What is Chronic Fatigue Syndrome - what else is it called?

Doctors regularly see patients whose main symptom is that of severe fatigue often associated with other symptoms, but not conforming to a clear cut medical diagnosis. A variety of terms have been devised to describe these conditions such as "irritable bowel syndrome" and "neurasthenia". Recently the terms "myalgic encephalomyelitis" ("ME") and "post viral fatigue syndrome" have been introduced. However, neither of these are particularly satisfying terms because encephalomyelitis refers to a distinct neuropathological process which is not found, and post viral fatigue syndrome implies that all cases occur after a viral illness which is not the case. Prospective controlled studies from the Institute of Psychiatry have shown that although most sufferers seen in our specialist clinic remember a viral infection as the trigger for their illness, common viral infections are not associated with the illness.

An international consensus has therefore been reached that the term "chronic fatigue syndrome" (CFS) a label which is both short and accurate should be used.

Symptoms and treatments

There are no diagnostic signs or symptoms of CFS. A variety of symptoms, such as post exertional fatigue or myalgia (muscle pain); difficulties in concentration and short term memory; subjective changes in temperature and many others have been reported but none are diagnostic. The diagnosis is therefore made in someone with excessive physical and mental fatigue, brought on by physical or mental effort, and with associated functional disability, for whom a conventional biomedical explanation cannot be found.

No specific treatment exists, although a variety of agents have been tried. Various antiviral drugs, or agents acting on the immune system, have been tested, but none can be recommended at present. Nutritional supplements are popular, and so long as they are cheap and free from side effects, may have a place.

Antidepressants are known to be successful in the related conditions of fibromyalgia, and should be used in patients with depressive features. It is also possible that antidepressants have a direct effect on fatigue and myalgia independent of mood disorder, but this is not yet established. The Institute of Psychiatry is participating in a current clinical trial to assess this further. The mainstay of treatment, however, remains rehabilitation. Thus researchers have developed a rehabilitation package using cognitive behaviour therapy to combat both physical deconditioning and psychological problems. They believe that the counselling previously recommended of rest is of little value, and may indeed prolong the symptoms of fatigue, pain and depression.

Research

Researchers are involved in research into the prevalence of CFS in the community. Results show that whereas fatigue is very common, few people are labelled as having "ME" or "post viral fatigue". Both groups have also confirmed that the stereotype of "Yuppie flu" is a myth, and that there is no excess of these illnesses in upper social classes.

Causes of the illness

The cause of chronic fatigue syndrome is unknown and is being investigated by researchers at the Institute of Psychiatry. For example, they are investigating whether there are immunological or virological explanations of CFS. It has been discovered that some patients show immunological abnormalities, such as high levels of circulating immune complexes, altered serum immunoglobulins and low levels of natural killer cells, but at present these findings are inconclusive.

The role of infection in CFS is also unclear. Certainly, fatigue syndromes do occur after many infections, both viral (e.g. infectious mononucleosis or influenza) and bacterial (e.g. brucellosis). However these syndromes may not be a major risk factor for abnormal fatigue of longer that six months duration. At present only Epstein Barr virus (EBV), the virus that causes glandular fever, is known to be associated with chronic fatigue syndrome. Research continues on other agents, but most studies have draw a blank. There is a close association with psychological disorder, with rates in excess of what could be expected as a reaction to physical illness. Up to 70% of those seen in primary or specialist care fulfil criteria for psychiatric disorders, particularly depression, anxiety and somatisation disorders. Not surprisingly some neurobiological and neuropsychological abnormalities have been identified, both by studies here and elsewhere. Whereas we have been unable to replicate some findings of abnormalities on structural neuroimaging, we have reported the finding of hypocortisolaemia and an underactive hypothalamo-pituitary axis together with preliminary evidence of increased central 5HT neurotransmission in some CFS patients. The significance of these observations remains unclear.

Risk factors

Certain factors are known to increase the risk of developing CFS. For example, it is more common in patients who have had previous psychiatric illness, particularly when associated with an infective illness. In addition, certain infections may also themselves predispose to CFS, in particular glandular fever, encephalitic illnesses, and also other causes of central nervous damage. Finally, lack of physical fitness, particularly in previously fit people forced into inactivity may play a role in perpetuating CFS.

Psychiatric illness and chronic fatigue syndrome

There is no doubt that the symptoms of CFS overlap with those of severe psychiatric disorders. Nearly all depressed patients report substantial fatigue, and for some it is the most distressing part of the illness. However, the precise role of psychiatric disorder in CFS is not yet clear. Psychiatric illness is occasionally a consequence of physical illness, but this does not explain the higher rates of psychiatric disorder found in CFS compared with other chronic illness. More work on possible brain dysfunctioning is being carried out at the Institute of Psychiatry to explore these links further.

What is very clear is that sufferers make dramatic alterations in lifestyle, resulting in frequent physical deconditioning. Despite these observations, many hold extremely strong views that the illness has a solely organic basis. Suggestions that psychological factors may be relevant, or even a psychiatric referral appropriate, will rarely be met with approval. We have carried out some sociological and historical research on the cultural reasons underlying CFS. We have shown how such factors as the perceived stigma of psychological illness, current views on viruses and immunity in disease, the role of physical attributions in protecting self esteem, and the role of social and personality factors in vulnerability to illness, are all relevant. Overall, the intense political controversy and passions aroused by CFS relate to the issue of what is, and what is not, a legitimate illness in current society.

The future

The Institute of Psychiatry has a unique role to play in investigating these disabling conditions. We have published studies on the neuroendocrinology, psychology, epidemiology, physiology, history and treatment of this condition. We have pioneered the development of an effective package based on the principles of cognitive behaviour therapy. We recently published the results of a 5 year follow up study of patients treated in an open fashion with this new approach, and showed that treatment gains were maintained over the period. As a result we undertook a formal randomised controlled trial, comparing the new technique with relaxation therapy. This was successful. Further trials are now underway looking at the new treatment in primary care, and also looking at the effects of a self help package. Finally, we are participating in a randomised controlled trial of a selective serotonin reuptake inhibitor, but focusing on non-depressed patients. Studies of neuropsychology have been undertaken, and it is hoped that a new study using neuroimaging will start soon.

Research has led to substantial advances in our understanding of the epidemiology, aetiology and mechanisms underlying CFS. Finally, no one should now say "CFS - there is nothing you can do about it".

Dr Anthony Cleare

Consultant Psychiatrist and Head of Section - Neurobiology of Mood Disorders

Neurobiology of Chronic Fatigue Syndrome

Introduction

The Chronic Fatigue Syndrome Research and Treatment Unit has now been running for nearly 10 years, and has seen around 1000 patients. During that time, we have made great inroads into defining the epidemiology of the illness (i.e. how much of it there is, who gets it, how long they have it for and what happens to them), unravelling the psychological components of the illness, and devising new and effective treatment programmes for patients. I joined the unit in 1995, and have been working since then on attempting to define the neurobiological components of the illness, and how they might interact with the psychological.

Background to the illness

Patients complaining of fatigue are common: 20-50% of the population report suffering from fatigue, while 10% of GP attenders report fatigue for 6 months or more. A smaller group can be shown to have significant disability resulting from their fatigue. In recent years, this severe end of the spectrum of chronic fatigue has been operationally defined as Chronic Fatigue Syndrome (CFS). The definition is of medically unexplained fatigue of at least 6 months duration that is of new onset, is not a result of ongoing exertion, is not substantially alleviated by rest, and leads to a substantial reduction in previous levels of activity. In addition, 4 or more of the following symptoms must be present: subjective memory impairment; sore throat; tender lymph nodes; muscle pain; joint pain; headache; unrefreshing sleep; and post exertional malaise delayed by 24 hours. Exclusion criteria for CFS include the presence of an underlying disease likely to cause fatigue, severe psychiatric illness (psychosis, melancholic or bipolar depression, dementia, eating disorder, substance misuse) or severe obesity. Myalgic Encephalomyelitis (ME) is a frequently used, though medically incorrect, popular term for this condition.

Recent estimates at the prevalence of CFS in the community vary from 0.5% to 1.5%. The only significant demographic difference is that of gender with the relative risk for women varying between 1.3 and 1.7. While those seen in specialist clinics are more often from higher social classes, this is likely to be a referral bias, since population surveys do not find that CFS is less likely to occur in groups of lower socio-economic status or in ethnic minorities.

Although it is unlikely that CFS is a single illness, efforts to define valid subgroups have not yet been fruitful. Differences do exist between the minority of cases with long illness histories, severe disability and multiple symptoms, who show overlap with the concept of somatisation disorder, and the larger group with less disability, fewer symptoms and shorter illness durations, who have a better prognosis. We take the view that CFS is an illness in which there are many different causal factors both between different patients and within individual patients. The aetiology represents an interaction of the biological, psychological and social realms

Research into the neurobiology of CFS

Genetics: Although systematic family studies have not been undertaken, recent twin studies from others at the Institute of Psychiatry do suggest a genetic propensity to suffer from chronic fatigue.

Viruses: In the clinic, the majority of patients with CFS date the onset of their symptoms to a viral infection of some sort. Many positive findings of 'the CFS virus' were published; however, even ignoring the major methodological problems in many studies, no findings of an association between CFS and the persistence of a certain virus have been replicated in different populations or by different research groups. We have recently begun testing again after reports of high rates of newly discovered viruses, and again have no evidence for specific viral persistence in our patients. We have, however, published evidence that certain severe viral infections (e.g. glandular fever or meningitis) are 'triggers' for CFS.

Hypothalamo-pituitary-adrenal axis: The hypothalamo-pituitary-adrenal (HPA) axis is the primary long-term mediator of the body's stress response. Initial interest in this axis was generated by the observation that Addison's disease (underactive adrenal glands) is characterised by many CFS-like symptoms. Recent research from our own group has revealed evidence of mildly reduced adrenal production of cortisol, both basal and after stimulation. We recently reviewed the literature and found support for this, although not all studies agree. The reason why cortisol levels are lowered is also unclear: many factors influence cortisol secretion, including changes in sleep, activity and appetite. For example, night shift working can produce similar changes to the HPA axis. It is probable that, once again, the HPA axis changes in CFS are due to several factors, and may be subtly different depending the exact factors present in each patient (e.g. sleep, physical activity, presence of depression, drugs taken, or circadian rhythm changes).

Other neuroendocrine changes: There were early reports of impaired growth hormone (GH) function in CFS. However, we recently undertook a thorough investigation of the GH-IGF axis in CFS, using basal IGF-1, IGF-2, IGFBP-1, IGFBP-2 & IGFBP-3 levels, 24-hour urinary GH, GHRH challenge testing and insulin stress testing. We found no impairment in GH-IGF function, and concluded that the axis was normal in CFS.

Immunology: Although there are several reports of alterations in immune parameters, most frequently of a mild immune activation, these are inconsistent. At present it is impossible to determine the significance of the observed changes in immunological status in CFS. Our own studies suggest no link between any immune changes and clinical symptoms or outcome [.

Neurochemistry: Changes in central serotonin (5-HT) levels have been hypothesised as a possible physiological mechanism underlying central fatigue. We have measured brain 5-HT function using the neuropharmacological challenge paradigm. For example, the prolactin response to a standardised dose of d-fenfluramine, a drug that selectively causes release of 5-HT in the brain, gives an indication of the responsiveness of brain 5-HT pathways. We found that CFS subjects show a higher prolactin response than controls, in contrast to depressed patients who have a reduced response [11], a finding confirmed by others. We are now using positron emission tomography (PET) to measure directly 5-HT receptors in CFS.

Muscle: Complaints of muscle pain or fatigability are common in CFS. However, most studies of neurophysiological function have been normal, particularly once the secondary effects of inactivity are taken into account.

Autonomic nervous system: Several studies have investigated the possible role of the autonomic nervous system in CFS. Most striking has been studies reporting an increased rate of neurally mediated hypotension, while there is also some evidence suggesting sympathetic overactivity and/or parasympathetic underactivity. However, it remains unclear whether or not these are causal factors in CFS, since both anxiety and prolonged inactivity are associated with similar changes.

Neuroimaging: There have been several recent studies using neuroimaging techniques such as SPET to study cerebral blood flow in CFS. Whilst a number of abnormalities have been found, including lowered perfusion of the brain stem and frontal lobes, many investigators have failed to replicate these findings. A review by Professor David of the Unit noted that one can often diagnose alternative illnesses or organic brain diseases in those showing abnormalities. Furthermore, depression or anxiety can be associated with similar changes in cerebral blood flow and many studies have not been rigorous enough in separating out these confounding influences. Nevertheless, neuroimaging remains a useful tool for the future. We are starting to undertake studies using functional magnetic resonance to identify the neural correlates of the subjective experience of fatigue; these may enhance our understanding of the brain mechanisms underlying the sense of effort, and possible disturbances in CFS.

Interaction with Psychological and Social Factors

It is clear that, as in most illnesses, there is an interaction of any biological processes with psychological and social ones. Briefly, any coherent explanation of CFS must try to integrate these findings. This is beyond the scope of this brief article, but examples of potential interactions coming out of our research include:
a) Life Events: Adverse life events are related to the development of acute fatigue, and to the subsequent chronicity of this fatigue, while positive life events may be protective. This may link with the neurobiological research on the stress axis outlined above.
b) Other precipitants to CFS: These include major surgery, overtraining, cancer treatment or drugs (e.g. interferon). We are currently investigating these specific conditions, but suggest that they all share the interaction of psychological and physiological factors in producing the final clinical picture.
c) Psychological Disorder: The relationship between psychiatric disorder and CFS remains controversial, but there is no doubt that such a relationship exists: between one half and two thirds of most clinical samples fulfil criteria for psychiatric disorder as well as CFS. The commonest psychiatric disorder reported in studies of CFS is depression (perhaps because of the overlap of the operationalised criteria). However, in some respects CFS shares more similarities with anxiety than depression - particularly in terms of neuroendocrine dysfunction, the role of fear and avoidance behaviour, and treatment response.
d) Neuropsychological function: Most patients attending clinics with CFS experience marked difficulties with various neuropsychological functions, such as memory, attention and concentration. Whilst objective tests have failed to document conventional cognitive impairments in keeping with the severity of subjective complaints, there is evidence for some disturbance of complex information processing and efficiency. It is plausible that sufferers find that everyday tasks require increased cognitive resources; although they are able to perform reasonably well on such tasks, it is at the price of increased mental effort. Once again, we are hoping to use neuroimaging to attempt to discern any underlying neural changes, a process begun by others.
e) Cognitive-behavioural factors: The cognitive behavioural model operates independently of the initial precipitants of fatigue, but separates out the components of CFS into those acting as risk factors, triggers and perpetuating factors. Thus, an initial physiological trigger for fatigue (a severe virus, or those mentioned in (b) above) can be perpetuated by these factors, including: physiological and psychological effects of inactivity; inconsistent activity patterns; illness beliefs; and symptom focusing. Social factors may act similarly
Implications for Treatment

The mainstays of treatment at present are based on Graded Exercise and Cognitive Behavioural Therapy, for which there is a good evidence base in the literature. In keeping with our integrative approach, we are currently study possible biological changes consequent to these therapies.

Studies of antidepressants in CFS have been few, and the results generally disappointing. Given our findings on opposing changes in 5-HT systems between depression and CFS, at least in those CFS patients who are not also depressed, these results may not be that surprising. More positively, there is preliminary evidence of a modest clinical response to the newer antidepressant moclobemide.

Following directly on from our findings of reduced cortisol levels in CFS, our group undertook a randomised, placebo-controlled trial of very small doses (5-10 mg daily for one month) of hydrocortisone (identical to cortisol) in an attempt to supplement the reduced endogenous production. This produced large reductions in fatigue in 28% of patients, compared to 9% in those receiving placebo. Importantly, this regime did not impair the ability of the adrenal glands to continue to produce cortisol, a risk with higher doses of hydrocortisone. Furthermore, those who responded to treatment reported reduced disability ratings, and endocrine testing showed a reversal of the pre-treatment deficient cortisol response to CRH challenge [7] Potential side effects and the lack of follow up data beyond one month preclude such strategies as routine treatments at present, but suggest that low cortisol levels and HPA axis disturbances may be one significant perpetuating factor in CFS.

Summary

CFS is not due to a single cause. As outlined above, the fullest understanding of CFS at the present time involves using a multi dimensional approach, in which due attention is given to both physical and psychological factors, and to their interaction. As with other multifactorial conditions, it is important to consider the roles of predisposing, precipitating and perpetuating factors from a biopsychosocial perspective. For now, the most effective interventions are aimed at possible perpetuating factors. As more is understood in the future, it is possible that there will be greater potential for targeting risk factors, the prevention of CFS after identified triggers, or the modification of the biological processes underlying fatigue. This remains a serious challenge for the new millennium.