Published by Oxford University Press on behalf of the International Epidemiological Association
© The Author 2005; all rights reserved. Advance Access publication 25 April 2005
International Journal of Epidemiology 2005;34:810–819
doi:10.1093/ije/dyi084
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,1
Deborah Glass,1 Jillian Ikin1 and Peter Ittak1
Accepted
21 March 2005
Methods
Our cross-sectional study compared 1424 male Australian Gulf War veterans
and a randomly sampled military comparison group (n = 1548). A postal
questionnaire asked about the presence of current neurological type symptoms,
medically diagnosed neurological conditions, and medical and chemical
exposures. A neurological examination was performed as part of a physical
assessment.
Results
Veterans have a higher prevalence of neurological type symptoms (ratio of means
1.4, 95% confidence interval (CI) 1.2–1.5). Although the odds ratio (OR) of
lower limb neurological type symptoms and signs in veterans compared with the
comparison 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 a
Neuropathy Score based on neurological signs alone (ratio of means 1.1, 95% CI
0.9–1.3). The increased OR of neurological type symptoms and signs suggestive
of a central nervous system disorder (OR = 1.8, 95% CI 1.0–3.1) was also of
borderline significance. Veterans were not more likely to have self-reported
medically diagnosed neurological conditions, or to have neurological type
symptoms 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 by
veterans, but not the Neuropathy Score, was associated with Gulf War related
exposures including immunizations and pyridostigmine bromide in
dose–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 objective
physical signs. There may be a number of factors, including information bias,
relating to increased neurological type symptom reporting in veterans.
Keywords
Gulf War veterans, nervous system diseases, chemical exposure, medical
exposure, pyridostigmine bromide, immunizations
1 Department of Epidemiology and Preventive Medicine, Monash University,
Melbourne, Victoria, Australia.
2 Department of Neurology, Austin Health, Heidelberg, Victoria, Australia.
3 Department of Medicine, University of Melbourne, Melbourne, Victoria,
Australia.
* Corresponding author. Department of Epidemiology and Preventive
Medicine, Monash University—Central and Eastern Clinical School, Alfred
Hospital, Commercial Road, Melbourne, Victoria 3004, Australia.
E-mail: [email protected]
Veterans of the 1991 Gulf War (veterans) from different
countries have consistently been found to report more
symptoms than their non-Gulf comparison groups,1–4
especially symptoms that are neuropsychological5 or
neuromuscular1,2,6 in nature. Two recent studies have reported
elevated rates of clinically confirmed amyotrophic lateral
sclerosis (ALS).7,8 Other neurological conditions, based on selfreport1,2 or symptom-based definitions,3 are also reported more
810
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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.
NEUROLOGICAL STATUS OF GULF WAR VETERANS
randomly sampled, non-Gulf-War veteran, military comparison
group. We also investigated whether veterans who received
immunizations, took medications such as PB and anti-biological
warfare tablets, or were exposed to chemicals such as solvents
and pesticides, had more neurological type symptoms or signs
than veterans who were not exposed.
Methods
Subjects
The study population was the entire cohort of 1871 Australian
veterans (1833 males, 38 females) who had served in the Gulf
region during the period from August 2, 1990 to September 4,
1991. A comparison group of 2924 subjects (2850 males,
74 females) was randomly selected from 26 411 ADF personnel
who were in operational units at the time of the Gulf War, but
were not deployed to that conflict. The comparison group was
frequency matched to the veteran group by sex, service type
(navy, army, air force), and 3 year age bands. The study was
conducted from August 2000 to April 2002. Subjects were
recruited via mailed invitation with two further mailings and
follow-up phone contact for non-responders.
Overall, 1808 eligible veterans (not including persons deceased
or overseas and unavailable for the medical assessment) and
2796 eligible comparison group, 1456 (80.5%) veterans and
1588 (56.8%) comparison group subjects participated.
Owing to small numbers of female Gulf War veterans,
analyses were limited to males. The study groups consisted of
1424 male Gulf War veterans (1232 navy, 87 army, 105 air
force) who completed a postal questionnaire, of whom 1382
undertook the neurological examination, and 1548 male
comparison group subjects (1123 navy, 172 army, 253 air force)
who completed a postal questionnaire, of whom 1376
undertook the neurological examination. Participating veterans
were slightly younger, more likely to have served in the navy,
less highly ranked and less likely to have tertiary education, i.e.
an undergraduate or post-graduate degree than comparison
group subjects. Further details of the recruitment, demographic
characteristics and smoking status, and the general health
symptoms and medical conditions reported by, the study groups
are provided by Ikin et al.27 and Kelsall et al.28,29
The Human Research Ethics Committees of Monash
University, Department of Veterans’ Affairs and the Department
of Defence approved the study.
Data collection
Participants completed a self-administered postal questionnaire,
which included questions about demographics, military service,
17 neurological type symptoms that may have been experienced in the past month, 63 recent general (including neurological) symptoms, medically diagnosed or treated conditions
including the year first diagnosed, medical and chemical
exposures including solvents, pesticides, insect repellents and
Gulf War immunizations, PB, anti-malarial and anti-biological
warfare tablets, the Alcohol Use Disorders Identification Test
(AUDIT),30 and the 12 item version of the Short Form Health
Survey (SF-12) version 1.31
Veterans were asked about the duration and quantity of PB,
anti-malarial or anti-biological warfare tablets taken, and were
asked to refer to their vaccination booklet, if available, for details
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commonly. Recently, it has been reported that veterans have an
increased risk of peripheral neuropathy9,10 although this has
not been a consistent finding.11–15
It is of interest to see whether these adverse neurological
outcomes are related to exposure to medications and chemicals
during the Gulf War,16,17 such as pyridostigmine bromide (PB),
immunizations, solvents, insect repellents containing N,Ndiethyl-meta-toluamide (DEET), and pesticides including
organophosphate insecticides, either singly or in combination.
PB is a reversible acetylcholinesterase inhibitor that was used
for nerve agent prophylaxis. It is one of the quaternary
ammonium anticholinesterase agents that is prevented from
entering the central nervous system (CNS) by the blood brain
barrier.18 It has been postulated that organophosphate
insecticides, nerve agent exposure, or combinations of possible
chemical exposures may work synergistically to produce
neurological effects,16 based on evidence from animal
studies.19,20 Concurrent exposure to PB, DEET, and permethrin
resulted in sensorimotor deficits and region-specific alterations
in the cholinergic system,20 and concurrent exposure to stress
may exacerbate neurotoxic effects,21 in rats. From this, it has
been hypothesized that genetic polymorphism of enzymes such
as paraoxonase/ arylesterase 1 and butyrylcholinesterase may
have increased the individual susceptibility of veterans to effects
from exposure to neurotoxic chemicals that require these
enzymes for detoxification.22,23 Serum paraoxonase activity
has been observed to be lower in UK Gulf War veterans
compared with non-Gulf comparison groups, although there
was no difference between symptomatic and nonsymptomatic
veteran groups.24 It has also been proposed that alterations in
functioning neuronal mass in the basal ganglia and in central
neurotransmitter production may, in part, explain the
neurological effects found in veterans.25 The evidence is not
conclusive in this field of study in humans, and methodological
problems have been acknowledged.26 In particular, previous
cross-sectional studies investigating neurological health of
veterans have generally relied on self-reported health outcomes
or lacked an adequate military comparison group.
Australia deployed 1871 defence personnel to the Gulf area as
part of a larger multinational response to the invasion of Kuwait
by Iraq on August 2, 1990. The majority of Australian Defence
Force (ADF) personnel were naval personnel deployed on
frigates, destroyers, or supply ships. Other ADF personnel included
medical and nursing staff, mine clearance divers, intelligence
officers, linguists, and weapons inspectors. Some ADF personnel
were deployed with US and British forces. Smaller numbers of
Royal Australian Air Force supplied transport and logistic
support, but did not fly combat missions. A health risk assessment
is undertaken for ADF deployments. Medical and preventive
health measures for ADF personnel deployed to the Gulf War
included immunizations, PB, anti-biological warfare, and antimalarial tablets, personal insect repellents (varieties of which
may have contained DEET), and pesticides.
We aimed to investigate whether Australian Gulf War
veterans (veterans) had a higher prevalence of symptoms and
signs suggestive of peripheral neuropathy (termed neurological
type symptoms and signs in this manuscript for brevity),
medically diagnosed neurological conditions, or combinations
of neurological signs and symptoms suggestive of myopathy,
anterior horn cell disease, CNS disorder or epilepsy than a
811
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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
about the total number, timing in relation to deployment, and
time period over which they received immunizations.
Participants undertook a health assessment at one of
10 medical clinics located around Australia. This included a
standardized neurological examination conducted by doctors,
not neurologists, especially trained for the study and blinded to
the participants’ Gulf War status. The doctors also asked about
each medically diagnosed or treated neurological condition
reported in the postal questionnaire and classified the likelihood
of diagnosis as ‘non-medical’, ‘unlikely’, ‘possible’, or ‘probable’. This was done to improve the accuracy of classification
of the self-reported medical diagnoses.
Definitions of possible neurological disorders
We used combinations of neurological type symptoms and signs
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’
Lower and upper limb
neurological type
symptoms
‘Numbness, “asleep feeling” or prickling sensation in your feet or legs and hands or arms’
Lower limb neurological
type symptoms and signs
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 sensation
on either foot or (b) one or more signs of big or little toe abnormal sensation and reduced or absent ankle reflexes
on either foot
Scoring of the neurological examination for the Neuropathy Scorea
Cranial nerves
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
Muscle weakness
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
17 upper and lower limb muscle groups
Reflexes
0 = normal, 1 = reduced, 2 = absent for each of the biceps, triceps, brachioradialis, quadriceps, and ankle reflexes
Sensation
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
Symptoms and signs of
●
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
reflexes
Symptoms and signs suggestive of a disorder of anterior horn cells
Symptoms and signs of
●
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
Symptoms and signs of
(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
Self-report of
●
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
diagnosis
a Neuropathy Score, modified from the Mayo Clinic Neuropathy Impairment Score.32–34
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Lower limb neurological
type symptoms
NEUROLOGICAL STATUS OF GULF WAR VETERANS
suitable, some neurological type symptoms suggestive of
peripheral neuropathy have been incorporated into the other
neurological definitions, such as one or more symptoms of
muscle weakness into the definition of symptoms and signs
suggestive of a CNS disorder. We also used a Neuropathy Score
modified from the Mayo Clinic Neuropathy Impairment
Score,32–34 a global score of muscle weakness and reflex and
sensory abnormalities suggestive of neuropathy, based solely on
signs elicited at a neurological examination. The Neuropathy
Score was obtained by adding subscores for cranial nerve,
muscle weakness, reflex and sensation abnormalities for the
right and left sides of the body and combining them into a score
for each person.
Statistical analyses were performed using Stata version 7.0.35
Associations between deployment to the Gulf War and the
presence of neurological type symptoms and other defined
outcomes, adjusting for potential confounding factors, were
assessed using logistic regression36 and reported as adjusted
prevalence OR with 95% CIs. The possible confounding factors
were chosen a priori and consisted of a core set (age, rank,
service type, marital status, and education) as well as factors
known to increase the risk of neurological disease (diabetes and
excessive alcohol use). Differences in the total number of neurological type symptoms and the Neuropathy Score between
the veterans and comparison group, adjusting for possible
confounding factors, were obtained by negative binomial
regression, which is a statistical technique applicable when
outcomes involve counts (which are typically not normally
distributed), and allows for greater dispersion of counted values
than does a Poisson regression.37,38 The measure of effect that
is produced from negative binomial regression is the ratio of the
mean counts across the two groups being compared. Likelihood
ratio tests36 were performed to investigate homogeneity of the
effects of study group across categories of age, rank, and service
type for the total number of neurological type symptoms and
the Neuropathy Score. These tests were performed using
interaction terms added to the regression models. The
exposures to be assessed in relation to health outcomes were
determined a priori. Dose–response trends were computed
using the number of immunizations as a linear variable with
trends reported per unit increase, and the number of PB tablets
taken as a categorical variable with trends reported per category
(none, 1–80, 81–180, 180 tablets) increase. Other exposures
were considered as binary covariates in the regressions. The
values of the unadjusted and the adjusted ORs and ratio of
means were found to be highly similar, and so only the adjusted
results are reported.
To investigate the possible effects of participation bias on our
results, we collected brief demographic and SF-1231 data from a
telephone survey of non-participants. Study participants, who
completed the postal questionnaire, also completed the SF-12.
A prediction model was used to compute an age-, rank- and
service-adjusted OR for the relative health outcome of veterans
vs comparison group subjects for having any neurological type
symptoms as if the study had achieved full participation. The
predicted ‘full participation’ adjusted ORs were averaged over
100 replications of the analyses.27
Results
Table 2 shows that more veterans reported at least one
neurological type symptom than the comparison group subjects,
and a greater number reported all individual neurological type
symptoms, with statistically significant differences for almost all
neurological type symptoms reported in the past month.
Furthermore, more veterans reported at least one symptom of
muscle weakness, sensory disturbance, and autonomic
dysfunction than did the comparison group. The total number
of neurological type symptoms reported by veterans [mean 1.7
(SD 2.5), median 1] was significantly higher than that reported
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 did
not vary with age, service type and rank (all interaction
P-values 0.37, data not shown). Adjustment for smoking
(categorized as 0, 10, 10–20, 20 pack years), in addition to
other possible confounding factors, made negligible differences
to the resulting adjusted ORs or adjusted ratios of means in
these or the following analyses (data not shown).
Peripheral neuropathies tend to affect the lower limbs before
the upper limbs, and people often report symptoms before signs
are detectable on physical examination. Therefore, we used four
operational definitions of increasing specificity to define neurological type symptoms and signs, as well as the Neuropathy
Score. Veterans generally reported more neurological type
symptoms and signs according to these operational definitions
(Table 3). The exception to this was ‘more severe lower limb
neurological type symptoms and signs’, where the numbers of
defined cases were too small to draw meaningful conclusions.
The increased OR of lower limb neurological type symptoms
and signs in veterans compared with the comparison group was
of borderline significance. The Neuropathy Score was similar in
the veteran and comparison groups [mean 2.0 (4.3), median 0
vs mean 2.0 (4.7), median 0, adjusted ratio of means 1.1, 95%
CI 0.9–1.3], and this overall result did not differ across
subgroups of age, service type, and rank (all interaction
P-values 0.45, data not shown). Similar proportions of
veterans (65.2%) and comparison group (66.4%) subjects had
a Neuropathy Score of zero.
Table 4 shows the proportions of the veterans and comparison
group who reported medically diagnosed or treated neurological conditions that had first been diagnosed since the Gulf
War. The results were similar and no important differences were
found. When the analysis was confined to conditions that had
been rated as a ‘possible’ or ‘probable’ diagnosis by the
examining doctors, the results were very similar.
Two veterans and one comparison group subject reported
medically diagnosed or treated motor neurone disease (MND)
(Table 4). Given recent reports of increased MND in Gulf War
veterans in overseas studies,7,8,39 we asked a neurologist, who
was blinded to the participants’ Gulf War status, to review the
medical information from the postal questionnaire and medical
assessment for these three subjects. The neurologist confirmed
that the findings were consistent with MND in one veteran and
not in the other. The subject reporting MND from the comparison group was found to have a compressive cervical
myelopathy due to spondylosis and not MND. Table 4 also
shows that a similar proportion of veteran and comparison
group subjects had symptoms and signs suggestive of a disorder
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Statistical analysis
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INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
Table 2 Neurological type symptoms in the past month in male Gulf War veterans and comparison group participants
Gulf War
veterans
n (%)
Comparison
group
n (%)
Adj ORa
95% CI
753 (53.0)
676 (43.7)
1.4
1.2–1.7
1 Symptom of muscle weakness
417 (29.3)
395 (25.5)
1.2
1.0–1.4
Difficulty lifting objects above head
Neurological type symptoms
1 Neurological type symptom
Symptoms of muscle weakness
193 (13.6)
179 (11.6)
1.3
1.0–1.6
Difficulty undoing buttons
45 (3.2)
31 (2.0)
1.7
1.1–2.8
Difficulty turning doorknobs/unscrewing jars
72 (5.1)
58 (3.8)
1.5
1.1–2.2
Difficulty getting up from sitting in a chair
276 (17.9)
1.2
1.0–1.5
94 (6.6)
74 (4.8)
1.4
1.0–2.0
Difficulty swallowing food (more than occasionally)
35 (2.5)
26 (1.7)
1.4
0.8–2.4
654 (46.0)
558 (36.1)
1.5
1.3–1.7
Difficulty recognizing hot from cold water
12 (0.8)
11 (0.7)
1.4
0.6–3.2
Difficulty feeling pain, cuts or injuries
45 (3.2)
20 (1.3)
2.7
1.5–4.6
Numbness, ‘asleep feeling’ or prickling sensation in hands or arms
367 (25.9)
278 (18.0)
1.6
1.3–1.9
Numbness, ‘asleep feeling’ or prickling sensation in feet or legs
306 (21.6)
248 (16.1)
1.4
1.2–1.7
108 (7.6)
84 (5.4)
1.5
1.1–2.0
164 (11.5)
141 (9.1)
1.3
1.1–1.7
100 (7.0)
58 (3.8)
2.0
1.4–2.8
1.0–1.9
Symptoms of sensory disturbance
1 Symptom of sensory disturbance
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
bedclothes rub against you
Feeling unsteady walking on uneven ground
Feeling unsteady walking in the dark
Feeling like you may fall over because of unsteadiness
103 (7.2)
87 (5.6)
1.4
142 (10.0)
96 (6.2)
1.7
1.3–2.2
81 (5.7)
60 (3.9)
1.5
1.1–2.2
187 (13.2)
144 (9.3)
1.4
1.1–1.7
Symptom of autonomic dysfunction
Feeling faint when standing up from lying or sitting
a ORs are adjusted for age on August 1, 1990 (20 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 of
education (10 years schooling, 11 or 12 years, certificate or diploma, tertiary), alcohol consumption (AUDIT score 8) 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
Operational definition
Gulf War
veterans
n (%)
Comparison
group
n (%)
Adj ORa
95% CI
Lower limb neurological type symptomsb
306 (21.6)
248 (16.1)
1.4
1.2–1.7
Lower and upper limb neurological type symptomsc
212 (15.0)
145 (9.4)
1.7
1.3–2.1
42 (3.0)
30 (2.2)
1.6
1.0–2.7
11 (0.8)
11 (0.8)
1.4
0.6–3.3
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
not identify those two subjects whose self-reported MND was
not confirmed by the above neurological review as having
symptoms and signs suggestive of a disorder of anterior horn
cells. Our definition excluded the veteran with MND, because
of self-reported sensory symptoms (although sensation was
normal on examination).
The increased OR of symptoms and signs suggestive of a CNS
disorder in veterans compared with the comparison group was of
borderline significance. Similar proportions of veterans and
comparison group subjects had symptoms and signs suggestive of
myopathy and of epilepsy, although the prevalences were small
and this limited the power of the study to detect differences and
to identify associations with Gulf War service (Table 4).
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293 (20.6)
Problems with tripping, or feet slapping, while walking
NEUROLOGICAL STATUS OF GULF WAR VETERANS
815
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
Gulf War
veterans
n (%)
Comparison
group
n (%)
Adj OR
Migraines
68 (5)
51 (4)
1.4a
1.0–2.1
Motor neurone disease
2 (1)
1 (1)
3.7b
0.2–220.0
Stroke
3 (1)
3 (1)
1.0b
0.1–8.0
Multiple sclerosis
1 (1)
3 (1)
0.3b
0.0–3.5
4 (1)
1 (1)
3.6b
0.4–177.0
Myopathy
18 (1.3)
13 (1.0)
1.4d
0.7–3.0
Anterior horn cell disease
20 (1.5)
27 (2.0)
0.9d
0.5–1.6
CNS disorder
35 (2.5)
21 (1.5)
1.8d
1.0–3.1
5 (0.3)
1.8d
0.6–5.9
95% CI
Self-reported neurological condition first
diagnosed in 1991 or later
Epilepsy
Operational definition of neurological
conditionc
8 (0.6)
for stratified 2 2 tables.
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
Similar proportions of veterans and comparison group subjects
reported exposure to pesticides (19.2% vs 15.9%) and solvents
(73.9% vs 67.7%) during their entire military career, and
exposure to pesticides (8.9% vs 9.8%) and solvents (30.0% vs
33.4%) during civilian jobs held for 6 months. Therefore,
such non-Gulf-War exposures were unlikely to confound any
of the following results.
In relation to their Gulf War deployment, 1298 (91.6%)
veterans reported receiving immunizations, including 342
(24.1%) who reported that they did not know how many
immunizations they had received, and 119 (8.4%) veterans
reported receiving none. Of 1113 veterans (for whom sufficient
data was available for calculation), 151 (13.6%) were defined as
having received a cluster of immunizations, that is, more than
five immunizations within a period of a week or less. Some
veterans were also uncertain about other medical exposures, and
reported that they did not know whether they had taken PB,
anti-biological warfare or anti-malarial tablets (Table 5 footnote).
The total number of neurological type symptoms was
associated with several Gulf War exposures including having
taken PB and anti-biological warfare tablets, and using solvents,
pesticides, and insect repellents during the Gulf War; but not
with some other exposures such as having received any
immunizations or a cluster of immunizations (Table 5).
Increasing number of immunizations and increasing number of
PB tablets received were associated with total number of
neurological type symptoms in a dose–response relationship.
The pattern of the relation between exposures and having any
neurological type symptoms (data not shown) was similar to
that observed for the total number of neurological type
symptoms. The Neuropathy Score was not associated with any
of the exposures examined.
Investigation of possible effects of
participation bias
The telephone survey for non-participants, upon which part of
the prediction model for assessing possible participation bias was
based, was completed by approximately one-quarter (n = 411)
of all study non-participants. The prediction model assumed that
the telephone respondents’ answers were representative of
those of the remainder of the non-participants.
The predicted ‘full participation’ age-adjusted, rank-adjusted
and service-adjusted prevalence OR of having any neurological
type symptom between veteran and comparison group subjects
was 1.36, which is only marginally lower than the corresponding OR of 1.42 observed for participants.
Discussion
We found increased reporting of neurological type symptoms
by Gulf War veterans, but no differences in reporting of medically diagnosed neurological conditions. We also found no
convincing evidence for increased neurological effects based on
combinations of neurological type symptoms and signs or on
signs alone in Gulf War veterans when compared with the
comparison group.
There has been limited study of peripheral neuropathy in
previous Gulf War epidemiological works with which to
compare our results. Cherry et al.6 found that 12.5% of the UK
Gulf War veterans reported neuropathic symptoms compared
with 6.8% of the non-Gulf comparison group. Our association,
also based on symptoms, was not as strong as this. Jamal et al.10
found that both the neurological symptom score and the mean
clinical signs score of 14 veterans with unexplained illnesses
were increased compared with that of 13 civilian controls.
However, they used small numbers of participants, a highly
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Epilepsy
a OR is adjusted for service type, rank, age, education, and marital status.
b ORs are adjusted for service type, rank and age (25 years vs 25 years). CI intervals and P-values for adjusted ORs were obtained using exact methods
816
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
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
n
Mean
(SD)
Adj ratio of meansa
95% CI
119
1.5
(2.6)
1.0
–
Immunizationsb
None
Any
956
1.5
(2.4)
1.1
0.8–1.5
1–4
267
1.1
(1.8)
0.8
0.6–1.1
5–9
564
1.6
(2.4)
1.1
0.8–1.5
10 or more
125
2.2
(3.1)
1.5
1.1–2.3
–
–
–
1.07
1.04–1.10
None
961
1.5
(2.4)
1.0
–
Anyd
151
1.7
(2.7)
1.1
0.8–1.5
None
371
1.2
(1.8)
1.0
–
Any
727
1.8
(2.6)
1.5
1.2–1.8
Dose–responsec
Clustering
1–80 tablets taken
151
1.5
(2.5)
1.4
1.0–1.8
81–180 tablets taken
156
2.1
(3.0)
1.6
1.2–2.1
180 tablets taken
148
2.0
(2.7)
1.6
1.2–2.1
–
–
–
1.18
1.07–1.29
Dose–responsee
Anti-malarialsb
None
283
1.2
(2.2)
1.0
–
Yes
586
1.8
(2.6)
1.3
1.0–1.6
Anti-biological warfare tabletsb
None
540
1.2
(2.1)
1.0
–
80
2.6
(3.4)
1.8
1.3–2.5
No
303
1.0
(1.7)
1.0
–
Yes
1110
1.8
(2.7)
1.8
1.4–2.2
Yes
Solvents
Pesticides
No
1036
1.4
(2.2)
1.0
–
Yes
366
2.5
(3.1)
1.7
1.4–2.0
No
862
1.5
(2.4)
1.0
–
Yes
504
2.0
(2.7)
1.3
1.1–1.5
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,
which makes meaningful interpretation difficult.
Our finding of increased neurological type symptom reporting
by veterans, but no difference between study groups in the
Neuropathy Score, is in general agreement with a recent study of
US veterans;15 which found increased neuropathic symptom
reporting in veterans, but no differences in prevalence of distal
symmetric polyneuropathy between veterans and a non-deployed
comparison group assessed by neurological physical examination
or electrophysiology or by the methods combined. In addition, the
US study reported a relation between the two objective methods
of neurological assessment; veterans who had abnormal
peripheral nerve conduction studies were found to be 3.89 times
more likely to have distal symmetric polyneuropathy found on
neurological physical examination.15 In other studies that used
objective neurological testing, findings have varied. Five
symptomatic veterans had some evidence of mild sensorimotor
deficits in peripheral nerve function on nerve conduction studies,
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Pyridostigmine bromideb
NEUROLOGICAL STATUS OF GULF WAR VETERANS
There are some limitations to our findings for neurological
health outcomes. The neurological type symptom questionnaire
was not a validated questionnaire. It did not include qualifying
questions around the duration of symptoms or differential
causes. Although the neurological type symptom questionnaire
and the definitions have face validity, they have not been
validated in clinical practice. Neurological signs may not always
be present even when symptoms and other features of the
clinical history strongly indicate that a neurological disorder is
present. The process of defining neurological outcomes used in
our study, based on symptoms and signs or signs alone (such as
in the Neuropathy Score), was not intended to be diagnostic.
In our study populations the prevalence of true neurological
disorders is likely to be fairly low and therefore a positive
finding according to our definitions should be interpreted
cautiously, in terms of their ability to predict true neurological
disease. Further evaluation, such as an assessment by a
neurologist or investigations such as electromyography or
magnetic resonance imaging (MRI), would be required to
determine whether the combinations of symptoms and physical
signs are really related to pathology affecting the peripheral or
CNS. Exposure assessment was based on self-report. The use of
preventive health medication and measures may have varied
between individuals, ships, and units depending on their
perceived risk of exposure and self-compliance with
medication. For example, the recommended PB dose of 30 mg
eight-hourly before and for the duration of the period of
exposure, was to be commenced on order of the Commanding
Officer, based on medical advice. DEET-based insect repellent
would probably have been issued to any ADF personnel going
on shore in the Gulf region, but were probably not required or
used at sea. Veterans’ uncertainty in relation to their medical
exposures could have influenced our results. There are several
reasons for this uncertainty, including the time that has elapsed
since the Gulf War and poor record keeping at the time of the
Gulf War. This aspect of exposure assessment highlights the
importance of medical record keeping in the defence forces.
The prevalences of some defined outcomes were small and this
limited the power of the study to detect differences and to
identify associations with Gulf War service. Finally, although we
did not find evidence of differential effects of Gulf War
deployment across subgroups of rank, service, or age, our ability
to detect small differential effects was limited, especially for
subgroups of limited size such as non-Navy service.
Despite a rigorous contact and recruitment strategy, the
comparison group participation rate was lower than that of
the veteran group. Our veteran group participation rate was
relatively high and the comparison group participation rate was
comparable with that of other major postal surveys of
veterans,1,2,4,41 and highlights the difficulties faced by
researchers in contacting and recruiting young, highly mobile,
military and ex-military populations. Our formal evaluation of
possible participation bias suggests that this is unlikely to fully
explain the differences (or lack thereof) that we found between
our study groups. In addition, we adjusted for possible
confounding factors such as age, rank, service type, marital
status, education and smoking, as well as diabetes and excessive
alcohol use that are known to increase the risk of neurological
disease. To minimize any interviewer bias, data were collected
in the same way using the same data collection forms for
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but electromyography was normal.9 In addition, another study
found a small but statistically significant elevated threshold to cold
sensation and differences in two other sensory nerve conduction
tests comparing selected veterans and civilian controls.10 No
objective abnormalities of neuromuscular disease were found in
other studies of veterans with neuropathic11,13 or neuromuscular
symptoms,12,40 although some veterans were found to have
carpal tunnel syndrome,11,13 ulnar neuropathy,11,12 or increased
lactate production during subanaerobic exercise.40 The research
in this field remains inconclusive, and acknowledged
methodological limitations include small sample sizes, use of
highly selected samples or self-referred veterans from registry
populations, lack of comparison groups or comparison with
civilian controls, possible participation bias11,15,26 and concerns
regarding the inclusion criteria used to define cases.17
In our study we used a combination of symptoms and signs in
defining a possible disorder of anterior horn cells such as ALS,
the most common form of MND. Two recently published studies
that used active and passive ascertainment of ALS cases,
confirmed by medical record or telephone or personal interview
or both, found an approximately 2-fold significantly increased
risk of ALS for US veterans overall7 and for US veterans
diagnosed 45 years.8 Haley8 attributes the increased risk of
ALS in younger veterans to an environmental trigger, and
predicts that the peak has not yet been reached. On the basis
of such findings,7 the US Department of Veterans Affairs has
accepted ALS as a Gulf-War-related condition.39 We found no
excess of symptoms and signs suggestive of a disorder of
anterior horn cells to support the US finding, but we had too
few defined cases to draw meaningful conclusions at this stage.
We found no important differences in reported medically
diagnosed neurological conditions in veterans compared with
the comparison group. Our analysis of the likelihood of
diagnosis of self-reported neurological conditions, based on
possible or probable diagnosis, suggests that veterans do not
appear to be over reporting medically diagnosed or treated
neurological conditions that were first diagnosed since the Gulf
War compared with the comparison group. More veterans and
comparison group subjects had symptoms and signs suggestive
of neurological conditions such as anterior horn cell disease or
CNS disorder than reported medically diagnosed or treated
conditions. Therefore, it is possible that subjects in both study
groups may have neurological conditions that have not yet been
diagnosed or come to medical attention.
The reporting of neurological type symptoms, but not the
Neuropathy Score, was associated with increasing numbers of
immunizations received and PB tablets taken, and with taking
anti-biological warfare tablets and using solvents, pesticides,
and insect repellents. The lack of any association between the
Neuropathy Score, defined solely on the basis of neurological
signs, and medical and chemical exposures suggests that other
factors such as information bias, including recall bias, need to be
considered when attempting to explain these associations.
One strength of our study is the use of a military comparison
group to whom the same definitions were applied, as this has
not always occurred in previous studies. In addition, we were
able to look at levels of reported chemical exposures in each
participant’s military career and civilian jobs. These were similar
in both study groups, suggesting that they do not explain the
differences between study groups.
817
818
INTERNATIONAL JOURNAL OF EPIDEMIOLOGY
In conclusion, our study demonstrates increased reporting
of neurological type symptoms by Australian Gulf War veterans, but no evidence for increased neurological effects
based on objective 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 objective physical
signs. There may be several factors contributing to increased
reporting of neurological type symptoms. While this may
indicate mild neurological effects in Gulf War veterans,
information bias including recall bias is also another plausible
explanation. Many of the conclusions of other epidemiological
studies of veterans’ neurological health have been based solely
on self-reported findings. Our study emphasizes the importance
of including objective physical signs in the future assessment of
veterans.
Acknowledgements
The study was funded by the Australian Government—
Department of Veterans’ Affairs. This study was overseen by a
Scientific Advisory Committee and by a veterans’ Consultative
Forum, and we are grateful to members for their contributions
and support. We acknowledge the contribution of Health
Services Australia who conducted the medical assessments. We
are grateful to Dr Wendyl D’Souza, neurologist, for his advice
on, and training of doctors for, the standardized neurological
examination performed in the study. We thank Dr Keith
Horsley, Dr Warren Harrex, Mr Bob Connolly and his contact
and recruitment team at the Department of Veterans’ Affairs,
Canberra. Finally, we thank the Gulf War veterans and
members of the comparison group for the time and effort they
made to participate in the study.
KEY MESSAGES
•
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
with caution.
•
There may be a number of factors, such as information including recall bias, relating to increased neurological type symptom
reporting in veterans.
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