BMJ No 7076 Volume 314
Editorial Saturday 25 January 1997
The first of the JAMA papers is a survey of all veterans, both deployed and non-deployed, from the state of Iowa.(1) It is the first population based survey of its kind and achieved an impressive response rate (76%). It provides strong evidence of a health problem associated with service in the Gulf,(5) since the military staff who were deployed were twice as likely to report symptoms as those not deployed (14.7% v 6.6% reporting two or more problems). The biggest differences in reporting rates were for cognitive dysfunction, fibromyalgia, depression, anxiety, alcohol misuse, respiratory problems, and chronic fatigue. There was no increase in risk of more specific illnesses such as cancers. These findings are similar to those reported in veterans of previous conflicts.(6) The researchers also asked about the whole range of possible exposures. Each exposure was associated with each outcome, suggesting either that each has the capacity to cause a wide range of problems or that the data were susceptible to recall bias.
The other three papers, from Robert Haley and colleagues, funded by the Perot foundation in Texas, tackled the same problem but came to different conclusions.(2-4) The authors have a commendably clear hypothesis, that the cause of the veterans' ill health was exposure to anticholinesterase inhibitors. Their sample consisted of a previously studied single Naval Reserve Construction Battalion ("Seabees"). Only 41% participated, but, of these, 70% reported serious health problems and all but one attributed them to service in the Gulf. The subjects completed a detailed questionnaire about their symptoms and service experiences. The researchers attempted to organise the different symptoms using factor analysis.(2) The first analysis suggested two syndromes, which the authors described as resembling chronic fatigue syndrome and post-traumatic stress disorder. Subsequent analyses suggested six syndromes, but a reliability test on split halves of the sample showed that only the first three syndromes were stable.
Haley et al went on to relate each of the syndromes to self reports of different hazardous exposures.(3) The most robust syndrome - labelled "impaired cognition," which included distractibility, memory problems, and fatigue - affected 5% of the veterans. It occurred in five of the 19 subjects (26%) who used flea collars to prevent insect bites but only seven of the 229 (3%) who did not. The second syndrome,"confusion ataxia," also included symptoms such as problems with thinking and reasoning and a diagnosis of post-traumatic stress disorder. Surprisingly, this was not associated with exposure to pesticides but was associated with recall of particularly severe side effects from pyridostigmine prophylaxis. Those currently experiencing joint and muscle pains and pins and needles ("arthromyoneuropathy") were more likely to report use of insect repellents containing N,N-diethyl-m-toluamide.
The researchers concluded that all of these syndromes are evidence of organophosphate induced delayed polyneuropathy. They claimed to rule out any contribution from psychological and stress related conditions on the basis of responses to a personality inventory. They also rejected recall bias since the reported associations were specific to cholinesterase inhibitors - unlike a larger study in similar units.(7) Dr Haley told a press conference that "the syndromes are due to subtle brain, spinal cord and nerve damage, but not stress," contradicting the conclusions of the American presidential advisory commission, which reported on the same day.(8)
Extrapolating directly from reports of physical symptoms to specific aetiologies is perilous - somatic symptoms are common and usually remain medically unexplained.(9) Haley and his team did not assess whether similar symptom clusters are present in samples of non-Gulf war veterans; one suspects at least some might be.(10) The same symptoms could be related to exposure to low levels of organophosphates(11) and high levels of stress.(12) The mistake is to assume that the two are mutually exclusive. Recent animal experiments have suggested that the two may be synergistic; agents that are without risk in normal situations may be more hazardous either in combination(13) or in battlefield conditions.(14)
The symptoms reported by the 21 veterans in Haley et al's second group ("confusion-ataxia") were also attributed, by 18 of the subjects, to exposure to chemical weapons. The issue of whether there actually was large scale exposure to such weapons is controversial. If it turns out that there was no such exposure then the symptoms could be put down to the natural terror that such a perceived threat would induce.
In the final paper, Haley's team looked for specific evidence of neurological damage.(4) They took the 23 most severely ill veterans and compared them with unaffected battalion members, a departure from standard case-control methodology. They used a variety of different approaches, resulting in 165 different comparisons. No diagnostic abnormalities were found on neurological examination or investigation. However, abnormalities and asymmetries were reported in sensory evoked potentials, eye movements, and neuropsychological test batteries. There were no significant abnormalities detected using functional or structural neuroimaging, and visual evoked potentials were normal. The authors concluded that the tests provided evidence of generalised injury to the nervous system. Possible confounders, such as excess alcohol use,(1) were not addressed.
As the accompanying editorial makes clear,(15) these papers are an important start but some of the conclusions may be a bridge too far. They are hypothesis generating rather than hypothesis testing. It is premature to assume that all the findings necessarily result from a specific exposure unique to service in the Gulf. What we need are comparisons of sick Gulf veterans with sick, rather than normal, controls. Sick veterans of other conflicts would also provide an informative comparison group. We should also take care before generalising the results to British veterans. Reserve troops may be more vulnerable to varioius outcomes because of differences in training, expectations, age, fitness, and combat exposure, and, according to the Iowa study, they were more likely to report exposure to a variety of agents including pesticides.(1) Compared with the United States, Britain made far less use of reservists.
No single health problem has yet emerged as a focus for aetiological studies. Despite the reassuring findings on mortality from all 700,000 American veterans(16) - the only increase found was in deaths by accidents - it is premature to exclude at this stage an association with diseases with long incubations such as cancer. An increase in more ill defined conditions such as chronic fatigue syndrome now seems likely but not certain. The issue of reproductive health still needs to be addressed, since some veterans and their spouses have given birth to children affected by various congenital abnormalities. Again, this is not prima facie evidence for a link with Gulf service.
The scientific case for large scale epidemiological studies remains overwhelming. Even when there is a consensus about the existence of any particular adverse outcome, linking it with particular exposures years after the event will be far from easy, as Haley et al's work shows. For this, contemporary records detailing individual exposures are desirable but may be difficult to obtain. Some will cry "cover up," although the military authorities would argue that their task was to fight a war not collect data for subsequent epidemiological studies.
In Britain, the Ministry of Defence, the Medical Research Council, and the United States Department of Defence have commissioned three epidemiological studies of possible adverse effects of Gulf war service. The London School of Hygiene and Tropical Medicine will be studying reproductive outcomes, while we at King's College, London, and Professor Nicola Cherry and colleagues at the University of Manchester will be looking at the pattern of illness in the veterans. In the meantime it is essential that attention continues to be paid to individual veterans. While the Ministry of Defence has been criticised for its slowness to commission systematic research, it deserves credit for its response to the individuals affected. The universally praised medical assessment programme, begun by Group Captain William Coker, recognises the need for every person with health problems that may be related to service in the Gulf to receive a high quality comprehensive medical assessment.
After six years many fundamental questions remain unanswered. But there is now widespread recognition of the need for a swift, rigorous, and effective post-conflict illness surveillance system.(8)(17) Let's hope we never have to use it.
References
1 The Iowa Persian Gulf Study Group. Self-reported illness and health status among gulf war veterans. JAMA 1997;277:238-45.
2 Haley R, Kurt T, Hom J. Is there a Gulf war syndrome? Searching for syndromes by factor analysis of symptoms. JAMA 1997;277:215-22.
3 Haley R, Kurt T. Self-reported exposure to neurotoxic chemical combinations in the Gulf war. JAMA 1997;217:231-7.
4 Haley R, Hom J, Roland P, Bryan W, Van Ness P, Bonte F, et al. Evaluation of neurologic function in Gulf war veterans: a blinded case-control study. JAMA 1997;277:223-30.
5 Stretch R, Bliese P, Marlowe D, Wright K, Knudson K, Hoover C. Physical health symptomatology of Gulf war-era service personnel from the States of Pennsylvania and Hawaii. Military Med 1995;160:131-6.
6 Hyams K, Wignall S, Roswell R. War syndromes and their evaluation: from the U.S. civil war to the Persian Gulf war. Am Intern Med 1996;125:398-405.
7 Kaiser K, Hawksworth A, Gray G. A comparison of self-reported symptoms among active-duty Seabees: Gulf war veterans versus era veterans. In: 123rd Annual Meeting of the American Public Health Association 1995, San Diego. Washington, DC: American Public Health Association, 1995.
8 Presidential Advisory Committee on Gulf War veterans' Illness. Executive summary. Washington, DC: US Government Printing Office, 1997.
9 Kroenke K, Mangelsdorff A. Common symptoms in ambulatory care: incidence, evaluation, therapy and outcome. Am J Med 1989;86:262-6.
10 Simon G, Gater R, Kisely S, Piccinelli M. Somatic symptoms of distress: an international primary care study. Psychosom Med 1996;58:481-8.
11 Stephens R, Spurgeon A, Calvert I, Beach J, Levy LS, Berry H, et al. Neurospsychological effects of long-term, exposure to organophosphates in sheep dip. Lancet 1995;345:1135-9.
12 McFarlane A, Atchison M, Rafalowicz E, Papay P. Physical symptoms in post traumatic stress disorder. J Psychosom Res 1994;38:715-26.
13 Abou-Donia M, Wilmarth K, Jensen K, Oehme F, Kurt T. Neurotoxicity resulting from exposure to pyridostigmine bromide, DEET, and permethrin. J Toxicol Environ Health 1996;48:35-56.
14 Friedman A, Kaufer D, Shemer J, Hendler I, Soreq H, Tur-Kaspa I. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nature Med 1996;2:1382-5.
15 Landrigan P. Illness in Gulf war veterans: causes and consequences. JAMA 1997;271:259-61.
16 Kang H, Bullman T. Mortality among US Veterans of the Persian Gulf war. N Engl J Med 1996;335:1498-504.
17 Bridging the Gulf. Lancet 1996;347:341.
Anthony David
Professor
Susan Ferry
Research coordinator
Simon Wessely
Professor
Department of Psychological Medicine,
King's College School of Medicine and Dentistry,
London SE5 8AF
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