A Pilot Study to Examine Psychological and Neuropsychological Outcomes and a Novel Detoxification Program for Gulf War Illness

ABSTRACT Introduction Exposures to environmental toxins have been associated with severe health problems for approximately one-quarter of the nearly 700,000 U.S. soldiers who served in the Gulf War between the years 1990 and 1991. Gulf War illness still affects about 30% of Gulf War veterans (GWV), causing reduced psychological wellness and neuropsychological function. Method and Materials This pilot study used a randomized wait-list control design to explore the feasibility and efficacy of a novel detoxification method for GWV exposed to toxicants such as pesticides, nerve gases, and pyridostigmine bromide. Our study included 32 GWV (67% male), with a mean age of 51 (range: 43-70, SD = 6.97), who participated in a 4- to 5-week treatment that was hypothesized to reduce the reported psychological and neuropsychological symptoms. Psychological measures used included tests given for the evaluation of neurocognitive function, including motor function for a dominant hand with the grooved pegboard test; verbal and visual immediate and delayed memory with the Wechsler Memory Scale III abbreviated subtests; executive function domains of attention, speed, and mental flexibility with trail making test parts A and B and Stroop color and word test. Psychological status was measured using the nine subscales of the Symptom Checklist-90-Revised. Results Primary outcomes included between-group differences in self-reported psychological measures and a neuropsychological battery at 7-day and 3-month assessments. Baseline comparison revealed improvements in 16 of 19 psychological and neuropsychological measures at 7-day assessment and that 13 remained stable at 3-month assessment. Conclusions We conclude that the detoxification procedure provided improvement in psychological and cognitive function for GWV and that future study is warranted.

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The relationship between Gulf War Illness symptom severity and heart rate variability: A pilot study

Life Sciences ◽

10.1016/j.lfs.2021.119663 ◽

2021 ◽

pp. 119663

Author(s):

Kyle J. Jaquess ◽

Nathaniel Allen ◽

Timothy J. Chun ◽

Lucas Crock ◽

Alexander A. Zajdel ◽

...

Keyword(s):

Heart Rate ◽

Heart Rate Variability ◽

Pilot Study ◽

Symptom Severity ◽

Gulf War ◽

Gulf War Illness ◽

The Relationship

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Gulf War illness: an overview of events, most prevalent health outcomes, exposures, and clues as to pathogenesis

Reviews on Environmental Health ◽

10.1515/reveh-2015-0032 ◽

2015 ◽

Vol 30 (4) ◽

Cited By ~ 21

Author(s):

Kathleen J. Kerr

Keyword(s):

Oxidant Stress ◽

Gastrointestinal Symptoms ◽

Epidemiologic Studies ◽

Gulf War ◽

Institute Of Medicine ◽

Gulf War Illness ◽

Gulf War Syndrome ◽

War Veterans ◽

Gulf War Veterans ◽

The Usa

AbstractIntroduction:During or very soon after the 1990–1991 Persian Gulf War, veterans of the conflict began to report symptoms of illness. Common complaints included combinations of cognitive difficulties, fatigue, myalgia, rashes, dyspnea, insomnia, gastrointestinal symptoms and sensitivity to odors. Gradually in the USA, and later in the UK, France, Canada, Denmark and Australia, governments implemented medical assessment programs and epidemiologic studies to determine the scope of what was popularly referred to as “the Gulf War syndrome”. Attention was drawn to numerous potentially toxic deployment-related exposures that appeared to vary by country of deployment, by location within the theater, by unit, and by personal job types. Identifying a single toxicant cause was considered unlikely and it was recognized that outcomes were influenced by genetic variability in xenobiotic metabolism.Methods:Derived from primary papers and key reports by the Research Advisory Committee on Gulf War Veterans’ Illnesses and the Institute of Medicine, a brief overview is presented of war related events, symptoms and diagnostic criteria for Gulf War illness (GWV), some international differences, the various war-related exposures and key epidemiologic studies. Possible exposure interactions and pathophysiologic mechanisms are discussed.Results:Exposures to pyridostigmine bromide, pesticides, sarin and mustard gas or combinations thereof were most associated with GWI, especially in some genotype subgroups. The resultant oxidant stress and background exposome must be assumed to have played a role.Conclusion:Gulf War (GW) exposures and their potential toxic effects should be considered in the context of the human genome, the human exposome and resultant oxidant stress to better characterize this unique environmentally-linked illness and, ultimately, provide a rationale for more effective interventions and future prevention efforts.

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Lack of serological evidence for Mycoplasma fermentans infection in army Gulf War veterans: a large scale case-control study

Epidemiology and Infection ◽

10.1017/s0950268800004891 ◽

2000 ◽

Vol 125 (3) ◽

pp. 609-616 ◽

Cited By ~ 10

Author(s):

S.-C. LO ◽

L. LEVIN ◽

J. RIBAS ◽

R. CHUNG ◽

R. Y.-H. WANG ◽

...

Keyword(s):

Case Control Study ◽

Gulf War ◽

Serological Evidence ◽

Gulf War Illness ◽

War Veterans ◽

Mycoplasma Fermentans ◽

Desert Storm ◽

Gulf War Veterans ◽

Operation Desert Storm ◽

Control Study

Mycoplasma fermentans is suspected in the development of ‘Gulf War illness’ in veterans of Operation Desert Storm. We conducted a matched case-control study for the prevalence of M. fermentans-specific antibodies before and after the operation, as well as seroconversion rates in veterans with and without complaints of ‘Gulf War illness’. Cases consisted of Gulf War veterans, who complained of various illnesses and were enrolled in the second phase of the health evaluation by the Army Comprehensive Clinical Examination Program (CCEP). Controls were selected from Gulf War veterans who did not participate in the registry and did not request a health evaluation by the CCEP. Before operation deployment, 34 out of 718 of the cases (4·8%) and 116 out of 2233 of the controls (5·2%) tested positive for M. fermentans-specific antibodies. There was no difference in rates of seroconversion between cases and controls (1·1 vs. 1·2%) to M. fermentans during Operation Desert Storm. Thus, there is no serological evidence that suggests infection by M. fermentans is associated with development of ‘Gulf War illness’.

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Human Leukocyte Antigen (HLA) and Gulf War Illness (GWI): HLA-DRB1*13:02 Spares Subcortical Atrophy in Gulf War Veterans

EBioMedicine ◽

10.1016/j.ebiom.2017.11.005 ◽

2017 ◽

Vol 26 ◽

pp. 126-131 ◽

Cited By ~ 8

Author(s):

Lisa M. James ◽

Peka Christova ◽

Brian E. Engdahl ◽

Scott M. Lewis ◽

Adam F. Carpenter ◽

...

Keyword(s):

Human Leukocyte Antigen ◽

Human Leukocyte ◽

Gulf War ◽

Gulf War Illness ◽

War Veterans ◽

Leukocyte Antigen ◽

Gulf War Veterans

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Reprogramming cells from Gulf War veterans into neurons to study Gulf War illness

Neurology ◽

10.1212/wnl.0000000000003938 ◽

2017 ◽

Vol 88 (20) ◽

pp. 1968-1975 ◽

Cited By ~ 4

Author(s):

Liang Qiang ◽

Anand N. Rao ◽

Gustavo Mostoslavsky ◽

Marianne F. James ◽

Nicole Comfort ◽

...

Keyword(s):

Cell Lines ◽

Cell Types ◽

Experimental Models ◽

Gulf War ◽

Gulf War Illness ◽

War Veterans ◽

Gulf War Veterans ◽

Chronic Headaches ◽

The Persian Gulf ◽

Impaired Sleep

Gulf War illness (GWI), which afflicts at least 25% of veterans who served in the 1990–1991 war in the Persian Gulf, is thought to be caused by deployment exposures to various neurotoxicants, including pesticides, anti–nerve gas pills, and low-level nerve agents including sarin/cyclosarin. GWI is a multisymptom disorder characterized by fatigue, joint pain, cognitive problems, and gastrointestinal complaints. The most prominent symptoms of GWI (memory problems, poor attention/concentration, chronic headaches, mood alterations, and impaired sleep) suggest that the disease primarily affects the CNS. Development of urgently needed treatments depends on experimental models appropriate for testing mechanistic hypotheses and for screening therapeutic compounds. Rodent models have been useful thus far, but are limited by their inability to assess the contribution of genetic or epigenetic background to the disease, and because disease-vulnerable proteins and pathways may be different in humans relative to rodents. As of yet, no postmortem tissue from the veterans has become available for research. We are moving forward with a paradigm shift in the study of GWI, which utilizes contemporary stem cell technology to convert somatic cells from Gulf War veterans into pluripotent cell lines that can be differentiated into various cell types, including neurons, glia, muscle, or other relevant cell types. Such cell lines are immortal and will be a resource for GWI researchers to pursue mechanistic hypotheses and therapeutics.

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White matter abnormalities in Gulf War veterans with posttraumatic stress disorder: A pilot study

Psychoneuroendocrinology ◽

10.1016/j.psyneuen.2014.11.007 ◽

2015 ◽

Vol 51 ◽

pp. 567-576 ◽

Cited By ~ 20

Author(s):

Linda M. Bierer ◽

Iliyan Ivanov ◽

David M. Carpenter ◽

Edmund W. Wong ◽

Julia A. Golier ◽

...

Keyword(s):

Posttraumatic Stress Disorder ◽

White Matter ◽

Pilot Study ◽

Posttraumatic Stress ◽

Stress Disorder ◽

Gulf War ◽

War Veterans ◽

White Matter Abnormalities ◽

Gulf War Veterans

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Effect of the low glutamate diet on inflammatory cytokines in veterans with Gulf War Illness (GWI): A pilot study

Life Sciences ◽

10.1016/j.lfs.2021.119637 ◽

2021 ◽

pp. 119637

Author(s):

Kathleen F. Holton ◽

Shalini S. Ramachandra ◽

Sidney L. Murray ◽

Michael Baron ◽

James N. Baraniuk

Keyword(s):

Pilot Study ◽

Inflammatory Cytokines ◽

Gulf War ◽

Gulf War Illness

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Coenzyme Q10 Benefits Symptoms in Gulf War Veterans: Results of a Randomized Double-Blind Study

Neural Computation ◽

10.1162/neco_a_00659 ◽

2014 ◽

Vol 26 (11) ◽

pp. 2594-2651 ◽

Cited By ~ 28

Author(s):

Beatrice A. Golomb ◽

Matthew Allison ◽

Sabrina Koperski ◽

Hayley J. Koslik ◽

Sridevi Devaraj ◽

...

Keyword(s):

Physical Function ◽

Coenzyme Q10 ◽

Gulf War ◽

Small Sample ◽

Controlled Study ◽

Double Blind Study ◽

Gulf War Illness ◽

War Veterans ◽

Double Blind ◽

Gulf War Veterans

We sought to assess whether coenzyme Q10 (CoQ10) benefits the chronic multisymptom problems that affect one-quarter to one-third of 1990–1 Gulf War veterans, using a randomized, double-blind, placebo-controlled study. Participants were 46 veterans meeting Kansas and Centers for Disease Control criteria for Gulf War illness. Intervention was PharmaNord (Denmark) CoQ10 100 mg per day (Q100), 300 mg per day (Q300), or an identical-appearing placebo for 3.5 [Formula: see text] 0.5 months. General self-rated health (GSRH), the primary outcome, differed across randomization arms at baseline, and sex significantly predicted GSRH change, compelling adjustment for baseline GSRH and prompting sex-stratified analysis. GSRH showed no significant benefit in the combined-sex sample. Among males (85% of participants), Q100 significantly benefited GSRH versus placebo and versus Q300, providing emphasis on Q100. Physical function (summary performance score, SPS) improved on Q100 versus placebo. A rise in CoQ10 approached significance as a predictor of improvement in GSRH and significantly predicted SPS improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on Q100 versus placebo was favorable for all except sleep problems; sign test 19:1, [Formula: see text]) with several symptoms individually significant. Significance for these symptoms despite the small sample underscores large effect sizes, and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. In conclusion, Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness. Examination in a larger sample is warranted, and findings from this study can inform the conduct of a larger trial.

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Characterising the gut microbiome in veterans with Gulf War Illness: a protocol for a longitudinal, prospective cohort study

BMJ Open ◽

10.1136/bmjopen-2019-031114 ◽

2019 ◽

Vol 9 (8) ◽

pp. e031114 ◽

Cited By ~ 1

Author(s):

Julie A Keating ◽

Catherine Shaughnessy ◽

Kelsey Baubie ◽

Ashley E Kates ◽

Nathan Putman-Buehler ◽

...

Keyword(s):

Cohort Study ◽

Gut Microbiome ◽

Chronic Fatigue ◽

Gulf War ◽

Case Definition ◽

Gulf War Illness ◽

War Veterans ◽

Gulf War Veterans ◽

Fatigue Syndrome ◽

Institutional Review

IntroductionApproximately 25%–35% of the 1991 Gulf War Veteran population report symptoms consistent with Gulf War Illness (GWI), a chronic, multi-symptom illness characterised by fatigue, pain, irritable bowel syndrome and problems with cognitive function. GWI is a disabling problem for Gulf War Veterans, and there remains a critical need to identify innovative, novel therapies.Gut microbiota perturbation plays a key role in the symptomatology of other chronic multi-symptom illnesses, including myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Given similarities between ME/CFS and GWI and the presence of gastrointestinal disorders in GWI patients, Veterans with GWI may also have gut abnormalities like those seen with ME/CFS. In this longitudinal cohort study, we are comparing the diversity (structure) and the metagenomes (function) of the gut microbiome between Gulf War Veterans with and without GWI. If we find differences in Veterans with GWI, the microbiome could be a target for therapeutic intervention to alleviate GWI symptoms.Methods and analysisParticipants answer questions about diet, exercise and lifestyle factors. Participants also complete a questionnaire (based on the Kansas case definition of GWI) regarding their medical history and symptoms; we use this questionnaire to group participants into GWI versus healthy control cohorts. We plan to enrol 52 deployed Gulf War Veterans: 26 with GWI and 26 healthy controls. Participants provide stool and saliva samples weekly for an 8-week period for microbiome analyses. Participants also provide blood samples at the beginning and end of this period, which we will use to compare measures of inflammation markers between the groups.Ethics and disseminationThe protocol was approved by the University of Wisconsin-Madison Health Sciences Institutional Review Board and the William S. Middleton Memorial Veterans Hospital Research and Development Committee. Results of this study will be submitted for publication in a peer-reviewed journal.

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Gulf War Veterans with Psychiatric Symptoms (Anxiety, Depression, and PTSD) Significantly Improve on a Low Glutamate Diet

Current Developments in Nutrition ◽

10.1093/cdn/nzaa057_008 ◽

2020 ◽

Vol 4 (Supplement_2) ◽

pp. 1192-1192

Author(s):

Elizabeth Brandley ◽

Anna Kirkland ◽

Kathleen Holton

Keyword(s):

Dietary Intervention ◽

Psychiatric Symptoms ◽

Gulf War ◽

Control Group ◽

Gulf War Illness ◽

War Veterans ◽

Double Blind ◽

Double Blind Placebo ◽

Gulf War Veterans ◽

Anxiety Depression

Abstract Objectives The objective of this study was to assess the effects of a low glutamate dietary intervention on measures of anxiety, depression, and PTSD in veterans with Gulf War Illness (GWI). Methods Forty Gulf War veterans were recruited from across the U.S. for a clinical trial examining the effects of a low glutamate diet on symptoms of GWI. During baseline testing, subjects completed the GAD-7 anxiety measure, the PCL-C PTSD scale, and the Center for Epidemiologic Studies Depression Scale (CES-D), and then were randomized to immediate dietary intervention or a wait-listed control group. All participants received intensive dietary training before starting the diet. After one month on the diet, post-diet testing was completed, then subjects were randomized into a double-blind, placebo-controlled crossover challenge with MSG/placebo to test for a return of symptoms. The challenge data has not yet been un-blinded; therefore, it will not be discussed in this abstract. Pre-post diet change scores were analyzed using the Wilcoxon Signed Rank tests via SPSS®v26. Results Results demonstrate highly significant improvements in psychiatric symptoms associated with GWI after one-month on a low glutamate diet. Scores were reduced from a median (IQ range) of 9(13) to 4(8), P = 0.001 for anxiety; from 27(15) to 19(10), P < 0.001 for depression; and from 57(32) to 39(32), P < 0.001 for PTSD. Conclusions These results suggest that a low glutamate diet may improve depression, anxiety, and PTSD in veterans with GWI. Future analysis of the double-blind, placebo-controlled crossover challenge data will provide a better understanding of whether challenge with glutamate can significantly increase anxiety, depression and PTSD relative to placebo. Funding Sources The US Army Medical Research Acquisition Activity, 820 Chandler St, Fort Detrick MD 21,702–5014 is the awarding and administering acquisition office. This work is supported by the Office of the Assistant Secretary of Defense for Health Affairs through the Gulf War Illness Research Program. Opinions, interpretations, conclusions and recommendations are those of the author and are not necessarily endorsed by the Department of Defense.

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