CHRONIC FATIGUE SYNDROME

CONSULTATION-LIAISON PSYCHIATRY

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CHRONIC FATIGUE SYNDROME Michael Sharpe, MA, MRCP, MRCPsych

Although similar illnesses have been described for many years, the chronic fatigue syndrome (CFS) was first operationally defined in 1988.48 It has subsequently become a topical and controversial illness and is now the subject of more than 800 indexed publications. Despite this volume of research, our understanding of the condition is poor and positive approaches to treatment few. A major reason for this slow progress has been the conceptual difficulties that are encountered when trying to understand illnesses that are unexplained by readily identifiable organic disease. These difficulties have hindered research into the nature and treatment of CFS and may even have played a part in shaping the illness itself. The first part of this article briefly examines the concept of medically unexplained illness and the implications for the definition of CFS. Research into the nature and cause of CFS is then reviewed. I conclude that whereas the current concept of CFS has major shortcomings, simply replacing a medical diagnosis with a psychiatric one does not solve the clinical problem. Instead, I advocate a systematic description of each case from biologic, psychological, and social perspectives. In the second part of the article a practical evidence-based guide to the management of CFS based on this approach is outlined. THENATUREANDCAUSEOFCFS Fatigue as a Symptom

Fatigue has been defined in a variety of ways.6 Here, however, we are concerned with fatigue as a subjective feezing of weariness, lack of The Oxford Chronic Fatigue Research group is supported by grants from the Linbury Trust and the Wellcome Trust.

From the Department of Psychiatry, The University of Oxford, Oxford, United Kingdom

THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 19 * NUMBER 3 SEPTEMBER 1996

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energy, and exhaustion." The feeling of fatigue is a common human experience and subjective ratings of its severity are continuously distributed in the population,78with approximately 20% of persons reporting fatigue to be a problem.62Although only a small minority of these people seek a medical opinion, fatigue is a common presenting symptom in 55 primary care.22, Fatigue as an Illness

A clinical syndrome in which the complaint of fatigue is severe, exacerbated by exertion, and accompanied by other symptoms including poor concentration, irritability, and muscle pain has been recognized at least since the last century and possibly before.lo0In the latter years of the last century, patients with this syndrome received the diagnosis of neurasthenia, a condition of uncertain cause commonly ascribed to the effect of the stresses of modern life on the human nervous ~ y s t e m As .~ the years passed the diagnosis of neurasthenia became too broadly defined to be useful and by the early 1900s it was falling out of common use. Although it is possible that the symptom of fatigue also waned in the population, it seems more likely that patients with similar symptoms were given alternative diagnoses. These diagnoses include hypothetical disease explanations, such as myalgic encephalomyelitis, chronic brucellosis, and chronic Epstein-Barr virus (EBV) infection, as well as the psychiatric syndromes of depression and anxiety."O In the last 10 years nonpsychiatric physicians have increasingly come to believe that the symptoms of most patients presenting to them with chronic severe fatigue are not readily explained either by recognized organic disease28or by depression and anxiety disorders. The syndrome of chronic fatigue has consequently become regarded as "medically ~nexplained"~~ and has gained a certain notoriety as a clinical conundrum. In hospital clinics the syndrome is most commonly seen in white females in early and midadulthood. It has been diagnosed in all age groups, including children.21 Clinical Example. A typical patient is found in the infectious disease department of the hospital. His or her principal complaint is of fatigue, poor concentration, and muscle pain. These symptoms are exacerbated by physical and mental exertion and have led to a substantial reduction in daily activities. The history is of an acute onset of symptoms after a viral illness. Appropriate inquiry often reveals symptoms suggestive of depression or anxiety but without prominent mood change. The patient believes the illness to be medical rather than psychiatric. When the patient admits to distress, he or she explains it as a result of the illness rather than its cause. How is this illness best understood?

The Problem of Medically Unexplained Illness Severe chronic fatigue is in fact only one of a number of highly prevalent medically unexplained somatic symptoms and

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Such illnesses are problematic because of both philosophic and moralistic prejudice that surrounds current notions of illness. The implicit assumption that mind and body are separate (dualism) leads to illness being categorized as either physical or mental. Moralistic prejudices lead to those illnesses classified as mental being regarded as implying personal weakness or inferiority on the part of the sufferer, whereas those considered physical by and large do Illnesses in which the patient’s main complaints are somatic, but where the physician can find no evidence of disease, do not fit neatly into this dichotomous and morally charged classification and consequently cause medical, social, and legal problems. The dualistic attitude to illness is readily observed in the classification of medically unexplained syndromes, which appear in both medical and psychiatric diagnostic systems but sit comfortably in neither. The medical approach to medically unexplained illness is to conceive of it as an organic disease of functional rather than structural nature and includes diagnoses, such as fibromyalgia, irritable bowel syndrome, and CFS.70The psychiatric approach is to regard these conditions as psychological disorders, such as depression or anxiety, which are presenting atypically with an emphasis on somatic rather than psychological symptoms. Where the illness cannot be squeezed into the categories of depression or anxiety the concept of a somatoform disorder (which also implies that the somatic symptoms are psychological in origin, but somatic in presentation) is invoked. Which of these approaches is correct? If the patient’s illness meets criteria for both a functional disease and a psychiatric disorder, are they best regarded as having a medical or a psychiatric illness? There clearly is no correct answer to this question, which must ultimately be resolved in terms of the clinical usefulness of each diagnos ~ s The . ~ ~answer that an individual patient or physician arrives at is influenced not only by the clinical features of the illness, but also by their own attitudes, beliefs, and values. In this way personal and social attitudes play an important role in both medical and lay thinking about medically unexplained illnesses in general, and CFS in particular.2 CFS

Once fatigue as illness became regarded as a medically unexplained syndrome, there was a need for an appropriate diagnostic label. The term chronic fatigue syndrome was coined.48CFS was originally conceived of as a functional disease. The case definition consequently required the patient to have multiple somatic symptoms and signs in the absence of other organic disease and psychiatric illness. It soon ran into problems. It was unwieldy, excluded many patients whom clinicians were interested in studying, and in practice was frequently modified by researche r ~ . ~ Alternative ~, definitions were consequently proposed.47,97 The original criteria were then modifieds9 and more recently the definition of CFS has been completely rewritten.34

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The new case definition for CFS is based on an international consensus of researchers. It represents a clear stepping back from the idea of identifying a new disease toward an explicit acceptance that it represents nothing more than a working definition of a clinical problem, pending further understanding. Most important, it represents an attempt to straddle the medical-psychiatric divide in thinking about the problem. This new simpler definition has reduced the number of symptoms required and calls for the exclusion of only a small number of specified psychiatric The diagnostic criteria are summarized in Table 1.

Issues for a Definition of CFS Given the conceptual difficulties outlined previously, it is perhaps not surprising that the new case definition still has major limitations. First, it overlaps with other functional medical diagnoses. Second, most patients who meet existing criteria can be given an alternative psychiatric diagnosis. Third, the homogeneity of the patient group it identifies is doubtful. Finally, it is increasingly apparent that a case definition

Table 1. CASE DEFINITION OF CFS Inclusion criteria Clinically evaluated, medically unexplained fatigue of at least 6 months’ duration that is Of new onset (not life long) Not result of ongoing exertion Not substantially alleviated by rest A substantial reduction in previous level of activities The occurrence of 4 or more of the following symptoms Subjective memory impairment Sore throat Tender lymph nodes Muscle pain Joint pain Headache Unrefreshing sleep Postexertional malaise lasting more than 24 hours Exclusion criteria Active, unresolved, or suspected disease Psychotic, melancholic, or bipolar depression (but not uncomplicated major depression) Psychotic disorders Dementia Anorexia or bulimia nervosa Alcohol or other substance misuse Severe obesity Data from Fukuda K, Straus SE, Hickie I, et al: Chronic fatigue syndrome: A comprehensive approach to its definition and management. Ann Intern Med 121:953, 1994.

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based only on somatic symptoms does not adequately capture the clinical phenomena presented by patients with chronic fatigue. Overlap with Other Medically Unexplained Syndromes

Medically unexplained chronic fatigue is common in patients with other functional syndromes, such as chronic pain,I2 fibr~myalgia,"~ and irritable bowel Although chronic pain syndromes are characterized by pain, fibromyalgia by tender points, and irritable bowel syndrome by altered bowel function, these syndromes are all also characterized by the symptom of fatigue.20,37 In fact, the observation that patients with one of these syndromes are likely also to suffer from the others has led to the proposal that they share a common pathophysiology and are best grouped together." Overlap with Psychiatric Syndromes

Most patients who meet criteria for CFS and related syndromes also fulfill the criteria for psychiatric diagnoses, particularly those of anxiety 49 From the psychiatrist's perspective it is parsimoniand depression.42, ous, therefore, to ask whether a diagnosis of CFS is necessary if the patient's symptoms can equally well be described by an existing psychiatric disorder. If the illness could be simply relabelled as psychiatric in this way it would have the advantage of allowing the patient to benefit from existing psychiatric knowledge. It would also make much current research into the cause and treatment of CFS unnecessary. How good is the evidence supporting the hypothesis that patients meeting criteria for CFS can be more adequately subsumed under existing categories of psychiatric disorder? Depression. There is considerable evidence to support the idea that CFS is associated with d e p r e ~ s i o n First, . ~ ~ if psychiatric patients with depression are asked about a wide range of somatic symptoms (which they are usually not), these are found to be surprisingly similar to those reported by patients with CFS.Il4Second, if operational criteria for depressive disorders are applied to patients with CFS, a high proportion meet these and an even higher proportion have a previous history of major d e p r e s ~ i o n .Third, ~ ~ , ~ in ~ those who meet criteria for both CFS and depression, the onset of depression and the onset of CFS commonly coincide.56, Finally, the prevalence of major depressive disorder in patients with CFS is substantially higher than that of patients with chronic disabling organic diseases.52, In conclusion, there is a strong association between major depressive disorder and CFS, but for as many as half the patients seen in hospital clinics the symptoms are not readily subsumed under an operationally defined diagnosis of major depressive disorder. Anxiety. If depression cannot provide the whole explanation for CFS, could some patients be better described as having anxiety disorders? Although less attention has so far been devoted to this question,

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examination of diagnostic criteria reveals that the typical somatic symptoms of anxiety are similar to those of CFS.lo5Furthermore, those studies that have applied diagnostic criteria for anxiety disorder to patients identified as suffering from CFS have found these to be relatively common.60Even when both depression and anxiety disorders are considered, however, neither all cases of CFS nor all the clinical features of individual cases1o2are adequately described by these diagnoses a10ne.I'~ Neurasthenia. Could patients who fail to meet criteria for depression or anxiety disorders be retained under existing psychiatric classifications by application of the old diagnosis of neurasthenia? The World Health Organization Classification of psychiatric disorders, 10th edition,'21 includes this diagnosis. It is now more narrowly defined than it was 100 years ago and requires that the patient suffer from fatigue that is exacerbated by exertion, as well as several other symptoms, but does not meet criteria for a depressive or anxiety disorder. One study found that many patients referred to a medical clinic with chronic fatigue met these newly defined criteria for ne~rasthenia.~~ Although its use therefore allows almost all cases of CFS to be given a psychiatric diagnosis, its clinical usefulness is unclear. Somatoform Disorders. According to the Diagnostic and Statistical Manual-IV (DSM-IV)3(which does not include a category of neurasthenia) the patient with CFS who does not meet criteria for an anxiety or depressive disorder is likely to be assigned to a somatoform disorder. These are a group of psychiatric syndromes characterized by medically unexplained symptoms that are of presumed psychological origin. There are several subcategories. Somatization disorder is used to describe patients who report multiple, recurrent, medically unexplained symptoms over a long period. A small number of patients with CFS meet criteria for this disorder.67Hypochondriasis describes a syndrome in which the patient's main concern is with the possibility that they are suffering from an organic disease. Although on initial inspection this diagnosis seems to be applicable to many patients with CFS, its use is in fact problematic in CFS, which many physicians as well as patients regard as an organic disease.91Furthermore, clinical experience suggests that most patients with CFS are more concerned about their symptoms and impaired functioning than they are about the precise medical diagnosis to which these are attributed. Although the diagnosis of hypochondriasis has the advantage of explicitly including patients' illness beliefs and behavior in its definition, it does not therefore readily fit the clinical phenomena of CFS. Finally, almost all patients with CFS not meeting criteria for any of the above DSM disorders may be placed into the undemanding catchall category of "undifferentiated somatoform disorder," the value of which is highly questionable. Conclusion. Many patients with CFS meet diagnostic criteria for a depressive disorder or for an anxiety disorder, although in practice the presentation is usually atypical. It is likely that patients who do not meet criteria for either could be regarded as suffering either from neurasthenia or from a somatoform disorder. Therefore, all patients labeled as

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having CFS can be given a psychiatric diagnosis if one wanted to pursue this approach to its logical conclusion. In many cases, however, it is less certain just how adequately this diagnosis describes the patient’s illness and how helpful it is in its implications for their clinical management. Is CFS a Homogenous Syndrome? At present there is no evidence that the existing case definition for CFS selects a patient group that is homogenous on any factor other than medically unexplained fatigue and associated symptoms.92In fact, CFS as defined is almost certainly heterogenous on a number of clinical variables including psychiatric diagnosis and illness beliefs. This problem raises questions about the usefulness of research findings based on this broad definition and indicates the urgent need for a workable subclassification of the Does the Current Diagnosis Capture the Important Clinical Phenomena?

The current diagnosis, like most medical diagnoses, is based only on somatic symptoms. It does not refer to mood, illness beliefs, or coping behavior despite the fact that these are prominent clinical features of patients seen in specialist clinics.114 The Current Status of CFS

What then is the status of CFS? The current broad definition simply describes a clinical presentation. A more adequate description of the patient requires that additional information be provided. Because the syndrome is medically unexplained, any subdivision must be on the basis of clinical characteristics rather than disease process. One approach, therefore, is to subdivide CFS according to the presence of the various syndromes described in existing psychiatric classifications. According to such a scheme CFS would be subclassified into CFS/ depression, CFS/anxiety, and CFS without depression or anxiety disorder (that is narrowly defined CFS, or CFS/neurasthenia). Although such a subclassification is possible, it is difficult to apply in practice because many patients do not fit comfortably into existing operational definitions of depression or anxiety, despite often having features suggestive of these syndromes. Another approach, which extends simple diagnosis, is systematically to describe a greater range of the patient’s clinical characteristics. Such an approach might include illness beliefs, mood, coping behavior, physiologic state, and social situation as well as symptoms. This multidimensional description may have considerable clinical 70 ~sefulness.~~,

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It is hoped that the best approach to defining and subclassifying the broad category of chronic fatigue will be guided by research. We now, therefore, turn to a review of the results of recent studies with the aim of summarizing current knowledge concerning the pathophysiology and psychopathology of CFS. Research into the Nature and Cause of CFS

A considerable amount of research has been done to investigate the nature and cause of CFS. Unfortunately, most of these studies have suffered from methodologic shortcomings. The principal shortcoming has been in patient selection. Patients have often been recruited from tertiary care clinics, using various diagnostic criteria that have been both modified and applied inc~nsistently.~~ Few studies have recruited patients directly from primary care or have studied subgroups of patients according to their psychiatric diagnosis. Only a minority of studies have included comparison groups of patients with diagnoses of depression or anxiety. Furthermore, because most studies have used a casecontrol design, it is often impossible to know whether the findings they report are causes or consequences of the illness. The questions addressed by researchers have been shaped by the conceptual dichotomy described previously. Thus, medical studies have sought objectively measurable signs and organic pathophysiology, and psychiatric, psychological, and anthropologic studies have examined the psychopathology and sociocultural context of CFS. Objective Evidence of Impairment Doubts about the reality of an illness that has no objective findings have encouraged some investigators to search for objective correlates of the patient's reported ability to function. Some abnormalities have been found. It is less clear, however, whether they reflect a specific disease process or are reflections of more nonspecific factors, such as depression or inactivity. Exercise Capacity and Muscle Function. Testing has confirmed poor performance and also abnormal physiologic responses to exercise.82 Although the majority of studies have concluded that muscle function is essentially there is some evidence that many patients suffer from physiologic deconditioning, secondary to i n a ~ t i v i t yThe . ~ ~ability to exercise is also reduced in patients suffering from although other more specific and as yet undefined pathophysiologic processes may also be present in CFS.59 Cognitive Functioning. Although some studies have found no objective impairment of cognitive functioning,88,90 others have suggested a subtle deficit in complex information processing.24,40 Similar deficits have, however, also been found in patients suffering from depres~ion.'~ Conclusion. Those investigators who had hoped that laboratory

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tests of patient’s physical and intellectual functioning would help us to decide whether CFS is an objectively demonstrable medical disease or a subjectively experienced psychiatric illness have been disappointed. The question was poorly conceived and the answer has steadfastly remained ambiguous. On the one hand, objective abnormalities have been demonstrated, whereas on the other hand they are not clearly different from those found in patients with uncomplicated depression. Nor do these subtle objectively demonstrable abnormalities fully explain patients’ subjective complaints. Pathophysiology

Clinical observations of patients with CFS have led to the investigation of a number of hypotheses about the underlying pathophysiologic mechanism. These are summarized in Table 2. Viral Infection. Perhaps because patients commonly describe their illness as beginning with flulike symptoms, many investigators have sought objective evidence of initiating or ongoing viral infection. A Table 2. PATHOPHYSIOLOGIC PROCESSES IN CFS AND DEPRESSION CFS

Depression

Patient history Investigated but no convincing evidence

Unusual Unknown

Reduced lymphocyte function

Reduced lymphocyte function

Physical function Exercise performance Muscle function

Reduced Normal

Reduced Normal

Cognitive function Information processing

Minor impairment

Minor impairment

Some evidence Not found

Not usual Typical

Some evidence Only minority of CFS patients

Unknown Only with anxiety

May be decreased May be increased activity

Typically increased Decreased activity

Reduced blood flow to certain areas Abnormalities of uncertain significance

Reduced blood flow to certain areas Abnormalities of uncertain significance

Infection Initiating virus infection Chronic virus infection Immunology Immune disturbance

Sleep abnormalities Reduced slow wave Reduced rapid eye movement latency Cardiorespiratory Hypotension Hyperventilation Neuroendocrine Cortisol Serotonergic system Brain imaging Functional Structural

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prospective follow up of people with positive evidence of EBV infection did find that some patients went on to develop a fatigue syndr~me.’~ A much larger prospective study in primary care, however, found no association at all between self-reported viral infections and subsequent fatigue.”’ So if viruses do play a role in precipitating CFS, it appears that it is only certain types of virus. Chronic virus infection has been a popular theory to explain the persistence of the symptoms of CFS. EBV has been one of the most likely suspects. Although recent studies have failed to implicate this agent, there may be an association between positive EBV serology and CFS.76 Other infectious agents that have been investigated, but not so far proved to have an etiologic role in CFS, include the entero~iruses’~~ and the retrovir~ses.~~ Immune Dysfunction. The evidence for an association between immunologic abnormalities and CFS is more consistent than that for infective agents, and several studies have suggested abnormalities in lymphocyte function.58Similar changes can, however, be found in patients with depressive and although some studies have at64 both the specificity and tempted to control for emotional causal importance of these observations remain unclear. Sleep Abnormalities. Unrefreshing sleep is an almost ubiquitous complaint of people suffering from CFS.99Whereas studies have identified major sleep disorders, such as sleep apnea and narcolepsy, in a minority of patient^,'^,^^ simple disruption of slow-wave sleep is a much more common ob~ervation.~~, Disrupted sleep has been claimed to have etiologic importance in fibromyalgia. Although inefficient sleep could contribute to the daytime fatigue reported in both conditions, its specificity and etiologic role are uncertain. Cardiovascular and Respiratory Abnormalities. Abnormalities in the cardiorespiratory systems that may underpin the exercise intolerance have been reported by several investigators; Hyperventilation has been suggested as a mechanism of symptom p r o d u ~ t i o n Although .~~ panic attacks are fairly commonly reported by patients with CFS, only a minority appear to have biochemically confirmed hyperventilation.86 Low blood pressure has long been associated with the symptoms of fatigue, and in parts of Europe unexplained fatigue is confidently ascribed to this clinical finding.lI3Postural hypotension has recently been noted in patients with CFS,85 and although this may be a cause of fatigue it may also be a consequence of i n a ~ t i v i t y .Finally, ~~ various abnormalities in cardiac function have also been reportedz6but are of uncertain significance. Neuroendocrine Abnormalities. The prominent fatigue of Addison’s disease has led several researchers to suggest the hypothesis that adrenal function is also impaired in patients with CFS80 In support of this suggestion there is some evidence that patients with chronic fatigue and fibromyalgia have both low levels of cortis01,2~and an abnormal adrenal response to stress and exertion.Io6These findings require replication. If they prove to be robust they may not only suggest a mechanism of symptom production in CFS but also represent a definite biologic differ-

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ence between CFS and depressive disorders, in which cortisol levels are typically elevated.2s Neurotransmitter Abnormalities. Changes in brain serotonergic systems have been implicated in many functional Serotonin has also been specifically linked to exertion-produced fatigue.11sRecent studies of patients with CFS have found evidence of abnormal functioning of cerebral serotonergic systems5,lo that differs from those found in patients with depression. Like the abnormalities in adrenal function, these findings are preliminary but of considerable potential interest. Brain Imaging. Finally, a variety of techniques have been used to examine both the function and structure of the brain in patients with CFS. Cerebral perfusion studies have shown abnormalities in patients, although similar, if not identical abnormalities are also found in patients 94 Structural changes reported on MR imaging scans with depres~ion.~~, are more controversial and harder to interpret.7s,93 Conclusions. Despite a considerable research effort, so far no single pathophysiologic process has been conclusively identified as a cause of CFS. There is some evidence for a loss of physical fitness and possibly for abnormalities of autonomic function. Viral infection may have a role as a precipitating agent, although its importance as a perpetuating factor is less certain. Immunologic abnormalities are common but of uncertain specificity. The current attention on neuroendocrine function takes the focus of investigation closer to those processes known to be associated with depressive states. Recent and intriguing observations, however, suggest that the neurotransmitter and neuroendocrine changes in patients with CFS may differ in direction from those commonly observed in patients with more typical depressive disorder. Further studies are needed to confirm these abnormalities and to clarify whether they are etiologically important or merely a consequence of factors, such as inactivity. In summary, no pathophysiologic mechanism has yet been established for CFS and the symptoms remain largely unexplained. Psychopathology

The initial psychiatric hypothesis to explain CFS was that it was identical to depressive disorder. This hypothesis relegated CFS to the status of mere misdiagnosis. This early view, however, was clearly an oversimplification and more complex explanations are required. A number of possible psychopathologic factors relevant to CFS are listed in Table 3. Somatization. A processes referred to as s o m ~ f i z a t i o is n ~commonly ~ invoked to explain why patients with emotional disturbances, such as depression, present with somatic complaints, such as fatigue, rather than with low mood. The term somatization implies that mental processes are causing somatic symptoms and is, therefore, essentially dualistic. The hypothesis that the somatic symptoms of CFS are readily understandable as part of somatized emotional disturbance is, however, a parsimonious alternative to some of the more elaborate pathophysiologic

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Table 3. PSYCHOPATHOLOGIC FACTORS IN CFS AND DEPRESSION

Personality Abnormal Cognitive-behavioral Attributions Coping style Life stresses Life events at onset Ongoing life stresses Sociocultural Media bias Medical confusion Social stigma

CFS

Depression

Obsessive

Various types

Organic disease Avoidant

Usually psychological Various

Some evidence Some evidence

Typical Common

Major factor Major factor Minor factor

Minor factor Minor factor Major factor

mechanisms outlined previously. This is a difficult hypothesis to test. It does, however, appear to require evidence both for the presence of emotional disturbance and for the factors that result in its somatized expression. These factors include specific types of attribution, coping behavior, perceptual process, personality, and social context. Attributions. One of the components of somatization that can be measured is the patient’s understanding of, and beliefs about, their illness. Systematic studies have confirmed that patients attending specialist clinics with CFS typically attribute their illness to organic disease even when no evidence of this can be found by their physicians. Perhaps more importantly they often resist psychological and psychiatric explanations for their symptoms, even when these seem to be appropriate.102,114 Whether these patients are biased against psychiatric diagnoses or are simply wiser than their physicians is unclear. Nonetheless, strong and exclusively physical disease attributions are important because they predict a poorer clinical outcome in patients with CFS.’16 Perceptual Processes. Another aspect of somatization is a focus on somatic symptoms. Patients with CFS do report a greater sense of effort in response to both psychological90and physical demands36 than is explicable from the objectively measurable impairments. This observation supports the idea that they are especially sensitive to bodily sensations, that is they amplify them.7 It is possible that, as in panic,18 the patients’ beliefs about their symptoms may lead them to focus attention in this way. Although a plausible hypothesis,lo2 there is so far little evidence that this process is important in patients with CFS. Coping Behavior. If patients conceive of their symptoms as indicating organic disease, certain ways of coping, such as avoiding any exacerbation of symptoms and resting, are likely to be adopted. A tendency to avoid activities that exacerbate symptoms has been shown to occur in patients with CFS. Activities avoided include not only physical activity but also the ingestion of certain foods and alcohol.99Furthermore, such avoidance is associated with persistent disability4 and has been sug-

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gested as the mechanism by which disease attributions for symptom predicts poor outcome.102 Personality Characteristics. Various personality characteristics have been associated with somatization, including an obsessional or anankastic personality type. Both research studies and clinical experience suggest that many persons with CFS have a tendency toward such hard driving, perfectionistic, or obsessive-compulsive personalities and an overactive Io7 premorbid lifestyle.lo2, Stigma, Bias, and Communication. Somatization is associated with sensitivity to the stigma of psychiatric illness. Patients with CFS may be more susceptible than the average person to this stigma.Io9Another potentially important social factor is the availability of biased information about the illness. Both self-help and the media65tend to emphasize disease explanations for the symptoms of CFS at the expense of more psychiatric or psychological conceptualizations. It has also been suggested that somatization may serve a culturally defined function of social cornm~nication.~~ In the case of CFS, this might be to allow a socially acceptable and hence nonpsychiatric expression of distress and protest about intolerable occupational and personal pressures. Conclusions. Psychopathologic explanations of CFS are clinically plausible and have enjoyed some degree of empirical support. In particular, a strong and exclusive medical disease attribution has been found to be a stronger predictor of poor prognosis than immunologic Social factors may also be important in shaping the illness. Enthusiasm for the role of these psychological and social factors, however, should not blind us to the potential role for pathophysiologic processes in the production of the symptoms of CFS.

Conclusions About the Nature and Cause of CFS Research into the causes of CFS has been hindered both by poorly conceived questions and by poor methodology. Nonetheless, replicable findings have been obtained. In particular, there is evidence of a measurable impairment of physical function and perhaps of cognitive function. Pathophysiologic abnormalities so far identified have not been substantial but do include some tantalizing indications of immune, neurotransmitter, and endocrine dysfunction. Psychopathologic enquiries have revealed convincing evidence of an association with depression and anxiety syndromes and also a tendency by patients to attribute their symptoms to physical disease rather than to psychiatric disorder. It now seems clear that rather than regarding pathophysiologic and psychopathologic studies as separate and competing approaches to the problem, it is more useful to combine them. This approach to CFS considers multiple etiologic in a biopsychosocial conceptualization of the problem.29,122 Table 4 summarizes these factors. According to this integrated scheme, causal factors are divided into

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Table 4. A HYPOTHETICAL CAUSAL MODEL OF CFS PredisDosinn

PreciDitatina

Pemetuatina

Biologic

Genetic Previous depression

Virus

Psychological

Personality (perfectionism)

Response to stress

Social

Stigma

Stresses

Immune disturbance Inactivity Other processes Disease attribution Avoidant coping Life conflicts Iatrogenic factors

those that predispose to the illness, those that precipitate it, and those that go on to perpetuate established illness. Predisposing factors include previous episodes of major depressive and perhaps also certain personality characteristics, particularly achievement orientation and perfectionism.108The precipitation of CFS by viral infection is clinically plausible, although unproven and life stresses also seem to be important.'*O Perpetuating factors may include emotional disorder, physical disease attributions, coping by avoidance, as well as chronic personal and occupational difficulties and media misinformation about the illness. It is likely that all these factors interact to perpetuate the pathophysiologic processes, and consequently the symptoms and disability of patients suffering from CFS.'"*

Is CFS a Useful Diagnosis? Should the clinician ever diagnose CFS? The answer I offer to this question is yes, but with four important caveats. First, CFS should be explicitly regarded as a presenting clinical syndrome, rather than a specific disease process. Although this is not to deny that there may be specific pathophysiologic processes underlying the symptoms, a balance must be struck betureen acceptance of this possibility and unjustified enthusiasm for each newly discovered etiologic agent. Second, psychiatric syndromes that have important clinical implications, such as major depressive disorder, should be sought and if present should be included in the diagnostic statement. Third, although the current case definition of CFS specifies only symptoms, patients' beliefs and behavior are often a prominent part of the clinical presentation and also need to be included in any useful summary of the case. Finally, rather than becoming sidetracked on the question of whether CFS is really medical or really psychiatric in nature, management is likely to be more effective if both the physician and the patient adopt an open-minded and pragmatic approach to this often frustrating clinical problem.

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THE MANAGEMENT OF PATIENTS PRESENTING WITH CFS

In this section I suggest a pragmatic approach to the management of patients presenting with chronic disabling medically unexplained 98*117 fatigue. Several useful accounts have been previously published.23, The approach I suggest is applicable to any medically unexplained illnes8, 91 The overriding principle to be adhered to when managing patients with syndromes that do not fit comfortably into either medical or psychiatric services is to ensure that they obtain the maximum benefit from both, while being harmed by neither. Assessing the Patient

A combined medical and psychiatric assessment is required in every case and is summarized as follows: Exclude organic disease Careful history and examination Special investigations only if indicated Keep an open mind Assess for psychiatric disorder Systematic enquiry Beware smiling facade Excluding Organic Disease

A few of those patients who present with severe chronic fatigue are found to have occult organic disease. How frequently organic disease is found depends on how thorough an assessment the patient has already received. Even if disease is not evident at assessment, it is wise to remain vigilant to this possibility and to reinvestigate if new clinical signs appear. The conditions to be considered include hypothyroidism, anemia, Addison's disease, and sleep In most cases of chronic fatigue a simple clinical assessment is adequate. Studies suggest that if a careful history and physical examination do not suggest a specific disease, routine laboratory investigations are likely to add little and should not therefore be routinely performed.61 Identifying Psychiatric Syndromes

All patients should have a psychiatric history taken and their mental state examined. The assessment should seek evidence of major depression, anxiety, and panic disorder and also evaluate any suicidal intent.' The psychiatric assessment should be systematic because hidden distress is common and casual estimates of the patient's degree of distress may be misleading.Io2

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Additional Patient Characteristics

Assessment must identify all the important obstacles to recovery. It often needs to go beyond diagnosis to include a systematic individualized description of each case. Aspects to be considered in the systematic description include the individual’s beliefs about their illness, their coping behavior, emotional state, and physiologic condition, as well as interpersonal and occupational problems and their family’s understanding of the illness. The patients’ illness beliefs are best elicited by asking them to describe how they understand the cause of their illness and then probing the answer with questions, such as ”what made you think that?” Such enquiries may reveal important misconceptions. A related question is how they cope with their symptoms. Here the assessor is particularly seeking evidence of avoidance of symptom-associated activities, unproductive attempts to function normally, or fluctuation between these states. Enquiries into the patient’s emotional state give clues to anxious, depressed, or frustrated reactions to the illness and other life difficulties that may not reach diagnostic criteria for emotional disorders. The patient’s physiologic state may be directly assessed in a variety of ways, although a clinical estimation is more common. For example, the capacity for exercise may be assessed by formal exercise testing, or the degree of physiologic deconditioning may be estimated from the duration of inactivity. Finally, it is almost always useful to interview other family members to obtain both an account of the patient’s premorbid personality as well as the families’ beliefs about the illness and its management.

Diagnosis and Formulation The choice of diagnosis should be pragmati~.’~, 79 There is little point in making a diagnosis of CFS if the patient’s symptoms are clearly those of depression or anxiety and they are accepting of this diagnosis. In other cases where the fit with depression or anxiety is less good or where such a diagnosis would be unacceptable to the patient, a diagnosis of CFS (with associated depression or anxiety if appropriate) may be the most useful. It offers the patient a coherent label for their symptoms and therefore lessens the risk that they will embark on a fruitless search for a better explanation, and it also avoids the misleading connotations of pseudo-disease labels, such as chronic EBV infection or myalgic encephalomyelitis. Above all, it is most important that the physician does not stop at this diagnosis, but goes on to identify obstacles to recovery in each case.

Individual Case Description A multidimensional description of the patient’s illness provides a comprehensive picture of the factors that may be relevant to the patient’s

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illness and is an important supplement to d i a g n ~ s i sThe . ~ ~ elements of a biopsychosocial assessment are as follows: Psychological Beliefs Coping behavior Mood Biologic Physical deconditioning Other processes Social Stressors Family beliefs Iatrogenic problems Its use can be illustrated by returning to the case example described previously. Clinical Example. Assessment of the patient described at the beginning of this article revealed that he/she believed that the symptoms were caused by an ongoing virus infection and that he /she should beware of exacerbating them. The patient consequently avoided activity and had been profoundly inactive for over a year, often lying in bed and sleeping for long periods. He/she was therefore likely to be physiologically deconditioned. The patient was frustrated with the inability to do things and sometimes felt low in mood about the predicament. The patient’s job had been very stressful but since becoming ill he/she had been unable to work. The patient had lost his/her job and was being cared for by his/her mother who also believed the patient had permanent disability. The doctor said that the best thing was rest.

How to Treat CFS

The management of patients with CFS should be based on both the diagnostic and individualized formulation of the problem. It can be divided into general and specific treatments as follows: General Accept illness Educate about multifactorial nature Encourage self-help and normal activity Pharmacologic Consider antidepressant drugs Avoid poly pharmacy Experimental drugs only in trials Nonpharmacologic Gradual increase in exercise Cognitive behavior therapy Other psychotherapies if acceptable and indicated

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General Care Five basic steps are essential to the care of patients with CFS. The first is to acknowledge the reality of patients’ symptoms and the distress and disability associated with them. The second is to provide appropriate education about the nature of the syndrome to both the patient and their family, while avoiding unproductive argument. The third is to treat identifiable depression and anxiety disorder. The fourth is gently to encourage a return to normal functioning by overcoming avoidance and regaining the capacity for physical activity. The fifth is to help the patient to overcome occupational and interpersonal obstacles while maintaining their self-esteem. This general approach is a prerequisite to any more specialized form of treatment. Pharmacologic Treatments Many pharmacologic treatments have been suggested for patients with CFS. To date, none are of proved efficacy and several are potentially harmful.35As described previously, however, patients who are clearly depressed should be offered treatment with so-called antidepressant drugs. There is some evidence to support the use of these drugs even in the absence of definite depressive disorder.38,45 Of available agents none is clearly superior for this patient group, although clinical experience suggests that the selective serotonin reuptake inhibitors may be better tolerated and the clinical similarities of CFS to atypical depression may suggest a role for monoamine oxidase inhibitors.81Patients are often reluctant to take antidepressants, however, and careful explanation and follow up are required. Other pharmacologic agents should only be used with care and preferably only as part of randomized controlled trials. Exercise Therapy This should be considered for patients who are physically inactive. In both fibromyalgia and CFS a modest amount of evidence suggests that graded increases in physical activity are helpful in improving function and relieving symptoms.16,72 The simplistic application of exercise regimens, however, particularly if given without explanation and follow up, is unlikely to be helpful and may be harmful by damaging the patient’s confidence in both the physician and in themselves. Psychotherapy Psychosocial difficulties may be targeted using psychotherapy. Reluctance to consider the role of psychological factors in CFS and related syndromes makes the application of psychotherapy potentially difficult, but not impossible.112Brief psychotherapeutic approaches have been

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helpful in other medically unexplained syndromes, including chronic pain70 and irritable bowel Although family therapy41 and brief psychodynamic therapylo4may have a place in the management of selected patients, cognitive behavioral approaches have been most systematically researched. This form of therapy is especially well fitted to the task of helping patients to achieve a more helpful view of the 95 illness and to adopt more effective coping strategies.23, Several forms of cognitive behavior therapy have been evaluated in patients diagnosed as having CFS. Encouraging results from an initial A study17 were unfortunately not replicated in two further trials.", more recent randomized trial of a form of cognitive behavior therapy especially designed for patients with CFS, however, achieved a considerable reduction in disability and fatigue compared with conservative medical care.96This form of cognitive behavior therapy was based on a multidimensional assessment and placed particular emphasis on helping patients to reappraise their illness beliefs as well as on increasing activity and solving social problems. It consisted of 16 weekly individual treatment sessions. An interesting aspect of the results was the late and continuing improvement in patient functioning during the 8-month posttreatment follow-up period. Although the results of further similar studies are awaited, we may conclude that cognitive behavior therapy offers a potentially useful approach to the rehabilitation of patients with CFS; however, it also has the limitations of requiring skilled therapists, does not help all patients, and has a relatively slow action. Potential Problems

Several issues may complicate the management of patients with CFS. These include the following. Strong Illness Beliefs. Difficulties are most likely to arise when patient and physician hold differing beliefs about the nature and management of the illness. This problem can often be overcome by the physician acknowledging the patient's beliefs without necessarily agreeing with them. If the patient's family, friends, or acquaintances suggest or encourage views that the physician regards as unhelpful, the problem is more difficult and a meeting with the other parties may be necessary. Alternative Therapies. Patients with CFS often turn to alternative medicine. Some complementary therapies may be continued in parallel with rehabilitative management. If, however, they interfere with that treatment, the need to pursue one approach at a time should be explained to the patient, who should be encouraged to defer their use of the competing therapy until the current management plan has been completed. Official Reports. Perhaps the greatest source of difficulty is encountered when the patient asks the physician to write reports on their behalf, saying that they suffer from permanent disability. On the one hand, the physician wants to help his or her patient, but on the other wants to avoid a self-fulfilling prophecy. This dilemma has no easy

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solution, but it is important not to confirm a negative prognosis until potentially effective treatments have been tried. Poor Prognosis Patients. For patients who have been identified as having a poor prognosis because of a long history of severely impaired functioning or poor response to treatment, regular if infrequent longterm follow up is at least likely to limit iatrogenic harm from unnecessary investigations and ineffective treatments and may actually improve the patient’s functioning in the longer term.

Services

In common with other patients suffering from medically unexplained syndromes, iatrogenic factors may have a negative influence on the course of the illness. Not only may physicians give misleading diagnoses and prescribe distracting but ineffective therapies, but the very organization of medical care may have a deleterious effect on the patient. The traditional division of medical knowledge and services into either medical or psychiatric, and the stigma attached to the latter, means that many patients who might benefit from psychiatric treatment do not receive it. Although good quality primary care and outpatient consultation liaison psychiatry offers a partial solution to this a more satisfactory solution awaits a more fundamental revision of medical services. Future services should be based on high-quality biopsychosocial assessment and management in primary care, complemented by integrated medical-psychiatric secondary and tertiary care services.1o1

CONCLUSIONS AND FUTURE DIRECTIONS

CFS is best regarded as a descriptive term for a type of clinical presentation. The patient group it defines is almost certainly etiologically heterogeneous and needs to be subclassified. Although psychiatric diagnosis provides one approach to subclassification, current diagnostic systems have significant limitations and a multidimensional description of the patient’s characteristics may be more clinically useful. The illness defined by the term CFS is important because it represents potentially treatable disability and suffering. It is also important because the clinical problems it gives rise to demand that we address shortcomings in our present approach to medically unexplained illness. Whatever is ultimately discovered about the causes of CFS, the attention it is receiving offers a golden opportunity to reappraise our understanding and classification of human illness and to re-examine our current organization of medical care.

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ACKNOWLEDGMENTS The author thanks Dr. Tim Peto for his support and colleagueship and Alison Clements for helpful comments on this manuscript.

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