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Gulf War syndrome

Gulf War syndrome (GWS) also known as Gulf War illness or chronic multi-symptom Illness, is a chronic and multi-symptomatic disorder affecting military veterans of the Gulf War (1990–1991). A wide range of acute and chronic symptoms have been linked to the illness, including fatigue, muscle pain, cognitive problems, insomnia, rashes and diarrhea. Approximately 250,000 of the 697,000 U.S. veterans who served in the Gulf War have an enduring chronic multi-symptom illness. From 1995 to 2005, the health of combat veterans worsened in comparison with nondeployed veterans, with the onset of more new chronic diseases, functional impairment, repeated clinic visits and hospitalizations, myalgic encephalomyelitis/chronic fatigue syndrome-like illness, post-traumatic stress disorder, and greater persistence of adverse health incidents.

Signs and symptoms
According to the Institute of Medicine (IOM), part of the U.S. National Academy of Sciences, 250,000 A 2008 report stated that "it is difficult to draw firm conclusions related to birth defects and pregnancy outcomes in Gulf War veterans", observing that while there have been "significant, but modest, excess rates of birth defects in children of Gulf War veterans", the "overall rates are still within the normal range found in the general population". The same report called for more research on the issue. Comorbid illnesses Persian Gulf War veterans have an increased risk of multiple sclerosis. A 2017 study by the U.S. Department of Veterans Affairs found that veterans possibly exposed to chemical warfare agents at Khamisiyah experienced different patterns of brain cancer mortality risk compared to the other groups, with veterans possibly exposed having a higher risk of brain cancer in the time period immediately following the Gulf War. Iraqi veterans Opposing Iraqi veterans of the Iraqi Army in the Gulf War also experienced acute and chronic symptoms associated with Gulf War syndrome, although this group is understudied compared to U.S. veterans. A 2011 study in the U.S. Army Medical Department Journal reported Iraqi veterans of the Gulf War had a higher prevalence of somatic disorders as compared to Iraqi civilians, with risk greater in troops stationed in Kuwait. In comparison to Allied troops, health symptoms were similar amongst Iraqi veterans: ::* Zone 1 = In Kuwait, Zone 3 = 360 km from Kuwait. == Causes ==
Causes
Many of the symptoms of Gulf War illness are similar to the symptoms of organophosphate, mustard gas, and nerve gas poisoning. Gulf War veterans were exposed to a number of sources of these compounds, including nerve gas and pesticides. In 2022, researchers led by Robert Haley, MD at University of Texas Southwestern Medical Center found that exposure to sarin nerve gas in soldiers who had a particular genetic mutation that prevented them from breaking down the nerve gas is likely to be responsible for the syndrome. In addition to the many physical and psychological issues involved in any war zone deployment, Gulf War veterans were exposed to a unique mix of hazards not previously experienced during wartime. These included pyridostigmine bromide pills (given to protect troops from the effects of nerve agents), depleted uranium munitions, and multiple simultaneous vaccinations including anthrax and botulinum toxin vaccines. The oil and smoke that spewed for months from hundreds of burning oil wells presented another exposure hazard not previously encountered in a war zone. Military personnel also had to cope with swarms of insects, requiring the widespread use of pesticides. High-powered microwaves were used to disrupt Iraqi communications, and though it is unknown whether this might have contributed to the syndrome, research has suggested that safety limits for electromagnetic radiation are too lenient. The Research Advisory Committee on Gulf War Veterans' Illnesses (RAC), a VA federal advisory committee mandated by Congress in legislation enacted in 1998, The RAC concluded However, in 1997, the US Government released an unclassified report that stated: : "The US Intelligence Community (IC) has assessed that Iraq did not use chemical weapons during the Gulf war. However, based on a comprehensive review of intelligence information and relevant information made available by the United Nations Special Commission (UNSCOM), we conclude that chemical warfare (CW) agent was released as a result of US postwar demolition of rockets with chemical warheads in a bunker (called Bunker 73 by Iraq) and a pit in an area known as Khamisiyah." Over 125,000 U.S. troops and 9,000 U.K. troops were exposed to nerve gas and mustard gas when the Iraqi depot in Khamisiyah was destroyed. Studies have confirmed earlier suspicions that exposure to sarin, in combination with other contaminants such as pesticides and PB were related to reports of veteran illness. Estimates range from 100,000 to 300,000 individuals exposed to nerve agents. The 2014 report by the U.S. Department of Veterans Affairs (VA) Research Advisory Committee on Gulf War illnesses (RAC) concluded that, "exposure to the nerve gas agents sarin/cyclosarin has been linked in two more studies to changes in structural magnetic resonance imaging findings that are associated with cognitive decrements, further supporting the conclusion from evidence reviewed in the 2008 report that exposure to these agents is etiologically important to the central nervous system dysfunction that occurs in some subsets of Gulf War veterans." Earlier considered potential causes Depleted uranium The Gulf War included the first widespread combat usage of depleted uranium (DU), in tank kinetic energy penetrator and autocannon rounds. DU has been suggested as a possible cause of Gulf War syndrome. A 2008 review by the U.S. Department of Veterans Affairs found no association between DU exposure and multisymptom illness, concluding that "exposure to DU munitions is not likely a primary cause of Gulf War illness". There is some evidence that long-term exposure to high doses of DU can cause other health problems that are unrelated to GWS. The Veterans Administration decides these claims on a case-by-case basis. A 2018 study stated that "the number of Gulf War veterans who developed the Gulf War syndrome following exposure to high quantities of DU has risen to about one-third of the 800,000 U.S. forces deployed", with 25,000 of those having had a premature death. A 2021 study by a team at the University of Portsmouth tested urine samples of 154 US veterans, reporting that no soldiers with the syndrome were exposed to significant amounts of depleted uranium and that DU "is not and never was in the bodies of those who are ill at sufficient quantities to cause disease". Pyridostigmine bromide nerve gas antidote The US military issued pyridostigmine bromide (PB) pills to protect against exposure to nerve gas agents such as sarin and soman. PB was used as a prophylactic against nerve agents; it is not a vaccine. Taken before exposure to nerve agents, PB was thought to increase the efficiency of nerve agent antidotes. PB had been used since 1955 for patients who have myasthenia gravis with doses up to 1,500 mg a day, far in excess of the 90 mg given to soldiers, and was considered safe by the FDA at either level for indefinite use and its use to pre-treat nerve agent exposure had recently been approved. Given both the large body of epidemiological data on myasthenia gravis patients and follow-up studies done on veterans, it was concluded that while it was unlikely that health effects reported today by Gulf War veterans are the result of exposure solely to PB, use of PB was causally associated with illness. Organophosphates Organophosphate-induced delayed neuropathy (OPIDN, aka organophosphate-induced delayed polyneuropathy) may contribute to the unexplained illnesses of the Gulf War veterans. Organophosphate pesticides The use of organophosphate pesticides and insect repellents during the first Gulf War is credited with keeping rates of pest-borne diseases low. Pesticide use is one of only two exposures consistently identified by Gulf War epidemiologic studies to be significantly associated with Gulf War illness. Multisymptom illness profiles similar to Gulf War illness have been associated with low-level pesticide exposures in other human populations. In addition, Gulf War studies have identified dose-response effects, indicating that greater pesticide use is more strongly associated with Gulf War illness than more limited use. Pesticide use during the Gulf War has also been associated with neurocognitive deficits and neuroendocrine alterations in Gulf War veterans in clinical studies conducted following the end of the war. The 2008 report concluded that "all available sources of evidence combine to support a consistent and compelling case that pesticide use during the Gulf War is causally associated with Gulf War illness." The VA's 2014 RAC report reinforced its 2008 report findings: "The research reviewed in this report supports and reinforces the conclusion in the 2008 RACGWVI report that exposures to pesticides and pyridostigmine bromide are causally associated with Gulf War illness. Evidence also continues to demonstrate that Gulf War illness is not the result of psychological stressors during the war." It also found additional evidence since the 2008 report for the role of sarin in GWI, but inadequate evidence regarding exposures to oil well fires, vaccines, and depleted uranium to make new conclusions about them. During Operation Desert Storm, 41% of U.S. combat soldiers and 75% of UK combat soldiers were vaccinated against anthrax. While the Food and Drug Administration (FDA) approved the vaccine, it never went through large-scale clinical trials. While recent studies have demonstrated the vaccine is highly reactogenic, there is no clear evidence or epidemiological studies on Gulf War veterans linking the vaccine to Gulf War illness. Combining this with the lack of symptoms from current deployments of individuals who have received the vaccine led the Committee on Gulf War Veterans' Illnesses to conclude that the vaccine is not a likely cause of Gulf War illness for most ill veterans. Their work of the researchers was profiled by Gary Matsumoto in "Vaccine A". This research and theory was later criticized, and further research has leaned heavily against squalene in vaccinations causing GWS; Perhaps the most important points against this theory include that squalene antibodies have been detected in populations not exposed to squalene containing vaccinations, and that the anthrax vaccines used in the Gulf War did not actually contain squalene in any form. Combat stress Research studies conducted since the war have consistently indicated that psychiatric illness, combat experience or other deployment-related stressors do not explain Gulf War veterans illnesses in the large majority of ill veterans, according to a U.S. Department of Veterans Affairs (VA) review committee. An April 2010 Institute of Medicine review found, "the excess of unexplained medical symptoms reported by deployed [1991] Gulf war veterans cannot be reliably ascribed to any known psychiatric disorder", although they also concluded that "the constellation of unexplained symptoms associated with the Gulf War illness complex could result from interplay between both biological and psychological factors." == Pathobiology ==
Pathobiology
Chronic inflammation The 2008 VA report on Gulf War illness and the Health of Gulf War Veterans suggested a possible link between GWI and chronic, nonspecific inflammation of the central nervous system that cause pain, fatigue and memory issues, possibly due to pathologically persistent increases in cytokines and suggested further research be conducted on this issue. == Diagnosis ==
Diagnosis
Clinical diagnosis of Gulf War illness has been complicated by multiple case definitions. In 2014, the National Academy of Sciences Institute of Medicine (IOM)—contracted by the U.S. Department of Veterans Affairs for the task—released a report concluding that the creation of a new case definition for chronic multisymptom illness in Gulf War veterans was not possible because of insufficient evidence in published studies regarding its onset, duration, severity, frequency of symptoms, exclusionary criteria, and laboratory findings. Instead, the report recommended the use of two case definitions, the "Kansas" definition and the "Centers for Disease Control and Prevention (CDC)" definition, noting: "There is a set of symptoms (fatigue, pain, neurocognitive) that are reported in all the studies that have been reviewed. The CDC definition captures those three symptoms; the Kansas definition also captures them, but it also includes the symptoms reported most frequently by Gulf War veterans." The Kansas case definition is more specific and may be more applicable for research settings, while the CDC case definition is more broad and may be more applicable for clinical settings. Before 1998, the terms ''Gulf War syndrome, Gulf War veterans' illness, unexplained illness, and undiagnosed illness were used interchangeably to describe chronic unexplained symptoms in veterans of the 1991 Gulf War. The term chronic multisymptom illness'' (CMI) was first used following publication of a 1998 study as do VA's Office of Research and Development (VA-ORD) and many recent VA research publications. However, VA's Public Health website still uses ''Gulf War veterans' medically unexplained illnesses, chronic multi-symptom illness (CMI), and undiagnosed illnesses'', but explains that VA doesn't use the term Gulf War syndrome because of varying symptoms. The Veterans Health Administration (VHA) originally classified individuals with related ailments believed to be connected to their service in the Persian Gulf a special non-ICD-9 code DX111, as well as ICD-9 code V65.5. The International Classification of Diseases added a formal diagnostic code for Gulf War illness in October 2025. Kansas definition In 1998, the State of Kansas Persian Gulf Veterans Health Initiative sponsored an epidemiological survey led by Dr. Lea Steele of deployment-related symptoms in 2,030 Gulf War veterans. The result was a "clinically based descriptive definition using correlated symptoms" in six symptom groups: fatigue and sleep problems, pain, neurologic and mood, gastrointestinal, respiratory symptoms, and skin (dermatologic) symptoms. To meet the "Kansas" case definition, a veteran of the 1990–91 Gulf War must have symptoms in at least three of the six symptom domains, which during the survey were scored based on severity ("severity"). Symptom onset must have developed during or after deploying to the 1990–91 Gulf War theatre of operations ("onset") and must have been present in the year before interview ("duration"). Participants were excluded if they had a diagnosis of or were being treated for any of several conditions that might otherwise explain their symptoms ("exclusionary criteria"), including cancer, diabetes, heart disease, chronic infectious disease, lupus, multiple sclerosis, stroke, or any serious psychiatric condition. Applying the Kansas case definition to the original Kansas study cohort resulted in a prevalence of Gulf War illness of 34.2% in Gulf War veterans and 8.3% in nondeployed Gulf War era veterans, or an excess rate of GWI of 26.3% in Gulf War veterans. CDC definition Also in 1998, a study published by Dr. Keiji Fukuda under the auspices of the U.S. Centers for Disease Control and Prevention (CDC) examined chronic multisymptom illness through a cross-sectional survey of 3,675 ill and healthy U.S. Air Force veterans of the 1990–91 Gulf War, including from a Pennsylvania-based Air National Guard unit and three comparison Air Force units. The CDC case definition was derived from clinical data and statistical analyses. The result was a symptom-category approach to a case definition, with three symptom categories: fatigue, mood–cognition, and musculoskeletal. To meet the case definition, the veteran of the 1990–91 Gulf War must have symptoms in two of the three categories and have experienced the illness for six months or longer ("duration"). The original study also including a determination of severity of symptoms ("severity"). "Severe cases were identified if at least one symptom in each of the required categories was rated as severe. Of 1,155 participating Gulf War veterans, 6% had severe CMI, and 39% had mild to moderate CMI; of the 2,520 nondeployed era veterans, 0.7% had severe and 14% had mild to moderate CMI." == Treatment ==
Treatment
A 2013 report by the Institute of Medicine reviewed the peer-reviewed published medical literature for evidence regarding treatments for symptoms associated with chronic multisymptom illness (CMI) in 1990–91 Gulf War veterans, and in other chronic multisymptom conditions. For the studies the report reviewed that were specifically regarding CMI in 1990–91 Gulf War veterans (Gulf War illness), the report made the following conclusions: Congressional appropriations for the GWIRP were $5 million for FY2006, (no funding for FY2007) $10 million for FY2008, $8 million for each year from FY2009 through FY2011, $10 million for FY2012, $20 million for each year from FY2013 through FY2017, $21 million for FY2018, and $22 million for each year from FY2019 through FY2021. Beginning with FY2022, research funding opportunities for Gulf War Illness were moved to the broadly focused Toxic Exposure Research Program (TERP) within the CDMRP. == Prognosis ==
Prognosis
According to the May 2018 DoD publication cited above, "Research suggests that the GWI symptomology experienced by Veterans has not improved over the last 25 years, with few experiencing improvement or recovery ... . Many [Gulf War] Veterans will soon begin to experience the common co-morbidities associated with aging. The effect that aging will have on this unique and vulnerable population remains a matter of significant concern, and population-based research to obtain a better understanding of mortality, morbidity, and symptomology over time is needed." == Prevalence ==
Prevalence
The 2008 and 2014 VA (RAC) reports and the 2010 IOM report found that the chronic multisymptom illness in Gulf War veterans—Gulf War illness—is more prevalent in Gulf War veterans than their non-deployed counterparts or veterans of previous conflicts. The VA's 2014 RAC report found Gulf War illness in "an excess of 26–32 percent of Gulf War veterans compared to nondeployed era veterans" in pre-2008 studies, and "an overall multisymptom illness prevalence of 37 percent in Gulf War veterans and an excess prevalence of 25 percent" in a later, larger VA study. == Research ==
Research
Epidemiologic studies have looked at many suspected causal factors for Gulf War illness as seen in veteran populations. Below is a summary of epidemiologic studies of veterans displaying multisymptom illness and their exposure to suspect conditions from the 2008 U.S. Department of Veterans Affairs report. A fuller understanding of immune function in ill Gulf War veterans is needed, particularly in veteran subgroups with different clinical characteristics and exposure histories. It is also important to determine the extent to which identified immune perturbations may be associated with altered neurological and endocrine processes that are associated with immune regulation. Very limited cancer data have been reported for U.S. Gulf War veterans in general, and no published research on cases occurring after 1999. Because of the extended latency periods associated with most cancers, it is important that cancer information is brought up to date and that cancer rates be assessed in Gulf War veterans on an ongoing basis. In addition, cancer rates should be evaluated in relation to identifiable exposure and location subgroups. == Controversies ==
Controversies
An early argument in the years following the Gulf War was that similar syndromes have been seen as an after effect of other conflicts — for example, "shell shock" after World War I, and post-traumatic stress disorder (PTSD) after the Vietnam War. Cited as evidence for this argument was a review of the medical records of 15,000 American Civil War soldiers showing that "those who lost at least 5% of their company had a 51% increased risk of later development of cardiac, gastrointestinal, or nervous disease." Early Gulf War research also failed to accurately account for the prevalence, duration, and health impact of Gulf War illness. For example, a November 1996 article in the New England Journal of Medicine found no difference in death rates, hospitalization rates, or self-reported symptoms between Persian Gulf veterans and non-Persian Gulf veterans. This article was a compilation of dozens of individual studies involving tens of thousands of veterans. The study did find a statistically significant elevation in the number of traffic accidents Gulf War veterans had. An April 1998 article in Emerging Infectious Diseases similarly found no increased rate of hospitalization and better health on average for veterans of the Persian Gulf War in comparison to those who stayed home. In contrast to those early studies, in January 2006, a study led by Melvin Blanchard published in the Journal of Epidemiology, part of the "National Health Survey of Gulf War-Era Veterans and Their Families", found that veterans deployed in the Persian Gulf War had nearly twice the prevalence of chronic multisymptom illness, a cluster of symptoms similar to a set of conditions often at that time called Gulf War Syndrome. . claimed Gulf War syndrome as a defense in his murder trial On November 17, 2008, the Department of Veterans Affairs (VA) Research Advisory Committee on Gulf War Veterans' Illnesses (RAC), a Congressionally mandated federal advisory committee composed of VA-appointed clinicians, researchers, and representative Gulf War veterans, issued a major report announcing scientific findings, in part, that "Gulf War illness is real", that GWI is a distinct physical condition, and that it is not psychological in nature. The 454 page report reviewed 1,840 published studies to form its conclusions identifying the high prevalence of Gulf War illness, suggesting likely causes rooted in toxic exposures while ruling out combat stress as a cause, and opining that treatments likely could be found. It recommended that Congress increase funding for treatment-focused Gulf War illness research to at least $60 million per year. By 2016, the National Academy of Sciences, Engineering, and Medicine (NASEM) concluded there was sufficient evidence of a positive association between deployment to the 1990–1991 Gulf War and Gulf War illness. Jones controversy Louis Jones Jr., the perpetrator of the 1995 murder of Tracie McBride, stated that the Gulf War syndrome caused him to commit the crime and he sought clemency, hoping to avoid the death sentence imposed on him by a federal court. Jones was executed in 2003. == Related legislation ==
Related legislation
On March 14, 2014, Representative Mike Coffman introduced the Gulf War Health Research Reform Act of 2014 (H.R. 4261; 113th Congress) into the United States House of Representatives, where it passed the House by unanimous consent but then died in Congress when the Senate failed to take action on it. The bill would have altered the relationship between the Research Advisory Committee on Gulf War Veterans' Illnesses (RAC) and the United States Department of Veterans Affairs (VA) under which the RAC is constituted. The bill would have made the RAC an independent organization within the VA, require that a majority of the RAC's members be appointed by Congress instead of the VA, and authorized the RAC to release its reports without needing prior approval from the VA Secretary. In the year prior to the consideration of this bill, the VA and the RAC were at odds with one another. While the law directing its creation mandated that it be established not later than January 1, 1999, The RAC convened for its first meetings on April 11–12, 2002. == See also ==
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