Fatigue is the normal result of over-exertion or lack of sleep and is defined as ‘extreme tiredness resulting from mental or physical exertion or illness’ (Oxford English Dictionary, 2017). Individuals experience an intense subjective sense of tiredness, energy depletion and weakness. Whether it is physical and/or cognitive in nature, fatigue can be interpreted differently by different individuals, ranging from tiredness to clinically relevant exhaustion. This makes the symptom difficult to quantify. It is also subjective. That is to say, the interpretation of the fatigue experienced is based on an individual’s personal opinion, interpretation, point of view, emotion and judgement. However, when it persists over time (i.e. is chronic in nature) and is unresolved by rest, fatigue can be extremely debilitating.
In order to understand the increasing problem chronic fatigue presents to healthcare, it is important first to consider the historical context. Although often thought of as an illness that emerged in the 1980s, chronic fatigue has been redefined over time, and this is reflected in the changes in nomenclature used to describe it and the way in which the scientific community has chosen to research it. In the early 1990s, Wessely presented an historical background of post-viral fatigue syndrome (PVFS) in the British Medical Bulletin (Wessely, 1991). This in-depth essay charted the appearance of the illness in the medical literature and went some way to explain the cultural attitudes towards chronic fatigue in society. An overview of the salient points will be presented here to put its importance in the medical and research literature into perspective (Thomas, 2009).
The history of chronic fatigue stretches back over one hundred years. Its appearance in the medical literature as neurasthenia can be traced back to the mid-nineteenth century. Described as a weakness in the nervous system, a diagnosis of neurasthenia was grounded in neurology, an emerging discipline. Seen almost as a badge of honour by experts and those diagnosed the condition at that time, neurasthenia was associated with hard-working, intellectual men from the higher social classes. Its increasing prevalence was ascribed to the ascent of capitalism and the raised expectations it produced and emphasis on personal productivity.
By the beginning of the twentieth century, it was viewed as exhaustion of the central nervous system (CNS) and attributed to a range of aetiologies including deficient energy sources, a genetic fault or as the result of toxic, metabolic or infective insults (Cobb, 1920; Forster, 1900; Pershing, 1904). As a consequence, clinicians postulated that treatments aiming to stimulate the CNS or sedate over-activity and/or those which might replace or recuperate lost energy would address symptoms. The suggested methods for replacing or recuperating energy included the application of electrical stimuli and the rest cure.
Dissenters then began to challenge the existence of an organic cause of neurasthenia, and the search for an aetiological explanation moved towards the then emerging discipline of psychiatry. Modifications to the definition of the illness also shifted to include mild melancholic, anxious or depressive states and proffered existing treatments with appropriate modifications.
The absence of a known cellular basis for the fatigue also led to clinicians asserting that the rest cure was ill-advised and unnecessary. Instead, activity or exercise along with psychotherapy were being suggested (Hall, 1905). A shift in terminology also occurred. Physical nomenclature such as ‘painful fatigue’ were being replaced with psychological terms such as ‘anhedonia’ (Myerson, 1922). By 1941, neurasthenia was described as being ‘in reality depression—perhaps minor, attenuated, atypical, masked, but always forms of anxious melancholia’ (Tinel, 1941, p. 926).
Notwithstanding, researchers continued to search for the thus far elusive organic cause of this chronic fatigue. Following on from suggestions by Van Deusen (1869), for example, that neurasthenia was a toxic state linked to an infective agent, the focus returned to the possible involvement of specific infectious agents such as influenza in triggering chronic fatigue. This association led to the emergence of the term post-viral fatigue syndrome (PVFS). However, it was later made clear that this fatigue state could follow any viral infection where anxiety and/or depression were a comorbid condition (Ash, 1909; Lane, 1906).
Despite this setback, researchers continued to pursue an aetiology based on infection until as recently as the 1980s. Straus and colleagues reported findings that suggested the causative agent of chronic fatigue was the Epstein–Barr virus (EBV) which causes infectious mononucleosis—also referred to as glandular fever (Straus et al., 1985). This association between a specific virus and fatigue led to the introduction of the label chronic Epstein–Barr infection. However, although glandular fever is very often accompanied by prolonged fatigue, this usually resolves within a six-month period post-infection.
Probably one of the most well-known terms associated with chronic fatigue in the medical history of the condition has been myalgic encephalomyelitis (ME). This diagnosis is also the one which has generated great interest within the scientific community and society. The first reported case of ME appeared in 1955 following a mysterious outbreak of a fatiguing illness which afflicted the majority of staff at the Royal Free Hospital in London—which was later documented by Ramsay in 1986 (Ramsay, 1986). This benign condition—encephalomyelitis—was thought to have its origins within the discipline of infectious diseases (Medical Staff of the Royal Free Hospital, 1976). The claims of the infectious nature of ME proved difficult to substantiate and, whilst agreeing that the outbreak was contagious, was famously contradicted by McEvedy and Beard (1970) who considered that the contagion was one of mass hysteria. The aetiology of ME remains contentious as neither view point has been corroborated and the matter remains unresolved. Although this could be disconcerting for those who experience such chronic fatigue, in the grand tradition of science, it did provide impetus for ongoing research that would ultimately lead to a better understanding of the origins of and mechanism behind this insidious condition.
Although sporadic cases of ME continued, its incidence as an epidemic waned over time (Smith, 1989). Intermittent cases of the condition became more widespread in the 1980s and the outlook for individuals with this condition became bleak. Again, appearing to mimic the history of neurasthenia, the fatigue experienced in ME was at first thought to be neuromuscular in origin and treatments once again centred on the rest cure. However, although the theories put forward were supported by data from electromyography (EMG) and nuclear magnetic resonance (NMR) studies, as reported in a review by Jamal and Millar (1991), there was some doubt as to their validity. Research then focussed on a possible aetiology involving changes in the CNS. When this direction of enquiry proved fruitless, and, in almost a repeat of what occurred previously in the history of unexplained fatigue, the aetiological route of ME finally arrived at the psychological direction.
The term Chronic Fatigue Syndrome (CFS) first appeared in the medical literature in 1988 in both the USA and Australia (Holmes et al., 1988; Lloyd, Wakefield, Boughton, & Dwyer, 1988; Straus et al., 1988). In the USA, it was also referred to as chronic fatigue and immune deficiency syndrome (CFIDS) by patient groups. In a departure from the history of neurasthenia and ME, the initial focus of research into the aetiology of CFS returned to focus on the role of viruses, namely the EBV—as investigated previously in the USA (Straus et al., 1985)—and enteroviruses—originally the polio virus—in the UK.
Again, however, this substantial body of research conducted over several years, aiming to identify not only a causative agent but biological diagnostic markers, was to no avail. Early reports of an association between chronic fatigue and a number of possible causative infective agents generated hope that an aetiology was imminent, and a treatment would closely follow. Unfortunately, these claims have yet to be substantiated (Dismukes, Wade, Lee, Dockery, & Hain, 1990; Straus et al., 1988). Nevertheless, it was thought that persistent viral infection could be a possible mechanism for perpetuation of the illness (Archard, Bowles, Behan, Bell, & Doyle, 1988; Bowles, 1993; Cunningham, Bowles, Lane, Dubowitz, & Archard, 1990). This was corroborated in some part by studies indicating increased susceptibility to infections in patients suffering psychological stress which might also explain the circumstances seen in CFS (Cohen, Tyrrell, Russell, Jarvis, & Smith, 1993; Cohen, Tyrrell, & Smith, 1991; Cohen & Williamson, 1991). In fact, a major impact of the disease on the patient has been described as one of a ‘chronic, recurring, flu-like illness’ (Dubois et al., 1984; Jones et al., 1985; Komaroff, 1991; Straus et al., 1988). Anecdotally, patients with CFS were frequently reporting symptoms which seemed to indicate recurrent infections and it was postulated that these infections could be implicated as a possible means whereby the illness is exacerbated (Smith, 1991). These claim...