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		Syndromes and Causes - Illness and Disease Dr Justine Ward, RMA Secretariat Paper presented at the RMA Forum March 2004 Syndromes and Causes - Illness and Disease Introduction The health problems of veterans of the first Gulf War have been extensively studied by various governments. The difficulty of defining and finding the causes of the diverse symptoms reported by veterans of the Gulf War has once again highlighted the problem of war syndromes and their evaluation. The Repatriation Medical Authority has a statutory responsibility to make Statements of Principles for syndromes, provided that they meet the legal requirements for definition of a disease under Section 5D of the Veterans' Entitlements Act (VEA). The problems with defining syndromes and evaluating their causes as they relate to the functions of the RMA will be outlined in this paper. The broader question of understanding health and illness will also be considered, as this question relates to how disease is defined and how symptoms are understood by individuals. Defining a Syndrome and Potential Consequences A syndrome is defined in Dorland's Medical dictionary as "a set of symptoms which occur together; the sum of signs of any morbid state; a symptom complex". To be able to recognise a syndrome there needs to be a repeatable grouping of particular symptoms. Often there is no known cause of a syndrome and sometimes a cause will subsequently be discovered. For example, acquired immune deficiency syndrome (AIDS) was initially described by a set of symptoms recognised by an astute group of clinicians and study of the syndrome eventually led to the discovery of a new virus. Illnesses that are well defined as diseases have more status than symptoms and this leads to a pressure to find a cause or at least define a syndrome. The naming of a syndrome, while providing the comfort of validation to sufferers, also has potential consequences which may be both adverse or beneficial to individuals. It essentially medicalises a set of symptoms, with major potential medical, legal, political and social consequences because of flow on effects to approaches to treatment, compensation and patient's lives. Giving a set of symptoms a medical name can place people in the sick role and actually impede their recovery. This was realised as far back as World Wars I and II, when it was found that soldiers with acute combat stress reaction were more likely to return to duty if they were treated quickly and near their combat units than if they were treated as patients in a hospital (Hyams, Wignall and Roswell 1996). An individual's expectations of his/her prognosis can have the effect of self-fulfilling prophecy. A poor self-rated health status has been found to be a predictor of mortality in longitudinal studies and this phenomenon is not entirely explained by existing illnesses and symptoms (Idler and Benyamini 1997). Self-rated health can influence behaviours that influence health status, for example smoking, alcohol use, less engagement in preventive practices such as physical activity and screening and poor compliance with medications. Reduced expectations may be reinforced by social factors, such as reduced employment opportunities for those with disabilities, financial incentives and behaviour of peers (Lupton and Najman 1989). Concerns about potential reproductive effects may make people worry about their children's health or even decide not to have children. Because of such potential adverse consequences, it is important that syndromes are not defined unless there is a sound scientific basis for doing so. Exposures and Possible Causes The problem of post combat syndromes has prompted considerable research and debate as to their aetiology. One possibility is that post combat syndromes are physiological diseases caused by unique environmental exposures. In every conflict there are unique exposures related to the place, the time and the conditions of war. In the Vietnam War there was Agent Orange/dioxin; in the Bosnian conflict there was depleted uranium; and in the Gulf Wars unique exposures have included smoke and oil cloud, vaccinations against plague and anthrax and the anti-nerve agent pyridostigmine bromide. Each conflict also has distinctive psychological stressors, such as heavy shelling of trenches in World War 1; not knowing which villagers were Viet Cong in the Vietnam conflict; and threat of being exposed to chemical, biological or radiological weapons in the Gulf War conflicts. Pervasive, unknown threats can be very hard to cope with psychologically. One veteran wrote in a letter home: "I can deal with getting shot at, because even if I got hit, I can be put back together- a missile, I can even accept that. But gas scares the hell out of me..." (Berstein and Kelley, 1995) There has been a great deal of effort made towards attempting to discover possible associations with exposures and various diseases. Despite this large research effort, chronic somatic symptoms have not consistently been linked to any particular exposure (Hyams, Wignell and Roswell 1996, Sim et al 2003). For more recent conflicts, there is a possibility that symptoms represent the early stage of disease or diseases which have yet to manifest fully with demonstrable physical signs or changes in laboratory tests. Further follow up is needed to ensure that diseases do not develop. Sufferers of the so called "effort syndrome" in World War I were followed up but did not show an increased mortality (Hyams, Wignell and Roswell 1996, Jones et al 2002). Studies of mortality in Gulf War veterans have not so far shown an increase in overall mortality relative to non-deployed veterans and no disease categories were significantly elevated in veterans (Research Working Group of Military and Veterans Health Coordination Board 2002). Although follow up will inevitably demonstrate the development of diseases over time, a link to exposures still needs to be made to establish causation. Another possible explanation for post combat symptoms is that, despite some unique war experiences, there is something about the overall war experience that produces a common response. It is interesting to examine the historical record relating to post-combat syndromes. Hyams et al (1996) has described war syndromes characterised by similar symptoms after every conflict since the US civil war. These symptoms include fatigue, shortness of breath, headache, sleep disturbance, forgetfulness and impaired concentration. These war syndromes were given different names after each conflict: "irritable heart syndrome" in the US Civil War; "effort syndrome" in World War I; "battle fatigue" in World War II; posttraumatic stress disorder after the Vietnam; and "Gulf War syndrome" after the first Gulf War. US, UK and Australian Gulf veterans report suffering from more symptoms than non-Gulf veterans. A range of neuropsychological symptoms was most commonly reported despite markedly different exposures of each veteran. Jones et al (2002) attempted to characterise post-combat syndromes by doing a historical cluster analysis of symptoms using war pension files from the Boer War to the first Gulf War. In this study the authors examined the veterans' own attribution of symptoms. Boer war and First World War servicemen with disordered action of the heart believed it to be due to physical illness or physical exertion. First World War veterans with neurasthenia attributed their symptoms to both physical exertion and the psychological stress of military service. Gulf War servicemen with predominantly debility symptomatalogy tended to attribute illness to physical illness, injury or environmental conditions, whereas those with neuropsychiatric symptoms tended to attribute symptoms to the psychological stress of war. This historical examination shows that experiences of symptoms, diagnostic labels and beliefs about causation are linked but change according the nature of combat, contemporary medical knowledge and prevailing health beliefs. These authors conclude that what has changed is not the symptoms themselves but the way in which they have been reported by veterans and doctors. It highlights the potential danger of allowing preconceptions to get in the way of scientific hypothesis formation and testing. Shared symptoms may represent a common reaction to stressors or other exposures whether they occur in military or civilian life. Australian Gulf War I veterans reported all fatigue related outcomes more commonly than the comparison group and had elevated amounts of symptoms in the groupings of psychophysiological, cognitive and athro-neuro-muscular (Sim et al 2003). There is an overlap in these symptoms and those experienced by civilians affected by multiple chemical sensitivities, fibromyalgia and chronic fatigue syndrome. Unexplained symptoms have also been reported by civilians after the World Trade Centre attacks (Clauw et al 2003). All these conditions or postulated conditions have in common that they are based on self-reported symptoms, lack objective verification of exposures and proven causative exposures, lack consistent abnormal physical findings and cannot be confirmed with any clinical test (American College of Occupational and Environmental Medicine 1999, Working group chronic fatigue syndrome 2002). It has been suggested that, rather than apply specific labels to groups of symptoms, particularly ones that imply a pathogenesis, a more clear and unbiased terminology should be used, for example "medically unexplained symptoms" (Clauw 2003). To add to the confusion, there is also an overlap of symptom based conditions with various psychiatric disorders which often manifest with somatic complaints, including anxiety, depression and somatoform disorders (Hyams 1998). This is not to suggest that the diagnosis of a psychiatric condition is in doubt, but it can be difficult to establish whether the psychiatric disorder is the primary cause of symptoms or a result of debilitating fatigue or pain. Methodological Problems With Studying Syndromes A syndrome is sometimes defined primarily for the purposes of study. Having a definition does not necessarily mean that a condition exists. Study designs require that people with a condition (cases) are compared to people without a condition (controls) for the prevalence of particular risk factors, or that exposed and unexposed groups of people are compared to see what proportion develop into cases. It is therefore necessary to develop at least a working definition of a case. However, the lack of specificity of such definitions means that they may not be reliable in distinguishing cases from non-cases (Hyams 1998). This reduces the power of the study to detect a difference in exposures between the two groups. When cases cannot be reliably identified it is also difficult to recognize the influence of bias and confounding (Hyams and Roswell 1998). It is hoped that progress in the study of symptom based conditions will eventually identify some consistent distinguishing laboratory features and make case definitions much more specific, at least in some instances. Chronic fatigue syndrome has been able to be characterised by a common set of diagnostic criteria (Fukuda 1994). In contrast, while the level of symptom reporting among Gulf War veterans was higher than in the comparison group, statistical analysis showed that the pattern of symptom reporting in the two groups was similar. This has suggested that the Gulf War veterans do not have a unique symptom complex or cluster (Sim et al 2003). Similarly, no consensus for proposed definitions for multiple chemical sensitivities has been able to be reached in the scientific community, in a large part because of the lack of ability to identify a specific group of symptoms. There were many methodological problems associated with studying Gulf War illnesses, especially problems with objectively measuring exposures and recall bias. The latter is a potential problem with all retrospective studies. People who are concerned about their symptoms or who have a disease are more likely to ascribe to a particular exposure or experience than people who feel well. Sufferers of symptom-based conditions have ascribed their symptoms to various temporally associated environmental exposures, including modern offices, chemicals, food allergies and silicone implants (Hyams 1998). Extensive questioning of veterans for health studies or health assessments has the potential to remind them of traumatic events and provoke symptoms. The authors of the Australian Gulf War health study state that some, but not all, symptom reporting could be explained by recall bias (Sim et al 2003). Their analysis also suggested a possible problem with recall bias in reporting of exposures. A study of recall of military hazards showed that reporting of military exposures can change over time, although consistency of reporting is better for some exposures than others (Wessely et al 2003). Furthermore, reporting new exposures was associated with worsening health perception while forgetting previous exposures was associated with improved perception. Ill-defined symptoms are common presenting complaints to primary care physicians. As many general practitioners can attest, it is not always easy to diagnose a disease because many diseases present with similar symptoms and signs. Without the ability to distinguish between them on the basis of signs or pathological tests, some diseases would be impossible to diagnose. Even if a physiological correlate of disease is found, it does not necessarily establish that it is causally related, as the abnormality could also be an effect of symptoms rather than the cause of them. Illness and Disease Part of the difficulty with dealing with medically unexplained symptoms may be due to an artificial dichotomy between disease and health. Dorland's medical dictionary defines disease as "any deviation from or interruption of the normal structure or function of a part, organ, or system of the body as manifested by characteristic symptoms and signs; the etiology, pathology, and prognosis may be known or unknown." The VEA has a slightly broader definition: (a) any physical or mental ailment, disorder, defect or morbid condition (whether of sudden onset or gradual development); or (b) the recurrence of such an ailment, disorder, defect or morbid condition. Disease definitions are useful for various purposes: for researchers to establish causation, for governments to base policies on compensation and for the medical profession to make decisions about treatment, especially if symptom clusters consistently respond to specific clinical strategies. However, disease definitions do not necessarily give an accurate reflection of how people experience their health on a day to day basis. Health is defined as a state of optimal physical, mental, and social well-being, and not merely the absence of disease and infirmity. In a review of the scientific literature pertaining to stressors and the Gulf War, Marshall (1999) pointed out that: "Illness and disease are overlapping, but distinct, constructs. Whereas disease refers to constellations of symptoms that define a diagnosable physical or psychiatric disorder, illness refers to the subjective experience of poor health. Illness manifests itself as somatic (bodily) or psychological symptoms, but may stem from multiple sources--including cognitive and social processes--and may or may not reflect the presence of an underlying disease (Kleinman, 1988). The relationship of illness to disease is complex. A person may experience ill health with no underlying disease. Conversely, he or she may suffer from an underlying disease without perceiving himself or herself as ill (Weiner, 1992)." Sociologists argue that it is not possible to separate the experience of health or ill health from its social context. Much poor health is a function of social circumstances and events (eg broken marriages, boring and repetitive work) and may have no pathophysiological basis (Lupton and Najman 1989). The traditional disease model looks simplistically for single or component causes with a biological basis, whereas an endpoint of complete health allows for a model of causation which accommodates a complex interaction of psychosocial and physical factors. Psychosocial factors include context, knowledge, attitudes, beliefs, personality, past experiences, peer values, and the social, legal and economic environment. All these factors affect the meaning or significance that is attached to symptoms. Causal models that rely on a more integrative approach, with stress and central nervous system responses as a final common pathway, may prove useful in explaining the effects of a multiplicity of environmental factors (Kipen and Fiedler 2002). Hyams et al (1996) suggest that it will not be possible to explain war-related syndromes until there is a better understanding of health and illness in the general population. Population based studies suggest that more than one third of symptoms may be medically unexplained (Clauw et al 2003). Hyams proposes two basic questions: 1. What is the relation between chronic, non-specific symptoms and physiologic and psychological illness? 2. What factors- medical, environmental, psychological, or social- create a personal sense of ill health? Many disease processes can be imagined as a continuum from complete health to ill health to disease. The division between what is called health and what is called disease is often determined by a cut off point. Cut off points are usually set where symptoms become very functionally disabling and/or where treatment has been shown to be beneficial to the majority of people from this point onwards. This cut off point is not fixed- it changes according to the sensitivity of diagnostic tests, scientific understanding about the benefits of treatment and the availability of treatment options. Common examples of this include treatment levels for hypertension, diabetes and hypercholesterolaemia. If the cut-off point is set too high, some people who would benefit from treatment will miss out. If the cut-off point is set too low, some people's health may actually be harmed because they will be labelled as sick and will receive treatment unnecessarily. Decisions about where symptoms, signs or tests are labelled "abnormal" need to keep this risk/benefit balance in mind and should be based on good evidence. At the clinical and social level, though, it is important to keep in mind that there is often a continuity between persons whose symptoms have been given disease status and those with unexplained symptoms. Just because medically unexplained symptoms do not appear to fit the traditional medical disease paradigm, are hard to study and are not easily accommodated within the legislative restrictions of the RMA, it does not mean that they are not real and legitimate. Whether symptoms may or may not be due to a disease process, they can be very disabling functionally and greatly impair quality of life. Despite an absence of proven causes, treatment is still very important, although care must be taken to avoid well intentioned but harmful interventions. There is little systematic evidence on which to base strong recommendations for interventions to prevent or mitigate post combat syndromes (Clauw et al 2003). There is some evidence that cognitive-behavioural interventions that prepare personnel for the realities of war offer some benefit (Clauw et al 2003). Social support appears to buffer the effect of stressful events. Critical incident debriefing does not appear to improve health outcomes and may do more harm than good. Constructive treatment after symptoms have developed involves management of symptoms and efforts to restore functioning, rather than focussing on exhaustive diagnostic testing. Outcomes are better if treatment is given early, before symptoms become chronic. Conclusion In summary, the objective strategies used to determine when symptoms without any identifiable pathological basis become a disease or syndrome include statistical clustering, response to treatment, expert consensus and symptom severity. The best approach relies on more than one method and should make clinical and pathophysiological sense. However, recognition of symptom clustering is also influenced by contemporary beliefs. Studies to date do not rule out the possibility of distinct clinical diseases being eventually found to be responsible for at least some chronic unexplained symptoms. In relation to Gulf War related symptoms and other chronic symptom-defined conditions, it is difficult to know if they reflect physiological or psychological diseases with single or multiple causes, or a normal response to the physical and psychological stresses of war. The evidence we have to date is not very helpful in distinguishing between these possibilities. A basic understanding of the prevalence of symptoms in the general population is needed. Studies of military populations also have much potential to help answer the questions of health and illness, particularly if they are prospective in nature and collect accurate data on exposures. It is important to know the psychological and physical state of soldiers prior to deployment, in order to establish that there has been a change. Follow up immediately after the conflict and periodically thereafter will clearly establish the timing of any adverse health effects. Adequate preparation may help prevent post combat symptoms and early treatment of symptoms regardless of cause will minimise chronic effects. Previous | Contents | Next This page last updated 22 March 2005.

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