Three Different Kinds of Gulf War Sickness, Report Says

The findings are published as a set of three articles in the January 15 issue of the Journal of the American Medical Association.

"Each of the JAMA articles solves a different piece of the puzzle that has baffled previous researchers of these mysterious illnesses," said Dr. Robert Haley, chief of epidemiology and the study's principal investigator. "Our findings provide the first evidence of associations between symptoms in Gulf War veterans and exposures to chemicals, including chemical nerve agents."

The researchers determined that the syndromes can be traced to the use of flea collars, insect repellant and anti-nerve gas pills, as well as exposure to chemical nerve agents. The syndromes are variants of a rare disorder called organophosphate-induced delayed polyneuropathy, which is caused by exposure to certain chemicals that inhibit cholinesterase, an enzyme important to nervous system function. For now, there is no accepted way of easily testing for the syndromes or treating them.

Although the mysterious illnesses suffered by some Gulf War veterans have been collectively described as a syndrome, UT Southwestern researchers first set out to determine whether any true syndromes exist. They administered an epidemiological survey in December 1994 and January 1995 to the 24th Naval Mobile Construction Battalion, whose members served throughout the Persian Gulf theater.

Two hundred forty-nine reservists completed a lengthy survey covering their wartime activities and their health since then. The researchers found that some of the veterans' symptoms were ambiguous, having different meanings to different veterans. Analyzing them in conventional ways produced an ill-defined picture and diagnoses such as chronic fatigue syndrome or post-traumatic stress disorder. But when researchers used a mathematical computer technique to split each symptom into more precise components, three primary and three secondary syndromes emerged. Each primary syndrome looked like a variation of a familiar nervous system injury caused by exposure to different chemicals.

"This was the first breakthrough," Haley said. "All this time researchers have been trying to identify syndromes from ambiguous symptoms. Only when we disentangled the different meanings of each symptom did the real syndromes jump out at us. But at that point the syndromes were just statistical findings; we needed to show whether they represented real disease."

To prove whether the three syndromes really were caused by nervous system injuries, the researchers conducted a blinded case-control study involving veterans from the reserve unit. The researchers brought 23 veterans with the new syndromes (the "cases") and 20 healthy veterans (the "controls") -- half of whom went to the Gulf War -- to UT Southwestern and administered a battery of sensitive neurological tests.

When a panel of top neurologists reviewed the findings on each veteran individually, they could not diagnose a known disease -- mirroring previous findings on tens of thousands of sick veterans by military and Department of Veterans Affairs doctors. When Haley compared the cases with the controls, however, he found that the cases as a group were significantly more impaired on most of the tests than the controls.

"Comparing sick and well veterans gave us our second break," Haley said. "No single test in an individual was abnormal enough to make a traditional diagnosis. But the group comparisons showed a pattern of damage to a few nerve cells here and there throughout the nervous system -- just what you would expect from chemical nerve damage."

Psychological testing performed by Dr. Jim Hom, a UT Southwestern neuropsychologist, ruled out post-traumatic stress disorder, combat stress, major depression, malingering and other psychological disorders as causes of the veterans' illnesses.

Finally, the UT Southwestern team examined risk factors for the three syndromes by using reports of wartime exposures the veterans gave in the original survey.

The analysis strategy worked. Risk factors suggesting interactions between low-level chemical nerve agents, the pyridostigmine bromide (PB) anti-nerve-gas pills that many Gulf War veterans were given by the military, and chemicals in insect repellents and pet flea collars used by some soldiers to fight insects, were four to eight times more common in the veterans with the syndromes. But risk factors for exposure to oil-well smoke, multiple immunizations, depleted uranium munitions, burning jet fuel in tents, combat stress and other publicized concerns were only weakly -- or not at all -- associated.

The evidence for chemical interactions was particularly strong. Veterans involved in what they believe was a chemical weapons attack on January 19 and 20, 1991, and who had particularly severe side effects from the PB tablets were five times more likely to have one of the syndromes than those with only one of these risk factors.

"This indicates a synergistic effect," Haley said. "This is a strong sign of truly causal events in epidemiology." The findings fit well with previous research on the neurotoxic effects of chemical nerve agents and chemical interactions.

Two years after the Gulf War, researchers in India found that low levels of sarin, the nerve agent detected by Czech experts in northern Saudi Arabia on January 19 and 20, 1991, caused chronic brain and nerve damage in experimental animals when given over several days. The nerve damage didn't show up until two weeks after the nerve-gas exposures began.

Earlier this year, the UT Southwestern team, working in collaboration with researchers at Duke University Medical Center, reported that combinations of DEET in insect repellent, chlorpyrifos (Dursban) in flea collars, and PB caused neurotoxicity in hens when given in two- or three-way combinations but not when given individually.

UT Southwestern's research into Gulf War illnesses continues. In December, Haley collaborated with researchers at the Dallas Veterans Affairs (VA) Medical Center to repeat the epidemiological study in Dallas-area veterans. Haley also plans to bring ill and well veterans back to Dallas for testing to pinpoint exactly where the chemical damage occurred in the nervous system. In addition, UT Southwestern is collaborating with other universities to study the basic mechanisms by which toxic chemicals may have worked together to cause the damage.

"We are looking forward to going over our findings with researchers in the Defense and Veterans Affairs departments," Haley said. "We think we now have enough insight to develop an efficient survey in a representative national sample of Gulf War veterans to estimate the extent of these syndromes we have identified."

Additional information is available through special "Gulf War syndromes" web pages at the University of Texas.