  6. qetzal says:

    @MedsVsTherapy:

    Not sure why acrobat search failed you, but I found 5 cited refs co-authored by Vasterling: #127, 1520, 1708, 1709, & 1710 of the reference list.

    FWIW, none of them is the 2006 JAMA paper you cited.

  7. bonedoc says:

    There is an important difference between the political and sociological decisions that must be made with respect to healthcare and those made with respect to the science of medicine. Patients are often compelled to show that their symptoms or illness was caused by another in order to be eligible for diagnosis and treatment.

    From a political and sociological point of view I believe it is the right thing to do to give veterans the benefit of the doubt and to accept the idea that the symptoms and illnesses that they label as Gulf War syndrome are worthy of evaluation and treatment. At minimum on that basis, I believe it is correct to provide medical care with respect to those complaints. In fact, I would go further. I have recommended that veterans deserve full medical coverage from their government without requiring the patient to prove a service connection first. (I am an orthopaedic surgeon employed by the Veterans Administration). Anyone who serves in the armed services has the potential to be put in harms way when the government determines that it is in the country’s best interest. Some pay a very high price for their service. I construe this willingness to be put in harms way as part of a social contract with the government who then has the obligation to care for those who have served.

    In contrast, it is important that labels and diagnoses in medicine be based on science and strict criteria. Proper treatment and proper understanding depend upon the ethical application of science.

    I believe we should be able to reassure veterans that their symptoms, illnesses, and mental health needs will be appropriately addressed and treated. In that way they will not need to feel threatened if the scientific evidence does not allow us to uniformly agree that “Gulf War Syndrome” is the appropriate diagnostic label to explain those symptoms, and they need not worry that the lack of that label would then deprive them of compassionate and adequate treatment. This would allow us to continue to treat veterans as patients and continue to study the scientific issues.

    A true diagnosis cannot be achieved by consensus without science but treatment should not be withheld or compromised because of the political controversies surrounding scientific uncertainty.

  8. MedsVsTherapy says:

    Qetzal- thanks. i will check it out when i have time to look this over more closely.

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