Cholinergic Autonomic Dysfunction in Veterans with Gulf War Illness

Abstract & Commentary

By Norman Latov, MD, PhD, Professor of Neurology, Department of Neurology, and Professor of Neuroscience. Brain and Mind Research Institute, Weill Cornell Medical College. Dr. Latov has served as a consultant to Griffols, Novartis, CSL Behring, Baxter Therapeutics, Pfizer, and Merck, and has stock in Therapath LLC.

Synopsis: Veterans with Gulf War illness had a statistically significant increase of autonomic symptoms, heart rate variability, and abnormalities in sudomotor function, as measured by the Quantitative Sudomotor Axon Reflex Test, compared to control subjects. The study found objective autonomic deficits in veterans with the Gulf War syndrome with autonomic syndrome.

Sources: Haley RW, et al. Cholinergic autonomic dysfunction is veterans with Gulf War illness. JAMA Neurol 2013;70:191-200.

Freeman R. Objective evidence of autonomic dysfunction and the role of stress in the Gulf War syndrome. Editorial. JAMA Neurol 2013;70:158-159.

In a nested case-control study, the authors evaluated autonomic symptoms and functions in a representative sample of veterans meeting validated case definition of Gulf War illness, and compared these to autonomic symptoms and functions in a control population consisting of a representative sample of randomly selected subjects from a U.S. military health survey. Validated outcome measures included the Autonomic Symptoms Profile Questionnaire, Composite Autonomic Severity Score, heart rate variability in a 24-hour electrocardiogram, and Quantitative Sudomotor Axon Reflex Test (QSART). The study found that veterans with the Gulf War illness had a significant increase of autonomic symptoms compared to controls including in orthostatic intolerance, secretomotor symptoms, upper gastrointestinal and urinary dysfunction, autonomic diarrhea or constipation, sleep disturbances, pupilomotor and vasomotor abnormalities, and erectile dysfunction. These were most consistent with cholinergic autonomic dysfunction. The autonomic symptoms correlated with objective measures of impairment in the Quantitative Sudomotor Axon Reflext Test (QSART) and high frequency of heart rate variability in a 24-hour electrocardiogram. The accompanying editorial discusses the potential role of stress in the development of autonomic dysfunction.

Commentary

The authors note that subjects with the Gulf War syndrome exhibited a reduction in sudomotor function that was most severe in the feet, indicating a length-dependent peripheral nerve deficit. Of note is that veterans with Gulf War illness also have a significantly higher incidence of fibromyalgia, the symptoms of which can overlap with those of small fiber neuropathy, in which there is degeneration of both autonomic and sensory nerve fibers.1 The cause is unknown, but prolonged exposures to organophosphates or hydrocarbon fumes have been implicated.2 Both are neurotoxic agents that can cause axonal degeneration.3,4 Additional studies, such as quantification of sudomotor innervation of sweat glands in skin biopsy specimens,5 might provide further insight regarding the neuropathological basis of the autonomic dysfunction.

This study is the first to provide objective evidence of organic disease in veterans with the Gulf War Illness, a syndrome that has been regarded by many to be largely psychosomatic. Further investigations into the pathological and physiological changes that are associated with this illness would help elucidate the responsible mechanism and develop more effective treatments and preventive measures.

References

1. Oaklander AL, et al. Prevalence of small fiber polyneuorpathy in fibromyalgia. Ann Neurol 2012;72(Suppl 16):S128.

2. Research Advisory Committee on Gulf War Veterans’ Illness. Gulf War Illness and the health of Gulf War veterans: Scientific findings and recommendations. Available at: www.va.gov/RAC-GWVI/docs/Committee_Documents/GWIandHealthofGWVeterans_RAC-GWVIReport_2008.pdf. Accessed October 18, 2012.

3. Emerick GL, et al. Mechanisms for consideration of intervention in the development of organophosphorous-induced delayed neuropathy. Chem Biol Interact 2012;199:177-184.

4. Griffin JW. Hexacarbon neurotoxicity. Neurobehav Toxicol Teratol 1981;3:437-444.

5. Gibbons CH, et al. Quantification of sudomotor innervation. A comparison of three methods. Muscle Nerve 2010;42:112-119.