Post-combat syndromes from the Boer war to the Gulf war: a cluster analysis of their nature and attribution

BMJ 2002; 324 doi: http://dx.doi.org/10.1136/bmj.324.7333.321 (Published 9 February 2002)
Cite this as: BMJ 2002;324:321

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4 April 2007

Gulf War veterans who developed GWS have a genetic defect that led to a deficiency of the enzyme Paraoxonase 1 (PON1), which was NOT seen in the controls [1]. PON1 metabolizes toxins and the pyridostigmine (antidote for sarin exposure) that was administered to the veterans, which means that the pyridostigmine did NOT get metabolized in the solders who later developed GWS. This will lead to nitric oxide poisoning via stimulation of muscarinic receptors [2, 3]. And since sarin also stimulates muscarinic receptors, and since the only source of protection against it was lost, any exposure would have aggravated the already-existing nitric oxide poisoning.

Additionally, MRS imaging studies show that veterans with GWS have severe loss of neuronal mass (in multiple brain regions in some cases) compared to healthy veterans. [4]

And as Albert Donnay (an environmental health engineer at MCS Referral and Resources) noted [5], the soldiers were chronically exposed to carbon monoxide (CO) from multiple sources, which is significant because chronic CO exposure is known to cause a delayed syndrome [6, 7]. CO is involved in over 100 pathways in the body [7], including the initiation of nitric oxide synthase (NOS). So when combined with the aforementioned problems chronic CO exposure becomes an obvious contributing culprit.

Finally, advocates of the PTSD view are unware of (or overlook) the fact that psychological trauma is known to increase nitric oxide production [8] and the expression of heme oxygenase-1 (HO-1 -- "the universal stress enzyme" that makes carbon monoxide) [7].

-- Patrick Casanova

REFERENCES:

1. Haley et al. Association of low PON1 type Q (type A) arylesterase with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology, volume 157, number 3, pages 227-233 (1999)

2. Van Zweiten, P.A. & H.N. Muscarinic receptors and drugs in cardiovascular medicine. Cardiovascular Drugs and Therapy, volume, 9, number 1, pages 159-167 (1995).

3. Pall. Elevated Nitric Oxide/Peroxynitrite Theory of Multiple Chemical Sensitivity: Central Role of N-Methyl-d-Aspartate Receptors in the Sensitivity Mechanism, volume 111, number 12, pages 1461-1464 (2003).

4. Haley et al. Brain abnormalities in Gulf War syndrome: evaluation by 1H magnetic resonance spectroscopy. Radiology, volume 215, number 3, pages 807-817 (2000).

5. Online rapid response to Edgar et al. Post-combat syndromes from the Boer war to the Gulf war: a cluster analysis of their nature and attribution. British Medical Journal, volume 324, number 7333, pages 321- 324. Donnay's rapid response is available here: http://www.bmj.com/cgi/eletters/324/7333/321#19676

6. Penney, D. Carbon Monoxide Toxicity. CRC, 2000.

7. Donnay's "Protocol For the Diagnosis and Treatment of Chronic Carbon Monoxide Poisoning" at http://www.mcsrr.org/resources/articles/P11.html

8. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome and posttraumatic stress disorder. Annals of the New York Academy of Sciences, volume 933, number 1, pages 323-329 (2001).

Competing interests: None declared

Competing interests: None declared

Patrick P Casanova, none

Fairfax, VA, 20030

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EDITOR – As a contribution to the themed issue of the British Medical Journal on War1 may we bring to your attention that NHS Executive Guidelines indicate that war pensioners may be eligible for priority treatment2. The Guidelines discuss preferential treatment “for war pensioners in NHS hospitals for the condition or conditions” for which the veterans received a pension or gratuity but not for unrelated conditions.

We believe that these Guidelines are insufficiently known or applied. It seems equitable that those who have been injured in the service of their country are entitled to receive prompt NHS help.

Roger Gabriel
civilian consultant physician

Harry A Lee
head

Gulf Veterans’ Medical Assessment Programme, Baird Health Centre, Gassiot House, St Thomas’ Hospital, LONDON SE1 7EH

References:

1. British Medical Journal 2002;324:309-374 (9 February).

2. NHS Executive. Health Service Guidelines HSG(97)31. Priority treatment for War Pensioners. (18 June 1997).

Competing interests: None declared

roger gabriel, civilian consultant physician

harry a lee

gulf veterans' medical assessment programme, st thomas' hospital, london se1 7eh

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The Editor

Jones E et al. Post-combat syndromes from the Boer war to the Gulf war: a cluster analysis of their nature and attribution. BMJ 2002, 324, 321-4 1, is an example of specious medicine and science that ill-serves the needs of the Gulf war veterans, GWVs, and makes light of their suffering and distress. It serves a military-political-corporate agenda and is unworthy of the British Medical Journal. My evidence?

It repeats an old story2 that has previously been used to suggest Gulf war syndrome/illness, GWS/I is nothing exceptional and is not associated with any specific exposures but rather to the general consequences of being engaged in warfare.

This thesis was rejected with contempt at the recent hearing in the House of Representatives on January 24th 20023, at which I was present as an observer. This committee challenged the Department of Defense, DoD, and the Veterans Administration, VA, to account for the very poor returns on the $350 million spent in investigating GWS/I by these organisations. Much has been spent on propaganda and assertion rather than careful investigation of the sick veterans. A letter from the DoD, from Dr Vesser, indicated that further investigation was not necessary since GWS/I was simply another reflection of war syndromes. Dr Vesser was associated with the "stress team" that had sought to present GWS/I as neuropsychiatric and/or somatisation illnesses without any organic basis. This was seen as a wilful refusal to face the now overwhelming facts associated with GWS/I. With the change in leadership in the USA official attitudes have changed radically.

A recent paper from the Medical Assessment Programme4 (Lee 2001) uses the same DoD ploy to explain the "bizarre" conclusion5 that 80% of the latest cohort of 1000 troops assessed were well- but well with symptoms or organic disease. Somatisation disorders were also invoked in this paper. It ignores all the evidence opposing these interpretations. The GWVs now boycott MAP which they regard as untrustworthy.

Jones et al by, combining different data sets from different eras and in some cases using a very small number of records, ignoring the particular environment of the different theatres of war, and the changes in scientific and medical knowledge, appear to be engaged more in obfuscation than clarity. For example, the Guards Memorial to the Crimean war has been described as a lie because it honours the 2162 men at Alma, Inkerman, Sebastopol who "fell during the war with Russia 1854-1855-1856". The lie is identified in the official returns, which show that 419 died in battle or from wounds received in battle. The remaining 1713 died from fever, dysentry, cholera, including some 212 through scurvy and frostbite6. What would be the chronic health effects of these infections and trauma?

War syndromes will arise from the exposure of naïve subjects to previously unencountered biological and chemical toxins in a new environment. The Gulf war was indisputably the most toxic war in Western Military history7 8. The multiple and excessive exposures to vaccines (wrongly administered and experimental in some cases), pyridostigmine bromide (used experimentally) and pesticides (initially denied), chemical war agents (still denied by the UK, but not the American, government), depleted uranium dust (known at the time to be hazardous) and oil and smoke and other toxins underlie the excessive levels of symptoms found among GWVs. The impact of these toxins on gene expression is now proposed as a comprehensive mechanism for the pattern of symptoms and illnesses identified among GWVs 9.

A vast amount of incontrovertible evidence of organic damage, in peer -reviewed literature is ignored9-17. Haley and colleagues using clinical tests and magnetic resonance spectroscopy, MRS, demonstrated extensive and comprehensive neurological damage with significant biochemical changes in the brain10 11. The latter has been confirmed in an unpublished study from the DoD18 that was claimed to have been deliberately withheld19.

Also ignored are a number of recent epidemiological reports. Steele et al20 found that the proportion of troops experiencing GWS/I depends, among other things, on location- with some 42% of those furthest forward and remaining longest in the battlefield area being affected. The same study also shows that 12% of vaccinated troops that were not deployed also have GWS/I. Among UK veterans, Cherry et al21 found vaccines and pesticides to be exposures that were strongly associated with the highest number of symptoms and confirmed the work of Unwin et al22, with regard to the role of vaccines but extended that analysis. A recent epidemiological study with advanced statistical analysis by Haley et al23 provides evidence for the existence of a single GWS using syndromes associated with pesticides, nerve agents and pyridostigmine bromide tablets.

Immunological studies briefly reported to the Shay's hearing24 claimed that a predicted immune imbalance25 has now been confirmed among UK GWVs. Evidence is also emerging of excess levels of rare diseases among GWVs. An American study has found twice the prevalence of motor neurone disease among their troops- some 40 cases to date3 26. A similar incidence is indicated from provisional unpublished figures, five at present, in the UK.

Three cases of renal cancers among UK veterans were discovered, fortuitously from routine ultrasound scans, among the 3000 troops examined by MAP27. A provisional calculation shows that this represents a 10-12- fold increase over civilian figures for the same age groups28. Five cases of lymphocytic leukaemia have been reported among the 2,500 veterans on the National Gulf Veterans and Families Association, NGV&FA, database. A preliminary calculation based on figures in the Oxford Textbook of Medicine29 indicates that this is a 6-10-fold excess over civilian cases for the same age groups. Whilst these figures are only provisional they represent defined illnesses that are the emerging "tip of the iceberg" recognised by Congressman Bernie Sanders of the Shay's Subcommittee.

In the face of all this evidence to attempt to suggest that GWS/I is neuropsychiatric and can be accommodated by terms such as neuraesthenia, neuropsychiatric and somatic symptoms is unacceptable, cruel, and biased. The support from major funding agencies for such work and peer review by uninformed referees only compounds the folly and shame that this paper represents. In the USA it was the introduction of private funding, particularly, $2 million from the Perot Foundation, that allowed independent research to be initiated that exposed the grave inadequacies of the officially funded studies.

The present paper, supported by funds from the DoD, colludes with Government, military and the corporations that prosecuted the war and reneges on the "debt of honour" recognised in the House of Commons Select Defence Committee report30. The public inquiry long called for by the Royal British Legion is now essential to clean out these 'Augean stables'.

References

1 Jones E, Hodgins-Vermas R, McCartney H, Everitt B, Beech C, Poynter D et al. Post-combat syndromes from the Boer war to the Gulf war: a ckuster analysis of their nature and attribution. BMJ 2002;324:324-4.

2 Hyams KC, Wignall FS, Roswell R. War Syndromes and Their Evaluation: From the U.S. Civil ar to the Persian Gulf War. Annals Internal Med. 1996;125:398-405.

3 US House of Representatives Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations, Chairman Christopher Shay, Rayburn House, January 24th 2002.

4 Lee HA, Gabriel R, Bale AJ, Blatchley NF. Clinical Findings of the second 1000 UK Gulf War Veterans, GWVs, who attended the Ministry of Defence's Medical Assessment Programme, MAP. J R Army Medical Corps 2000;147:153-160.

5 Lord Clement-Jones Hansard House of Lords 17th October 2001 (LD0028- PAG1/53).

6 Punch or the London Charivari July 27th 1861. I am grateful to Lt Col AH Wilson-Ing for this reference.

7 Hooper M. The Most Toxic War in Western Military History. Evidence submitted to the House of Commons Select Defence Committee, December 1999. Published in 7th Report of Defence Select Committee. Gulf Veterans' Illnesses. Report and proceedings of the Committee with Minutes of Evidence and Appendices, April 19th 2000.

8 Gulf War and Health vol 1 &2, editors Fulco CE, Liverman CT, Sox HC. Institute of Medicine, Washington, National Academy Press, 2000.

9 Urnovitz HB. Written Testimony to Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations, Chairman Christopher Shay, Rayburn House, January 24th 2002. See also www.chronicillnet.org for further references.

10 Haley RW, Fleckenstein, JL, Bonte FJ, Devous MD, Marshall WW, McDonald, GG, Petty, F. Brain Abnormalities in Gulf War Syndrome: Evaluation with 1H MR Spectroscopy. Radiology 2000;215:807-817 and references cited therein.

11 Haley RW, Fleckenstein JL, Marshall WW, McDonald GG, Kramer GL, Petty F. Effect of basal ganglia injury on central dopamine activity in Gulf war syndrome. Arch Neurol. 2000;57:1281-5.

12 Nicolson GL. Written Testimony to Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations, Chairman Christopher Shay, Rayburn House, January 24th 2002. See also www.immed.org/ for further references.

13 Jamal, G.A. Gulf War Syndrome-a model for the complexity of biological and environmental interaction with human health. Adverse Drug React. Toxicol. Rev. 1998;17:1-17.

14 Jamal GA, Hansen S, Apartopoulos F, Peden A. The "Gulf War syndrome". Is there evidence of dysfunction in the nervous system. J Neurology Neurosurgery and Psychiatry 1996;60:449-450.

15 Mackness B, Durrington PN, Mackness MI. Low paraoxonase in Persian Gulf War Veterans Self-Reporting Gulf War Syndrome. Biochem Biophys Res Comm 2000, 276, 729-733.

16 McDiarmid MA, Keogh JP, Hooper FJ, McPhaul K, Squibb K, Kane R, DiPino R, Kabat M, Kaup B, Anderson L, Hoover D, Brown L, Hamilton M, Jacobson- Kram D, Burrows B, Walsh M. Health effects of depleted uranium on exposed Gulf War veterans. Environmental Research 2000, 82, 168-180.

17 Durakovic A, Dietz KA, Horan P. Quantitative analysis of uranium isotopes in Canadian, US, and British Gulf war veterans. Eur J Nucl Med. 2000;27:5-75.

18 Feussner JR, written testimony to US House of Representatives Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations, Chairman Christopher Shay, Rayburn House, January 24th 2002.

19 Haley RW, oral evidence to US House of Representatives Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations, Chairman Christopher Shay, Rayburn House, January 24th 2002.

20 Steele L Prevalence and patterns of Gulf war illness in Kansas veterans: association of symptoms with characteristics of person, place, and time of military service. Am J Epidemiol. 2000;152:992-1002. Ibid idem 2001;154:406-7.

21 Cherry N, Creed F, Silman A, Dunn G, Smedley J, Taylor S, Macfarlane GJ. Health and exposures of United Kingdom Gulf war veterans. Pt I: the pattern and extent of ill health. Occup Environ Med 2000;58:291-298. Ibid Health and exposures of United Kingdom Gulf war veterans. Pt II: The relation of health to exposure. idem. 299-306.

22 Unwin, C., Blatchley, N., Coker, W., Ferry, S., Hotopf, M., Hull, L., Ismail, K., Palmer, I., David, A., Wessley, S. Health of UK servicemen who served in the Persian Gulf War. Lancet, 1999;353:169-178.

23 Haley RW, Luk GD, Petty F. Use of structural equation modeling to test the construct validity of a case definition of Gulf War syndrome: Invariance over developmental and validation samples, service branches and publicity. Psychiatry Research 2001;102:175-200.

24 Lord Morris of Manchester verbal report to the US House of Representatives Committee on Government Reform. Subcommittee on National Security, Veterans Affairs and International Relations, Chairman Christopher Shay, Rayburn House, January 24th 2002.

25 Rook, G. and Zumla, A. Gulf War Syndrome: is it due to a systemic shift in cytokine balance towards a Th2 Profile? Lancet 1997;349:1831-33.

26 Charatan F. US links motor neurone disease with Gulf war service. BMJ 2002;324:65.

27 Lee H. reported to meeting between Ministry of Defence, MAP and NGV&FA St Christopher's House, Southwark Street, London, 9th January 2002.

28 Busby C. unpublished data.

29 Oxford Textbook of Medicine, editors Weatherall DJ, Ledingham, Warrell DA, 3rd Edition, Oxford University Press, Oxford, 1996, p.214, 3419.

30 7th Report of Defence Select Committee. Gulf Veterans' Illnesses, House of Commons, April 19th 2000.

Competing interests: None declared

Malcolm Hooper, Emeritus Professor of Medicinal Chemistry

University of Sunderland SR2 7EE

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Jones et al do a nice job of showing the symptomatic similarities between post-combat syndromes from the Boer War to Gulf War, but they err in inferring that the three syndromes they identified "are unrelated to any particular exposure as they occurred during several wars."(1) They fail to mention the one toxic exposure common to all these wars, namely carbon monoxide (CO), which has long been both a well known and unfortunately also commonly overlooked cause of all the post-combat symptoms they identified (2).

Military personnel are exposed to CO not just from the firing and detonation of munitions of all kinds (an invisible ingredient in the "fog of war") but also from the engine exhaust of military vehicles, ships and planes and from the combustion by-products of heaters, stoves and cooking fires, especially in poorly ventilated tents and trenches. And they like everyone else are continuously exposed to CO produced endogenously (along with iron and biliverdin) from the breakdown of heme proteins by heme oxygenase-1. HO-1 is known as the "universal stress enzyme" because its activity is greatly induced by exposure to mental, physical or environmental stressors of any kind and particularly by heat and trauma, which are common in combat.

While Jones et al found some variations in the relative frequency of "unexplained symptoms" associated with various wars and were able to distinguish three post-conflict syndromes by cluster analysis, none of these findings are inconsistent with CO poisoning, which has long been known as The Great Imitator and is already associated with numerous disorders as diverse as angina, asthma, chronic fatigue syndrome, diabetes, neurasthenia, multiple chemical sensitivity and Parkinson's (3).

The good news for both veterans and civilians suffering CO symptoms from any of these disorders is that they may be treated safely and easily with supplemental oxygen, just as in any case of CO poisoning. The bad news is that so few physicians ever consider this most obvious possibility. Have they forgotten Occam's razor?

--Albert Donnay, MHS Environmental Health Engineer and Certified CO Analyst

References

(1) Jones E et al. Post-combat syndromes from the Boer war to the Gulf war: a cluster analysis of their nature and attribution. BMJ 2002; 324: 321

(2) Rutherford W. Carbon monoxide poisoning in warfare. The Lancet 1920; 198: 184-188.

(3) Donnay A. Carbon Monoxide as an Unrecognized Cause of Neurasthenia: A History. In: Penney, D. ed. Carbon Monoxide Toxicity. 2000. Boca Raton FL : CRC Press.

Competing interests: None declared

Albert H Donnay, President, MCS Referral & Resources, www.mcsrr.org

no other contributors and no competing interests (BMJ should provide another box for this)

508 Westgate Rd, Baltimore MD 21229

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Editor

I read this paper with great interest, and I find that my view as to the significance of the contribution made to medical literature by such researchers as Jones and his colleagues is further reinforced.

Many doctors and most general practitioners will be only too well aware that problems presented in the consulting room are not always as they seem. Distressed people need to construe their physical and emotional pain in terms that are acceptable to both themselves and their doctors. It takes courage to confront this reality, as I am aware that at least one of the authors of this paper (a psychiatrist for whom I have the greatest admiration) has found to his cost. For it is in this context that we must strive to understand many presentations of such symptom complexes as myalgic encephalomyelitis (ME), fibromyalgia, chronic fatigue - as well as post-combat syndromes - if we are to approach our patients' distress with compassion while at the same time avoiding inflicting further damage by initiating irrelevant investigations and treatment regimes, and compounding the hurt with spurious, inaccurate - even constructed - diagnoses.

Jones and his co-authors are to be congratulated for this enlightening piece of research, although I suspect that their dispassionate presentation of certain facts may not be so palatable in some quarters.

Competing interests: None declared

Henry Tegner, General Practitioner

1, Forest Hill Road, London, SE22 0SQ

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It is now recognised that Battle Fatigue (BF)is more than a military condition and that the factors causing Post combat Stress Disorder (PCSD)can be found In civilian life. It can be found in doctors, teachers, policeman, nurses in fact all walks of life. There is now a set criteria for the treatment of such disorders in the United States Military.

In 1970 the American Journal of Psychology completed an in depth survey of servicemen who had been in combat operations in both the Korean War and the Second World War, they even produced a term for a serviceman who had been in combat for more than 25 Days - "A Long rifleman". They found that there was no set illness or any statistical anlysis to prove that conditions of service caused a deterioration in health.

At the end of the Great War Sir W. G. McPherson edited a twelve volume medical history entitles, "The Medical Services". They discussed the factors effecting the soldier, even the introduction of the steel helmet which produced a rise in moral. McPherson could come to no conclusion regarding the non battle damage illnesses to soldiers. It was exactely the same at the end of the Second World War with returning soldiers.

Gulf War Syndrome would seem to be the old condition of untreated Battle Fatigue, producing Post Trauma Stress Disorder. And the Answer - treat it accordingly!

Select Bibliography

History of the Great War, Medical Services, Sir W.G.McPherson, HMSO, 12 Vols (ND)

Medical Research Committee/Council, First committee report upon injuries of the nervous system, 1920.

Medical Research committee, Incidents of neurosis, 1947

Medical Research Committee, Studies in wound infection, 1920

Medical Research Committee, Treatment of wound shock, 1957

Planning for Health Service Support, F.M.8 - 53 Chapter 12, U.S.Army (N.D.)

First Aid For Psychological Reactions, F.M.21 - 11, Chapter 8. U.S.Army (N.D.)

Competing interests: None declared

Charles E. Mac Kay, Archivist/researcher

Morris Furniture, 147 Drakemire Drive,Glasgow, G45 9SS

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11 February 2002

Editor

In Mr Jones`s article it states in the "what this study adds" section - " there seems to be a growing reluctance to consider the stress of military service as a cause".

I would refute this statement - it is well known and documented that Military service in a conflict situation causes changes to the personality of the individual, as seen by familly and friends of the individual. Most service personnel are aware that there may be some change in their personality after service in a combat scenario.

In relation to service in the gulf conflict "some" of the health problems suffered by veterans are consistent with other conflicts - P.T.S.D., etc

However, a "stress response" does not account for the wide range of health problems currently being experienced by gulf veterans.

I feel that Doctors and researchers and allied health personnel need to be careful as to the wording of their statements so as to not "cluster" all health problems to a single cause e.g. stress, if this cannot be conclusively proven as is the case in Gulf War Illnesses (syndrome - as the media first used - not the gulf veterans).

The authors acknowledge one of the possible causes for a "Changing" scenario of illness as the development and nature of modern warfare - I fully agree with this point and believe it to be a very important issue to realise.

Competing interests: None declared

Philip C Garner, retired Staff Nurse, ill Gulf War veteran

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