Chronic fatigue syndrome

Page 2 (of 4)

Clinical practice guidelines - 2002

Produced by a Working Group convened under the auspices of the Royal Australasian College of Physicians
This supplement to the MJA was funded by a grant from the Commonwealth Department of Health and Ageing.
MJA 6 May 2002 176 (9 Suppl): S17-S55

What is the natural history of fatigue states?

In the early stages of an illness characterised by prolonged fatigue, spontaneous recovery is common.[139] After infectious mononucleosis 41% of patients reported prominent fatigue during the acute illness, of whom 71% had prolonged fatigue one month later, 43% at two months, and 9% at six months.[67]

By contrast, full recovery in patients with established CFS is less common. In prospective studies, rates of self-reported improvement vary from 11%-64%,[140-143] and worsening at 12-18 months was reported in 15%-20%.[140,143] A US population surveillance study estimated a cumulative five-year recovery rate of 31%.[144]

The long-term outcome of CFS has been evaluated mostly in people treated within tertiary referral settings.[140,145-150] Such patient samples are biased towards chronic illness and limited patterns of recovery.[60,91,139] Patient reports drawn from self-help group populations show similar biases with respect to functional impairment.[146] In an Australian study conducted in a specialist setting,[150] 65 of 103 patients (63%) who had had symptoms for about five years reported abatement of symptoms and improvement in functional capacity over the next three years, but complete recovery was uncommon (6%). During follow-up, patients were very unlikely to develop other medical disorders (2%), but a significant number did develop other psychological disorders (19%), notably major depression and anxiety. Similar outcomes were confirmed in several other retrospective studies from tertiary referral centres.

Factors associated with poorer outcomes include illness duration, subjective cognitive impairment and somatic symptoms,[143-151] as well as high levels of fatigue or functional impairment and a low sense of control over symptoms.[140] Outcome has not been found to be associated with sex or life stress events,[146-152] or with laboratory parameters, such as viral antibody titres and immunological measures (including T-cell-subset measurements).[153]

At the more severe end of the clinical spectrum, although improvement over time can occur, the prognosis for recovery is poor.[154,155] Patients who have had CFS for more than 10 years are more disabled than those with shorter-duration illness, and have significantly more severe symptoms (particularly cognitive impairment) and more frequent symptoms of fibromyalgia.[156]

Among 2075 people followed up in 19 published studies of the outcome of prolonged fatigue and CFS, there was one death by suicide and two unrelated deaths.[139] These studies included mean follow-up periods ranging from six months to four years, suggesting that suicide rates and overall mortality are not increased in people with CFS.

In studies of children and adolescents with CFS the outcome is significantly better than in adults. Two studies evaluating chronic fatigue in children reported that 77%-94% recovered or their condition improved.[157,158] The average duration of illness is 2-4 years [see Chapter 4].[159-163]

What is known about the pathophysiology of CFS?

The pathophysiological basis of CFS is unclear. The leading hypotheses put forward over the past decade are summarised in Boxes 1.3, 1.4, 1.5, 1.6, and 1.7 and include:

• a unique pattern of infection with a recognised or novel pathogen;[164]
• altered central nervous system (CNS) function resulting from an abnormal immune response against a common antigen;[16,165,166]
• a neuroendocrine disturbance;[167,168]
• a neuropsychiatric disorder with clinical and neurobiological aspects suggesting a link to depressive disorders;169 and
• a psychologically determined response to infection or other stimuli occurring in "vulnerable" individuals.[110,170-172]

Other hypotheses exist but have not been scientifically evaluated. The probable heterogeneity within patient groups labelled as having CFS[18,28,82,83,113] makes it highly likely that there are multiple contributing factors in the disorder.

What is the cost of CFS to the community?

The financial impact of CFS on those affected and on the community has been evaluated.[22] A conservative Australian estimate of the direct costs (those incurred in diagnosis and management) was $1936 per case per annum (in 1988/89 dollars). After inclusion of indirect costs (from lost productivity associated with the disorder) the aggregate annual cost of CFS was $9436 per case (1988/89 dollars). In 2000/01 dollars, this represents a direct cost of $2764 per case and an annual aggregate cost of $13 471 to the community. Based on a conservative assumption of a community prevalence of CFS of 0.2% (200 cases per 100 000 population), this implies an annual cost to the Australian community of $525 million

2: Evaluating people with fatigue

What is "fatigue"?

Patients who complain of persisting "fatigue" or "tiredness" may be describing any one of a diverse range of clinical phenomena, ranging from muscle weakness to dyspnoea or depressed mood. The initial task is to clarify the nature of the "fatigue". Fatigue, like pain, is intrinsically a brain-mediated sensation. As with pain, most people report that the fatigue is experienced as a peripheral phenomenon, apparently occurring in musculoskeletal regions. When questioned closely, most people with CFS report that they also experience "mental fatigue", typically precipitated by complex neuropsychological tasks.[74,426]

To differentiate the various causes of mental and physical fatigue, doctors should focus on the description of the complaint (Box 2.1). Fatigue in people with CFS is typically exacerbated by physical tasks previously achieved with ease, and recovery from periods of worsened fatigue can take hours or even days. Pathological fatigue can be differentiated from:

• somnolence (or "sleepiness"), as it is not relieved by sleep;
• neuromuscular weakness, as people with CFS can generate muscle strength and endurance when circumstances demand;[24,400,427] and
• the lack of motivation and loss of pleasure from usual daily activities that characterise depressive illness.

How should fatigue be evaluated?

CFS is distinguished from similar fatigue-related illnesses not only by carefully characterising the fatigue itself, but also by evaluating associated symptoms and signs. People with CFS also report:

• unrefreshing sleep;
• myalgia:
• arthralgia;
• loss of concentration;
• memory impairment;
• irritable mood, and
• postexertional malaise (may be delayed).

Any of these associated features may be exacerbated by minor physical activity.

Although these symptoms are common in people with CFS, they are not specific and may occur in a range of other medical and neuropsychiatric disorders. In adults presenting for medical assessment with fatigue states the most common alternative diagnosis to consider is major depression.[25,36,39,40,66,74,92-94,96,97] Other commonly detected disorders (Box 2.3) are sleep apnoea, hypothyroidism, anaemia, coeliac disease, chronic hepatitis, panic disorder, generalised anxiety, and somatoform disorders.[16,27,39,40,78,81,90,109]

When taking a medical history, the questions should focus on key symptoms that might suggest alternative explanations for the fatigue state (see Box 2.1 and Box 2.3). Fatigue accompanied by fever, malaise and weight loss suggests an inflammatory or infective process, and fatigue accompanied by weight gain and cold intolerance may indicate hypothyroidism. Fatigue commonly accompanies many other medical conditions, particularly those directly involving the central nervous system and affecting information processing, the sleep-wake cycle, or arousal mechanisms (eg, multiple sclerosis). Many commonly prescribed medications (such as antihistamines and sedatives) and other substances (such as alcohol, marijuana and amphetamines) cause fatigue directly, or indirectly by disturbing the sleep-wake cycle.

Similarly, physical examination should be directed towards elucidating alternative diagnoses. Apart from minor, non-specific signs of illness, the physical examination in people with CFS is normal.(6) Evidence of objective muscle weakness, hard neurological signs, cardiorespiratory disease or fever should alert the doctor to diagnoses other than CFS (see Box 2.3). Although people with CFS often complain of tender cervical lymph nodes, demonstrable lymphadenopathy is not a feature.(6)

When patients have been definitively diagnosed with a medical or psychiatric condition known to be associated with marked fatigue, a separate diagnosis of CFS is generally not justified.

What psychological evaluation is required?

A formal diagnosis of CFS should not be made without an appropriate psychological evaluation of the patient.[6] Although this need not be done by a specialist psychiatrist or psychologist, referral can be useful in selected cases for both diagnostic and treatment purposes. Like the medical evaluation, the psychiatric assessment consists of two distinct parts: the history and the mental state examination.

Brief standardised approaches to psychological evaluation in primary care are available and have been shown to be effective.429 These include self-report questionnaires such as the GHQ-30430 and SPHERE,61,431 or structured interview schedules such as PRIME-MD.432 Important features of the history include prior episodes of anxiety or depression; a past history of multiple, unexplained physical symptoms; and prior alcohol or other substance misuse.

Many people with depressive disorders complain of fatigue or pain, rather than overt psychological symptoms such as tearfulness or sadness. The family history should be reviewed for depressive disorder, self-destructive behaviour or substance misuse. The relationship between the onset of the fatigue state and relevant psychosocial stressors should be noted. Whenever possible, an independent, corroborating history should be sought from a spouse, partner or other family member.

The characteristic mood state of people with CFS is irritation, frustration and transient depression, rather than persistent and profound sadness. This is unlike people with major depression, who report marked anorexia, weight loss, self-reproach and guilt, suicidal plans, persistent loss of motivation or a pervasive loss of pleasure.[25,107,108,111]

A careful review of the history of ill-health before the onset of CFS is the key to resolving the differential diagnosis of somatoform and somatisation disorders. A long-standing history of frequent medical investigation and treatment for unexplained physical symptoms, persistent fear of medical ill-health despite adequate assessment, preoccupation with unusual physical explanations of illness, and persistent rejection of the potential relevance of psychosocial factors may suggest the diagnosis.[107,108]

The mental state examination of people with prolonged fatigue should focus on the observed behavioural features rather than simply those reported by the person. These include psychomotor slowing (which may suggest a serious depressive disorder),(433,434) demonstrable cognitive impairment (suggesting intoxication, delirium or a dementia syndrome), odd or bizarre interpersonal behaviour (suggesting a psychosis), and hostile, angry or excessively irritable responses (suggesting a personality disorder).

Evaluating a person's risk of suicide is an important task. The major psychological risk factor for suicide is untreated depression. Most people who attempt suicide first present to a healthcare agency, although they typically complain of non-specific symptoms such as poor sleep, poor appetite and tiredness rather than depressed mood.[435-437] Other risk factors for suicide include being male, social isolation, concurrent drug and alcohol use and access to lethal means.[438,439]

How should the context of the illness be assessed?

As in the management of other chronic medical conditions, assessing the social circumstances and interpersonal relationships of the patient with CFS is a key component of the medical evaluation.

Important issues to be addressed include:

• the effect of the illness on the person's ability to participate in work or school;
• the effect of the illness on key relationships (eg, partner, parents, friends); and
• the financial impact of the illness on the person with CFS and family.

The functional impairment of people with CFS has been shown to be similar to or greater than that of people with other chronic disabling medical conditions (eg, multiple sclerosis)[440] and psychological conditions (eg, major depression).[20,21] Accordingly, the patient's current level of disability should be carefully assessed, with a review of the duration and intensity of physical activity that can be undertaken without precipitating prolonged fatigue. For example, it may be evident that an adolescent's 45-minute walk to school produces fatigue and other symptoms that last all day. At the severe end of the spectrum of CFS, people may be housebound and experience profound fatigue simply from the necessities of self-care, such as showering or dressing.

A diagnosis of CFS is made after six months or more of disabling symptoms. By this time, people with CFS are commonly in crisis with their school or workplace because of the accumulated time lost as a result of the illness. Similarly, by the time of diagnosis, parents, friends and partners of people with CFS are often questioning the nature of the unexplained illness. The effect of the illness upon the patient's key interpersonal relationships,[441-443] work or educational activities should be specifically evaluated. This will enable doctors to act as advocates for their patients by providing appropriate information to relevant individuals and institutions.

What laboratory tests are appropriate?

Despite the wide range of serological, immunological, virological, psychometric and neuroimaging investigations that have been reported in case-control series of people with CFS (see Boxes 1.3, 1.4, 1.5, 1.6), no specific diagnostic test for the disorder has emerged.[6] For any laboratory test to be accepted as having diagnostic validity, it would need to demonstrate both high sensitivity (ie, almost all people with CFS have a positive result - few false negatives) and high specificity (ie, almost all healthy persons, and people with fatigue not due to CFS, have a negative result - few false positives). In fact, as the diagnosis of CFS currently identifies a heterogeneous group of people,[16,113] it is unlikely that a single, reliable diagnostic test will emerge.

The only laboratory tests currently recommended for the routine evaluation of people with fatigue states (Box 2.4) are aimed at detecting alternative medical conditions. The diagnostic yield of investigations beyond this restricted list is very low.[444-447] If specific alternative diagnoses are suggested by the clinical history or examination (eg, sleep apnoea or multiple sclerosis), further investigations may be warranted.

Many other laboratory procedures have been proposed as "diagnostic tests" by non-medical or alternative practitioners, but have not been subjected to rigorous evaluation. Such "tests" (eg, dark field blood testing for red cell morphology or "candida" identification; stool tests for "dysbiosis"; environmental sensitivity testing) have no basis in evidence and are not recommended.

When should another opinion be sought?

Given the lack of diagnostic certainty in people with CFS and the reliance on clinical history and examination, it may be appropriate to seek another medical opinion during evaluation or treatment. Another opinion by an experienced primary care practitioner may be sufficient, but specific issues in diagnostic assessment or treatment planning sometimes require consultation with the specialist most relevant to the individual's needs.

For example, a history of snoring and daytime somnolence is an appropriate indication for assessment by a sleep physician, which may be followed by overnight sleep study. People with severe or prolonged depression, severe anxiety symptoms, or those assessed as being at risk of self-harm may require psychiatric evaluation. Adolescents who are absent from school or occupational training for prolonged periods may benefit from assessment by a paediatrician. People who are persistently housebound with severe disability arising from CFS may require the assessment and advice of a team, including specialists in rehabilitation medicine, pain management, physiotherapy, occupational therapy, and social work.

3: Managing patients with CFS

Principles of management

Once the diagnosis of CFS is made, the doctor should establish an individualised management plan through a process of active discussion with the patient. The available pharmacological and non-pharmacological approaches should first be outlined, along with the role of continuing medical care and the place for physical, social and workplace (or school) rehabilitation programs. The importance of a collaborative approach between patient and doctor should be stressed. The plan should be designed within the framework of the patient's attitudes towards different modes of treatment, bearing in mind the limitations of existing evidence.[448]

The goal of treatment should be improvement towards and maintenance of maximal achievable functional capacity. While it is very unlikely that any single treatment will provide a "cure", current treatment approaches can result in significant reduction in disability over time.

It is important to give the patient a clear expectation that sustained improvements are rarely achieved in short time frames (days to weeks), but many patients can return to acceptable levels of functioning over longer periods (eg, three to six months).

Sustained improvements are rarely achieved without some setbacks and exacerbations of symptoms along the way. Frequent switching from one form of treatment to another in search of an elusive "cure" should be discouraged, as it is likely to result only in frustration and continuing disability. If patients are made aware of these possibilities at the outset, they will be less likely to abandon useful treatments prematurely.

To facilitate the reduction of disability, active control of key symptoms (eg, pain, sleep disturbance and depressed mood) with standard treatments should be explored. These may include the use of analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), antidepressants or hypnosedatives. If these pharmacological agents prove helpful for the patient, their ongoing use should be reviewed regularly and coordinated with appropriate non-pharmacological forms of care. For example, short-term use of hypnosedatives may assist at the beginning of a structured sleep-wake cycle modification program.[449] Similarly, use of analgesics, NSAIDs or both may be necessary during the early phase of a physical rehabilitation approach. Or, if an antidepressant agent (eg, moclobemide) improves a patient's subjective sense of energy and wakefulness,[450] this can provide an opportunity to embark on a return to school or work, or a social activity program.

As with other chronic disorders, the patient's attitude to his or her illness experience, understanding of the nature of the disorder and its likely course over time, and the relationship between doctor and patient, are all likely to have a significant impact on long-term outcome.[451] Doctors who take an active approach to providing accurate information and to discussing key issues with their patients on an ongoing basis are likely to achieve the best results. This does not mean that the patient and doctor need necessarily agree about all treatment decisions (eg, the use of alternative therapies). It does, however, mean that they should agree on realistic goals for the outcomes of conventional medical treatments. The significant non-specific (placebo) response rate in some controlled treatment trials for people with CFS is likely to be a reflection of these essential components of good clinical practice.[452,453]As a general principle of good management of patients with CFS, it can be useful to introduce the concept of self-monitoring of key symptoms and associated disability. This can be achieved through a variety of standardised instruments (eg, SPHERE,431 Brief Disability Questionnaire) and activity, sleep-wake cycle or pain diaries. These allow both the doctor and patient to develop an accurate picture of whether progress is being made with a particular treatment, or whether there has been spontaneous improvement over time. Such monitoring may also alert the doctor to the emergence of a change in key symptoms or disability.

When people with CFS develop significant new symptoms, or experience a marked change in symptoms, they should be carefully reassessed. New symptoms should not automatically be assumed to be part of the CFS symptom complex. Within this context the emergence of depression and other psychiatric complications is particularly relevant.[450]

Pharmacological treatments for CFS

A range of antiviral, immunoregulatory, antidepressant and metabolic drug regimens have been evaluated in double-blind, placebo-controlled trials in people with CFS. Although limited positive responses have been reported, no agent has consistently shown long-term efficacy in well-designed studies.[35]

Intravenous immunoglobulin (IVIG): Four double-blind, placebo-controlled trials of therapy with IVIG (based on a hypothesis of disturbed immunity in people with CFS) have been published.[264,273,454,455] Two of these trials conducted by one research group in Australia produced conflicting results, with the larger, dose-ranging study showing no significant benefit.[273,455] IVIG is not recommended for adults with CFS.

Antidepressants and other CNS agents: Given the high rate of depression, and depression-related symptoms such as fatigue, sleep disturbance, poor concentration and irritability in people with CFS, antidepressant therapies have received considerable attention. To date, there has been no evidence that patients respond in the way that would be expected if CFS were simply misdiagnosed or "masked" major depression. However, certain agents have been found to be beneficial for patients with CFS, particularly those with significant mood or sleep disturbances. Moclobemide (a reversible monoamine oxidase inhibitor) has been evaluated in a large double-blind, placebo-controlled trial.[450] Limited evidence of benefit was observed, with an improvement in the subjective sense of vigour and energy that was not associated with any alteration in mood. Similarly, selegiline (a specific monoamine oxidase inhibitor) has been reported to relieve tension and anxiety, and improve vigour and sexual relations.[456] All of these agents are somewhat "amphetamine-like" in their actions. While this may assist with key symptoms like fatigue, wakefulness and concentration, they should be used cautiously and closely monitored for side effects such as agitation and insomnia. Their most effective use may be in combination with an active sleep-wake cycle approach.[449]

While the new serotonergic agents are particularly popular for treating major depression, there has been little evidence of their overall usefulness in patients with CFS. In one of the first large trials, fluoxetine (a selective serotonin reuptake inhibitor [SSRI]) showed no more benefit than placebo.[457] However, SSRIs may have a place in patients with concurrent major depression or a strong personal or family vulnerability to anxiety or depression. SSRI therapy needs to be closely monitored for adverse side effects such as nausea, agitation and gastrointestinal disturbances in the early stages of treatment. As SSRIs may disturb sleep-wake architecture during the first few weeks of treatment, patients should also be closely monitored for any exacerbation of the CFS symptom complex. From this perspective, the older tricyclic agents and some of the new antidepressants with more sedative properties (eg, nefazodone) may be more suitable for some patients.

Studies of combination therapy with a low dose tricyclic antidepressant and an NSAID in people with fibromyalgia showed beneficial effects on muscle pain and sleep disturbance, but not on fatigue or mood.[458,459]

Corticosteroids: Two short-term, placebo-controlled trials of low-dose hydrocortisone therapy in patients with CFS showed a reduction in fatigue and improvement in "wellness", but this was associated with a significant depression of adrenal function.[460,461] Given the serious morbidity associated with long-term use,[462] corticosteroids cannot be recommended for CFS based on current evidence.

Mineralocorticoids: Although some patients have been found to have postural blood pressure changes consistent with neurally mediated hypotension (Box 1.5), mineralocorticoid therapy has not been found to be beneficial.[463,464]

The role of rehabilitation, behavioural and cognitive treatment approaches

Rehabilitation, behavioural and cognitive approaches link the principles of good clinical management with varying degrees of graded physical activity and psychological intervention.[153,465,466] They have been evaluated not only in patients with CFS, but in a wide variety of other closely related and often chronically debilitating medical and psychological disorders (eg, chronic pain, chronic daily headache, irritable bowel syndrome and chronic depression). Such treatments are not designed to achieve rapid symptomatic relief. Rather, they are aimed at maximising functional capacity over longer periods. For clinical trial purposes, a specific number of structured treatments are packaged over a set time period. In routine clinical practice, however, the initial treatment strategy is usually individualised according to the patient's level of disability and personal preferences, and subsequently modified according to the response. This is sometimes referred to as "pacing".[448]

The rationale for these approaches is outlined in Box 3.1.

The behavioural component encourages planned and supervised resumption of appropriate physical and mental tasks. A physical activity program is individually designed to take account of the patient's current level of disability.[467,468] After a prolonged period of illness and inactivity, new activities are introduced gradually and, most importantly, are "paced" (ie, scheduled to stop before they produce a significant exacerbation of symptoms). Over time the level of activity attempted is slowly increased at a rate determined by the patient's response.

The cognitive component aims to identify beliefs, attitudes and behaviours that may impair recovery.[469-471] Examples include a fear that any increased physical activity will cause harm or prolong illness; a belief that all treatment is futile and that only complete rest will help; a belief that complete withdrawal from work, school and social activities is necessary; a belief that occult chronic infection or chemical exposure has caused permanent injury. The existence of such beliefs is ascertained by exploring the person's causal attributions and his or her understanding of the illness.

As simplistic illness attributions may be associated with poor outcomes,[470] people with CFS should be encouraged to adopt the widest possible view of the medical, physical, and psychosocial management strategies to assist in coping with the illness.[472,473] The doctor and patient should work cooperatively to improve understanding, attitudes and behaviours that can help maximise long-term function.

In general, trials with more substantial differences between the intervention and the control treatment arms show the greatest benefits.[474] Active treatment programs that emphasise strong behavioural components (physical activity, rehabilitation) achieve good short-term results, but studies that incorporate a cognitive component produce more sustained long-term improvements. This may be because patients more readily adopt lifestyle changes that help maintain improved functional capacity beyond the formal treatment period.[465,475-477]

On balance, current evidence suggests that rehabilitative, behavioural and cognitive approaches should be an integral component of managing people with CFS.[478] This contrasts with previous beliefs that prolonged rest and social withdrawal should be advocated.[479] By the time patients present with established CFS, many have already experimented with prolonged rest and have found it unhelpful. In some, it may be associated with an exacerbation of sleep-wake difficulties and fatigue. Doctors should ensure that patients are informed of the dangers of prolonged rest[480] and the psychological risks of social isolation.

Applying management principles

In routine clinical practice these management principles can be applied within any of the following conceptual frameworks, depending on the preferences of the patient and the expertise of the doctor:

A cognitive behaviour therapy model: This tends to suit practitioners and patients who are comfortable working with an overtly behavioural approach to managing CFS.[466] Some patients find psychological terminology alienating, believing it to imply that their symptoms and disability are imaginary, contrived or "psychosomatic". Such beliefs are unfounded. Skilled practitioners who are able to explain the role of behavioural and psychological factors in a wide range of medical disorders can often overcome a patient's initial reservations and gain his or her confidence. When properly used, a cognitive behavioural management approach promotes active patient participation with self-monitoring, and takes account of previous experiences, both beneficial and adverse. Contrary to popular myths, this approach does not simplistically impose a psychological model of causation. Rather, it encourages patients to adopt a wider view of the range of medical and psychological approaches that can promote optimal long-term functioning.

A disease education model: This approach is used in other chronic and relapsing conditions such as diabetes or asthma, and therefore best suits patients and practitioners who are most comfortable with an overtly "medical" management model.[481] Within this framework (as with the cognitive behaviour approach) patients can be helped to gain a deeper understanding of their illness, adopt appropriate management strategies, avoid harmful treatments, and develop practical coping skills. As with many other chronic medical disorders, it is better for patients with CFS to be empowered through appropriate self-management and self-monitoring techniques[482] rather than passively submitting to fruitless investigations and marginally effective medical interventions.

A rehabilitation model: This is akin to approaches used for disabling medical conditions such as brain or spinal injury, stroke, or chronic heart and lung diseases.[483] In the context of CFS, this model is best suited to doctors and patients who feel most comfortable focusing primarily on physical aspects of management.

Limitations of the evidence

There have now been a number of controlled or partially controlled studies of the various components of cognitive behavioural management approaches. Although most have shown significant short-term or longer-term benefit (or both), improvement has not been observed in all patients or in all studies,[484,485] and, when observed, may be modest.[486]

It is important to note that studies differ substantially in patient selection, intensity and duration of treatment provided, and suitability of the "control" interventions used for comparison. In most studies patients were only included if they were physically well enough to attend clinics for assessment, treatment and follow-up. It is therefore difficult to extrapolate the results to patients with more severe disability. Moreover, many studies have significant refusal and drop-out rates, which may reflect on the acceptability of the treatment regimens. These factors significantly limit the generalisability of the findings.[478]

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