The biggest scientific breakthrough was reflected in the publication this month of Dr. Howard Urnovitz ’s research.   A press release about the research is enclosed. Reuter’s News Service’s article on the research on May 3, 1999, was reprinted in the May 10 - May 23, 1999, Stars & Stripes. A blood plasma RNA test from a clinical reference laboratory is available for a $250 charge, if you want to have yourself tested. The information about the test is on the Immuno Diagnostic website ( http://www/idl-labs.com.introorder.htm), and the telephone number is: 1-800-888-1113 If you have the test performed, please go ahead and send us a copy of the results for your file. Ill Gulf War veterans showed positive 50% of the time in the research while none of the nonmilitary controls were positive.

The Centers for Disease Control and Prevention (CDC) published research in the September 16, 1998 Journal of the American Medical Association, which established a case definition for Gulf War Illness. The CDC defined Gulf War Illness as a “chronic multi-symptom condition significantly associated with deployment to the Gulf War,” consisting of the following: One or more chronic symptoms (present for more than six months) from, at least, two of the following categories:

1.)   Fatigue; 2.)   Mood and cognition (symptoms of feeling depressed, difficulty remembering or  concentrating, feeling moody, feeling anxious, trouble finding words, or difficulty sleeping); and 3.) Musculoskeletal (symptoms of joint pain, joint stiffness, or muscle pain).

The prevalence of mild-to-moderate and severe cases were 39% and 6% respectively, among 1,155 Gulf War veterans compared with 14% and 0.7% among 2,520 nondeployed personnel.  Illness was not associated with place of deployment or with the duties during the war. “Veterans who met the definition had significantly diminished functioning and well-being.”

The V.A. is trying a $12 million treatment trial of exercise and behavioral therapy at 20 sites across the country with about 1,300 veterans, with the objective of evaluating non-drug therapies for reducing the severity of symptoms. Many veterans have been critical of the use of the money on this treatment approach.

Another treatment trial is testing whether the antibiotic doxycycline (a tetracycline) improves the health of Gulf War veterans who test positive for infection with the common microorganism mycoplasma and otherwise have Gulf War Illness symptoms. This trial will involve more than 400 veterans at 30 medical centers. Anyone interested in volunteering to participating in either treatment trial may call Walter Reed Army Medical Center at (202)782-6563.

The Litigation

On December 15, 1998, Texas State District Judge Ben Hardin ruled that two Defendants who had tried to avoid personal jurisdiction in this case are indeed subject to it. The Defendants, American Type Culture Collection, which sold anthrax and other biological warfare materials to Saddam, and Preussag, A.G., both argued that they did not have enough contacts with Texas to properly be sued here. They have both filed appeals to the Judge’s decision, which are expedited appeals. There are other Defendants who are also trying to avoid personal jurisdiction in this case. Court hearings concerning them are scheduled in August, and the Court will make a decision concerning them subsequent to that.

New Law Giving Presumption of Service Connection

Important and long-awaited legislation was enacted into law on October 19, 1998. It is entitled “Service Connection for Persian Gulf War Illnesses,” and is Title XVI of Division C of Public Law 105-277. It amends Subchapter II (Wartime Disability Compensation) of Chapter 11 (Compensation for Service-Connected Disability or Death) of Title 38 (Veterans Benefits) of the United States Code. The structure of this new law is very similar to the Agent Orange Act of 1991 (38 U.S. Code § 1116) which finally gave a presumption of service connection for toxic exposure to Vietnam veterans.

The new law is a favorable legal framework, but will still require the Secretary of Veterans Affairs to fill in the framework with implementing regulations. The presumption of service connection for Gulf War Illness will be binding if the V.A. Secretary “determines in regulations” that such a presumption is warranted. It will be warranted if there is a “positive association” with exposure to a chemical, biological, or other toxic agent or environmental hazard and the illness becomes manifest within a veteran within a time to be set by regulation (probably an extended period in the future given the incubation period for cancer). It does not matter that there was no record of such illness while in the service. It does not matter if the illness has been diagnosed or undiagnosed.

The important question is if there is a “positive association” between a toxic exposure that Gulf War veterans were exposed to and illness that has presented since then. The determination of a “positive association” is to be “based on sound medical and scientific evidence.” In making this determination, the V.A. Secretary is to take into account reports from the National Academy of Sciences (an independent nonprofit organization) and “all other sound medical and scientific information and analysis available.” In considering such reports, information, and analysis, the V.A. Secretary “shall take into consideration whether the results are statistically significant, are capable of replication, and withstand peer view.” Ultimately, a “positive association is equal to or outweighs the credible evidence against the association.” Ultimately, the doctors and scientists studying illnesses from the exposures are being relied on.

The law lists 9 groups of toxins, including 33 individual toxins, that Gulf War veterans are known to have been exposed to, including: low-level nerve gases, Sarin and Tabun, and their precursors; low-level mustard gas; p.b. anti-nerve gas pills; pesticides; oil fire smoke; depleted uranium; and others. The National Academy of Sciences is given six months from the enactment of the law to submit a report reviewing and summarizing the relevant scientific evidence and determining “whether a statistical association exists” between exposure to the particular toxin and illness, whether there is an increased risk of illness from the exposure, and “whether a plausible biological mechanism or other evidence of a casual relationship” exists between the toxic exposure and illness.

For each illness identified, the National Academy of Sciences is then supposed to review the available science regarding treatment for the illnesses. They are also supposed to make recommendations for additional appropriate scientific studies, including studies regarding treatment. The National Academy of Sciences is supposed to continue reviewing the evidence and data after their initial report and will provide a subsequent report every two years until 2008.

Once a “positive association” between a toxic exposure and an illness has been determined there will be regulations stating the association. Then, any veteran who served in the theater of operations during the Gulf War who has such an associated illness will be presumed to have been exposed and made ill due to the related toxin during the Gulf War. In order to rebut this presumption, the V.A. would have to have “conclusive evidence” establishing that the veteran was not exposed to the toxin during the Gulf War. Due to missing chemical warfare logbooks and missing or nonexistent records regarding the other toxic exposures, it will be very difficult for the V.A. to have “conclusive evidence” establishing that there was not any exposure of a veteran to a number of toxins, especially low-level exposures to nerve and mustard gases, given the large number of chemical alarms throughout the theater of operations during the bombing of Iraq’s chemical warfare facilities.

This law further states the illness determined to be presumed from a toxic exposure during the Gulf War will be regardless of whether the toxic exposure was a single, repeated, or constant exposure or whether it was in combination with other toxic exposures.

This law covers military veterans of the Gulf War but does not cover the approximately 3,000 American civilians who were in the theater of operations supporting the war, maintaining high-tech military equipment for the most part. Hopefully, Congress will cover them by similar legislation in the future. Ongoing Investigation of Chemical Warfare Exposure

In March, 1999, the General Accounting Office (GAO) issued a report examining six of the investigation narratives of the Office of the Special Assistant for Gulf War Illness (OSAGWI). They found half of them to be flawed. They found that OSAGWI overlooked information in its possession and did not include all relevant information in its case narrative. It also failed to confirm key evidence with appropriate individuals, according to the GAO. Congressman Lane Evans, ranking Democrat on the Veterans Affairs Committee said, “ Unfortunately, OSAGWI seem to have paid more attention to reassuring the public than to thoroughly investigating and reporting on incidents of possible chemical warfare agent exposures.”

The National Gulf War Resource Center, Inc., has pressed OSAGWI to investigate from between 5 and 35 bunker demolition events similar to the March 10, 1991, Khamisiyah explosion. OSAGWI has not yet released any findings on these.

By late 1998, OSAGWI had increased staffing from 12 to 200. Many of those working there are doing so in good faith; and hopefully, the DOD’s historical bias against admissions of the probability of low-level chemical exposures will eventually evaporate. In modeling the extent of the chemical agent plume from Khamisiyah, for example, OSAGWI eventually chose the broader interpretation of the area covered.

To help the move away from the historical bias, a Special Presidential Oversight Committee is now supervising OSAGWI and the government’s efforts concerning Gulf War illness. It is chaired by former Senator Warren Rudman, and consists of former V.A. Secretary Jesse Brown, Admiral (Ret.) Elmo Zumwalt, Lt. Gen. Ret.) Marc Cisneros, Sgt. Maj. (Ret.) David Moore, R. Adm. Ret.) Alan Steinman, and Dr. Vinh Cam. Its interim report is due August 19, 1999; and its final report is due May 19, 2000. It will eventually have a webpage.

Former Senate investigator James Tuite summarized the problem in his November 19, 1998, presentation to the Oversight Committee:

Chemical warfare agent attacks against Iraqi rebels, which occurred only a few miles from U.S. troop positions; the fallout from the destruction not only of the Iraqi chemical warfare agent infrastructure. but also the chemical, pesticide, and petrochemical industry infrastructures; the subsequent Czech detections, credible by the Pentagon’s own admission of airborne nerve and blister agents; the hundreds of thousands of liters of nerve agent precursor materials, some of which is cholinergic and was forward deployed; the thousands of bunkers destroyed but never inventoried whose contents will never be known; the animals dead and dying in the desert; and the chemical alarms sounding with the initiation of the air war have all been ignored or minimized by the Pentagon as indicators of potential or actual health hazards to our troops.

The Frozen Iraqi Assets

The Office of the Foreign Assets Control of the U.S. Department of the Treasury still has under its jurisdiction the Iraqi assets frozen at the time of the August 6, 1990, invasion of Kuwait. They presently amount to about $2.2 billion. About $1.6 billion are in bank deposits inside the U.S., and about $.6 billion are in U.S. banks’ foreign branches. This figure does not include $211 million of the frozen Iraqi money that was given to the U.N. under U.N. Security Counsel Resolution 778. The remaining frozen money is in interest bearing accounts. Delissa Ridgway, Chairwoman of the Justice Department ’s Foreign Claims Settlement Commission has estimated that from the time of the transfer of the assets to their jurisdiction it would probably take, about 1 to 2 years to collect and adjudicate claims and see compensation award checks being sent.

The bill that was in the 105th Congress that would allow the ill Gulf War veterans to make a claim against the Iraqi assets has been reintroduced in the 106th Congress by Congressman Lloyd Doggett. It is H.R. 618, and is entitled “The Gulf War Veterans’ Iraqi Claims Protection Act of 1999.” Under it all claims would receive their award amount or $100,000 whichever is less. Only the veterans would have priority for their awards up to $100,000.  After that all awards would be paid prorata from assets available. This bill was referred on 2/8/99 to the House Committee on International Relations and then on 2/23/99 to the Subcommittee on International Economic Policy and Trade.

If you would like to press Congress on this matter, write or call your member of Congress, and ask him or her to become a co-sponsor of the bill. It would also help to write the chairman and chairwoman and ranking Democrats of the two committees where the bill is located, and ask them to have hearings on the bill and bring it forward for a vote on be House floor:

Honorable Benjamin A. Gilman, Chairman				Honorable Sam Gejdenson, Ranking Democrat
House Committee on International Relations				House Committee on International Relations
2170 Rayburn House Office Building				2304 Rayburn House Office Building
Washington, D.C. 20515				Washington, D.C. 20515
(202) 225-3776				(202) 225-2076
				email: Bozrah@Mail.House.Gov
Honorable Ileana Ros-Lehtine, Chairwoman				Honorable Robert Menendez, Ranking Democrat
House Subcommittee on International Economic				House Subcommittee on International Economic
Policy and Trade				Policy and Trade
HI-701 O’ Neill House Office Building				405 Cannon House Office Building
Washington, D.C. 20515				Washington, D.C. 20515
(202) 225-3931				(202) 225-7919

Senator Jesse Helms, of North Carolina, the chairman of the Senate Foreign Relations Committee has yet to compromise on letting the Gulf War veterans make a claim against the Iraqi assets. As you may recall, there are competing corporate claims, including very large claims by the tobacco companies for the money. After the National Academy of Sciences’ initial report comes out and the presumption of service connection law goes into effect, or after your letters get to Congress, or at some other point in the progress of Congressional business, there may be enough impetus to get this bill onto the floors of Congress for a vote. If Senator Helms refuses to compromise and continues to successfully bottle up the progress of the kill and the money politically, there is also the possibility that he will not seek reelection when his term expires in 2002, or that he will not be reelected.

If the bill ever makes it to the floor of the House or Senate, it should succeed, as reflected in the October, 1997 vote of 412 to 5 in the vote in the House instructing the House and Senate Conference Committee to allow Gulf War veterans to make a claim against the money.

Annual Gulf War Veterans' Conference

The National Gulf War Resource Center, Inc., (NGWRC) has been the most dynamic and influential of the Gulf War veterans' organizations. The NGWRC successfully led the fight to get the new law providing a presumption of service connection for Gulf War veterans. It is a national umbrella organization for 58 grassroots groups. Its address is 1224 M Street, N.W. Washington, D.C. 20005. Its phone is (202) 628-2700, ext. 162. Its web address is http://www.gulfweb.org/NGWRC, and its e-mail address is ngwrc@vva.org.

The NGWRC will hold its 1999 conference at the Palace Station Hotel in Las Vegas, Nevada from September 19-21, 1999. Plan to attend.  Information will be sent to those on its mailing list in June. So you should get on its mailing list as soon as possible, if you would like additional information.

Other Matters

If you were ever in a hospital while you were deployed in the Gulf and have not been able to obtain copies of your inpatient records, you can call the Special Assistant's office at 1-800-497-6261 to request a search from the new consolidated retrieval database. They will forward a request form for you to sign and mail to the records center.   You should try to obtain a copy of all of your medical records since the Gulf War and keep those where we can get a copy from you on short notice. We do not need for you to forward them yet unless we specifically call and ask for them. You should also try to get a copy of your Gulf War Registry CCEP examination records.                                                  

I shall write to you again either at the end of the year or the first part of next year, unless something dramatic happens in the meantime.

As always, I appreciate the opportunity to represent our extended military family in this matter.

Best regards.

Very truly yours,

PITTS & ASSOCIATES ORIGINAL SIGNED Gary B. Pitts

 GBP:miv

Press Release

May 3, 1999 (Washington, D.C.) - Researchers at the Chronic Illness Research Foundation, working in collaboration with researchers torn the University of Michigan School of Medicine and a California Department of Veterans Affairs facility, have uncovered evidence that may link the exposures of veterans of the 1991 Persian Gulf War to a potential new mechanism in the human genetic response to hazardous exposures. The discovery of rearranged genetic intermediates, known as RNA, in the cell free portion of blood appears to have originated, in part, from a chromosome "hotspot" region known for its ability to rearrange. These areas of the chromosome are called "hotspots" because of their responsiveness to toxic exposures.

The scientific research article published in the May 1999 issue of Clinical and Diagnostic Laboratory Immunology, a publication of the American Society for Microbiology, was the culmination of a three year effort to identify the source of novel genetic material found in the serum of nearly 50% of the sick Gulf War veterans (n=24), but in none of the age and sex matched healthy non-military controls (n= 50).

Since the 1991 Gulf War, a significant proportion of Persian Gulf War Veterans have developed a pattern of symptomatic health disorders that have been referred to as Persian Gulf War Related Illnesses or Gulf War Syndrome. The pattern of illness is reasonably consistent: rash; fatigue; muscle and joint pain; headache; irritability; depression; unrefreshing sleep; gastrointestinal and respiratory disorders; and cognitive defects.

The research, funded privately set out to search for objective markers of the wartime exposures of Gulf War veterans which included: low-level chemical warfare agents; investigational drugs; the time-compressed administration of multiple immunizations; organophosphate, curbamate, and other pesticides; insect repellents; low level nuclear and electromagnetic radiation; toxic combustion

products of oil well fires; diesel exhaust products; and, airborne particulates.

The published research shows that novel RNAs, which contain a number of significant sections of genetic material known to occur only in regions of chromosome 22, have been identified in the serum of these veterans.  The exact region of chromosome 22 is referred to as 22q11.2. This chromosome region has been extensively researched as an area of the human genome susceptible to genetic rearrangements, translocations, deletions and mutations.  Further, many of the hazardous exposures identified as present during the conflict are known or suspected to be genotoxic or gene-damaging substances.

Other published research has demonstrated links between damage, deletions, or rearrangements of chromosome 22q11.2 to:

• DiGeorge Syndrome (birth defect disorder involving heart, facial and immunological defects now referred to as chromosome 22q11.2 deletions syndrome”)

• Multiple myeloma cancer (a bone marrow cancer associated with chemical exposure and a significant illness among Vietnam War veterans)

• Idiopathic’ thrombocytopenia purpura (an autoimmune disorder)

• Juvenile rheumatoid arthritis-like polyarthritis.

Chronic Illness Research Foundation

Page 2

The discovery of RNA in the cell free fractions of blood, called serum or plasma, is an anomaly. Once outside the cell, RNA is degraded by special proteins called enzymes.   RNA can exist outside the cell only if it is protected, as in the case of RNA viruses. This resistant RNA may hold the clue to common mechanisms in other chronic diseases.

According to the study’s principal investigator and Director of Science at the Chronic Illness Research Foundation, Howard B. Urnovitz, PhD, “Gulf War Syndrome is like most chronic illnesses; it has been difficult to link hazardous exposures to clinical symptoms.  Our studies in Gulf War Syndrome, cancer, AIDS and multiple sclerosis have focused on looking for common mechanisms rather than causative agents. It would appear that several of the chronic illnesses we have studied share the common finding that RNA in the serum or plasma”

The potential implications of this discovery are far reaching. while the epidemiologic link between a variety of toxic exposures and catastrophic chronic disease is well established, this publication is among the first papers to begin to establish the etiologic (cause-effect) link between toxic exposure and chronic disease.

This ability to detect and determine the gene sequence of the rearranged RNA is an important discovery for several lines of scientific research:

• Epidemiologists and forensic scientists may be able to identify linkages between specific environmental/industrial contaminants and clusters of chronic disorders.

• Standards for environmental exposures can be established based on indices that measure the "rearrangement" (actual damage) potential of toxic substances.

• Emerging infectious diseases can be monitored for their ability to ‘swap out’ genetic material from the human genome and the subsequent potential for increased pathogenicity.

• Viral infections leading to catastrophic chronic diseases such as hepatitis and HIV-1 and their associated cancers can be studied with respect to their effects on genetic rearrangement.

• Measuring serum/plasma RNA may be able to assist clinicians to fashion combinations of medicines to lower the RNA load in the blood as is being done with HIV-l and anti-retroviral therapies.

Tuite also authored a series of reports for the U.S. Senate in 1993 and 1994 in which many of the now confirmed exposures suffered by veterans of the Gulf War were first identified.  The Chairman of the U.S. Senate Committee on Banking, Housing, and Urban Affairs, who assigned Tuite to investigate this issue, former U.S. Senator Donald W. Riegle said, “after long years of suffering by Gulf War veterans, this vital independent research may now finally lead us to possible methods of treatment that can actually help sick veterans and their families.” Chronic Illness Research Foundation is a non-profit 501 (c)(3) foundation in Berkeley, California funded by private contributions. The foundation focuses on discovering common mechanisms among chronic illnesses with the goal of identifying more effective methods of diagnosing, treating and preventing of disabling and catastrophic chronic diseases. More information can be obtained by visiting the Chronic Illness Research Foundation Internet site, “chronicIllnet” at http://www.chronicillnet.org/PGWS.

Books, Journals, New Media - November 25, 1998

Chemical Exposures: Low Levels and High Stakes, by Nicholas A. Ashford and Claudia S. Miller, 2nd ed, 440 pp, with illus, $39.95, ISBN 0-4712-9240-0, New York, NY, Van Nostrand Reinhold/Wiley, 1998.

The debate over the toxic effects of low-level exposures to a wide range of chemical substances in the modern environment continues. It has been amplified by illness reports from veterans of the Gulf War of 1990-1991 that bear striking resemblance to complaints heard over the past 20 to 30 years from civilians, diagnosed variously as chronic fatigue syndrome, fibromyalgia syndrome, or multiple chemical sensitivities. Chemical Exposures provides a scorecard for this debate, effectively updating the first edition by adding four new chapters on recent developments: summaries of major workshops, legal developments, research findings, and polemics. It ends with the authors' view of a future research agenda. Two useful appendices have been added on health effects associated with chemicals and foods, and clinical tests and a questionnaire used by one of the authors to evaluate patients with potential chemical sensitivities.

The authors point out that the medical literature on multiple chemical sensitivities reflects what Thomas Kuhn has called the "pre-paradigm period," characterized by frequent deep debates over legitimate methods, problems, and standards of solution, resulting in divergent schools of thought rather than progress toward a consensus. Thus, theories about the mechanism of development of multiple chemical sensitivities abound, ranging from olfactory-limbic kindling to psychological remnants of child abuse.

The authors put forward a term for what they propose to be a new class or family of disorders: toxicant-induced loss of tolerance or TILT. This concept draws heavily on certain aspects of the literature of addiction research but attempts to unify observations that overlap the fields of allergy and toxicology. How to explain the observed loss of tolerance in some individuals following acute or chronic exposures to pesticides or carpet vapors, followed by apparent triggering of symptoms involving multiple organ systems by minute quantities of formerly tolerated chemical substances? Despite the efforts of a relatively small number of researchers and increased but still minuscule governmental efforts, we seem no closer to answering this question than we were 7 years ago, when the first edition was published.

Nevertheless, patients with as yet poorly understood illnesses, such as multiple chemical sensitivities, still consult their clinicians with an expectation that we listen carefully to their complaints, evaluate the potential causes, and recommend reasonable approaches to treatment, which up to now has meant primarily avoidance of offending exposures. Although tending toward the polemical at times in response to criticisms of the first edition, this book provides the clinician with a lamp to help find the way through this rather uncharted terrain.

James E. Cone, MD, MPH 

University of California 

San Francisco School of Medicine 

(JAMA. 1998;280:1797-1798)

Editorial - January 15, 1997

Editorials represent the opinions of the authors and The Journal and not those of the American Medical Association.

Philip J. Landrigan, MD, MSc

In 1990 and 1991, 697,000 men and women of the US armed forces served in the Persian Gulf. During their service these veterans were exposed to a wide array of known and potential hazards to health. These risk factors included extremes of heat and cold, blowing dust, smoke from oil well fires, petroleum fuels and their combustion products, pyridostigmine bromide (administered as pretreatment for potential poison gas exposure), anthrax and botulinum toxoid vaccines, depleted uranium (used in certain artillery shells), infectious diseases, chemical warfare agents, pesticides, and pervasive psychological and physiological stress.[1]

Since returning home, many Persian Gulf War veterans have developed illness. Some have specific diseases that clearly resulted from their military service.[2] For example, 32 veterans have been diagnosed with leishmaniasis, and 7 have developed malaria. Several dozen retain fragments of depleted uranium embedded in their bodies, and others sustained traumatic injuries. But perhaps most notably, many more veterans have returned with an array of symptoms--including fatigue, joint pain, gastrointestinal complaints, memory problems, emotional change, impotence, and insomnia--that defy diagnostic classification.

Epidemiologic studies designed to answer fundamental questions about the prevalence, distribution, and causes of illness among Gulf War veterans have been initiated and will continue for many years. A recently published analysis found a 9% higher death rate in Persian Gulf War veterans as compared with other veterans of the same era.[3] This excess mortality was entirely attributable to "external causes," with a particularly striking excess of deaths from motor vehicle injuries, although no excesses of deaths from suicide, homicide, or specific diseases were observed.[3] A study of hospitalization in military hospitals of 547,000 Gulf War veterans who had remained on active duty in the 2 years following the war found no consistent pattern for excess of any particular diseases.[4] Other analyses of illness in specific groups of veterans who had reported high rates of symptoms have confirmed the existence of fatigue, headache, emotional change, and joint pain in these men and women.[5] [6] [7] While carefully done, all of these cluster studies have involved relatively small groups of veterans, and all have 2 basic limitations: the groups under investigation are self-selected and their symptoms are self-reported. Consequently, none of these studies has identified specific diagnoses or specific etiologic factors responsible for the veterans' symptoms. Additional epidemiologic studies that have examined cognitive function in selected groups of Gulf War veterans[8] [9] [10] have shown slight decrements in memory and concentration.

The 3 reports in this issue of THE JOURNAL by Haley and colleagues[11] [12] [13] as well as the study by Schwartz et al[14] represent further important efforts to classify and categorize symptoms in Gulf War veterans.

The studies by Haley et al were performed in 249 members of a Reserve Naval Mobile Construction Battalion that served in the Gulf. Illness has been common in this group, and cognitive function in some members was evaluated previously at the Birmingham Veterans Center.[10] To examine patterns of illness, Haley et al administered a detailed symptom questionnaire to the veterans, 70% of whom reported having had serious health concerns. Then through factor analysis, the authors identified 6 clusters of self-reported symptoms that they grouped into syndromes, with the most strongly clustered symptoms characterized as impaired cognition, confusion-ataxia, and arthromyoneuropathy.[11] To further explore the nature of those syndromes, the investigators performed detailed neuropsychologic studies in 23 veterans with clinical symptoms and in 20 controls. They found evidence of neuropsychologic impairment in the symptomatic veterans as measured by decrements in test scores and evidence of neurologic dysfunction, as characterized by asymmetry in evoked potentials and abnormalities of audiovestibular function.[12] Then, on the basis of structured interviews regarding exposures sustained in the Gulf, Haley et al concluded that some cases of neuropsychologic impairment might have been due to DEET and other pesticides, that some may have been due to exposures to chemical warfare agents, and that some may be linked to pyridostigmine bromide.[13]

The study by Schwartz et al is a population-based survey undertaken among a sample of Gulf War veterans from Iowa.[14] Participants were drawn from all branches of the armed services and represented more than 800 military units. Symptom prevalence rates were examined in Gulf War veterans and in Iowa military personnel of the same era who were deployed elsewhere. Compared with military personnel not deployed to the Persian Gulf, Gulf War veterans were found to have significantly higher prevalences of medical and psychological symptoms including depression, cognitive dysfunction, and fibromyalgia. Among Persian Gulf veterans, these conditions were more common among those reporting exposures to solvents, smoke, pesticides, pyridostigmine, and chemical warfare agents than among those not reporting such exposures.

Most important, these studies confirm previous clinical and epidemiologic investigations[5-7] showing that many Persian Gulf War veterans have a variety of troubling and sometimes disabling symptoms. The data of Haley et al confirm previous reports that symptoms are linked in at least some veterans to neuropsychological impairment.[8-10] Each of the studies asks important etiologic questions.

The study by Schwartz et al is particularly robust. It includes a representative sample of all veterans from Iowa who served in the Persian Gulf. Participation rates were high. Meticulous attention was paid to issues of quality control and study methods. A limitation in the study, which Schwartz et al acknowledge, is that all symptoms as well as all exposures were self-reported and thus are subject to recall bias. A second problem derives from the broad range of military units covered. While this breadth enhances the generalizability of the findings, the lack of concentration on any particular unit precludes detailed examination of hazards that may have affected only certain groups of veterans.

The studies by Haley et al[11-13] are ambitious and sophisticated, but have limitations that substantially weaken the authors' strong conclusions. First, the studies are not population based, but rather are focused on a single battalion of naval construction workers, a group whose exposures and experiences may have been quite different from those of most veterans. This aspect increases the depth of the studies, but limits the generalizability of the findings. Second, only 41% of the battalion participated in the examinations. That relatively low participation rate raises the possibility of selection bias; ie, those who participated may be significantly different in certain important characteristics from those who chose not to join the study--for example, in the prevalence, severity, or patterns of illness. In fact, only 43% of nonparticipants who were surveyed reported serious health problems since the war, compared with 70% of participants who did so. Third, virtually all information on illnesses is self-reported; detailed clinical and neuropsychological examinations were performed on only 23 symptomatic veterans (less than 4% of the battalion), and measurements of motor nerve conduction velocity, the classic test to confirm organophosphate-induced delayed peripheral neuropathy,[15] were made on only 5 veterans. Finally, all exposure data were self-reported. The investigators made no effort to independently or objectively verify exposures.

Haley et al suggest that some cases of illness in members of their population may represent chronic neurotoxicity caused by low-dose exposures to chemical warfare agents. This is an important question that demands serious investigation. The issue of chemical warfare exposure in the Persian Gulf first came to prominence in 1996. At that time the US Department of Defense belatedly acknowledged--after persistent questioning from the Presidential Advisory Committee on Gulf War Veterans' Illnesses--that neurotoxic chemical warfare agents, notably sarin, had been released in certain areas of the Gulf during the destruction after the war of Iraqi ammunition bunkers. A well-documented release occurred during the destruction by US troops of a bunker at Khamisiyah. The veterans examined by Haley et al apparently were not involved in the episode at Khamisiyah.

Acute high-dose exposure to chemical warfare agents, many of which, such as sarin, are based on organophosphate molecules, can cause devastating damage to the nervous system.[16] Survivors of acute sarin poisoning also have been reported to manifest chronic neurotoxity.[17] [18] Less is known about the possible chronic consequences of lower-dose, asymptomatic exposures to these agents. The available data argue against the existence of low-dose or delayed neurotoxicity in the absence of acute symptoms, but those data are sparse. [19] [20] Further research is needed to determine whether low-dose exposure to chemical warfare agents can cause chronic neurotoxicity. Such research is now under way at the Boston and Portland Veterans Environmental Health Research Centers.

The data on symptoms confirm what many physicians caring for Gulf War veterans already know, namely, that the illnesses in these men and women are quite real. Whatever their precise etiology, the health problems that Gulf War veterans are experiencing clearly are not the result of malingering or desire for compensation.

The findings on risk factors should instill a sense of etiologic caution in medical practitioners. Clinicians need to recognize that the precise causation of illness in most Persian Gulf War veterans may never be known with certainty. The information on chemical warfare exposure is fascinating, and the delays in release of those data are troubling. However, the link between chemical warfare exposure and disease in Gulf War veterans certainly has not been proven by these studies. Many Gulf War veterans will continue to experience nonspecific symptoms of imprecise etiology. Counseling, support, and symptomatic treatment will continue to be very important. Physicians need to acknowledge that many Gulf War veterans are experiencing stress-related disorders and the physical consequences of stress.[21] [22] [23] These conditions should not be hidden or denied, but rather are well-recognized entities that have been studied extensively in survivors of past wars, most notably the Vietnam conflict. As physicians, we should not accept a diagnosis of stress-related disorder in veterans prior to excluding treatable physical factors, but at the same time, we need to recognize the pervasive presence of stress-related illness such as hypertension, fibromyalgia, and chronic fatigue among Persian Gulf War veterans and manage these illnesses appropriately. As a nation, we need to get beyond the fallacious idea that diseases of the mind either are not real or are shameful and to better recognize that the mind and the body are inextricably linked.

The central lesson is that of prevention. In future conflicts and peace-keeping actions, US troops will be exposed to myriad adverse physical factors, potentially including chemical warfare and biological warfare agents, as well as high levels of stress. Good baseline examinations will need to be done on service personnel prior to future deployment to form a basis for clinical and epidemiologic studies, and the Department of Defense is now developing plans for such evaluations. A recurrent problem in the epidemiologic studies of Gulf War veterans is that they have been mounted after the fact with little baseline data available. In addition, it will be important in the future to intervene proactively to prevent stress-related disorders. The Department of Defense has now deployed a Combat Stress Reduction Team with troops in Bosnia and plans to do so elsewhere in the future. While clearly these results need to be monitored, this direction is highly laudable and needs to be encouraged.

Physicians may expect to continue to see Persian Gulf War veterans as patients for many years to come. In some instances, we may identify specific diseases in these men and women, but in others, symptoms will remain ill defined, etiology will be imprecise, and disability will persist. However, despite the limitations of current epidemiologic studies and clinical investigations and regardless of the unanswered questions surrounding the hazards of potential exposures during the Persian Gulf War, these veterans will need all the resources and all of the care that they are owed by this nation that they have so generously and gallantly served.

Philip J. Landrigan, MD, MSc

Editorials represent the opinions of the authors and The Journal and not those of the American Medical Association.

References:

1. Institute of Medicine. Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action. Washington, DC: National Academy Press; 1995.

2. Institute of Medicine. Health Consequences of Service During the Persian Gulf War: Recommendations for Research and Information Systems. Washington, DC: National Academy Press; 1996.

3. Kang HK, Bullman TA. Mortality among U.S. veterans of the Persian Gulf War. N Engl J Med. 1996;335:1498-1504.

4. Gray GC, Coate BD, Anderson CM, et al. The postwar hospitalization experience of U.S. veterans of the Persian Gulf War. N Engl J Med. 1996;335:1505-1513.

5. Defraites RF, Wanat ER, Norwood AE, Williams S, Cowan D, Callahan T. Investigation of a Suspected Outbreak of an Unknown Disease among Veterans of Operation Desert Shield/Storm, 123d Army Reserve Command, Fort Benjamin Harrison, Indiana, April 1992. Washington, DC: Walter Reed Army Institute of Research; 1992.

6. Centers for Disease Control and Prevention. Unexplained Illness among Persian Gulf War Veterans in an Air National Guard Unit: preliminary report--August 1990-March 1995. MMWR Morb Mortal Wkly Rep. 1995;44:443-447.

7. Pierce PF. Physical and emotional health of Gulf War veteran women. Aviation Space Environ Med. In press.

8. Goldstein G, Beers SR, Morrow LA, Shemansky WJ, Steinhauer SR. A preliminary neuropsychological study of Persian Gulf veterans. J Int Neuropsychol Soc. 1996;2:368-371.

9. Vastering JJ, Brailey K, Constans JI, et al. Assessment of intellectual resources in Gulf War veterans: relationship to PTSD. Assessment. In press.

10. Kotler-Cope S, Milby JB, et al. Neuropsychological deficits in Persian Gulf War veterans: a preliminary report. Presented at the annual meeting of the International Neuropsychological Society; Chicago, Ill; 1996.

11. Haley RW, Kurt TL, Hom J. Is there a Gulf War syndrome? searching for syndromes by factor analysis of symptoms. JAMA. 1997;277:215-222.

12. Haley RW, Hom J, Roland PS, et al. Evaluation of neurologic function in Gulf War veterans: a blinded case-control study. JAMA. 1997;277:223-230.

13. Haley RW, Kurt TL. Self-reported exposure to neurotoxic chemical combinations in the Gulf War: a cross-sectional epidemiologic study. JAMA. 1997;277:231-237.

14. The Iowa Persian Gulf Study Group. Self-reported illness and health status among Persian Gulf War veterans: a population-based study. JAMA. 1997;277:238-245.

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17. Burchfiel JL, Duffy FH. Organophosphate neurotoxicity: chronic effects of sarin on the electroencephalogram of monkey and man. Neurobehav Toxicol Teratol. 1982;4:767-778.

18. Duffy FH, Burchfiel JL. Long term effects of the organophosphate sarin on EEGs in monkeys and humans. Neurotoxicology. 1980;1:667-689.

19. National Research Council. Possible Long-term Health Effects of Short-term Exposure to Chemical Agents, Volume 1: Anticholinesterase and Anticholinergics. Washington, DC: National Academy Press; 1982.

20. National Research Council. Possible Long-term Health Effects of Short-term Exposure to Chemical Agents, Volume 3: Final Report on Current Health Status of Test Subjects. Washington, DC: National Academy Press; 1985.

21. Hyams KC, Wignall FS, Roswell R. War syndromes and their evaluation: from the U.S. Civil War to the Persian Gulf War. Ann Intern Med. 1996;125:398-405.

22. Chrousos GP, Gold PW. The concepts of stress and stress system disorders: overview of physical and behavioral homeostasis. JAMA. 1992;267:1244-1252.

23. Stretch RH, Marlowe DH, Wright KM, et al. Post-traumatic stress disorder symptoms among Gulf War veterans. Mil Med. 1996;161:407-410.

Three primary syndromes and three secondary syndromes were identified. The three primary syndromes are:

Syndrome-1 or "Impaired Cognition" Syndrome - characterized by distractibility, difficulty remembering, depression, insomnia, fatigue, slurring of speech, confused thought process, and migraine-like headaches.

Syndrome-2 or "Confusion-ataxia" Syndrome - characterized by problems with thinking and reasoning processes such as reading, writing, and spelling; getting confused; getting disoriented when trying to locate a car in a parking lot; having problems with balance; having a physician's diagnosis of post-traumatic stress disorder, depression, or liver disease; and sexual impotence.

Syndrome-3 or "Arthro-myo-neuropathy" Syndrome - characterized by generalized joint and muscle pains, increased difficulty lifting heavy objects, fatigue, and tingling or numbness of the hands, arms, feet, and legs.

The authors suggest that most of the symptoms that comprise the syndromes could be explained by varying combinations of injury to the brain, spinal cord, and peripheral nerves.

Three Clusters Signal Neurologic Damage

Following the identification of the six syndromes, Dr. Haley and colleagues conducted a second investigation. Detailed neuropsychologic exams were performed on 23 symptomatic veterans and 20 well veterans.

The researchers found that the three primary syndromes "appear to represent variants of a generalized injury to the nervous system." The 23 symptomatic veterans consistently scored more in the abnormal direction on objective tests of neurologic function than the well veterans.

The differences in illness severity among the veterans may be due to differences in the age of the veterans at the time of the war, according to the researchers. They found that syndrome-1 was most common among younger veterans, while the risk for syndromes 2-3 increased with age.

Read the abstract for the first Haley article, read the abstract for the second Haley article, read the abstract for the third Haley article or go back to the top.

Note: This study was supported by a cooperative agreement with the Iowa Department of Public Health and the University of Iowa from the National Centers for Environmental Health, CDC, Atlanta, Ga.

WASHINGTON, D.C.- New studies presenting important findings that confirm previous clinical and epidemiologic investigations showing that Persian Gulf War veterans have a variety of troubling and sometimes disabling symptoms, according to an editorial in the January 15 issue of The Journal of the American Medical Association (JAMA).

In his editorial, Philip J. Landrigan, M.D., M.Sc., from the Department of Community Medicine at Mount Sinai School of Medicine, New York, N.Y., examines four Persian Gulf War studies appearing in the same issue of JAMA. He presented the information today (Jan. 8) at a press conference.

Dr. Landrigan writes: "The findings on risk factors should instill a sense of etiologic caution in medical practitioners. Clinicians need to recognize that the precise causation of illness in most Persian Gulf War veterans may never be known with certainty. The information on chemical warfare exposure is fascinating, and the delays in release of those data are troubling. However, the link between chemical warfare exposure and disease in Gulf War veterans certainly has not been proven by these studies."

He asks for continued counseling, support, and symptomatic treatment of Gulf War veterans: "As physicians we should not accept a diagnosis of stress- related disorder in veterans prior to excluding treatable physical factors, but at the same time, we need to recognize the pervasive presence of stress-related illness such as hypertension, fibromyalgia, and chronic fatigue among Persian Gulf War veterans and manage these illnesses appropriately. As a nation, we need to get beyond the fallacious idea that diseases of the mind either are not real or are shameful and to better recognize that the mind and body are inextricably linked."

In 1990 and 1991, 697,000 men and women of the U.S. armed forces served in the Persian Gulf War. During their service these veterans were exposed to wide array of known and potential hazards to health. These risk factors include extremes of heat and cold, blowing dust, smoke from oil well fires, petroleum fuels and their combustion products, pyridostigmine bromide (administered as pretreatment for potential poison gas exposure), anthrax and botulinum toxoid vaccines, depleted uranium (used in certain artillery shells), infectious diseases, chemical warfare agents, pesticides, and pervasive psychological and physiological stress, according to information in the editorial.

Dr. Landrigan states: "Since returning home, many Persian Gulf War veterans have developed illness. Some have specific diseases that clearly resulted from their military service ... But perhaps most notably, many more veterans have returned with an array of symptoms including fatigue, joint pain, gastrointestinal complaints, memory problems, emotional change, impotence, and insomnia--that defy diagnostic classification."

He continues: "In future conflicts and peace-keeping actions, U.S. troops will be exposed to myriad adverse physical factors, potentially including chemical warfare and biological warfare agents, as well as high levels of stress. Good baseline examinations will need to be done on service personnel prior to future deployment to form a basis for clinical and epidemiologic studies... A recurrent problem in the epidemiologic studies of Gulf War veterans is that they have been mounted after the fact with little baseline data available. In addition, it will be important in the future to intervene proactively to prevent stress-related disorders. The Department of Defense has now deployed a Combat Stress Reduction Team with troops in Bosnia and plans to do so elsewhere in the future. While clearly these results need to be to be monitored, this direction is highly laudable and needs to be encouraged."

Dr. Landrigan concludes: "Despite the limitations of current epidemiologic studies and clinical investigations and regardless of the unanswered questions surrounding the hazards of potential exposures during the Persian Gulf War, these veterans will need all the resources and all of the care they are owed by this nation that they have so generously and gallantly served."

In an accompanying editorial, Joyce C. Lashof, M.D., of the University of California at Berkeley, and Joseph S. Cassells, M.D., M.P.H., of the Institute of Medicine, Washington, D.C., write: "It is essential that lessons learned from the Gulf War experience are applied to prevent or at least minimize the occurrence of such illnesses in the future. Service personnel should be informed fully about the need for all immunizations and prophylactic medications. Medical records should be complete and accurate. Environmental exposures should be documented thoroughly. Veterans returning from areas of conflict should be monitored carefully, their symptoms or signs should be investigated promptly and comprehensively, and any illnesses discovered should be treated appropriately."

The authors add: "Of paramount importance is the need to acknowledge and validate that Gulf War veterans are experiencing real illnesses and must receive proper care. Despite the absence of a definitive cause of these illnesses, treatment of symptoms can be effective. Clinicians need to help these patients learn to cope better with their chronic symptoms, increase their daily level of functioning and help them focus on treatment rather than cause."

(JAMA. 1998;280:1010=1011)