ME International

1997 CFS Clinical Practice Guidelines
Overview

Introduction

Prolonged fatigue is a common complaint in the community and is usually transitory. If fatigue continues for more than six months, is disabling, and is accompanied by other constitutional and neuropsychiatric symptoms, then a diagnosis of chronic fatigue syndrome (CFS) should be considered.

Although the symptoms of CFS are currently hypothesised to be due to abnormal brain function, the underlying pathophysiology is not known at present. Therefore, CFS cannot currently be defined as a specific "disease" entity. Indeed, there is growing evidence that the disorder is heterogeneous, and it will probably prove to have no single or simple aetiology.

Nevertheless, the suffering and disability -- physical, psychological and social -- caused by the illness can be very considerable, in many cases comparable to that seen in multiple sclerosis and rheumatoid arthritis. It is therefore important that doctors convey to people with CFS their recognition of the reality and seriousness of the suffering and associated disability, even though an underlying disease process cannot presently be defined.

Diagnosis of CFS

A diagnosis of CFS is made on clinical grounds. It relies on the presence of characteristic symptoms (see Box 1), and the exclusion of alternative medical and psychiatric diagnoses. In individual patients, the symptoms of CFS may overlap with other common syndromes such as fibromyalgia and irritable bowel syndrome, and the primary diagnosis will depend on which symptoms are the most dominant and disabling. People with CFS often have concurrent depression, and this need not be considered an alternative primary diagnosis.

As similar symptoms may also occur in a range of other disorders (e.g., thyroid disease, anaemia, major depression), the first priority in clinical assessment is to exclude alternative explanations. This can be achieved by a careful history, physical examination and a restricted set of laboratory investigations.

Clinical history

The history should closely examine the character of the "fatigue". In people with CFS, fatigue is typically exacerbated by relatively minor physical or mental activity, and is associated with a protracted recovery period lasting hours or even days. The fatigue should be differentiated specifically from weakness (neuromuscular disease), dyspnoea and effort intolerance (cardiac or respiratory disease), somnolence (primary sleep disorders), and loss of motivation and pleasure (major depression).

Additional clues which could point to alternative diagnoses include: unexplained weight loss (occult infection, malignancy, thyrotoxicosis, Crohn's disease); dry skin and cold intolerance (hypothyroidism); snoring and daytime somnolence (sleep apnoea); risk factors for transmission of blood-borne infections (HIV, hepatitis C); prior episodes of depression or anxiety (vulnerability to psychiatric disorder); arthralgia or rash (connective tissue disease); and prescribed or illicit drug abuse. A history of altered bowel habit may indicate an underlying gastrointestinal infection (e.g., giardiasis), coeliac disease, thyroid disease, or inflammatory bowel disease.

Examination

Characteristically, there are no abnormal physical findings in people with CFS. The physical examination and mental state examination are therefore primarily directed towards excluding other disorders. A careful assessment for neurological deficits or signs of anaemia, cardiac failure, respiratory disease, hidden infection, connective tissue disease or tumour should be conducted. The presence of persistent fever, lymphadenopathy, or enlargement of the liver or spleen are not features of CFS and always warrant further investigation.

The behavioural signs of psychiatric disorder should also be sought, including psychomotor slowing (major depression), physiological arousal (anxiety states and panic disorder) and cognitive deficits (delirium or dementia).

Investigation

There are currently no validated laboratory tests to confirm the diagnosis of CFS, assess its severity or monitor progress. Hence, the purpose of laboratory investigation is to help exclude other disorders.
Recommended screening investigations are:

• full blood count and ESR
• serum levels of electrolytes, calcium and creatinine
• biochemical liver function tests
• thyroid function tests (TSH)
• urinalysis for blood, protein and sugar.

Additional investigations should be ordered only if the history or examination plausibly suggests other diagnoses (e.g., antinuclear antibodies if an autoimmune connective tissue disease is suspected), or if abnormalities are found in the screening investigations. Routine analysis of immune function (lymphocyte subsets, immunoglobulin levels), infectious disease serology, or environmental toxins is not recommended.

Specialist referral

In most cases, a general practitioner should be able to make a confident diagnosis of CFS. However, if, after a careful history, examination and screening investigations, the diagnosis remains in doubt, the opinion of a specialist physician should be sought. Referral to a psychiatrist may also be useful for people with profound or prolonged depression or anxiety states. Specialist referral may also help in formulating an appropriate management plan (see below).

Management

As most prolonged fatigue syndromes will resolve spontaneously, reassurance and supportive care is generally all that is required for early management. In people with established CFS, providing a definite diagnosis along with general information about the nature of the illness and its prognosis are important starting points for good clinical care.

Doctors who display empathy, acceptance of their patient's suffering, a non-judgemental style, and a commitment to continued care are likely to establish a beneficial therapeutic relationship. Conversely, doctors who reject the patient's illness experience are likely to promote feelings of alienation and to perpetuate ill health.

In managing people with CFS it is important to:

• develop an individualised management plan for physical and social rehabilitation
• discourage excessive rest and social withdrawal
• maintain regular contact
• evaluate the basis of any new symptom or deterioration in function
• provide support for the person and his or her family, including access to social security, educational assistance and disability services where appropriate.

Understanding the illness

Helping the person with CFS to have a clear understanding of the nature of the illness is an important element of management. For example, some people harbour fears that they may be "going mad", or that minute amounts of environmental toxins may be causing irreversible immunological or neurological damage. Unwarranted concerns of this kind may lead to maladaptive attitudes and behaviours which may themselves increase disability and retard recovery.

Both the doctor and the patient should avoid simplistic attributions of CFS to "a virus", "immune dysfunction", "malingering", or "mere depression". Instead, it should be recognised that the illness is likely to be multifactorial in origin. A broad perspective that encompasses medical, psychological, and social aspects of the individual's disability is more appropriate.

  No pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore directed at minimising impediments to recovery, notably, loss of aerobic fitness, disruption of the sleep-wake cycle, intercurrent depression and social isolation. These strategies, together with promotion of a clear understanding of the illness, are sometimes termed cognitive behavioural therapy (see Box 4.4).    

Physical activity

In the early stages of the illness, many people with CFS make the mistake of putting off chores or social engagements until they feel better, then pushing themselves too hard on "good days" to make up for lost time. The subsequent worsening of symptoms and delayed recovery can establish a cyclic pattern of illness and disability.

It is also important to discuss with the person with CFS the vicious circle whereby initial avoidance of physical activity may lead to longer-term avoidance of all activity.

In general, people with CFS should begin by undertaking physical and intellectual tasks in divided sessions of relatively short duration, rather than engaging in extended periods of activity. As exercise tolerance improves, activity can be gradually increased. Graded exercise programs have been shown to be safe for people with CFS, and can improve both aerobic capacity and functional status.

An individualised management program should be carefully negotiated between the patient and doctor, with particular attention to:

• commencing at a level of activity which can be achieved without exacerbation of symptoms
• undertaking activity on a regular basis in sessions of limited duration
• planning for regular reviews to achieve feasible increases in activity over a realistic time-frame (e.g., several months).

Sleep

Unrefreshing sleep is extremely common in people with CFS. Although they usually report an increased total sleep time, typically it has a broken and restless pattern. A shift from regular night-time sleep to day-time naps and a late-night to late-morning sleep cycle is also common.

It is known that this type of disruption to a healthy sleep pattern can induce prolonged symptoms in healthy volunteers, including prominent fatigue, musculoskeletal pain, irritability and concentration impairment.

Restoration of a regular, unbroken, night-time sleep of about eight hours duration should be a goal of management of people with CFS. This goal may be achieved by:

• avoiding day-time naps
• gentle exercise late in the day or early evening
• establishing a regular bed-time routine
• analgesics and/or non-steroidal anti-inflammatory drugs (NSAIDs) for relief of musculoskeletal pain or headache and, if necessary
• sedative-hypnotic medication to achieve sleep.

Some people develop habituated patterns of "phase-shifted" sleep (typically midnight to midday), or of initial insomnia (spending several hours in bed before falling asleep). These patterns may require a structured sleep hygiene program to restore a more normal regimen. In general, such sleep interventions in people with CFS can significantly reduce symptoms and improve functional capacity. Where appropriate, the advice of a specialist sleep physician should be sought.

Symptomatic drug treatment

No medication has yet been demonstrated to provide long-term remission or "cure" in people with CFS. However, there is a place for symptomatic treatment for relief of specific symptoms if they are sufficiently distressing. As such treatments for CFS are empirical, each patient should be monitored carefully to ensure that the treatment offers more symptomatic benefits than harmful side effects.

People with CFS may have increased susceptibility to drug side effects, and it is generally wise to begin with small doses when introducing potent agents to a patient whose response cannot be predicted.

Although depression is a common symptom in people with CFS, the illness as a whole cannot be attributed simply to major depression. Hence, antidepressant drugs do not provide a panacea for CFS. At least one agent (fluoxetine) has been specifically shown to be ineffective.

However, the antidepressant group of drugs includes several different classes of pharmacological agents, each of which may have particular activity in relation to one or more symptoms of CFS, such as subjective energy (moclobemide), sleep disturbance (amitryptyline, nefazodone), muscle and joint pain (amitryptyline), concentration (moclobemide), and depressed mood (sertraline, paroxetine, nefazodone).

A reasonable approach is to consider undertaking a therapeutic trial of a selected drug based upon this broad pattern of effects on brain function. Given that these drug therapies are increasingly varied and complex, there is an important role for the specialist physician or psychiatrist to guide the choice of drugs and their monitoring.

In people with the overlapping syndrome of fibromyalgia the use of symptomatic treatments such as analgesics and NSAIDs, in combination with tricyclic agents, can be effective in improving sleep and reducing pain.

Psychological and social support

As with other chronic illnesses, managing people with CFS requires consideration of the psychological and social impacts of the illness. People with CFS may be unable to continue full-time work, so financial difficulties may rapidly develop. Similarly, CFS frequently disrupts high school or university studies.

A successful return to work or school after a prolonged illness with CFS often requires a rehabilitation program incorporating medical treatments, psychological support and occupational therapy, and the doctor may need to coordinate the help of other health care and educational professionals to implement this where appropriate.

Consideration should also be given to the impact of the illness on the person's family. In some circumstances it may be useful for people with CFS to bring their spouse or partner to a consultation, both to help them better understand the illness, and to discuss their difficulties in coping. Parents of children and adolescents with CFS should be seen regularly, and may require additional support and counselling.

Doctors should be prepared to act as advocates for their patients in negotiations with employers, educational institutions and social welfare organisations. For instance, part-time work or school alternatives may need arranging, or disability allowances may need to be sought.

Joining a patient support group may be valuable for some people. CFS Societies can offer individual and group support, education, and advice regarding access to social welfare agencies. Support groups also provide an opportunity for individuals to exchange information on how to cope with the many practical day-to-day difficulties which arise for those living with this debilitating condition.

2002 CFS Clinical Practice Guidelines
Overview

What is CFS?

"CFS" is a descriptive term used to define a recognisable pattern of symptoms that cannot be attributed to any alternative condition. The symptoms are currently believed to be the result of disturbed brain function, but the underlying pathophysiology is not known. Therefore, CFS cannot be defined as a specific "disease" entity at present. Indeed, there is growing evidence that the disorder is heterogeneous, and it will probably prove to have no single or simple aetiology.

It is important for practitioners to appreciate the distinction between disease, illness and disability.

Diseases are defined and categorised according to our contemporary understanding of causal mechanisms and pathophysiology. As new knowledge emerges, disease definitions and terminology change. Illness, by contrast, is the subjective experience of suffering and, as such, can only be defined by reference to the sick person. Disability is the functional impairment — physical, psychological and social — caused by disease and illness.

Even though an underlying disease process cannot presently be defined in patients with CFS, the suffering and disability caused by the illness can be very considerable — in many cases comparable to that seen in multiple sclerosis and rheumatoid arthritis. It is therefore important that doctors acknowledge the reality and seriousness of the suffering and disability experienced by people with CFS. Our goal as physicians is not only to identify and treat disease, but also to help relieve suffering and disability, whatever the cause.

Diagnosis

CFS is diagnosed on clinical grounds. It relies on the presence of characteristic symptoms (see Box B), and the exclusion of alternative medical and psychiatric diagnoses. In individual patients, the symptoms of CFS may overlap with other common syndromes such as fibromyalgia and irritable-bowel syndrome, and the primary diagnosis will depend on which symptoms are the most dominant and disabling. People with CFS often have concurrent depression, and this need not exclude the diagnosis.

As similar symptoms can also occur in a range of other disorders (eg, thyroid disease, anaemia, major depression), the first priority in clinical assessment is to exclude alternative explanations. This can be achieved by careful history-taking, physical examination and a restricted set of laboratory investigations.

B: Diagnostic criteria for chronic fatigue syndrome

1. Fatigue
   • Clinically evaluated, unexplained, persistent or relapsing fatigue persistent for six months or more, that:
   • is of new or definite onset;
   • is not the result of ongoing exertion;
   • is not substantially alleviated by rest;
   • results in substantial reduction in previous levels of occupational, educational, social or personal activities;
   
   and
   
   
2. Other symptoms
   Four or more of the following symptoms that are concurrent, persistent for six months or more and which did not predate the fatigue:
1. Impaired short term memory or concentration
2. Sore throat
3. Tender cervical or axillary lymph nodes
4. Muscle pain
5. Multi-joint pain without arthritis
6. Headaches of a new type, pattern, or severity
7. Unrefreshing sleep
8. Post-exertional malaise lasting more than 24 hours

Clinical history

It is important to take careful note of the character of the fatigue. In people with CFS, fatigue is typically exacerbated by relatively minor physical or mental activity, and is associated with a protracted recovery period lasting hours or days. The fatigue should be differentiated specifically from weakness (neuromuscular disease), dyspnoea and effort intolerance (cardiac or respiratory disease), somnolence (primary sleep disorders), and loss of motivation and pleasure (major depression).

Additional clues which could point to alternative diagnoses include unexplained weight loss (occult infection, malignancy, thyrotoxicosis, Crohn's disease); dry skin and cold intolerance (hypothyroidism); snoring and daytime sleepiness (sleep apnoea); risk factors for transmission of blood-borne infections (HIV, hepatitis C); prior episodes of depression or anxiety (vulnerability to psychiatric disorder); arthralgia or rash (connective tissue disease); and prescribed or illicit drug misuse. A history of altered bowel habit may indicate an underlying gastrointestinal infection (eg, giardiasis), coeliac disease, thyroid disease, or inflammatory bowel disease.

Examination

Characteristically, there are no abnormal physical findings in people with CFS. The physical examination and mental state examination are therefore primarily directed towards excluding other disorders. A careful assessment for neurological deficits or signs of anaemia, cardiac failure, respiratory disease, hidden infection, connective tissue disease or tumour should be conducted. The presence of persistent fever, lymphadenopathy, or enlargement of the liver or spleen are not features of CFS and always warrant further investigation.

The behavioural signs of psychiatric disorder should also be sought, including psychomotor slowing (major depression), physiological arousal (anxiety states and panic disorder) and cognitive deficits (delirium or dementia).

Investigation

There are currently no validated laboratory tests to confirm the diagnosis of CFS, assess its severity or monitor progress. Hence, the purpose of laboratory investigation is to help exclude other disorders.

Recommended screening investigations are:

• full blood count and erythrocyte sedimentation rate;
• serum electrolyte, calcium and creatinine levels;
• biochemical liver function tests;
• thyroid function tests (TSH); and
• urinalysis for blood, protein and glucose.

Additional investigations should be ordered only if the history or examination plausibly suggests other diagnoses (eg, autoimmune connective tissue disease, coeliac disease), or if abnormalities are found in the screening investigations. Routine analysis of immune function (lymphocyte subsets, immunoglobulin levels), infectious disease serology, or environmental toxins are not recommended.

Unvalidated diagnostic tests should only be performed in the context of an appropriately designed and ethically approved clinical trial.

Specialist referral

In most cases, a general practitioner should be able to diagnose CFS. However, if, after a careful history, examination and screening investigations, the diagnosis remains uncertain, the opinion of a specialist physician, adolescent physician or paediatrician should be sought. Referral to a psychiatrist may also be useful for people with profound or prolonged depression or anxiety states. Specialist referral may also help in formulating an appropriate management plan (see below).

Management

In the early stages reassurance and supportive care is generally all that is required, as most prolonged fatigue states will resolve spontaneously. In people with established CFS, providing a definite diagnosis, along with general information about the illness and its natural history, are important starting points for good clinical care.

A definitive diagnosis also serves to validate the patient's experience of illness and suffering. Doctors who display empathy, acceptance of their patient's suffering, a non-judgemental style and a commitment to continued care are likely to establish a beneficial therapeutic relationship. Conversely, doctors who reject or trivialise the patient's illness experience are likely to promote feelings of alienation and to perpetuate ill health.

In managing people with CFS it is important to:

• develop an individualised management plan for physical and social rehabilitation;
• discourage excessive rest and minimise social isolation;
• maintain regular contact;
• evaluate the basis of any new symptom or deterioration in function; and
• provide support for the person and his or her family, including access to social security, educational assistance and disability services where appropriate.

  To date, no pharmacological agent has been reliably shown to be effective treatment for CFS. Management strategies are therefore primarily directed at relief of symptoms (eg, headache, muscle pain) and minimising impediments to recovery (loss of functional capacity, disruption of the sleep–wake cycle, intercurrent depression and social isolation). Additional elements of good clinical management are the development of a clear and mutual understanding of the nature of the illness; a sensible approach to physical and mental activity; and realistic expectations about long-term outcome possibilities.    

Understanding the illness

Helping people with CFS understand the nature of their illness is an important element of good clinical management. For example, some people harbour fears that an occult infection, environmental pollutants or electromagnetic fields may be causing irreversible neurological or immunological damage. Others may have been led to believe that any physical activity at all could be harmful. Unwarranted concerns of this kind may lead to maladaptive attitudes and behaviours that may increase disability and retard recovery.

Doctors should also avoid simplistic attributions of CFS to "chronic infection", "immune dysfunction", "malingering", or "mere depression". Instead, it should be recognised that the illness is likely to be multifactorial in origin. A broad perspective that encompasses medical, psychological, and social aspects is more appropriate.

Physical activity

In general, people with CFS should be encouraged to undertake physical and intellectual tasks, starting at a level that is tolerated without significant exacerbation of symptoms. This should initially be in divided sessions of relatively short duration. As exercise tolerance improves, duration and intensity of activity can be gradually increased. Graded exercise programs have been shown to be beneficial for some people with CFS, and can improve functional status.

It is important to discuss with the patient the vicious circle whereby initial avoidance of physical activity may lead to longer-term avoidance of all activity. In the early stages of the illness, many people with CFS put off chores or social engagements until they feel better, then push themselves excessively on "good days" to make up for lost time. The subsequent worsening of symptoms and delayed recovery can establish a cyclic pattern of illness and disability.

An individualised management program should be carefully negotiated between the patient and doctor, with particular attention to:

* starting at a level of activity that can be achieved without exacerbation of symptoms — abrupt resumption of strenuous activity after prolonged periods of inactivity should be discouraged;

* undertaking activity on a regular basis, with sessions of limited duration; and

* planning for regular reviews to achieve feasible increases in activity over a realistic time-frame (eg, several months).

In formulating a management plan, it is important to be aware that in many people with CFS the degree of fatigue can fluctuate unpredictably from day to day and week to week. Flexibility in the level of physical and mental activity undertaken to allow for such fluctuations ("pacing") should be explicitly discussed.

Sleep

Unrefreshing sleep is extremely common in people with CFS. Patients usually report a longer time to fall asleep, an increased time in bed awake, and a broken and restless sleep pattern. A shift from regular night-time sleep to daytime naps and a late-night to late-morning sleep cycle is sometimes noted. It is known that chronic disruption of the normal sleep pattern can induce symptoms in healthy volunteers, including fatigue, musculoskeletal pains, irritability and impairment of concentration.

The general goals of sleep management are to establish a regular, unbroken, night-time sleep pattern and to improve perceptions of the quality of sleep. Although direct evidence of benefit in CFS is currently lacking, the following strategies may be helpful:

1. establishing a regular bed-time routine — going to bed when "sleepy" rather than "tired"; putting the light out immediately rather than reading or watching television in bed; and "anchoring" the sleep routine by setting the alarm to the same rising time every day;

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2. judicious use of sedative-hypnotic medication to achieve sleep;
3. use of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) for relief of musculoskeletal pain;
4. avoiding (preferably) daytime naps or keeping them under 30 minutes;
5. gentle exercise during the day (within the limits of the individual's functional capacity).

Where appropriate, the advice of a specialist sleep physician should be sought, either to exclude a primary sleep disorder or to manage the sleep disturbance. Sleep hygiene strategies can also be incorporated into a "cognitive behaviour" therapy program (see Chapter 3). Clinical experience suggests that sleep interventions in people with CFS may reduce symptoms and improve functional capacity, although direct evidence for this is lacking.

Symptomatic drug treatment

No medication has yet been shown to provide long term remission or "cure" in people with CFS. However, there is a place for symptomatic treatment for relief of specific symptoms if they are sufficiently distressing. As such treatments for CFS are empirical, each patient should be monitored carefully to ensure that the symptomatic benefits outweigh any side effects.

Many people with CFS report an increased susceptibility to drug side effects, and it is advisable to begin with small doses when introducing new agents.

Although depression is a common symptom in people with CFS, the disorder as a whole cannot be regarded simply as a "somatised" variant of a depressive illness. Overall, clinical trials of antidepressant drugs show no consistent pattern of improvement. However, judicious use of particular agents may provide symptomatic improvement in subjective energy (moclobemide), sleep disturbance (amitryptyline, nefazodone), muscle and joint pain (amitryptyline), and depressed mood (sertraline, paroxetine, nefazodone). A reasonable approach is to consider undertaking an "N = 1" therapeutic trial of a selected drug based on this broad pattern of effects on brain function. Given that these drug therapies are increasingly varied and complex, there is an important role for the specialist physician or psychiatrist to guide the choice of drugs and their monitoring.

In people with the overlapping syndrome of fibromyalgia, the use of symptomatic treatments such as analgesics and NSAIDs, in combination with tricyclic agents, can be effective in reducing pain and improving sleep.

Psychological and social support

As with other chronic illnesses, managing people with CFS requires consideration of the psychological and social impacts of the illness.

People with CFS may be unable to continue full-time work, so financial difficulties may rapidly develop. Similarly, CFS frequently disrupts high school or university studies. Successful return to work or school after a prolonged illness with CFS often requires a rehabilitation program incorporating medical treatments, psychological support and occupational therapy. Doctors may need to coordinate the help of other healthcare and educational professionals to implement this.

The impact of the illness on the person's family should also be considered. In some circumstances it may be useful for people with CFS to bring their spouse or partner to a consultation, both to help them better understand the illness and to discuss their difficulties in coping. Parents of children and adolescents with CFS should be seen regularly, and may require additional support and counselling.

Doctors should be prepared to act as advocates for their patients in negotiations with employers, educational institutions and social welfare organisations. For instance, part-time work or school alternatives may need to be arranged, or disability allowances may need to be sought.

Joining a patient support group may be valuable for some people. CFS societies can offer individual and group support, education, and advice about access to social welfare agencies (Box C). Individuals may also benefit from the opportunity to exchange information on how to cope with the many practical day-to-day difficulties that arise for those living with this debilitating condition. However, the quality of advice given can vary and it is therefore useful for the doctor to have ongoing knowledge of the activities and attitudes of local support groups.

4.4: Breaking vicious circles - a rationale for therapy

Should a doctor put the person with CFS in contact with support groups?

Support groups have become an important adjunct to medical practice by providing services that traditionally have been poorly catered for within the health care system. They can:

• provide individual and group support to people with CFS and their families
• collect practical information with regard to the availability and quality of medical and government services
• disseminate scientific information to lay people
• lobby government agencies to improve funding for patient services
• promote service delivery and research by raising funds
• increase community awareness of the plight of sufferers.

Inevitably, members of CFS support groups tend to include those with the most prolonged illnesses (Sharpe et al. 1992). Therefore, the groups may inadvertently reinforce stereotypes of chronicity and disability. Depending on the nature of the groups, some may serve to increase alienation from medical and government agencies and encourage forms of treatment that lack scientific evaluation.

Sharpe M, Hawton K, Seagroatt V, Pasvol G. Follow up of patients presenting with fatigue to an infectious diseases clinic. BMJ 1992; 305: 147-152. PubMed abstract

C: Support and resources for people with CFS

CFS = chronic fatigue syndrome; HACC = home and community care.