Gulf War Syndrome: A lot of questions, few answers

Twenty years ago, the United States sent almost 700,000 soldiers to Kuwait and Iraq as part of Operation Desert Shield and Operation Desert Storm. The war was quick. Bombing began on January 17th and the whole thing was officially over by February 28th. If you started a semester of school just before the first Gulf War began, the conflict would have ended before you even took your midterm exams.

But this short war left a long tail of consequences.

Shortly after the War ended, people who’d served in the Gulf began to turn up in Veterans Hospitals, complaining of a range of symptoms: Fatigue, unexplained pain in their joints and muscles, memory problems and cognitive impairment, malfunctioning digestive systems, and more. There wasn’t a clear pattern—different soldiers reported different clusters of symptoms, some of the people who had symptoms had arrived in the Gulf after the fighting ended, other soldiers had boots on the ground from the beginning but no symptoms. As the years went by, epidemiological studies showed no increase in cancers or other deaths in Gulf War veterans, aside from suicides and accidents. Yet, the symptoms were quite clearly linked to service in the Gulf. The same symptoms occur among other groups of military veterans, but are significantly less common. Today, more than 250,000 U.S. veterans report suffering from one or more unexplained symptoms that have, together, come to be known as Gulf War Syndrome. Scientists are still debating the cause, or even if there is one cause.

In the October 2011 issue of the journal Radiology, Dr. Robert Haley and his colleagues at the University of Texas Southwestern Medical Center published research that identified a nervous system abnormality that exists in some Gulf War Syndrome patients, but not in the healthy veterans who served with them. Haley says it’s evidence that the Syndrome is actually the result of exposure to a miasma of toxins, particularly low doses of sarin nerve gas, extremely high doses of various pesticides, and a drug meant to protect users from the effects of nerve gas.

But, while everybody agrees veterans are suffering, not everyone agrees with Haley’s conclusions, or his evidence. In fact, some big reviews have discounted it completely. There’s a lot we don’t know, but the stakes aren’t just academic. Research on the cause of Gulf War Syndrome affects the funding, benefits, and well-being of the veterans. Ultimately, this Syndrome represents a big, fat example of what happens when the timetables of good science don’t match up with the timetables of individual health needs.

It all began at Khamisiyah. This town in Iraq was the site of a storage center, filled with munitions, including warheads loaded with two different nerve agents, sarin and cyclosarin. In March of 1991, American soldiers blew up the Khamisiyah storage depot, not realizing that there were chemical weapons inside. The diluted chemicals fell on thousands of soldiers who were downwind of the explosion. Nobody was monitoring the air for chemical weapons at the time, and no one reported or was treated for symptoms consistent with nerve gas exposure. But in very low levels, the chemicals were there.

It doesn’t take much sarin or cyclosarin to cause noticeable symptoms. And we know what those symptoms are. As the chemicals attack the central nervous system, victims first get runny noses, watery eyes, and feel a tightness in their chests. As the poisoning progresses, they lose control of bodily functions, twitch and jerk uncontrollably, and finally lose consciousness. That’s all well documented.

But we don’t really know what happens to people exposed to minute amounts of sarin. If the chemical is there, but the dose is so low there’s no symptoms, can it still have an effect on your body years later? That’s where sarin and Gulf War Syndrome cross paths.

Robert Haley thinks he’s found a way to prove that the poison and the illness are more than just passing strangers. His study focused on a neurotransmitter called acetylcholine. Sarin (and certain pesticides that work through a similar mechanism) attack the enzymes that break down acetylcholine. The rhythym of a burst of acetylcholine, followed by breakdown of acetylcholine, followed by a new burst is what allows information to be sent from one neuron to another. If the breakdown doesn’t happen reliably, the message disappears, like an image on a black and white TV suddenly going all white. Haley hypothesized that soldiers who suffered from symptoms associated with Gulf War Syndrome would also have suffered long-term damage to this system.

To test that, Haley measured blood flow in soldiers’ brains. Anything that inhibits the enzymes that break acetylcholine down should also slow blood flow to certain parts of the brain, including the hippocampus. If previous exposure to sarin had damaged those systems, Haley thought, then the brain might not respond in a normal way when the acetylcholine system was put to the test. He took 57 soldiers from a single battalion, some who had symptoms associated with Gulf War Syndrome and some who didn’t. The soldiers were assigned, at random, to get either an injection of a saline placebo, or an injection of a drug that would inhibit acetylcholine breakdown. Then Haley looked at how the different brains responded.

He saw a clear difference. Both healthy soldiers and those with symptoms of Gulf War Syndrome showed normal blood flow to the hippocampus under normal conditions, and with the saline injection. With the injection of the inhibiting drug, however, the picture changed. The healthy soldiers’ brains responded exactly as expected: Blood flow to the hippocampus slowed, and the people got tired. Some of the sick soldiers, however, had a very different experience. When exposed to the drug, their brains didn’t seem to know how to respond. In some, blood flow to the hippocampus actually increased, in others it decreased far more than was normal, and for some blood flow stayed exactly the same. Haley says this is evidence of damage. Those soldiers’ acetylcholine systems no longer functioned as they should.

That seems pretty damning, but Haley’s new study has its faults. While it does mark a replication of results from one of his own earlier studies, Haley’s research has focused exclusively on small sample sizes within a single unit—the 24th Reserve Naval Construction Battalion. When the Khamisiyah storage depot was demolished, that unit wasn’t in a location where they would have been likely to receive even a small dose of the sarin. Haley believes they may still have been exposed to sarin gas from another source, or that the damage is due to exposure to the high levels of pesticides that Gulf War veterans remember applying directly to their clothing and skin.

Haley has also chosen to define Gulf War Syndrome differently than most other researchers. The Centers for Disease Control defines it as, “as the presence, for 6 months or longer, of one or more symptoms from at least two of the following clusters: general fatigue, mood and cognitive abnormalities, and musculoskeletal pain.”

Instead, Haley has used surveys of the 24th Reserve Naval Construction Battalion to split the Syndrome into Syndromes, based on clusters of symptoms. In a 1997 paper, he identified six different syndromes. This new paper focused on three of those: Veterans who reported problems with attention, memory, and reasoning; those who reported far more serious cognitive problems with disorientation, confusion, and balance; and veterans whose symptoms clustered around joint and muscle pain and fatigue.

That makes it difficult to directly compare Haley’s results to those of other scientists. It also muddies the results of his own work. The veterans with confusion and muscular-skeletal symptoms showed damage to their acetylcholine systems, just as I told you before. But the veterans with memory and attention problems didn’t. Their brains seemed to be functioning normally, and it’s hard to say what, if anything, that means.

Haley’s work hasn’t been replicated by others, says Simon Wessely, head of the department of psychological medicine at King’s College, London. Using larger samples, drawn from multiple British military units, Wessely found no neurological differences between people experiencing symptoms of Gulf War Illness, and those who were not. A 2004 American study turned up similar results. All of this suggests to Wessely, and other researchers, that Gulf War Syndrome is psychological in nature—not that soldiers are making up their symptoms, or that they really aren’t impaired, but that the symptoms stem from legitimate psychological causes, like post-traumatic stress disorder.

There could be more to it than that, however. Other researchers have found neurological differences between Gulf War veterans who were likely to be downwind of Khamisiyah and those who weren’t.

Roberta White, professor of environmental health at Boston University, found that the volume of white matter in veterans’ brains varied with their exposure to Khamisiyah—those who likely had high exposures had lower volumes of white matter. In a separate study, White’s team found that likely higher exposure to sarin from Khamisiyah also correlated with poor performance on cognitive tests.

The confusing part is that results like these doesn’t necessarily tell you much about Gulf War Syndrome. Linda Chao, with the Center for Imaging of Neurodegenerative Disease and and the department of radiology at the University of California San Francisco, has run a couple of studies looking for neurological differences in a group of more than 400 Gulf War Veterans. She found that neurological damage didn't correlate with people who experienced Haley’s definition of Gulf War Syndrome, nor with people who experienced the Syndrome the way the CDC defines it. But she did find that neurological damage correlated with likely exposure to sarin from Khamisiyah.

In other words, the people with neurological damage were exposed to sarin, and some of them show observable evidence of that damage, but those people aren’t necessarily ones reporting symptoms of Gulf War Syndrome.

Right now, Gulf War Syndrome is like a puzzle with pieces missing. The theory linking it to toxin exposure makes sense in a lot of ways, but doesn’t line up with all the evidence. Studies are often contradictory, seldom replicated by independent researchers, and frequently use small sample sizes. Meanwhile, hundreds of thousands of people are receiving treatment and benefits (or not, as the case may be) based on an incomplete picture. Haley’s new, small study presents some important questions, but doesn’t do much to help clarify the situation.

Instead, if we really want to understand Gulf War Syndrome we need two things: More studies using large sample sizes drawn from a wide swath of Gulf War veterans (something Haley says he’s turning his research towards next), and more attempts to replicate the findings of other researchers. Without that, all we have is a lot of important questions, and no answers.

Find Out More:

• The Gulf War and Health — National Academies summary of research, published in 2010.

• Acetylcholinesterase Inhibitors and Gulf War Illness — a 2008 research paper by Beatrice Golomb of the University of California San Diego. It looks at epidemiological evidence of whether sarin and pesticides can damage the acetylcholine system in the way Haley has proposed, and what the symptoms of that damage would likely be.

• GulfLink — The primary Department of Defense website for Gulf War Illness information.