Gulf War Illness Linked to Cholinergic Abnormalities

Pauline Anderson

November 26, 2012

A large new study seems to confirm that the illness plaguing so many veterans of the 1990-1991 Gulf War is due to cholinergic dysfunction.

The study represents "a real game-changer" in terms of how experts should view Gulf War illness, which is characterized by such varied symptoms as cognitive impairment, chronic headaches, joint pain, unexplained fatigue, chronic diarrhea, and respiratory problems, according to the study's lead author Robert W. Haley, MD, professor, internal medicine, and chief, Division of Epidemiology, University of Texas Southwestern Medical Center, Dallas.

"It suddenly takes this out of the realm of a psychological illness and into the realm of a brain illness," said Dr. Haley. "Now we need to turn our attention to looking at treatments that neurologists and internists and other doctors can provide for conditions that involve abnormalities in the cholinergic parts of the nervous system."

Although the study doesn't make any conclusions about the cause of the illness, Dr. Haley believes it's due to exposure to low doses of nerve gas and to pesticides.

The study, published online November 26 in the Archives of Neurology, is the largest to date among a series of studies attempting to track autonomic nervous system abnormalities in soldiers with Gulf War illness.

Controversial Illness

In the early 1990s, about 700,000 US troops were deployed to the Middle East to take part in a 5-week air bombing campaign and a 5-day ground operation that involved almost no traditional combat. Of these soldiers, about 150,000 subsequently became ill, almost all had to leave the service, and many remain unemployable, said Dr. Haley.

Dr. Robert W. Haley

Their illness is controversial; the US government has never acknowledged that Gulf War syndrome is a real illness, and many people still believe it's psychological, he said.

For this latest study, researchers randomly selected 8020 representative Gulf War veterans for detailed interviews and included 97 in the current study. Of these, 66 met the case definition of Gulf War illness that Dr. Haley and his colleagues had previously validated. These case veterans represented 3 forms of the illness included in that definition:

  • Syndrome 1 (mild cognitive impairment; 21 cases): These soldiers have difficulty thinking, concentrating, and remembering, and some have symptoms of depression.

  • Syndrome 2: (confusion-ataxia; 24 cases): Veterans with this form of the illness have balance problems and what Dr. Haley described as "early Alzheimer's disease that doesn't get worse" or chronic neurotoxic encephalopathy.

  • Syndrome 3 (central neuropathic pain; 21 cases): Soldiers with this syndrome describe having a constant pain between their shoulders and down their arms and thighs. They have difficulty riding in a car because of the pain, and nothing seems to relieve it, said Dr. Haley.

Also included in the study were 31 control veterans: 16 who were deployed but did not meet the case definition of Gulf War illness and 15 who were in the military but not deployed

The soldiers completed questionnaires and underwent a battery of standard tests to assess autonomic function and objective tests of autonomic dysfunction.

Symptom Score Elevations

The study found that in the various symptom domains of the Autonomic Symptom Profile (eg, orthostatic intolerance, sleep dysfunction, autonomic diarrhea, pupillomotor symptoms, sexual dysfunction), those with syndrome 2 had the highest scores, but the pattern of symptom score elevations was similar among all 3 syndrome groups.

On objective autonomic tests, those with Gulf War illness differed most from controls on the Quantitative Sudomotor Axon Reflex Test (for example, P ≤ .001 compared with controls for the foot). The degree of difference on this test was related to peripheral nerve length, typical of a length-dependent neuropathy of small-caliber, unmyelinated, peripheral nerve fibers, said the authors.

Veterans with syndrome 2 and 3 had a statistically significant increase in cooling detection threshold. This, said the authors, might also reflect underlying small-fiber impairment.

The Composite Autonomic Severity Score (CASS) varied significantly across the clinical groups (P = .045) and was higher in the syndrome 2 group than in the controls (P = .02).

Circadian Abnormality

Analysis of 24-hour electrocardiogram monitoring showed that high-frequency heart rate variability (HF HRV) increased normally at night in the control group but not in the 3 syndrome groups.

"Because peripheral vagal baroreflex function was not significantly impaired, this abnormality of circadian variation in HF HRV suggests dysfunction in the central nervous system control of parasympathetic outflow," the authors write. Impaired HF HRV was not explained by smoking, creatinine clearance, psychiatric comorbidity, diagnosis of heart disease, glycated hemoglobin level, body mass index, or medications.

During the day, HF HRV in veterans with syndrome 1 did not differ from controls but the syndrome 2 group had significantly lower HF HRV than controls. Those with syndrome 3 had significantly higher HF HRV than controls, particularly during the morning hours. .

The Composite Autonomic Symptom Scale (COMPASS) of all autonomic symptoms was inversely correlated with HF HRV and was directly correlated with the CASS subscales. The correlation was highest with HF HRV during the day and with the CASS sudomotor subscale. The correlation was lowest with the CASS cardiovagal and adrenergic subscales.

The pattern of autonomic symptoms and objective test results suggest dysfunction in both central and peripheral cholinergic functions, the authors concluded.

Dr. Haley believes that soldiers with syndrome 2, who have the worst symptoms, suffered damage to the hippocampus during their deployment. He described an experiment in which veterans responded abnormally to a cholinergic challenge with an agent that simulates re-exposure to nerve gas.

"The hypothesis was that if nerve gas damaged acetylcholine receptors in these guys' brain — and there's reason to believe that that's what nerve gas does — then their cholinergic receptors wouldn't respond normally to acetylcholine. That's what we found. Those with syndrome 1 responded normally, just like the controls, whereas those in the syndrome 2 and 3 groups didn't slow down; in fact the brain sped up indicating there's an abnormality of cholinergic receptors."

During the 1990-1991 Gulf War, Iraq had large stockpiles of the nerve gas sarin, a colorless, odorless liquid that had been used as a chemical weapon. Production and stockpiling of sarin were outlawed in 1993.

Soon after the end of the Gulf War, an expert panel came up with a dozen or so environmental exposures that might have caused Gulf War illness, said Dr. Haley. Since then, some epidemiologic studies have narrowed the culprit down to low-level nerve gas resulting from US bombing of Iraqi storage facilities. "We bombed big storage warehouses producing fall out clouds that drifted over our troops and rained fallout on them," said Dr. Haley.

Soldiers who were exposed to this nerve gas who also have a weak form of the PON1 gene, which produces an antidote to nerve gas, are the most prone to Gulf War illness, said Dr. Haley. About 20% of veterans have a weak form of this gene, which helps explain why not all exposed soldiers got ill.

Another explanation is that not all soldiers had the same level of exposure to the nerve gas, said Dr. Haley. "The cloud didn't go everywhere, but if you were exposed to the cloud and you had the weak form of the gene, you've got a huge risk of being sick with chronic neurotoxic encephalopathy" which characterizes the syndrome 2 variant of Gulf War illness, he said.

Pesticide 'Overuse'

Dr. Haley is convinced that soldiers with syndrome 1 (mild cognitive impairment) were exposed not to nerve gas but perhaps to a pesticide. During the Gulf War, there was "great overuse of pesticides," which has been linked to cognitive disturbances, he said. "We think that syndrome 1 may be a pesticide problem and that 2 and 3 are very strongly associated with nerve gas exposure and the PON gene."

Another paper that he and his colleagues have prepared is set for publication within the next few months. It includes all the evidence showing how nerve gas might cause symptoms of Gulf War illness and should "end the discussion" on this topic, said Dr. Haley.

This research should set the stage for the development of objective tests that the Department of Veterans Affairs and other groups could run on Gulf War veterans to identify those who have sustained damage to their brain due to their deployment. "That will do 2 things," said Dr. Haley. "One, it will give an objective basis in terms of who to put on disability and who to provide service-connected benefits to. It's also a really important clue as to how to treat this."

Why did it take 2 decades to seemingly get to the bottom of Gulf War illness? Part of it was that veterans, like everyone else, have difficulty expressing issues related to heart rate, digestion, sexual desire, and other aspects of the autonomic nervous system, said Dr. Haley.

Symptoms and health problems similar to those experienced by US troops were also reported by servicemen and -women from Canada, the United Kingdom, Australia, and Denmark. There were also reports of a higher incidence of cancers, amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, birth defects, and other disorders.

Manifestations of Stress

Not everyone is convinced that psychological stressors have no role in the Gulf War illness. In an accompanying editorial, Roy Freeman, MBChB, Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, provides extensive data from various experiments and studies showing a wide array of objective structural, physiologic, and clinical manifestations of stress.

Proposing a primary, supplementary, or synergistic role for stress in the Gulf War syndrome neither invalidates nor minimizes the associated symptoms, suffering, health outcomes, and public health import of the syndrome Dr. Roy Freeman

"Proposing a primary, supplementary, or synergistic role for stress in the Gulf War syndrome neither invalidates nor minimizes the associated symptoms, suffering, health outcomes, and public health import of the syndrome," he writes. "On the contrary, it provides a framework for valid scientific analysis, study, and rational dissection of the clinical features of the disorder."

Dr. Freeman pointed out that there is no widely accepted cause of the symptoms and health problems experienced by Gulf War veterans.

"Independent reviews of the evidence to date have reached discrepant conclusions," he writes. "On the one hand, the Institute of Medicine report concluded that the current evidence was inadequate to determine whether an association exists between multisymptom illness and any specific battlefield exposure(s). In contrast, a report by the Research Advisory Committee on Gulf War Veterans' Illnesses concluded that Gulf War illness was a direct consequence of exposure to toxins including pyridostigmine bromide [which was taken as nerve gas prophylaxis] and pesticides."

This study was supported by Indefinite Delivery Indefinite Quantity contract VA549-P- 0027, awarded and administered by the Department of Veterans Affairs Medical Center, Dallas, Texas; by grant DAMD17-01-1-0741 from the US Army Medical Research and Materiel Command; and by grant UL1RR024982-05, titled North and Central Texas Clinical and Translational Science Initiative, from the National Center for Research Resources, a component of the National Institutes of Health (NIH) and NIH Roadmap for Medical Research. Dr. Haley received an honorarium from Targeted Medical Pharma Inc for critical review of a Food and Drug Administration new drug application for a nonpharmaceutical medication to treat fatiguing illness of possible benefit to Gulf War veterans. Dr. Freeman has disclosed no relevant financial relationships.

Arch Neurol. Published online November 26, 2012. Abstract Editorial