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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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2

CASE DEFINITIONS

This chapter considers some of the challenges in defining chronic multisymptom illness (CMI), including the array of symptoms experienced by Gulf War veterans, the absence of a clear etiology, the sparseness of data on onset or illness duration, the lack of diagnostic tests, and the many names and methods by which this illness has been characterized. It then focuses on the general elements of a case definition and examines case definitions of other symptom-based disorders.

ADDRESSING CHRONIC MULTISYMPTOM ILLNESS IN GULF WAR VETERANS

Although many Gulf War veterans suffer from an array of health problems and symptoms (such as fatigue, muscle and joint pain, memory loss, and gastrointestinal disorders), those health issues are not necessarily peculiar to any identified disease and are not satisfactorily classified by standard diagnostic coding systems (IOM, 2010). Population-based studies have found a higher prevalence of symptom reporting in Gulf War veterans than in nondeployed Gulf War era veterans or other control groups (Goss Gilroy Inc., 1998; Iowa Persian Gulf Study Group, 1997; Unwin et al., 1999), as discussed in Chapter 3. The wide variation in symptoms reported by Gulf War veterans has complicated efforts to determine whether there is a unique Gulf War syndrome or whether symptom patterns are more consistent with other known symptom-based disorders. Consequently, the array of symptoms suffered by many Gulf War veterans does not often point to an obvious diagnosis, etiology, or specific treatment.

The search for a definitive cause of CMI also has been difficult. The veterans of the 1990–1991 Gulf War were exposed to an impressive array of biologic and chemical agents, as noted in Chapter 1. Numerous studies have been conducted over the last 20 years to determine an etiology based on exposure to many substances, such as pyridostigmine bromide (PB), anthrax vaccine, tent-heater fumes, oil-fire smoke, and chemical odors (Wolfe et al., 2002); jet fuel (Bell et al., 2005); sarin and cyclosarin (Chao et al., 2011); and combinations of organophosphate pesticides, chemical nerve agents, DEET insect repellent, and PB (Haley and Kurt, 1997; Haley et al., 1999). However, exposures during the Gulf War were not reliably measured (if they were measured at all), and most often exposure has been evaluated through surveys or health examinations some years after it occurred (Gray et al., 2004). The association between retrospective recall of exposures and self-reported health outcomes is subject to recall bias (discussed in Chapter 3). No coherent mechanism of action or definitive causal association

Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
×

between the exposures and the range of symptoms reported has been established (Barrett et al., 2002).

Even the terminology used over the years has at times been perplexing. Initially, the term Gulf War syndrome was used; numerous other terms—such as Gulf War illness, unexplained illness, medically unexplained symptoms, medically unexplained physical symptoms, and chronic multisymptom illness—appeared in the medical and scientific literature. Many of the symptoms of CMI overlap with those of other diseases and ill-defined conditions, such as fibromyalgia (FM) and chronic fatigue syndrome (CFS). As noted by Ismail and Lewis (2006), when several symptoms are reported together in the absence of evidence of a physical cause, they are often termed medically unexplained syndromes. It adds to the difficulty of defining CMI and finding a common etiology that the literature contains a number of discussions that refer to different postwar syndromes (see Table 2.1) as possible explanations of the illnesses in Gulf War veterans (e.g., Engel, 2004; Hyams et al., 1996).

Many similarities between previously identified postwar syndromes and CMI have been noted. More generally, all modern wars have been associated with medically unexplained symptoms or syndromes (Jones et al., 2002). Thus, if military personnel are deployed to war zones, some of those returning will have such illnesses. For instance, a systematic comparison of UK pension files from previous wars (the Boer War, World War I, and World War I) with clinical files from the Gulf War, revealed that CMI is similar to many postconflict syndromes. During the Boer War, soldiers complained primarily of fatigue, rheumatic pains, weakness, shortness of breath, rapid heart rate, headache, and dizziness. In World Wars I and II, primary symptom complaints were chest pain, breathlessness, dizziness, and fatigue and to a lesser extent headache and anxiety (King’s College London, 2010).

TABLE 2.1 Postwar Illnesses

War Syndrome or Illness
US Civil War Da Costa syndrome, irritable heart syndrome
World War I Soldier’s heart or the effort syndrome
World War II Acute combat stress reaction, battle fatigue, combat exhaustion
Korean Conflict Acute combat stress reaction
Vietnam War Post-Vietnam syndrome, posttraumatic stress disorder

With regard to specific symptoms reported by the veterans of the 1990–1991 Gulf War, numerous studies have been conducted and details of the symptoms reported. The studies have been summarized and evaluated by previous Institute of Medicine committees (IOM, 2006, 2010), and many are discussed in Chapters 3 and 4 of the present report. A 10-year followup study that tracked the health of 1990–1991 Gulf War veterans found that deployed veterans continued to report persistently poorer health than nondeployed veterans (Li et al., 2011). It was also found that the deployed veterans were less likely to improve and more likely to experience a new onset of adverse health outcomes, including fatigue, than their nondeployed counterparts. In brief, the studies showed that symptom reporting was inconsistent among studies and that no single symptom complex, or syndrome, was identified. However, deployed 1990–1991 Gulf War veterans reported a higher prevalence of fatigue, nervous system symptoms, respiratory symptoms, chronic musculoskeletal pain, gastrointestinal symptoms, mood and cognitive abnormalities, and sleep disturbance than did nondeployed 1991 Gulf War–era veterans.

Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Furthermore, estimates of the prevalence of CMI among deployed 1991 Gulf War veterans vary widely by study population (see Chapter 3).

DEVELOPING CASE DEFINITIONS

In the United States, state and local health officials are required by state laws or regulations to report some diseases. Having standard case definitions for reportable diseases is critical for physicians, health care providers, and other health officials so that they can provide local and federal organizations with information about outbreaks, poisonings, and so on. And having criteria for accurate diagnosis of particular diseases or conditions enables health care providers to prescribe standard treatments. It enables researchers to enroll patients into research and drug trials that are aimed at bringing about cures or treatments. Having defined case definitions also enhances the search for commonalities among cases in an effort to identify causative agents.

According to the Centers for Disease Control and Prevention (CDC), case definitions, particularly related to outbreaks, include criteria associated with persons, places, times, and clinical features (see Table 2.2). Case definitions are important for standardizing criteria for identification of cases.

TABLE 2.2 Elements of a Case Definition

Element Descriptive Feature
Person Age
  Sex
  Occupation
  Exclusion criteria
  Race
Place Geographic location
Time Illness onset
Clinical features Depend on the condition to be defined
Laboratory criteria Blood tests, imaging, and so on

Adapted from CDC, 2008.

A case definition may include criteria that can be used effectively to identify a patient population and distinguish it from patient populations that have similar recognized diagnoses. Case definitions may be derived through clinical evaluation. Clinically derived case definitions are usually formulated a priori by investigators on the basis of commonly reported symptoms. The development of a first case definition may be more like a hypothesis than a conclusion; it is an early step in the process of identifying a new clinical entity and depends on further research. Case definitions commonly change as new evidence becomes available.

Issues of sensitivity and specificity arise in case definitions. A sensitive case definition might be broad in its reach in an effort to capture all people who have the disease but may inadvertently capture some who do not have the disease, whereas a more specific definition might be too narrow and include only people who have the disease but will probably miss some cases. Therefore, case definitions are often adapted for different uses. For example, for particular research purposes, a sample with high positive predictive value might be desirable; that is, a pure

Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
×

sample in which all the subjects who are called cases have a very high probability of actually being cases. For physicians, the primary purposes of a consensus case definition may be to serve as the basis for determining appropriate clinical approaches to evaluation and treatment of those who are affected and to inform the natural history of the condition so that it may be studied (Wegman et al., 1997).

Case Definitions of Symptom-Based Disorders

It is not unusual for some disorders and syndromes not to have an agreed-on case definition or to have multiple case definitions. It is difficult to identify cases in the absence of confirmatory physical signs or laboratory findings and without a known etiology or pathophysiology. The use of case-definition criteria to identify symptoms and validate many serious disorders, such as irritable bowel syndrome (IBS), has been difficult, frustrating, costly, and time-consuming for clinicians, patients, family members, and caretakers. Often, the first attempts at classifying the symptoms for a case definition are not widely accepted—for example, the Manning criteria for IBS followed by the Rome criteria in 1988 (Rome III: The Functional Gastrointestinal Disorders, 2006; Talley et al., 1990). The criteria must be validated to assess their usefulness in clinical and research settings. In many instances, diagnosis of symptom-based conditions requires the exclusion of other conditions, and this may place a serious burden on the patient and the health-care system. In addition, symptom-based criteria may be used inappropriately and might be limited to specific populations (Yale et al., 2008).

The case definitions of chronic fatigue syndrome (CFS) have met with similar problems. For the last 25 years, a wealth of information regarding myalgic encephalomyelitis (ME) and CFS (ME/CFS) has been accumulated. Despite the progress, however, there is still no accurate diagnostic test or proven treatment. Like chronic multisymptom illness, the term chronic fatigue syndrome has been criticized as being vague and trivializing the illness. A number of overlapping case definitions have been published; however, the great majority of research studies use the CDC definition of CFS1 (Fukuda et al., 1994). Like the diagnosis of CMI, the diagnosis of CFS is based on patient-reported symptoms; there is no validated diagnostic test. The diagnosis of ME/CFS is based on the patient’s history, the pattern of symptoms, and the exclusion of other fatiguing illnesses. A symptom-based diagnosis can be made on the basis of published criteria. The 2003 Canadian clinical case definition of ME/CFS (Carruthers et al., 2003) and the 2011 international clinical criteria for ME (Carruthers et al., 2011) are intended to emphasize clearly described core symptoms of the illness. The 1994 Fukuda criteria for CFS are used primarily for research purposes, however, they may be used clinically, and may be required for disability determinations in the United States and elsewhere.

Like CMI and many other symptom-based illnesses, ME/CFS is not without controversy, particularly regarding whether they are mental disorders or physical health disorders (IACFSME, 2012). The committee notes that this either–or approach is not useful, for several reasons. The distinction between mental and physical disorders is often arbitrary, and most patients' experiences of any illness are influenced by biologic, psychologic, and social factors. Either–or thinking leads too often to a presumption that medically unexplained symptoms must be psychogenic. In addition, psychiatric symptoms may not be fully evaluated if a patient’s

_________________________

1CDC was the first agency to define CFS.

Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
×

symptoms are psychogenic. Although physical and psychologic stress can exacerbate many chronic conditions—including chronic pain, headache, respiratory, and gastrointestinal symptoms—there is an inherent risk in assuming that medically unexplained symptoms assume a “stress-induced” etiology. Nearly one-third of physical symptoms presenting in primary care are psychiatric or medically unexplained (Kroenke and Price, 1993). There has been a tendency to dismiss medically unexplained symptoms, but they are disabling and associated with poor quality of life (Ismail and Lewis, 2006).

Case Definitions of Chronic Multisymptom Illness in Gulf War Veterans

One of the tasks of the committee was to examine the peer-reviewed literature specific to deployed Gulf War veterans’ symptomatology in an effort to develop or identify a case definition that will show adequate sensitivity and specificity for research and treatment purposes. In the numerous symptom studies reviewed by the committee, the array of symptoms reported makes it difficult to identify hallmark characteristics of the illness. In addition, the symptoms detailed in Gulf War veterans are shared by other symptom-based disorders, such as CFS and FM, and are seen in the general adult population. There are no objective diagnostic criteria, such as laboratory abnormalities or characteristic physical signs, so diagnosing symptom-based conditions, such as CMI, often must depend on the exclusion of other causes. Thus, specificity becomes a major limitation in developing a case definition of CMI. As noted by Hyams (1998), specificity requires a low proportion of false positives; however, without diagnostic criteria that exclude well-recognized medical and psychiatric causes of symptoms and distinguish them from other symptom-based conditions, a specific diagnosis has not been possible.

Studies that do present a case definition of CMI do not often satisfy the criteria required for a case definition as described above. Although researchers can identify the exposed population (the 1990–1991 Gulf War veterans), it is difficult to assign uniform clinical criteria to all suspected cases or to know the exact time of onset, the duration and severity of symptoms, and so on. Thus, case definitions of symptom-based disorders are often difficult to develop and require continued attention and adjustment as new information becomes available.

REFERENCES

Barrett, D. H., G. C. Gray, B. N. Doebbeling, D. J. Clauw, and W. C. Reeves. 2002. Prevalence of symptoms and symptom-based conditions among Gulf War veterans: current status of research findings. Epidemiologic Reviews 24(2):218-227.

Bell, I. R., A. J. Brooks, C. M. Baldwin, M. Fernandez, A. J. Figueredo, and M. L. Witten. 2005. JP-8 jet fuel exposure and divided attention test performance in 1991 Gulf War veterans. Aviation Space and Environmental Medicine 76(12):1136-1144.

Blanchard, M. S., S. A. Eisen, R. Alpern, J. Karlinsky, R. Toomey, D. J. Reda, F. M. Murphy, L. W. Jackson, and H. K. Kang. 2006. Chronic multisymptom illness complex in Gulf War I veterans 10 years later. American Journal of Epidemiology 163(1):66-75.

Carruthers, B. M., M. I. van de Sande, K. L. De Meirleir, N. G. Klimas, G. Broderick, T. Mitchell, D. Staines, A. C. Powles, N. Speight, R. Vallings, L. Bateman, B. Baumgarten-Austrheim, D. S. Bell, N. Carlo-Stella, J. Chia, A. Darragh, D. Jo, D. Lewis, A. R. Light, S. Marshall-Gradisbik, I. Mena, J. A. Mikovits, K. Miwa, M. Murovska, M. L. Pall, and S. Stevens. 2011. Myalgic encephalomyelitis: International Consensus Criteria. Journal of Internal Medicine 270(4):327-338.

Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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CDC (Centers for Disease Control and Prevention). 2008. Outbreak Case Definitions. http://emergency.cdc.gov/urdo/pdf/CaseDefinitions.pdf (accessed August 8, 2013).

Chao, L. L., L. Abadjian, J. Hlavin, D. J. Meyerhoff, and M. W. Weiner. 2011. Effects of low-level sarin and cyclosarin exposure and Gulf War Illness on brain structure and function: a study at 4T. Neurotoxicology 32(6):814-822.

Engel, C. C., Jr. 2004. Post-war syndromes: Illustrating the impact of the social psyche on notions of risk, responsibility, reason, and remedy. Journal of the American Academy of Psychoanalysis and Dynamic Psychiatry 32(2):321-334; discussion 335-343.

Fukuda, K., R. Nisenbaum, G. Stewart, W. W. Thompson, L. Robin, R. M. Washko, D. L. Noah, D. H. Barrett, B. Randall, B. L. Herwaldt, A. C. Mawle, and W. C. Reeves. 1998. Chronic multisymptom illness affecting Air Force Veterans of the Gulf War. Journal of the American Medical Association 280(11):981-988.

Fukuda, K., S. E. Straus, I. Hickie, M. C. Sharpe, J. G. Dobbins, and A. Komaroff. 1994. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Annals of Internal Medicine 121(12):953-959.

Goss Gilroy Inc. 1998. Health Study of Canadian Forces Personnel Involved in the 1991 Conflict in the Persian Gulf. Ottawa, Canada: Goss Gilroy Inc. Department of National Defence.

Gray, G. C., G. D. Gackstetter, H. K. Kang, J. T. Graham, and K. C. Scott. 2004. After more than 10 years of Gulf War veteran medical evaluations, what have we learned? American Journal of Preventive Medicine 26(5):443-452.

Haley, R. W., S. Billecke, and B. N. La Du. 1999. Association of low PON1 type Q (type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicology and Applied Pharmacology 157(3):227-233.

Haley, R. W., and T. L. Kurt. 1997. Self-reported exposure to neurotoxic chemical combinations in the Gulf War. A cross-sectional epidemiologic study. Journal of the American Medical Association 277(3):231-237.

Hyams, K. C. 1998. Developing case definitions for symptom-based conditions: The problem of specificity. Epidemiologic Reviews 20(2):148-156.

Hyams, K. C., F. S. Wignall, and R. Roswell. 1996. War Syndromes and Their Evaluation: From the U.S. Civil War to the Persian Gulf War. Annals of Internal Medicine 125(5):398-405.

IACFSME (International Association for Chronic Fatigue Syndrome/Myalgic Encephalomyelitis). 2012. ME/CFS: A Primer for Clinical Practioners. www.iacfsme.org/portals/0/pdf/primerfinal3.pdf (accessed August 8, 2013).

IOM (Institute of Medicine). 2006. Gulf War and Health, Volume 4: Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press.

IOM. 2010. Gulf War and Health, Volume 8: Update of Health Effects of Serving in the Gulf War. Washington, DC: The National Academies Press.

Iowa Persian Gulf Study Group. 1997. Self-reported illness and health status among Gulf War veterans: A population-based study. Journal of the American Medical Association 277(3):238-245.

Ismail, K., and G. Lewis. 2006. Multi-symptom illnesses, unexplained illness and Gulf War Syndrome. Philosophical Transactions of the Royal Society B: Biological Sciences 361(1468):543-551.

Jones, E., R. Hodgins-Vermaas, H. McCartney, B. Everitt, C. Beech, D. Poynter, I. Palmer, K. Hyams, and S. Wessely. 2002. Post-combat syndromes from the Boer War to the Gulf War: A cluster analysis of their nature and attribution. British Medical Journal 324(7333):321-324.

King’s College London. 2010. King's Centre for Military Health Research: A fifteen Year Report. What has been Achieved by Fifteen Years of Research into the Health of the UK Armed Forces? University of London.

Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Kroenke, K., and R. Price. 1993. Symptoms in the community: prevalence, classification and psychiatric comorbidity. Archives of Internal Medicine 153:2474–2480.

Li, B., C. M. Mahan, H. K. Kang, S. A. Eisen, and C. C. Engel. 2011. Longitudinal health study of US 1991 Gulf War veterans: changes in health status at 10-year follow-up. American Journal of Epidemiology 174(7):761-768.

Rome III: The Functional Gastrointestinal Disorders. 2006. Edited by D. A. Drossman. Vol. 3: Rome Foundation.

Talley, N. J., S. F. Phillips, L. J. Melton, C. Mulvihill, C. Wiltgen, and A. R. Zinsmeister. 1990. Diagnostic value of the Manning criteria in irritable bowel syndrome. Gut 31(1):77-81.

Unwin, C., N. Blatchley, W. Coker, S. Ferry, M. Hotopf, L. Hull, K. Ismail, I. Palmer, A. David, and S. Wessely. 1999. Health of UK servicemen who served in Persian Gulf War. Lancet 353(9148):169-178.

Wegman, D. H., N. F. Woods, and J. C. Bailar. 1997. Invited commentary: how would we know a Gulf War syndrome if we saw one? American Journal of Epidemiology 146(9):704-711; discussion 712.

Wolfe, J., S. P. Proctor, D. J. Erickson, and H. Hu. 2002. Risk Factors for Multisymptom Illness in US Army Veterans of the Gulf War. Journal of Occupational and Environmental Medicine 44(3):271-281.

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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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Suggested Citation:"2 Case Definitions." Institute of Medicine. 2014. Chronic Multisymptom Illness in Gulf War Veterans: Case Definitions Reexamined. Washington, DC: The National Academies Press. doi: 10.17226/18623.
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More than 2 decades have passed since the 1990-1991 conflict in the Persian Gulf. During the intervening years, many Gulf War veterans have experienced various unexplained symptoms that many associate with service in the gulf region, but no specific exposure has been definitively associated with symptoms. Numerous researchers have described the pattern of signs and symptoms found in deployed Gulf War veterans and noted that they report unexplained symptoms at higher rates than nondeployed veterans or veterans deployed elsewhere during the same period. Gulf War veterans have consistently shown a higher level of morbidity than the nondeployed, in some cases with severe and debilitating consequences. However, efforts to define a unique illness or syndrome in Gulf War veterans have failed, as have attempts to develop a uniformly accepted case definition.

Chronic Multisymptom Illness in Gulf War Veterans is a comprehensive review of the available scientific and medical literature regarding symptoms for chronic multisymptom illness (CMI) among the 1991 Gulf War Veterans. This report evaluates and summarizes the literature in an effort to identify appropriate terminology to use in referring to CMI in Gulf War Veterans. While the report does not recommend one specific case definition over another, Chronic Multisymptom Illness in Gulf War Veterans does recommend the consideration of two case definitions on the basis of their concordance with the evidence and their ability to identify specific symptoms commonly reported by Gulf War veterans. This report recommends that the Department of Veterans Affairs use the term Gulf War illness rather than CMI. The report recommends that that the Department of Veterans Affairs, to the extent possible, systematically assess existing data to identify additional features of Gulf War illness, such as onset, duration, severity, frequency of symptoms, and exclusionary criteria to produce a more robust case definition.

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