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2 Characterizing Chronic Multisymptom Illness Before evaluating treatments for chronic multisymptom illness (CMI), the committee defined it. The terminology surrounding CMI can be confus- ing, and it is inconsistently defined in the literature. This chapter covers the following issues: • Terms used to characterize conditions that are similar to CMI. These terms sometimes are used interchangeably and at other times have distinct meanings. • The committee’s definition of CMI. • What is known about CMI in the general, military, and veteran populations. • The goals of treating for CMI. TERMINOLOGY The term chronic multisymptom illness was first used to describe chronic unexplained symptoms in Air Force veterans of the 1991 Gulf War (Fukuda et al., 1998). CMI was defined as the report by a veteran of one or more chronic unexplained symptoms (present for 6 months or longer) in at least two of the following categories: • Fatigue. • Mood and cognition (symptoms of feeling depressed, difficulty in remembering or concentrating, feeling moody, feeling anxious, trouble in finding words, or difficulty in sleeping). 21

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22 GULF WAR AND HEALTH • Musculoskeletal (symptoms of joint pain, joint stiffness, or muscle pain). Because the study was funded and conducted by the Centers for Disease Control and Prevention (CDC), that characterization is often referred to as CDC’s case definition of CMI. 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. Earlier committees of the Institute of Medicine (IOM) found no evidence of a specific symptom complex (or syndrome) that was peculiar to deployed Gulf War veterans (IOM, 2006, 2010). Reports of chronic unexplained symptoms are not peculiar to Gulf War veterans; this phenomenon has been documented in military personnel throughout modern history (Hyams et al., 1996; IOM, 2010; Jones, 2006). Before World War I, such chronic unexplained symptoms as fatigue, short- ness of breath, and chest pain were referred to as irritable heart, soldier’s heart, Da Costa’s syndrome, and others. Other terms associated with the adverse effects of combat experience on health and well-being include shell shock (World War I), psychoneurosis (World War II and the Korean War), and post-Vietnam syndrome, later identified as posttraumatic stress disorder (PTSD) (Jones, 2006). A cluster analysis of common symptoms in veterans from 1900 to the 1991 Gulf War did not reveal a unique set of symptoms that were associated with each war (Jones and Wessely, 2005; Jones et al., 2002). However, veterans of the 1991 Gulf War have reported more cases of chronic medically unexplained symptoms than veterans of prior conflicts (Hunt, 2012). Chronic unexplained symptoms are common in civilians. Such terms as medically unexplained symptoms, medically unexplained physical symp- toms, somatoform disorders (for example, somatization disorder, undiffer- entiated somatoform disorder, and pain disorder), and functional somatic syndromes are often used to describe the disorders of civilians who have chronic unexplained symptoms. The common thread among the terms is that symptoms experienced by patients cannot be explained as patho- logically defined, or organic, disease (Sharpe and Carson, 2001). Such syndromes as irritable bowel syndrome (IBS), chronic fatigue syndrome (CFS, also called myalgic encephalomyelitis), and fibromyalgia often are included in this group of unexplained illnesses, as are chronic unexplained symptoms that do not meet case definitions for IBS, CFS, fibromyalgia, and other functional somatic syndromes that have specified diagnostic criteria.

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CHARACTERIZING CHRONIC MULTISYMPTOM ILLNESS 23 THE COMMITTEE’S WORKING DEFINITION OF CHRONIC MULTISYMPTOM ILLNESS To approach its task, the committee first developed a working defini- tion of CMI. It began by considering the CDC definition described above. Fukuda et al. (1998) arrived at their case definition for CMI by using both a statistical approach called factor analysis and a clinical approach in which symptoms had to be reported for at least 6 months by at least 25% of 1991 Gulf War Air Force veterans enrolled in the study and by deployed veterans ­ at least 2.5 times more often than by nondeployed military personnel. Three categories of symptoms were included in their case definition: fatigue, mood and cognition, and musculoskeletal. Other types of reported symptoms— including gastrointestinal, respiratory, and neurologic—did not meet the threshold for the case definition. The committee decided to broaden its working definition to include respiratory, gastrointestinal, and neurologic symptoms because previous IOM reports found that these types of symp- toms were commonly reported by 1991 Gulf War veterans (IOM, 2006, 2010). As suggested in the 1995 IOM report Health Consequences of Ser- vice During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action, a reasonable case definition of CMI is necessary for VA hospitals to identify veterans who are eligible for care for their symp- toms (IOM, 1995). Correctly identifying a health condition may improve patient care and avoid unnecessary tests (Wegman et al., 1997). CMI is a complex, amorphous condition and its case definition may change as new scientific information emerges. For the purpose of this report, the committee defined CMI as follows: The presence of a spectrum of chronic symptoms experienced for 6 months or longer in at least two of six categories—fatigue, mood and cognition, musculoskeletal, gastrointestinal, respiratory, and neurologic—that may overlap with but are not fully captured by known syndromes (such as IBS, CFS, and fibromyalgia) or other diagnoses. It is important to note that the committee’s definition does not include syndromes that have well-defined diagnostic criteria, such as IBS, CFS, and fibromyalgia. However, because of the shared symptoms, effective therapies for those defined syndromes may be beneficial to patients who have CMI. Chapter 5 of this report explores the evidence that supports therapies for the other syndromes and discusses the possible application of the therapies for managing CMI. As discussed in Chapter 7, the Department of Veterans Affairs (VA) provides disability compensation for CMI associated with Gulf War service without regard to cause (38 CFR Sec. 3.317).

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24 GULF WAR AND HEALTH CHRONIC MULTISYMPTOM ILLNESS IN CIVILIAN AND VETERAN POPULATIONS Most people experience some unexplained symptoms—symptoms that cannot be attributed to any organic cause—during their lifetimes; u ­ nexplained symptoms can account for one-fourth to half of all patient visits to primary care clinicians (Burton, 2003; Janca et al., 2006; Kroenke et al., 1990). Patients who have unexplained symptoms are seen in primary care practices and in medical specialty practices (for example, gynecology, gastro­ nterology, and rheumatology) (Nimnuan et al., 2001). e However, some people have such symptoms repeatedly. In general, chronic medically unexplained symptoms (lasting 6 months or more) remain unexplained and unresolved. One study reported that the symptoms of almost 60% of patients who had unexplained symptoms remained unex- plained over a 12-month period (Koch et al., 2009). The longer the patient had the symptoms before presentation, the poorer the long-term prognosis. A comprehensive review of the literature on unexplained symptoms found that “many patients with MUPS [medically unexplained physical symptoms] have no definite psychological illness” (Burton, 2003, p. 235). O ­ thers have concluded that unexplained symptoms are likely to be multi­ factorial and include physiologic, psychologic, and social factors (Sharpe and Mayou, 2004). Numerous studies have examined the symptoms reported by veterans of the 1991 Gulf War. They have been summarized and evaluated by IOM (2006, 2010) and will not be reexamined here. Briefly, although symp- tom reporting was inconsistent among studies and no single symptom complex, or syndrome, was identified, deployed 1991 Gulf War veterans reported increased prevalence of fatigue, nervous system symptoms, respira- tory symptoms, chronic musculoskeletal pain, gastrointestinal symptoms, mood and cognitive abnormalities, and sleep disturbance compared with nondeployed 1991 Gulf War–era veterans. Estimates of the prevalence of CMI among deployed 1991 Gulf War veterans indicate that CMI is twice as common in deployed veterans as in nondeployed 1991 Gulf War–era veterans. In one study, 45% of Air Force veterans of the 1991 Gulf War met the criteria for CMI compared with 15% of nondeployed 1991 Gulf War–era veterans (Fukuda et al., 1998). In a separate study that used the same definition of CMI as Fukuda et al. (1998), the prevalence of CMI was 29% among deployed 1991 Gulf War veterans and 16% among nondeployed 1991 Gulf War–era veterans 10 years after the end of the Gulf War (Blanchard et al., 2006). In these studies, CMI was statistically significantly associated with service in the Gulf War, enlisted rank, female sex, and smoking (Fukuda et al., 1998) and prewar depression and anxiety (Blanchard et al., 2006). A 10-year

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CHARACTERIZING CHRONIC MULTISYMPTOM ILLNESS 25 follow-up study that tracked the health of 1991 Gulf War veterans found that deployed veterans continued to report persistently poorer health than nondeployed veterans (Li et al., 2011). It was 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. VA continues to conduct research to follow the health of the 1991 Gulf War veterans (VA, 2012b). The most recent survey in the series began in May 2012 and includes questions related to CMI. Information about the prevalence of medically unexplained symptoms in veterans of the Iraq and Afghanistan wars is sparse. The most common health outcomes reported in the literature associated with service in the Iraq and Afghanistan wars are PTSD, mild traumatic brain injury, and pain (Walker et al., 2010). One study reported that the prevalence of that triad of conditions in veterans of the Iraq and Afghanistan wars who were seen in a VA polytrauma clinic was 42% (Lew et al., 2009). Veterans of the Iraq and Afghanistan wars report a number of symp- toms (see Box 2-1). Some—sleep disturbance; concentration, attention, BOX 2-1 Symptoms and Related Functional Impairment Reported by Veterans of Operation Iraqi Freedom, Operation Enduring Freedom, and Operation New Dawn • Sleep disturbance • Low frustration tolerance and irritability • Concentration, attention, and memory problems • Fatigue • Headaches • Musculoskeletal disorders • Affective disturbance • Apathy • Personality change • Substance misuse (including opioid misuse) • Activity avoidance and kinesiophobia • Hypervigilance • Employment or school difficulties • Relationship conflict SOURCE: Adapted from Walker et al., 2010. Original print available in the public domain.

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26 GULF WAR AND HEALTH and memory problems; fatigue; headaches; and musculoskeletal pain p ­ roblems—also have been reported by 1991 Gulf War veterans. Walker et al. (2010) have proposed that the presentation of symptoms in veterans of the Iraq and Afghanistan wars be called “postdeployment multisymptom disorder.” One of the more common diagnoses among veterans of the Iraq and Afghanistan wars (nearly 52% of the veterans) is symptoms, signs, and ill-defined conditions (that is, conditions that do not have an immediately obvious cause or isolated laboratory-test abnormalities) (VA, 2012a). Among 335 responses to the 1-year postdeployment assessment com- pleted by National Guard and Army service members participating in the HEROES study, 57.2% met the definition of CMI proposed by Fukuda et al. (1998). Risk factors associated with CMI identified from this cohort include combat exposure, number of stressful deployment experiences, PTSD symptoms, predeployment stressful life events, and severe nonspecific physical symptoms before deployment (McAndrew et al., 2012). VETERAN VS CIVILIAN POPULATIONS In this report, the committee uses, as part of its evidence base, studies conducted in populations other than Gulf War veterans. As noted above, experiencing chronic unexplained symptoms is not peculiar to Gulf War veterans and in fact is common in the general population. Veterans of the 1991 Gulf War may have a higher prevalence of u ­ nexplained symptoms than veterans of previous conflicts (Hunt, 2012), but the types of symptoms appear to be consistent with the types experi- enced by veterans of other wars and by civilians. There are important differences between studies of civilians and studies of veterans. For example, in studies of unexplained symptoms in civilians, the samples tend to be mostly white women of middle age; only about 7% of military personnel in the 1991 Gulf War were women, and the overall mean age was 28 years. MANAGING VS CURING CHRONIC MULTISYMPTOM ILLNESS It is important to continue to describe, classify, and explain CMI. Many clinicians, patients, and family members are understandably focused on finding a specific etiology and cure. In the meantime, veterans who have CMI and the clinicians who care for them have clamored for assistance in improving function and outcomes of those who have the condition. Vet- erans must find a way to live productive lives in spite of their CMI, and clinicians must offer care for patients who have conditions that remain unexplained. The experience with medically unexplained symptoms and similar syndromes in the general population suggests that although a cure

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CHARACTERIZING CHRONIC MULTISYMPTOM ILLNESS 27 for CMI may be elusive, effective management is possible. Many patients are deprived of the benefits of an organized, systematic approach to the clinical management of CMI. The present committee’s goal is to pro- vide an organized, systematic approach to management for veterans who have CMI. REFERENCES 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. Burton, C. 2003. Beyond somatisation: A review of the understanding and treatment of medically unexplained physical symptoms (MUPS). British Journal of General Practice 53(488):231-239. 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. Hunt, S. C. 2012. VA Approaches to the Management of Chronic Multi-symptom Illness in Gulf War I Veterans. Presentation at the Third Committee Meeting, April 12, 2012, Irvine, CA. Hyams, K. C., F. S. Wignall, and R. Roswell. 1996. War syndromes and their evaluation: From the US Civil War to the Persian Gulf War. Annals of Internal Medicine 125(5):398-405. IOM (Institute of Medicine). 1995. Health Consequences of Service During the Persian Gulf War: Initial Findings and Recommendations for Immediate Action. Washington, DC: National Academy Press. IOM. 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. Janca, A., M. Isaac, and J. Ventouras. 2006. Towards better understanding and management of somatoform disorders. International Review of Psychiatry 18(1):5-12. Jones, E. 2006. Historical approaches to post-combat disorders. Philosophical Transactions of the Royal Society of London—Series B: Biological Sciences 361(1468):533-542. Jones, E., and S. Wessely. 2005. War syndromes: The impact of culture on medically unex- plained symptoms. Medical History 49(1):55-78. 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. [erratum appears in BMJ 324(7334):397]. British Medical Journal 324(7333):321-324. Koch, H., M. A. van Bokhoven, P. J. E. Bindels, T. van der Weijden, G. J. Dinant, and G. ter Riet. 2009. The course of newly presented unexplained complaints in general practice patients: A prospective cohort study. Family Practice 26(6):455-465. Kroenke, K., M. E. Arrington, and A. D. Mangelsdorff. 1990. The prevalence of symptoms in medical outpatients and the adequacy of therapy. Archives of Internal Medicine 150(8):1685-1689. Lew, H. L., J. D. Otis, C. Tun, R. D. Kerns, M. E. Clark, and D. X. Cifu. 2009. Prevalence of chronic pain, posttraumatic stress disorder, and persistent postconcussive symptoms in OIF/OEF veterans: Polytrauma clinical triad. Journal of Rehabilitation Research and Development 46(6):697-702.

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28 GULF WAR AND HEALTH 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. McAndrew, L. M., H. K. Chandler, E. A. D’Andrea, G. Lang, C. Engel, and K. S. Quigley. 2012. Chronic Multisymptom Illness: An Unrecognized Public Health Concern Among OEF/OIF Veterans. Paper presented at HSR&D/QUERI National Conference 2012, National Harbor, MD. http://www.hsrd.research.va.gov/meetings/2012/abstract-display. cfm?RecordID=590 (accessed September 12, 2012). Nimnuan, C., M. Hotopf, and S. Wessely. 2001. Medically unexplained symptoms: An epide- miological study in seven specialities. Journal of Psychosomatic Research 51(1):361-367. Sharpe, M., and A. Carson. 2001. “Unexplained” somatic symptoms, functional syn- dromes, and somatization: Do we need a paradigm shift? Annals of Internal Medicine 134(9 Pt 2):926-930. Sharpe, M., and R. Mayou. 2004. Somatoform disorders: A help or hindrance to good patient care? British Journal of Psychiatry 184:465-467. VA (Department of Veterans Affairs). 2012a. Analysis of VA Health Care Utilization Among Operation Enduring Freedom (OEF), Operation Iraqi Freedom (OIF), and Opera- tion New Dawn (OND) Veterans. http://www.publichealth.va.gov/docs/epidemiology/ healthcare-utilization-report-fy2012-qtr2.pdf (accessed September 12, 2012). VA. 2012b. Gulf War Follow-Up Study. http://www.publichealth.va.gov/epidemiology/studies/ gulf-war-follow-up.asp (accessed September 12, 2012). Walker, R. L., M. E. Clark, and S. H. Sanders. 2010. The “postdeployment multi-symptom disorder”: An emerging syndrome in need of a new treatment paradigm. Psychological Services 7(3):136-147. 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.