Chronic Fatigue: Symptom and Syndrome

The symptom of fatigue remains elusive and fascinating. Of all the symptoms discussed at the Regenstrief Conference, none has the potential to arouse as much bafflement and controversy as this one. First, the symptom is ubiquitous. The association between fatigue and nearly every condition covered in The Oxford Textbook of Medicine or The Oxford Textbook of Psychiatry means that the symptom tends to be held in low esteem by physicians and that the presence of fatigue gives little specific diagnostic information (1). Second, the lack of congruence between the patient's report of feeling tired and exhausted and objective measures of fatigability (whether neuropsychological or physiologic) further frustrates clinicians and investigators. Finally, the chronic fatigue syndrome, a condition that has excessive fatigue and fatigability at its heart, has come to symbolize much of the frustrations and limitations of modern medicine (2). After years of relative neglect, the subject of fatigue has, for many reasons, returned to center stage. A database maintained in the Department of Psychological Medicine at Guy's, King's, and St Thomas' School of Medicine now contains more than 3000 references, 300 of which were added in 1999 alone. It is impossible to do justice here to such a complex subject, so instead I consider only the nature of fatigue, its measurement, and the relationship between fatigue and the chronic fatigue syndrome. I conclude with some observations on treatment and the way forward. Measuring and Defining Fatigue It is almost unnecessary to again draw attention to the ubiquity of the symptom of fatigue. Numerous population studies all confirm that fatigue is always among the most common somatic symptoms; in many studies, it is the most common. The prevalence depends on measurement and definition, but whenever many symptoms are considered together, fatigue is in the top three. Fatigue is not something that one has or does not have. We all experience fatigue, but some have it for longer periods or at a greater intensity than others. To quote the late Geoffrey Rose (3), the real question in population studies is not Has he got it? , but How much of it has he got? In both the community and primary care settings, fatigue, like almost every somatic or psychological symptom, follows a normal distribution (4, 5). Fatigue as it is occurs in the community resists simple measurement. When patients or clinicians refer to fatigue, they use the term differently than physiologists do. Fatigue as defined by the physiologistloss of power over time, first described by Mosso and his ergograph (6)differs greatly from the subjective fatigue experienced by patients. Put simply, 20% or 30% of the population has chronic fatigue, but these people are not abnormally fatigable. Although the literature is not unanimous, compelling evidence of abnormal neuromuscular fatigability in patients with the chronic fatigue syndrome is also lacking. After World War I, one of the tasks of the British Industrial Fatigue Board was to develop a measure of fatigue. This enterprise failed (7); the conclusion was that it was impossible to test for fatigue. This difficulty of measuring fatigue stems from the multidimensional nature of the condition. For example, for neurophysiologists, fatigue can be a mechanism open to precise definition and measurement and exemplified by such conditions as myasthenia gravis. Fatigue can also be a mechanism studied by neuropsychologistshere one encounters studies of progressive failure of cognitive performance on formal testing or attempts to use information processing theory to explore the idea that fatigue can be explained by the limited capacity of the nervous system. Fatigue can also be related to psychological variables, such as belief and expectation, and experimental evidence now suggests that a person's beliefs about fatigue can influence performance. However, fatigue is also a feeling state, and a fundamental part of our current understanding of fatigue is that the feeling of fatigue is distinct from, and barely overlaps with, the behavioral aspects of performance decrement. The number of synonyms that exist for fatiguelack of energy, weakness, effort, sleepiness, tiredness, lassitude, and so onindicates the magnitude of the nosologic task. Similarly, general fatigue seems to be twice as common as exhaustion (8) and nearly 10 times more common than feeling generally run down (9). Small changes in the wording used to ask patients about fatigue or postexertional malaise can profoundly affect prevalence (Jason L. Personal communication). Different groups also use terms in different ways; for example, of 16 adjectives used by psychiatrists to signify sadness, 6 were applied by patients to states of fatigue (10). The Choice of Measures Objective measures of fatigue, independent of the subjective experience of the patient, remain an unattainable Holy Grail. However, investigators have made progress in measuring the subjective symptom of fatigue, and numerous scales are available for this purpose. Some, such as the Fatigue Severity Scale (11) and the Profile of Fatigue Related Symptoms (12), measure several dimensions of illness, such as symptoms and disability. Others, such as the Chalder Scale (13), try to restrict themselves to mental and physical fatigue alone. There is no clear consensus on whether multidimensional or unidimensional measures are preferable (14); I try to use one measure for one dimension and hence separately measure mood, fatigue, symptoms, and disability. The issues involved in this are comprehensively discussed by Jason and Friedberg (15). Is Fatigue Heterogeneous, Multifactorial, or Both? Clearly, fatigue has many causes. The differential diagnosis of fatigue in clinical practice is beyond the scope of this paper, but where discrete causes exist, the combination of history, physical and mental examination, and routine laboratory testing reveals the cause or at least identifies patients for whom further pursuit is worthwhile (16). In addition to the fact that many discrete conditions cause fatigue (heterogeneity), the causes of fatigue may be multifactorial in the same person. For example, the literature on the occurrence and nature of fatigue in numerous discrete diagnostic categories, such as cancer (17), neurologic diseases (18), and rheumatologic diseases (19), is rapidly expanding. Almost invariably, fatigue is found to be common and to be associated with considerable distress and disability. However, most studies fail to link measures of individual disease activity with subjective fatigue; instead, depression, beliefs about illness, and lack of activity figure more prominently (20, 21). It is simple to postulate many discrete mechanisms for fatigue in disparate physical illnesses (22), but it is more difficult to pin these down in practice. Similarly, just as experts debate whether pain due to cancer should be considered, sui generis, as different from chronic nonmalignant pain (with the lumpers gaining ground over the splitters), similar arguments can be found in the literature on chronic fatigue. It is when we move out of the literature on fatigue and discrete disease categories to the wider problem of fatigue in the community or primary care settings, where discrete causes are uncommon (23), that the evidence for multiple simultaneous causes of fatigue becomes overwhelming. I know of no population-based study that has not found chronic fatigue to be associated with a range of variables: demographic, social, cultural, physical, behavioral, and psychological (2, 24-28). So What about the Chronic Fatigue Syndrome? Two conceptual ways to address the problem of the chronic fatigue syndrome are available. First, is the relationship between chronic fatigue and the chronic fatigue syndrome the same as that between moderate hypertension and severe hypertension? In other words, is the chronic fatigue syndrome associated with greater morbidity than but not fundamentally different from chronic fatigue? Or are the two conditions different beasts entirely? Should we lump or split? At the moment, we don't know, but it is worth analyzing the question itself because of some unexpected insights it gives us. It is a relief to note that in general, we have moved on from one form of splitting: the tedious and repetitive rhetoric that pits the it's real against the oh no it's not lobbies, which generate much heat and little light. However, what has succeeded this is a debate about subgroups. Is there one chronic fatigue syndrome, or many? Is there one somatic syndrome, or many? The first argument concerns whether the chronic fatigue syndrome can be considered distinct from all of the other topics being discussed at Regenstrief Conference. The literature on the various symptom-defined conditions indicates that many have tried but failed to produce firm evidence of clear-cut, meaningful distinctions among, for example, the chronic fatigue syndrome, fibromyalgia, and the irritable bowel syndrome (29). It has therefore been argued that splitting these conditions up solely on the basis of symptoms alone (as all current definitions do) is not meaningful and that the current symptom-based definitions do not cleave nature at the joints (30). This is not to say that all patients with unexplained symptoms are the same; it is rather to say that the boundaries between certain conditions are not currently visible. With a greater knowledge of pathophysiology we will no doubt do better, but until we know where the divisions are, a healthy skepticism toward premature splitting is necessary. The next argument is that chronic fatigue syndrome is a broad category and that it must contain several subgroups. Although this theory is plausible, considerable uncertainty exists about what the subgroups might be. Post hoc subgroup analysis is notoriously prone to error, but accumulating evidence suggests that dividing patients u