Research Advisory Committee on Gulf War Veterans Illnesses
pgw...@cox.net
Interim Report
June 1, 2002
A. Conclusions
1. Gulf War veterans are ill. (See Appendix A.)
-- They suffer from a pattern of health problems that significantly
exceeds those seen in comparable populations, beyond that which is
explained by stress or psychiatric diagnoses.
-- Different epidemiological studies consistently show 25-30% of the
veterans who served in the Gulf are ill, over and above the control
population chosen for the study.
2. It is increasingly evident that at least one important
category of illness in Gulf War veterans is neurological in character,
according to recent scientific studies. (See Appendix B) While these
studies are not conclusive, there is enough evidence at present to
conclude that this line of inquiry represents a potential breakthrough
which should be aggressively pursued.
-- Magnetic resonance spectroscopy suggests a loss of neurons in
selected brain areas in ill veterans, particularly in the basal
ganglia and brainstem. The areas of neuronal deficiency relate to
veterans’ symptoms. Veterans with cognitive problems show neuronal
loss in the basal ganglia; those with muscle and joint problems show
loss in the brainstem.
-- Heart rate measurements show dysregulation of the autonomic nervous
system in ill veterans
-- Gulf War veterans are suffering from ALS at twice the expected
rate.
-- A substantial increase in the cold sensory threshold has been
measured in ill Gulf War veterans.
-- Audio vestibular tests show abnormalities of central vestibular
function.
-- Ill veterans show elevated brain dopamine production.
-- Ill veterans have low levels of an enzyme, paraoxonase, that is
involved in breaking down organophosphates, and are more likely to
have genotypes poor at metabolizing certain organophosphates,
suggesting biochemical and genetic explanations for why some veterans
became ill and others in the same location did not.
3. Most risk factors associated with Gulf War Illnesses are
present today in Southwest Asia.
-- Risk factors include exposures to environmental toxins, low-level
nerve agents, stress, medical countermeasures to biowarfare and nerve
agents, infectious diseases, and combinations of these factors.
-- Several exposures, that are of concern for their possible
relationship to illness, are also germane to domestic terrorism
preparedness. Nerve agent exposure is a terrorist concern; and medical
countermeasures for chem-bio warfare are relevant to homeland as well
as military defense.
-- Research on Gulf War Illnesses has broad implications to the war on
terrorism.
B. Recommendations
1. Enlist the expertise of specialists in neurobiology and
neurological illness in the national research effort on Gulf War
Illnesses.
-- This effort should include both individual experts from academia
and the private sector as well as government agencies with relevant
expertise like the National Institute of Neurological Diseases and
Stroke and the Environmental Protection Agency.
-- In addition to seeking advice, the research effort should seek the
participation of these individuals and agencies in promoting and
funding high quality Gulf War Illnesses research.
2. Designate as a research priority the investigation of
neurological mechanisms, including acetylcholine dysregulation and
other acetylcholinesterase inhibitor-induced pathology, that
potentially explain the disease process (in an important subset of ill
veterans) and may lead to the development of treatments. (See
Appendix C.)
-- Immediately solicit and fund research proposals on this priority
topic.
3. Conduct a study linking objective markers with exposures and
health symptoms in Gulf War veterans and controls (See Appendix D).
This approach has potential to unveil distinct patterns of illness,
with distinct causes and differential response to treatments. Future
trials of treatments may depend on results of such a study.
4. Make full use of existing data on veterans’ health and
treatments.
-- Determining whether veterans find treatments to
work or not work would be a service to veterans and their doctors and
would develop the best treatment candidates for clinical trials.
-- Screen veterans’ health records for drugs
prescribed for the treatment of symptoms. Conduct follow-up study of
individual veterans to determine effectiveness of treatments.
-- Include, in future studies and surveys of veterans,
questions on treatments tried, including both conventional and
alternative treatments, and perceived impact.
-- Merge Department of Defense databases on veterans’
locations and exposures into the Veterans Benefits Administration data
base on veterans’ health claims and diagnoses.
5. Manage for results.
-- Solving a complex medical research problem requires sound
scientific management of the overall program as much as well-executed
individual studies. It is not surprising that the existing management
structure has not produced the desired results.
-- Create a single business plan to drive the research program,
identifying objectives and milestones, revised at least annually, and
approved by the Secretary of Veterans Affairs and the Secretary of
Defense.
-- Open all research solicitations to open competition, allowing
external as well as internal researchers to participate, as is
presently done at the Department of Defense but not the Department of
Veterans Affairs.
-- Make peer review practices more open. To ensure customer
orientation, place veterans on peer review panels after receiving peer
review training,
-- Place responsibility for the national research program in a central
organization with the scientific expertise to manage it, and with no
institutional conflicts of interest Candidate organizations include 1)
the National Institute of Neurological Diseases and Stroke, or another
structure within the NIH, 2) a National Center for Military Deployment
Health Research as proposed by the Institute of Medicine in 1999 (see
Appendix E); or 3) an outside private contractor with a results
orientation.
6. Increase Funding.
-- The opportunity to achieve a potential breakthrough in defeating
Gulf War Illnesses through neuroscience research, the potential
contribution to defeating other neurological diseases like ALS, and
the need to protect current American forces and civilians as well as
treat veterans, merit an increase in funding from current levels.
-- An adequate funding commitment is important to attract the best
minds to the problem.
-- Provided management reforms are made to ensure funds are
effectively spent, commit $150 million in federal funding for each of
the next three years (compared to $350 million spent to date,
according to the Department of Defense). Consider increasing this
amount if initial results warrant.
APPENDIX A: SUMMARY OF EPIDEMIOLOGICAL EVIDENCE
Summary to follow
APPENDIX B: SUMMARY OF NEUROLOGICAL FINDINGS
Summary of the Evidence on the Physiologic Basis for Gulf War Syndrome
I. Early Findings Suggesting a Possible Neurologic Syndrome
Evidence of a Gulf War Syndrome
In 1997 Haley, Kurt and Hom reported three primary
syndrome-like symptom complexes identified by exploratory factor
analysis of typical symptoms of Gulf War syndrome in a battalion of
U.S. Naval Reserve construction troops.1 Haley syndrome 1 comprised
distractibility, forgetfulness, depression, and daytime somnolence,
etc. (“impaired cognition”); syndrome 2, more profound reduced
intellectual processing, confusion, frequent disorientation and
episodes of vertigo (“confusion-ataxia”); and syndrome 3, chronic
somatic pain and paresthesias of the extremities (“central pain”).
These syndromic constructs were replicated by confirmatory factor
analysis in which a model of simultaneous structural equations from
the first study was demonstrated to fit well the symptom data of an
independent sample of 335 regular U.S. Army veterans of the Gulf War.2
In a survey of over 20,000 from random samples of the
deployed and nondeployed Gulf War-era veteran populations, Kang et al.
of the VA Central Office performed an exploratory factor analysis and
identified three syndrome factors closely resembling the three Haley
syndrome factors and concluded that syndrome factor 2, found only in
the deployed population, represented a “unique Gulf War syndrome.”
This study was presented as a poster and published as an abstract at
the 1999 Conference on Federally Sponsored Research on Gulf War
Illness3 but has not been published in a peer-reviewed journal.
Recently, Cherry et al. reported the results of a survey in a random
sample of deployed and nondeployed British Gulf War-era veterans in
which exploratory factor analysis obtained syndrome factors named
“psychological,” “neurological” and “peripheral,” among others, which
appeared similar to the three Haley syndromes.4
Other research groups attempted to apply exploratory factor analysis
to previously collected survey data with mixed results. Fukuda et al.
of CDC identified two factors resembling Haley factors 1 and 3 but had
not measured the symptoms to identify factor 2.5,6 The surveys of
Knoke et al.7,8 and Doebbeling et al.9,10 measured symptoms of common
psychiatric diseases rather than those of Gulf War syndrome and
consequently derived factors reflecting these extraneous conditions.
Ismail et al., studying British Gulf War veterans, measured symptom
sets too different to evaluate the Haley syndrome factors.11,12 The
conflicting findings from the studies that measured mostly common
psychiatric and atypical symptoms have prevented a consensus on
whether a neurologically based syndrome exists.
Studies of functional status and neuropsychological measures have also
suggested neurologic involvement but have not been compelling.
Functional Status Measures
In their 1997 report Haley, Kurt and Hom reported that
Gulf War veterans meeting their case definition of syndrome 2
(“confusion-ataxia”), but not those with the other two syndromes, were
far more likely to be unemployed than the well veterans in the
battalion.1
In a large random sample survey of Gulf War veterans from Iowa, the
Gulf War veteran population as a whole scored 3-7 points lower (on a
100-point scale) on all measures of the MOS SF-36 test of functional
status than the non-deployed veteran population.13 Although these
differences were statistically significant, they greatly
underestimated the extent of impairment by combining the relatively
small percentage of deployed veterans who are ill with the much larger
number of deployed veterans who remained well.10
Recently, Haley, Maddrey and Gershenfeld addressed this problem by
administering the MOS SF-36 to groups of ill Gulf War veterans fitting
the Haley syndromes versus controls and found substantial functional
impairment (40-60 points lower than well veterans) comparable to
common disabling diseases including congestive heart failure, recent
myocardial infarction, diabetes, and emphysema.14
Neuropsychological Tests
A large body of studies in the Gulf War illness literature
have involved psychological and neuropsychological tests.for
example,15-19,19,20 The preponderance of findings indicate subtle
deficits on a variety of measures in ill veterans compared with either
deployed or nondeployed controls. Subtle neurocognitive deficits tend
to be correlated with psychological measures of depression and somatic
complaints, a pattern found commonly in both major depressive
disorders and in neurologic disorders, and the various research groups
disagree on the implications of this broad array of subtle
abnormalities. Consequently, the contribution of neuropsychological
testing to understanding the problem has been limited.
II. Objective Markers of Neurological Disease
Neurophysiologic Tests
Cold Sensory Threshold. As early as 1996 Jamal et al.
reported the results of neurophysiologic tests, including quantitative
sensory tests, sensory and motor nerve conduction studies, visual,
somatosensory and brainstem auditory evoked potentials, and
electromyography in a pilot study including 14 Gulf War veterans with
fatigue, weakness, paresthesias, numbness, temperature disturbances,
and somatic pain, and 13 well civilian controls.21 They found a
substantial increase in the cold sensory threshold (cases 0.55 C°,
controls 0.25 C°, p < 0.0002) but no difference in warm or vibratory
thresholds and only marginally significant differences on 2 of 12
nerve conduction parameters.
Haley et al. recently replicated Jamal’s finding of an increased cold
threshold and the absence of abnormalities on the other neuromuscular
tests in their series of cases and controls (unpublished data).
Audiovestibular Tests. In their 1997 report Haley et al.
presented the results of audiovestibular tests that would be sensitive
to subtle damage to brainstem reflex pathways.22,23 Compared with the
23 age-sex-education-matched controls, the veterans with Haley
syndromes 2 were significantly more likely to have pathologic
nystagmus and abnormal ocular motility, and increased interocular
asymmetry of saccadic velocity (eye reflexes), and to have
significantly reduced saccadic velocity after caloric vestibular
stimulation, increased intraocular asymmetry of gain on sinusoidal
harmonic acceleration, and interside asymmetry of wave I-III latency
on auditory brainstem evoked response. Syndromes 1 and 3 generally
scored between the more nearly abnormal syndrome 2 patients and the
controls. The investigators concluded that the findings were most
compatible with a subtle abnormality of central vestibular function
involving the vestibulo-ocular reflex mediated by neural pathways in
the brainstem or basal ganglia.23
Autonomic Nervous System Function. Haley et al. recently
completed a thorough evaluation of autonomic nervous system function,
including 24-hour measurements of heart rate variability, blood
pressure and body temperature, direct recording of sympathetic nerve
activity in a peripheral nerve at rest and under orthostatic stress,
tests of sudomotor function, sleep studies, etc., in 22 ill Gulf War
veterans and 18 age-sex-education-matched control veterans from the
same battalion. The report, presented at the 2000 Conference on
Federally Sponsored Research on Gulf War Illness24 and presently
undergoing journal peer review, documents substantial blunting of the
normal increase in high frequency heart rate variability during sleep,
the most sensitive sign of early autonomic nervous system dysfunction.
If accepted by journal peer review and more widely verified, this
finding could explain common Gulf War symptoms such as the perception
of poor sleep, morning fatigue, chronic pathogen-free diarrhea and the
reported increase in cholecystitis and cholecystectomies in young male
Gulf War veterans compared with other veterans.25
Neuroimaging Studies
Initial MR Spectroscopy Studies. In their initial 1997
nested case-control study, Haley et al. performed standard brain
magnetic resonance imaging (MRI) and found no structural
differences.22 Noting the similarity of the symptoms of GW syndrome
and the early presenting symptoms of primary diseases of basal
ganglia, Huntington’s, Wilson’s and Fahr’s diseases,26 in a subsequent
study they performed long echo time (TE=272) proton (1H) magnetic
resonance spectroscopy
(MRS) of 4x2x2-cm single voxels in right and left basal ganglia (deep
brain structures) and a 2x2x2-cm single voxel in the pons
(brainstem).27 The ratio of N-acetyl-aspartate to creatine (NAA/Cr), a
non-specific measure of functional neuronal mass (brain cell health),
was significantly lower in all three brain regions in the 22 ill Gulf
War veterans than in the 18 age-sex-education-matched control veterans
(p = 0.007). The NAA/Cr ratio was reduced in all three brain regions
in the veterans with Haley syndrome 2 (for example, in the right basal
ganglia, cases 3.60±0.11, controls 4.08 ± 0.13, a 12% difference, p =
0.003). The NAA/Cr ratio was marginally reduced only in both basal
ganglia but not in the pons in syndrome 1, and only in the pons but
not in the basal ganglia in syndrome 3. The NAA/Cr ratio was also
lower in all three brain regions of 6 additional ill veterans with
Haley syndrome 2, recruited from a new survey U.S. Army veterans in
North Texas as a replication sample. The investigators concluded that
Gulf War veterans with different clinical syndromes have biochemical
evidence of neuronal damage in different distributions in the basal
ganglia and brainstem
Independent Replication. Following the initial report of
the Haley et al. MRS finding at the 1999 Radiological Society of North
America, Weiner and colleagues at the San Francisco VA Medical Center
and UCSF Medical School undertook a study to test the finding in an
independent group of veterans. In 11 ill Gulf War veterans fitting
the definition of Haley syndrome 2 and 11 non-veteran controls, all
without history of alcohol abuse, major depression or PTSD, the
investigators performed a similar protocol of long echo time, proton
MRS on the right basal ganglia, with additional methodologic
refinements (e.g., MRI segmentation). The results showed a similar
reduction in the NAA/Cr ratio (cases 3.62 ± 0.41, controls 4.06 ±
0.72, p = 0.05), not confounded by partial-volume effects.28
Neurohormonal Studies
Simultaneous with the neuroimaging study, the Haley group
hospitalized the 23 ill Gulf War veterans and 20 controls in the
General Clinical Research Center (GCRC) of UT Southwestern Medical
Center for 6 days in a low-stress environment with a standardized
high-salt, low tyrosine diet. At the end of the period, a venous
blood sample was drawn at exactly 7:30 AM after a 14-hour overnight
fast, and assays were run for homovanillic acid (HVA) and 3-methoxy-4-
hydroxyphenlyglycol (MHPG). In the syndrome 2 veterans versus the
controls the HVA/MHPG ratio, an index of central nervous system
dopamine production rate, was found to have a strong inverse
association with the NAA/Cr ratio of the left basal ganglia (R2 =
0.56, p < 0.0001) but not with that of the right basal ganglia or the
pons, following the laterality of dopamine effects in striatal
ablation studies in rodents.29 Specifically, veterans with more brain
cell damage in the left basal ganglia (lower NAA/Cr ratio) had higher
brain dopamine production, a finding compatible with upregulation of
dopamine receptors after damage to dopaminergic pathways in the basal
ganglia. The investigators concluded that the finding supports the
theory that Gulf War syndrome is a neurologic illness, in part related
to injury to dopaminergic neurons in the basal ganglia.
Genetic Predisposition
Initial Genetic Studies. In their initial 1997
epidemiologic report, Haley and Kurt reported that all three Haley
syndromes were strongly associated with risk factors for exposure to
cholinesterase-inhibiting organophosphate or carbamate chemicals:
namely, syndrome 1 was associated with organophosphate pesticides in
flea collars (relative risk, RR, 8.2, p = 0.001.) ; syndrome 2, with
apparent low-level nerve agent exposure (RR 7.8, p < 0.0001) and with
advanced side effects of pyridostigmine bromide anti-nerve agent
prophylactic medication (RR 32, p < 0.0001); and syndrome 3, with
high-concentration DEET insect repellant, p < 0.0001) and with
advanced side effects of pyridostigmine (RR 3.9, p < 0.0001).30 The
unpublished survey by Kang et al. found virtually the same association
of syndrome 2 with low-level nerve agent exposure (RR 6.9, p <
0.0001).3 Cherry et al. found days handling pesticides to be strongly
associated with their “neurological” factor and with symptoms
consistent with toxic neuropathy.31
From these epidemiologic findings, Haley, Billecke and La
Du reasoned that, if Gulf War syndromes had been caused by exposure to
cholinesterase-inhibiting organophosphate and carbamate chemicals
(e.g., chemical nerve agent, pesticides, and pyridostigmine),
individuals born with lower blood levels of enzymes that inactivate
these chemicals would have been more susceptible and thus would have
been more likely to be injured by their exposures.32 As part of the
nested case-control study in the UT Southwestern GCRC, they obtained a
venous blood sample for assay of plasma activity of
butyrylcholinesterase (BChE) and the allozymes of
paraoxonase/arylesterase, the two enzymes that inactivate
organophosphates, and for genotypic determination for BChE variants
and polymorphisms of the PON1 gene for paraoxonase/arylesterase (type
Q vs type R). Compared with the 20 age-sex-education-matched control
veterans, the 26 Gulf War veterans with Haley syndromes had much lower
plasma levels of the type Q paraoxonase/arylesterase enzyme. The
difference was greatest for Haley syndrome 2 and intermediate for
syndromes 1 and 3, again reflecting the relative degrees of severity
of the three syndromes. The cases and controls did not differ on the
type R paraoxonase/arylesterase allozyme, total paraoxonase or BChE
levels. Veterans in the lowest quartile of type Q activity were 9
times more likely to have syndrome 2 than those with higher levels (p
= 0.009). Genotype (having the R allele) was also predictive (odds
ratio 3.3, p = 0.05). The allozyme-specificity of the finding was
important because the type Q allozyme has high hydrolytic activity
against the organophosphate nerve agents sarin and soman but low
activity against common pesticides such as parathion and malathion;
whereas, the type R allozyme has the converse. Blood levels of
paraoxonase/arylesterase allozymes remain unchanged throughout life;
whereas, BChE levels may be reduced by organophosphate or carbamate
chemical exposures. The investigators concluded that the findings
further support the proposal that neurologic symptoms in some Gulf War
veterans were caused by environmental chemical exposures.
Replication Studies. The plasma samples from the Haley,
Billecke, La Du study were transferred to the laboratory of C. A.
Broomfield in the Biochemical Pharmacology Branch, U.S. Army Medical
Research Institute of Chemical Defense, Aberdeen Proving Ground,
Maryland, where they were tested for enzymatic activity against sarin
and soman chemical nerve agents. The purposes of the experiment were
to determine if the type Q paraoxonase/arylesterase activity measured
in the prior study actually reflected hydrolytic activity against the
presumed cause of the Haley syndromes and to attempt to replicate the
test results in an independent laboratory. The results demonstrated
that the hydrolytic activity against sarin and soman was significantly
lower in the Haley syndrome patients than in the controls just as in
the prior study.32
Mackness et al. recently published a report from a privately funded
study demonstrating that the total paraoxonase blood level of 152 ill
Gulf War veterans was less than 50% that of 152 civilian controls
(100.3 vs 215, p < 0.0001) but that the genotype did not differ
significantly between the groups.33
Related Studies. Cherry, Mackness et al. recently reported reduced
paraoxonase and R allele predominance in British sheep dippers with
fatigue-cognitive-pain syndromes similar to Gulf War syndrome and
chronic fatigue syndrome.34 Japanese researchers have cited the
racial predominance of the PON R allele and low type Q allozyme levels
in Asians as a possible explanation for the high attack rate of the
low level sarin exposures in the 1995 Aum Shinrichyo terrorist attacks
in the Tokyo and Matsumoto subways.35 The R allele predominance in
the PON1 genotype has also been found to be associated (odds ratio,
1.6) with the development of Parkinson’s disease.36
III. Relationship Between Gulf War Syndrome and Neurodegenerative
Diseases
The studies described above have raised questions of
whether Gulf War veterans may be at higher risk of prematurely
developing neurodegenerative diseases as a result of environmental
exposures in the Gulf War.
Amyotrophic Lateral Sclerosis
VA researchers have completed an epidemiologic study of
ALS demonstrating that those Gulf War veterans who served in the Air
Force were 2.7 times more likely to contract ALS, and those in the
Army were twice as likely, than Gulf War-era veterans who did not
serve in the Gulf War. Although the report of these findings remains
in journal peer review at present, the epidemiologic connection
appears likely, and the Secretary of Veterans Affairs has approved
service-connected benefits for Gulf War veterans with ALS. Exposure
to organophosphates, a class of chemicals including pesticides and
nerve gas to which soldiers were exposed in the Gulf War, is one of
the risk factors for ALS that has been identified in previous
epidemiologic studies.37,38
Parkinson’s Disease
At present there is no definite evidence that Parkinson’s
disease is occurring at increased rates or at unusually early ages in
Gulf War veterans; however, emerging threads of evidence suggest that
such could occur. Several researchers have observed anecdotal cases
of tremors or movement impairment, usually in the hands, in atypically
young Gulf War veterans, who say that the problems began during or
just after the war (unpublished data). As noted above, symptoms of
Gulf War syndrome resemble those of the early presenting symptoms of
primary degenerative diseases of basal ganglia, a brain region that is
also affected in Parkinson’s disease.26,27 The genetic profile (low
blood PON1 paraoxonase enzyme concentration and R allele predominance)
found to be a risk factor for Gulf War syndrome32 has also been found
to predispose to Parkinson’s disease.36 Brain dopamine production,
which is an important abnormality leading to Parkinson’s disease, has
also been found to be abnormal in Gulf War syndrome.29
Implications for Preventing Neurodegenerative Diseases
The possibility of links between Gulf War syndrome and the
later development of neurodegerative diseases like ALS and Parkinson’s
disease increases the urgency of research to clarify these issues.
Confirmation of such links would suggest a need to develop ways of
screening veterans for susceptibility or early signs so that
preventive strategies could be tried. Possible preventive strategies
might include avoidance of further organophosphate exposures and
administration of neuroprotective medications.
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Kansas veterans
helping
Kansas veterans
http://www.kansasvets.org
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