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Published by Oxford University Press on behalf of the International Epidemiological Association International Journal of Epidemiology 2005;34:810–819
The Author 2005; all rights reserved. Advance Access publication 25 April 2005 Neurological status of Australian veterans of
the 1991 Gulf War and the effect of
medical and chemical exposures
Helen Kelsall,1* Richard Macdonell,2,3 Malcolm Sim,1 Andrew Forbes,1 Dean McKenzie,1Deborah Glass,1 Jillian Ikin1 and Peter Ittak1 Background Since the 1991 Gulf War, concerns have been voiced about the effects on the health of veterans of Gulf War related medical and chemical exposures.
Our cross-sectional study compared 1424 male Australian Gulf War veteransand a randomly sampled military comparison group (n = 1548). A postalquestionnaire asked about the presence of current neurological type symptoms, medically diagnosed neurological conditions, and medical and chemicalexposures. A neurological examination was performed as part of a physicalassessment.
Veterans have a higher prevalence of neurological type symptoms (ratio of means1.4, 95% confidence interval (CI) 1.2–1.5). Although the odds ratio (OR) oflower limb neurological type symptoms and signs in veterans compared with thecomparison group was increased (OR = 1.6, 95% CI 1.0–2.7), it was of borderline significance, and there was no difference between groups according to aNeuropathy Score based on neurological signs alone (ratio of means 1.1, 95% CI0.9–1.3). The increased OR of neurological type symptoms and signs suggestiveof a central nervous system disorder (OR = 1.8, 95% CI 1.0–3.1) was also ofborderline significance. Veterans were not more likely to have self-reportedmedically diagnosed neurological conditions, or to have neurological typesymptoms and signs suggestive of an anterior horn cell disorder (OR = 0.9, 95%CI 0.5–1.6). The total number of neurological type symptoms reported byveterans, but not the Neuropathy Score, was associated with Gulf War relatedexposures including immunizations and pyridostigmine bromide indose–response relationships, anti-biological warfare tablets, solvents, pesticides,and insect repellents.
Conclusions This study shows increased reporting of neurological type symptoms in Gulf War veterans, but no evidence for increased neurological effects based on objectivephysical signs. There may be a number of factors, including information bias,relating to increased neurological type symptom reporting in veterans.
Gulf War veterans, nervous system diseases, chemical exposure, medicalexposure, pyridostigmine bromide, immunizations 1 Department of Epidemiology and Preventive Medicine, Monash University, Veterans of the 1991 Gulf War (veterans) from different countries have consistently been found to report more 2 Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
symptoms than their non-Gulf comparison groups,1–4 3 Department of Medicine, University of Melbourne, Melbourne, Victoria, especially symptoms that are neuropsychological5 neuromuscular1,2,6 in nature. Two recent studies have reported * Corresponding author. Department of Epidemiology and Preventive elevated rates of clinically confirmed amyotrophic lateral Medicine, Monash University—Central and Eastern Clinical School, AlfredHospital, Commercial Road, Melbourne, Victoria 3004, Australia. sclerosis (ALS).7,8 Other neurological conditions, based on self- report1,2 or symptom-based definitions,3 are also reported more commonly. Recently, it has been reported that veterans have an randomly sampled, non-Gulf-War veteran, military comparison increased risk of peripheral neuropathy9,10 although this has group. We also investigated whether veterans who received immunizations, took medications such as PB and anti-biological It is of interest to see whether these adverse neurological warfare tablets, or were exposed to chemicals such as solvents outcomes are related to exposure to medications and chemicals and pesticides, had more neurological type symptoms or signs during the Gulf War,16,17 such as pyridostigmine bromide (PB), immunizations, solvents, insect repellents containing N,N-diethyl-meta-toluamide (DEET), and pesticides including organophosphate insecticides, either singly or in combination.
PB is a reversible acetylcholinesterase inhibitor that was used Subjects
for nerve agent prophylaxis. It is one of the quaternary The study population was the entire cohort of 1871 Australian ammonium anticholinesterase agents that is prevented from veterans (1833 males, 38 females) who had served in the Gulf entering the central nervous system (CNS) by the blood brain region during the period from August 2, 1990 to September 4, barrier.18 It has been postulated that organophosphate 1991. A comparison group of 2924 subjects (2850 males, insecticides, nerve agent exposure, or combinations of possible 74 females) was randomly selected from 26 411 ADF personnel chemical exposures may work synergistically to produce who were in operational units at the time of the Gulf War, but neurological effects,16 based on evidence from animal were not deployed to that conflict. The comparison group was studies.19,20 Concurrent exposure to PB, DEET, and permethrin frequency matched to the veteran group by sex, service type resulted in sensorimotor deficits and region-specific alterations (navy, army, air force), and 3 year age bands. The study was in the cholinergic system,20 and concurrent exposure to stress conducted from August 2000 to April 2002. Subjects were may exacerbate neurotoxic effects,21 in rats. From this, it has recruited via mailed invitation with two further mailings and been hypothesized that genetic polymorphism of enzymes such follow-up phone contact for non-responders.
as paraoxonase/ arylesterase 1 and butyrylcholinesterase may Overall, 1808 eligible veterans (not including persons deceased have increased the individual susceptibility of veterans to effects or overseas and unavailable for the medical assessment) and from exposure to neurotoxic chemicals that require these 2796 eligible comparison group, 1456 (80.5%) veterans and enzymes for detoxification.22,23 Serum paraoxonase activity 1588 (56.8%) comparison group subjects participated.
has been observed to be lower in UK Gulf War veterans Owing to small numbers of female Gulf War veterans, compared with non-Gulf comparison groups, although there analyses were limited to males. The study groups consisted of was no difference between symptomatic and nonsymptomatic 1424 male Gulf War veterans (1232 navy, 87 army, 105 air veteran groups.24 It has also been proposed that alterations in force) who completed a postal questionnaire, of whom 1382 functioning neuronal mass in the basal ganglia and in central undertook the neurological examination, and 1548 male neurotransmitter production may, in part, explain the comparison group subjects (1123 navy, 172 army, 253 air force) neurological effects found in veterans.25 The evidence is not who completed a postal questionnaire, of whom 1376 conclusive in this field of study in humans, and methodological undertook the neurological examination. Participating veterans problems have been acknowledged.26 In particular, previous were slightly younger, more likely to have served in the navy, cross-sectional studies investigating neurological health of less highly ranked and less likely to have tertiary education, i.e.
veterans have generally relied on self-reported health outcomes an undergraduate or post-graduate degree than comparison or lacked an adequate military comparison group.
group subjects. Further details of the recruitment, demographic Australia deployed 1871 defence personnel to the Gulf area as characteristics and smoking status, and the general health part of a larger multinational response to the invasion of Kuwait symptoms and medical conditions reported by, the study groups by Iraq on August 2, 1990. The majority of Australian Defence are provided by Ikin et al.27 and Kelsall et al.28,29 Force (ADF) personnel were naval personnel deployed on The Human Research Ethics Committees of Monash frigates, destroyers, or supply ships. Other ADF personnel included University, Department of Veterans’ Affairs and the Department medical and nursing staff, mine clearance divers, intelligence officers, linguists, and weapons inspectors. Some ADF personnelwere deployed with US and British forces. Smaller numbers of Data collection
Royal Australian Air Force supplied transport and logistic Participants completed a self-administered postal questionnaire, support, but did not fly combat missions. A health risk assessment which included questions about demographics, military service, is undertaken for ADF deployments. Medical and preventive 17 neurological type symptoms that may have been experi- health measures for ADF personnel deployed to the Gulf War enced in the past month, 63 recent general (including neurolo- included immunizations, PB, anti-biological warfare, and anti- gical) symptoms, medically diagnosed or treated conditions malarial tablets, personal insect repellents (varieties of which including the year first diagnosed, medical and chemical may have contained DEET), and pesticides.
exposures including solvents, pesticides, insect repellents and We aimed to investigate whether Australian Gulf War Gulf War immunizations, PB, anti-malarial and anti-biological veterans (veterans) had a higher prevalence of symptoms and warfare tablets, the Alcohol Use Disorders Identification Test signs suggestive of peripheral neuropathy (termed neurological (AUDIT),30 and the 12 item version of the Short Form Health type symptoms and signs in this manuscript for brevity), medically diagnosed neurological conditions, or combinations Veterans were asked about the duration and quantity of PB, of neurological signs and symptoms suggestive of myopathy, anti-malarial or anti-biological warfare tablets taken, and were anterior horn cell disease, CNS disorder or epilepsy than a asked to refer to their vaccination booklet, if available, for details about the total number, timing in relation to deployment, and reported in the postal questionnaire and classified the likelihood time period over which they received immunizations.
of diagnosis as ‘non-medical’, ‘unlikely’, ‘possible’, or ‘pro- Participants undertook a health assessment at one of bable’. This was done to improve the accuracy of classification 10 medical clinics located around Australia. This included a of the self-reported medical diagnoses.
standardized neurological examination conducted by doctors,not neurologists, especially trained for the study and blinded to Definitions of possible neurological disorders
the participants’ Gulf War status. The doctors also asked about We used combinations of neurological type symptoms and signs each medically diagnosed or treated neurological condition to define possible neurological disorders (Table 1). Where Table 1 Neurological symptoms and signs used to define possible neurological entities and scoring of the neurological examination for the
Neuropathy Score
Neurological condition
Operational definition
Neurological type symptoms and signs
‘Numbness, “asleep feeling” or prickling sensation in your feet or legs’ ‘Numbness, “asleep feeling” or prickling sensation in your feet or legs and hands or arms’ Moderate = lower limb neurological type sensory and one or more gait unsteadiness symptoms, as well as either (a) one or more signs of abnormal big or little toe sensation on either foot or (b) reduced or absent ankle reflexes on either foot; and a subset of these were defined as: severe = lower limb neurological type sensory and two or more gait unsteadiness symptoms, as well as either (a) two or more signs of abnormal big or little toe sensationon either foot or (b) one or more signs of big or little toe abnormal sensation and reduced or absent ankle reflexeson either foot Scoring of the neurological examination for the Neuropathy Scorea
0 = normal, 2 = abnormal for each of the 3rd and 6th cranial nerves; 0 = normal, 2 = weak, 4 = absent for facial movements; and 0 = normal, 2 = weak for tongue movements 0 = normal power, 1 = active movement against gravity and resistance, 2 = active movement against gravity, 3 = active movement with gravity eliminated, 4 = flicker or trace of contraction or no contraction, for each of 0 = normal, 1 = reduced, 2 = absent for each of the biceps, triceps, brachioradialis, quadriceps, and ankle reflexes 0 = normal, 1 = decreased, 2 = absent for pinprick sensation of each thumb and big toe; 0 = normal, 1 = decreased for vibratory and joint position sensation of each index finger and big toe Symptoms and signs of possible myopathy
● proximal upper or lower limb muscle weakness on either side, and ● normal reflexes, sensation and upper or lower limb muscle tone, no tremor, downgoing or equivocal plantar Symptoms and signs suggestive of a disorder of anterior horn cells
● one or more symptoms of muscle weakness, and ● one or more signs of muscle fasciculations or wasting or weakness in any muscle group, and ● normal sensation and no symptoms of sensory disturbance (not including symptoms of gait disturbance) Symptoms and signs suggestive of a CNS disorder
(a) one or more symptoms of muscles weakness, or (b) one or more symptoms of fatigue, loss of concentration, tingling/burning or loss of sensation in hands or feet, problems with sexual functioning, loss of balance or coordination, loss of control over bladder or bowels,double vision or passing urine more often; and one or more of the following combinations: ● increased upper or lower limb tone and reflexes or upgoing plantar reflex, as well as decreased power in any muscle group, on the same side of the body; or ● sensory abnormality in the upper and lower limbs or nipple or umbilicus level, decreased or absent sensation in the big or little toe, and normal or increased reflexes on the same side of the body; or ● coordination abnormality on the finger nose or heel-shin test Epilepsy
● seizures or convulsions experienced in the past month, or ● medically diagnosed or treated epilepsy diagnosed in 1991 or later that was rated as a possible or probable a Neuropathy Score, modified from the Mayo Clinic Neuropathy Impairment Score.32–34 suitable, some neurological type symptoms suggestive of peripheral neuropathy have been incorporated into the other Table 2 shows that more veterans reported at least one neurological definitions, such as one or more symptoms of neurological type symptom than the comparison group subjects, muscle weakness into the definition of symptoms and signs and a greater number reported all individual neurological type suggestive of a CNS disorder. We also used a Neuropathy Score symptoms, with statistically significant differences for almost all modified from the Mayo Clinic Neuropathy Impairment neurological type symptoms reported in the past month.
Score,32–34 a global score of muscle weakness and reflex and Furthermore, more veterans reported at least one symptom of sensory abnormalities suggestive of neuropathy, based solely on muscle weakness, sensory disturbance, and autonomic signs elicited at a neurological examination. The Neuropathy dysfunction than did the comparison group. The total number Score was obtained by adding subscores for cranial nerve, of neurological type symptoms reported by veterans [mean 1.7 muscle weakness, reflex and sensation abnormalities for the (SD 2.5), median 1] was significantly higher than that reported right and left sides of the body and combining them into a score in the comparison group [mean 1.2 (SD 2.0), median 0, adjusted ratio of means 1.4, 95% CI 1.2–1.5]. This increase didnot vary with age, service type and rank (all interaction Statistical analysis
P-values Ͼ0.37, data not shown). Adjustment for smoking Statistical analyses were performed using Stata version 7.0.35 (categorized as 0, Ͻ10, 10–20, Ͼ20 pack years), in addition to Associations between deployment to the Gulf War and the other possible confounding factors, made negligible differences presence of neurological type symptoms and other defined to the resulting adjusted ORs or adjusted ratios of means in outcomes, adjusting for potential confounding factors, were these or the following analyses (data not shown).
assessed using logistic regression36 and reported as adjusted Peripheral neuropathies tend to affect the lower limbs before prevalence OR with 95% CIs. The possible confounding factors the upper limbs, and people often report symptoms before signs were chosen a priori and consisted of a core set (age, rank, are detectable on physical examination. Therefore, we used four service type, marital status, and education) as well as factors operational definitions of increasing specificity to define neuro- known to increase the risk of neurological disease (diabetes and logical type symptoms and signs, as well as the Neuropathy excessive alcohol use). Differences in the total number of neu- Score. Veterans generally reported more neurological type rological type symptoms and the Neuropathy Score between symptoms and signs according to these operational definitions the veterans and comparison group, adjusting for possible (Table 3). The exception to this was ‘more severe lower limb confounding factors, were obtained by negative binomial neurological type symptoms and signs’, where the numbers of regression, which is a statistical technique applicable when defined cases were too small to draw meaningful conclusions.
outcomes involve counts (which are typically not normally The increased OR of lower limb neurological type symptoms distributed), and allows for greater dispersion of counted values and signs in veterans compared with the comparison group was than does a Poisson regression.37,38 The measure of effect that of borderline significance. The Neuropathy Score was similar in is produced from negative binomial regression is the ratio of the the veteran and comparison groups [mean 2.0 (4.3), median 0 mean counts across the two groups being compared. Likelihood vs mean 2.0 (4.7), median 0, adjusted ratio of means 1.1, 95% ratio tests36 were performed to investigate homogeneity of the CI 0.9–1.3], and this overall result did not differ across effects of study group across categories of age, rank, and service subgroups of age, service type, and rank (all interaction type for the total number of neurological type symptoms and P-values Ͼ0.45, data not shown). Similar proportions of the Neuropathy Score. These tests were performed using veterans (65.2%) and comparison group (66.4%) subjects had interaction terms added to the regression models. The exposures to be assessed in relation to health outcomes were Table 4 shows the proportions of the veterans and comparison determined a priori. Dose–response trends were computed group who reported medically diagnosed or treated neuro- using the number of immunizations as a linear variable with logical conditions that had first been diagnosed since the Gulf trends reported per unit increase, and the number of PB tablets War. The results were similar and no important differences were taken as a categorical variable with trends reported per category found. When the analysis was confined to conditions that had (none, 1–80, 81–180, Ͼ180 tablets) increase. Other exposures been rated as a ‘possible’ or ‘probable’ diagnosis by the were considered as binary covariates in the regressions. The examining doctors, the results were very similar.
values of the unadjusted and the adjusted ORs and ratio of Two veterans and one comparison group subject reported means were found to be highly similar, and so only the adjusted medically diagnosed or treated motor neurone disease (MND) (Table 4). Given recent reports of increased MND in Gulf War To investigate the possible effects of participation bias on our veterans in overseas studies,7,8,39 we asked a neurologist, who results, we collected brief demographic and SF-1231 data from a was blinded to the participants’ Gulf War status, to review the telephone survey of non-participants. Study participants, who medical information from the postal questionnaire and medical completed the postal questionnaire, also completed the SF-12.
assessment for these three subjects. The neurologist confirmed A prediction model was used to compute an age-, rank- and that the findings were consistent with MND in one veteran and service-adjusted OR for the relative health outcome of veterans not in the other. The subject reporting MND from the com- vs comparison group subjects for having any neurological type parison group was found to have a compressive cervical symptoms as if the study had achieved full participation. The myelopathy due to spondylosis and not MND. Table 4 also predicted ‘full participation’ adjusted ORs were averaged over shows that a similar proportion of veteran and comparison group subjects had symptoms and signs suggestive of a disorder Table 2 Neurological type symptoms in the past month in male Gulf War veterans and comparison group participants
Comparison
veterans
n (%)
n (%)
Neurological type symptoms
Symptoms of muscle weakness
Difficulty turning doorknobs/unscrewing jars Difficulty getting up from sitting in a chair Problems with tripping, or feet slapping, while walking Difficulty swallowing food (more than occasionally) Symptoms of sensory disturbance
Difficulty recognizing hot from cold water Difficulty feeling pain, cuts or injuries Numbness, ‘asleep feeling’ or prickling sensation in hands or arms Numbness, ‘asleep feeling’ or prickling sensation in feet or legs Burning, deep aching pain or tenderness in hands or arms Burning, deep aching pain or tenderness in feet or legs Unusual sensitivity or tenderness of your skin when clothes or Feeling unsteady walking on uneven ground Feeling like you may fall over because of unsteadiness Symptom of autonomic dysfunction
Feeling faint when standing up from lying or sitting a ORs are adjusted for age on August 1, 1990 (Ͻ20 years, 20–24, 25–34, 35+ years), rank (officer, other rank—supervisory, other rank—nonsupervisory), service type (navy, army, air force), current marital status (married or de facto; separated, divorced or widowed; single, never married), highest level ofeducation (р10 years schooling, 11 or 12 years, certificate or diploma, tertiary), alcohol consumption (AUDIT score у8) and a history of diabetes.
Table 3 Increasingly specific operational definitions based on neurological type symptoms and signs in male Gulf War veterans and
comparison group participants
Comparison
veterans
Operational definition
n (%)
n (%)
Lower and upper limb neurological type symptomsc Lower limb neurological type symptoms and signs More severe lower limb neurological type symptoms and signs a ORs are adjusted for age, rank, service type, current marital status, highest level of education, alcohol consumption, and a history of diabetes.
b Numbness, ‘asleep feeling’ or prickling sensation in your feet or legs.
c Numbness, ‘asleep feeling’ or prickling sensation in your feet or legs and hands or arms.
of anterior horn cells such as MND. Our definition correctly did The increased OR of symptoms and signs suggestive of a CNS not identify those two subjects whose self-reported MND was disorder in veterans compared with the comparison group was of not confirmed by the above neurological review as having borderline significance. Similar proportions of veterans and symptoms and signs suggestive of a disorder of anterior horn comparison group subjects had symptoms and signs suggestive of cells. Our definition excluded the veteran with MND, because myopathy and of epilepsy, although the prevalences were small of self-reported sensory symptoms (although sensation was and this limited the power of the study to detect differences and to identify associations with Gulf War service (Table 4).
Table 4 Self-reported medically diagnosed or treated conditions first diagnosed in 1991 or later and operational definitions of symptoms and signs
suggestive of myopathy, a disorder of anterior horn cells, CNS disorder or epilepsy in male Gulf War veterans and comparison group participants
Comparison
veterans
n (%)
n (%)
Self-reported neurological condition first
diagnosed in 1991 or later
Operational definition of neurological
conditionc
OR is adjusted for service type, rank, age, education, and marital status.
b ORs are adjusted for service type, rank and age (Ͻ25 years vs Ͼ25 years). CI intervals and P-values for adjusted ORs were obtained using exact methods c Operational definition of neurological conditions based on neurological or neurological type symptoms and signs as defined in Table 1.
d ORs are adjusted for age, rank, service type, marital status, education, alcohol consumption, and a history of diabetes.
Medical and chemical exposures
Investigation of possible effects of
Similar proportions of veterans and comparison group subjects participation bias
reported exposure to pesticides (19.2% vs 15.9%) and solvents The telephone survey for non-participants, upon which part of (73.9% vs 67.7%) during their entire military career, and the prediction model for assessing possible participation bias was exposure to pesticides (8.9% vs 9.8%) and solvents (30.0% vs based, was completed by approximately one-quarter (n = 411) 33.4%) during civilian jobs held for у6 months. Therefore, of all study non-participants. The prediction model assumed that such non-Gulf-War exposures were unlikely to confound any the telephone respondents’ answers were representative of those of the remainder of the non-participants.
In relation to their Gulf War deployment, 1298 (91.6%) The predicted ‘full participation’ age-adjusted, rank-adjusted veterans reported receiving immunizations, including 342 and service-adjusted prevalence OR of having any neurological (24.1%) who reported that they did not know how many type symptom between veteran and comparison group subjects immunizations they had received, and 119 (8.4%) veterans was 1.36, which is only marginally lower than the corre- reported receiving none. Of 1113 veterans (for whom sufficient sponding OR of 1.42 observed for participants.
data was available for calculation), 151 (13.6%) were defined ashaving received a cluster of immunizations, that is, more than five immunizations within a period of a week or less. Someveterans were also uncertain about other medical exposures, and We found increased reporting of neurological type symptoms reported that they did not know whether they had taken PB, by Gulf War veterans, but no differences in reporting of med- anti-biological warfare or anti-malarial tablets (Table 5 footnote).
ically diagnosed neurological conditions. We also found no The total number of neurological type symptoms was convincing evidence for increased neurological effects based on associated with several Gulf War exposures including having combinations of neurological type symptoms and signs or on taken PB and anti-biological warfare tablets, and using solvents, signs alone in Gulf War veterans when compared with the pesticides, and insect repellents during the Gulf War; but not with some other exposures such as having received any There has been limited study of peripheral neuropathy in immunizations or a cluster of immunizations (Table 5).
previous Gulf War epidemiological works with which to Increasing number of immunizations and increasing number of compare our results. Cherry et al.6 found that 12.5% of the UK PB tablets received were associated with total number of Gulf War veterans reported neuropathic symptoms compared neurological type symptoms in a dose–response relationship.
with 6.8% of the non-Gulf comparison group. Our association, The pattern of the relation between exposures and having any also based on symptoms, was not as strong as this. Jamal et al.10 neurological type symptoms (data not shown) was similar to found that both the neurological symptom score and the mean that observed for the total number of neurological type clinical signs score of 14 veterans with unexplained illnesses symptoms. The Neuropathy Score was not associated with any were increased compared with that of 13 civilian controls.
However, they used small numbers of participants, a highly Table 5 Analysis of total number of neurological type symptoms in Gulf War veterans by Gulf War service related immunizations and medical
and chemical exposures
Total number of neurological type symptoms
Gulf War exposure
Immunizationsb
Pyridostigmine bromideb
Anti-malarialsb
Anti-biological warfare tabletsb
Solvents
Pesticides
Insect repellents
a Ratio of means are adjusted for age, rank, service type, current marital status, highest level of education, alcohol consumption, and a history of diabetes.
b Some veterans reported that they did not know the number of immunizations received (n = 342) and whether they had taken PB (n = 318), anti-malarial (n = 543) or anti-biological warfare (n = 793) tablets. A smaller number of responses were missing values.
c Dose–response per unit increase in immunizations in those who had received at least one immunization.
d A cluster of immunizations was defined as more than five immunizations in one week or less.
e Dose–response per category increase in number of PB tablets taken.
selected veteran sample and civilian controls for comparison, or electrophysiology or by the methods combined. In addition, the which makes meaningful interpretation difficult.
US study reported a relation between the two objective methods Our finding of increased neurological type symptom reporting of neurological assessment; veterans who had abnormal by veterans, but no difference between study groups in the peripheral nerve conduction studies were found to be 3.89 times Neuropathy Score, is in general agreement with a recent study of more likely to have distal symmetric polyneuropathy found on US veterans;15 which found increased neuropathic symptom neurological physical examination.15 In other studies that used reporting in veterans, but no differences in prevalence of distal objective neurological testing, findings have varied. Five symmetric polyneuropathy between veterans and a non-deployed symptomatic veterans had some evidence of mild sensorimotor comparison group assessed by neurological physical examination deficits in peripheral nerve function on nerve conduction studies, but electromyography was normal.9 In addition, another study There are some limitations to our findings for neurological found a small but statistically significant elevated threshold to cold health outcomes. The neurological type symptom questionnaire sensation and differences in two other sensory nerve conduction was not a validated questionnaire. It did not include qualifying tests comparing selected veterans and civilian controls.10 No questions around the duration of symptoms or differential objective abnormalities of neuromuscular disease were found in causes. Although the neurological type symptom questionnaire other studies of veterans with neuropathic11,13 or neuromuscular and the definitions have face validity, they have not been symptoms,12,40 although some veterans were found to have validated in clinical practice. Neurological signs may not always carpal tunnel syndrome,11,13 ulnar neuropathy,11,12 or increased be present even when symptoms and other features of the lactate production during subanaerobic exercise.40 The research clinical history strongly indicate that a neurological disorder is in this field remains inconclusive, and acknowledged present. The process of defining neurological outcomes used in methodological limitations include small sample sizes, use of our study, based on symptoms and signs or signs alone (such as highly selected samples or self-referred veterans from registry in the Neuropathy Score), was not intended to be diagnostic.
populations, lack of comparison groups or comparison with In our study populations the prevalence of true neurological civilian controls, possible participation bias11,15,26 and concerns disorders is likely to be fairly low and therefore a positive regarding the inclusion criteria used to define cases.17 finding according to our definitions should be interpreted In our study we used a combination of symptoms and signs in cautiously, in terms of their ability to predict true neurological defining a possible disorder of anterior horn cells such as ALS, disease. Further evaluation, such as an assessment by a the most common form of MND. Two recently published studies neurologist or investigations such as electromyography or that used active and passive ascertainment of ALS cases, magnetic resonance imaging (MRI), would be required to confirmed by medical record or telephone or personal interview determine whether the combinations of symptoms and physical or both, found an approximately 2-fold significantly increased signs are really related to pathology affecting the peripheral or risk of ALS for US veterans overall7 and for US veterans CNS. Exposure assessment was based on self-report. The use of diagnosed Ͻ45 years.8 Haley8 attributes the increased risk of preventive health medication and measures may have varied ALS in younger veterans to an environmental trigger, and between individuals, ships, and units depending on their predicts that the peak has not yet been reached. On the basis perceived risk of exposure and self-compliance with of such findings,7 the US Department of Veterans Affairs has medication. For example, the recommended PB dose of 30 mg accepted ALS as a Gulf-War-related condition.39 We found no eight-hourly before and for the duration of the period of excess of symptoms and signs suggestive of a disorder of exposure, was to be commenced on order of the Commanding anterior horn cells to support the US finding, but we had too Officer, based on medical advice. DEET-based insect repellent few defined cases to draw meaningful conclusions at this stage.
would probably have been issued to any ADF personnel going We found no important differences in reported medically on shore in the Gulf region, but were probably not required or diagnosed neurological conditions in veterans compared with used at sea. Veterans’ uncertainty in relation to their medical the comparison group. Our analysis of the likelihood of exposures could have influenced our results. There are several diagnosis of self-reported neurological conditions, based on reasons for this uncertainty, including the time that has elapsed possible or probable diagnosis, suggests that veterans do not since the Gulf War and poor record keeping at the time of the appear to be over reporting medically diagnosed or treated Gulf War. This aspect of exposure assessment highlights the neurological conditions that were first diagnosed since the Gulf importance of medical record keeping in the defence forces.
War compared with the comparison group. More veterans and The prevalences of some defined outcomes were small and this comparison group subjects had symptoms and signs suggestive limited the power of the study to detect differences and to of neurological conditions such as anterior horn cell disease or identify associations with Gulf War service. Finally, although we CNS disorder than reported medically diagnosed or treated did not find evidence of differential effects of Gulf War conditions. Therefore, it is possible that subjects in both study deployment across subgroups of rank, service, or age, our ability groups may have neurological conditions that have not yet been to detect small differential effects was limited, especially for diagnosed or come to medical attention.
subgroups of limited size such as non-Navy service.
The reporting of neurological type symptoms, but not the Despite a rigorous contact and recruitment strategy, the Neuropathy Score, was associated with increasing numbers of comparison group participation rate was lower than that of immunizations received and PB tablets taken, and with taking the veteran group. Our veteran group participation rate was anti-biological warfare tablets and using solvents, pesticides, relatively high and the comparison group participation rate was and insect repellents. The lack of any association between the comparable with that of other major postal surveys of Neuropathy Score, defined solely on the basis of neurological veterans,1,2,4,41 and highlights the difficulties faced by signs, and medical and chemical exposures suggests that other researchers in contacting and recruiting young, highly mobile, factors such as information bias, including recall bias, need to be military and ex-military populations. Our formal evaluation of considered when attempting to explain these associations.
possible participation bias suggests that this is unlikely to fully One strength of our study is the use of a military comparison explain the differences (or lack thereof) that we found between group to whom the same definitions were applied, as this has our study groups. In addition, we adjusted for possible not always occurred in previous studies. In addition, we were confounding factors such as age, rank, service type, marital able to look at levels of reported chemical exposures in each status, education and smoking, as well as diabetes and excessive participant’s military career and civilian jobs. These were similar alcohol use that are known to increase the risk of neurological in both study groups, suggesting that they do not explain the disease. To minimize any interviewer bias, data were collected in the same way using the same data collection forms for veteran and comparison group subjects, and examining doctors In conclusion, our study demonstrates increased reporting were blinded to participants’ Gulf War status.
of neurological type symptoms by Australian Gulf War vet- There may be a number of explanations for the observed erans, but no evidence for increased neurological effects increase in neurological type symptoms reported by veterans over based on objective physical signs. The relation with Gulf what was reported by a comparable group of military personnel.
War exposures followed a similar pattern; associations with The increase may really reflect a greater level of mild neurological medical and chemical exposures were found only for effects in veterans. Alternatively, the increase in neurological type neurological type symptoms and not for objective physical symptom reporting may be owing to information bias including signs. There may be several factors contributing to increased recall bias. Veterans may be susceptible to publicity about ‘Gulf reporting of neurological type symptoms. While this may War problems’, and if so may be more likely to self-report indicate mild neurological effects in Gulf War veterans, neurological type symptoms in the past month. Recall bias may information bias including recall bias is also another plausible have occurred, as those who experienced symptoms may be more explanation. Many of the conclusions of other epidemiological likely to report exposures.42 Wessely et al.43 found that worsening studies of veterans’ neurological health have been based solely health perception (though not physical health or psychological on self-reported findings. Our study emphasizes the importance morbidity) in UK veterans over time was associated with of including objective physical signs in the future assessment of increasing new reporting of exposures. Participant awareness of the study’s purpose may have exacerbated the possible effects ofresponse frame,44 and veterans may have tended towards a response set of how veterans are ‘expected’ to appear. Theincrease in reported neurological type symptoms may also be part The study was funded by the Australian Government— of the increased general ill health in veterans based on increased Department of Veterans’ Affairs. This study was overseen by a reporting of all general health symptoms and of symptom-based Scientific Advisory Committee and by a veterans’ Consultative medical conditions;29,41,45 and with the increased reporting of Forum, and we are grateful to members for their contributions multiple46 and sometimes unexplained47 symptoms following and support. We acknowledge the contribution of Health deployment to war,47 something that is not generally well Services Australia who conducted the medical assessments. We understood.45 Post-combat syndromes over the past 100 years are grateful to Dr Wendyl D’Souza, neurologist, for his advice have, however, been characterized by a general shift from debility on, and training of doctors for, the standardized neurological type symptoms to psychological or cognitive symptoms with a examination performed in the study. We thank Dr Keith Horsley, Dr Warren Harrex, Mr Bob Connolly and his contact These possible biases should have had less of an effect on and recruitment team at the Department of Veterans’ Affairs, neurological health outcomes that we defined using Canberra. Finally, we thank the Gulf War veterans and combinations of symptoms and physical signs, and no effect on members of the comparison group for the time and effort they the Neuropathy Score that was defined solely by physical signs.
Our study demonstrates increased reporting of neurological type symptoms by Australian Gulf War veterans, but no evidence for increased neurological effects based on objective neurological physical signs.
The relation with Gulf War exposures followed a similar pattern; associations with medical and chemical exposures were found only for neurological type symptoms and not for physical signs.
Gulf War veterans were not more likely to have neurological type symptoms and signs suggestive of a disorder of anterior horn cells such as ALS, the most common form of motor neurone disease, although the numbers are small and need to be interpreted There may be a number of factors, such as information including recall bias, relating to increased neurological type symptom 4 Ishoy T, Suadicani P, Guldager B, Appleyard M, Hein HO, Gyntelberg F.
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