Article - Chronic fatigue syndrome.(Statistical Data Included)

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Chronic fatigue syndrome.(Statistical Data Included)

Author/s: Reid

Background

Definition Chronic fatigue syndrome is characterised by severe, disabling

fatigue and other symptoms, including musculoskeletal pain, sleep

disturbance, impaired concentration, and headaches. Two widely used

definitions of chronic fatigue syndrome (from the US Centers for Disease

Control and Prevention[1] and from Oxford[2]--see table) were developed as

operational criteria for research. There are two important differences

between these definitions. The British criteria insist on the presence of

mental fatigue; the American criteria include a requirement for several

physical symptoms, reflecting the belief that chronic fatigue syndrome has

an underlying immunological or infective pathology.

Incidence/prevalence Community and primary care based studies have reported

the prevalence of chronic fatigue syndrome to be 0.2-2.6%, depending on the

criteria used.[3 4] Systematic population surveys have found similar rates

of the syndrome in people of different socioeconomic status, and in all

ethnic groups.[4 5] Female sex is the only demographic risk factor (relative

risk 1.3 to 1.7 depending on diagnostic criteria used).[6]

Aetiology The cause of chronic fatigue syndrome is poorly understood.

Prognosis Studies of prognosis in chronic fatigue syndrome have focused on

people attending specialist clinics, who are likely to have had the

condition for longer and to have a poorer outlook. Children with the

syndrome seem to have a notably better outcome: 54-94% of children show

definite improvement (after up to six years' follow up); 20-50% of adults

show some improvement in the medium term and only 6% return to premorbid

levels of functioning.[7] Despite the considerable burden of morbidity

associated with chronic fatigue syndrome, there is no evidence of increased

mortality. Outcome is influenced by the presence of psychiatric disorders

and beliefs about causation and treatment.[7]

Aims To reduce levels of fatigue and associated symptoms; to increase levels

of activity; to improve quality of life.

Outcomes Severity of symptoms; effects on physical function and quality of

life measured in several different ways by: the medical outcomes survey

short form general health survey (SF-36), a rating scale measuring

limitation of physical functioning caused by ill health[8]; the Karnofsky

scale, a modified questionnaire originally developed for the rating of

quality of life in people undergoing chemotherapy for malignancy[9]; the

Beck depression inventory[10]; the sickness impact profile, a measure of the

influence of symptoms on social and physical functioning[11]; and self

reported severity of symptoms and levels of activity.

Methods

Clinical Evidence search and appraisal January 1999. All randomised

controlled trials (RCTs) meeting Clinical Evidence criteria were reviewed.

We found that the evidence on which to base clinical decisions was slender.

Even where good evidence exists, there are likely to be large gaps in

provision of services and expertise (for example, for cognitive behavioural

therapies). Hence, for many practitioners it will be necessary to use

clinical judgment linked with expertise derived from related areas, such as

the management of chronic pain.

Question: What are the effects of treatments?

Option: Antidepressants

We found limited data from RCTs, providing insufficient evidence to support

the use of antidepressants in people with chronic fatigue syndrome. However,

research evidence suggests that antidepressants may be useful in treating

associated depression, insomnia, or myalgia.

Benefits

We found no systematic reviews. Versus placebo: We found three RCTs. One

that compared fluoxetine with placebo in 96 people found no significant

benefit on outcomes used (the Beck depression inventory and the sickness

impact profile).[12] Another allocated 136 people to four groups: exercise

plus fluoxetine; exercise plus placebo; appointments to review activity

diary with physiotherapist plus fiuoxetine, and appointments to review

activity diary with physiotherapist plus placebo. It found no significant

difference in outcome (level of fatigue), although there was a trend

indicating some benefit and there were modest improvements in measures of

depression.[13] The first study used shorter treatment and studied people

with a long duration of illness, which may explain the differing results. A

third trial compared the monoamine oxidase inhibitor phenelzine versus

placebo in 24 people with chronic fatigue syndrome, using a modified

Karnofsky scale and other outcome measures.[14] This also found a

nonsignificant trend toward improvement. Versus each other: We found one RCT

comparing sertraline with clomipramine in people with chronic fatigue

syndrome, but the lack of a placebo group makes it hard to draw useful

conclusions.[15]

Harms

Up to 15% of participants withdrew from active treatment because of adverse

drug effects.[12-15]

Comment

To date, clinical trials have taken place in specialist clinics, which may

actively select for people whose condition is more resistant to treatment.

Option: Corticosteroids

Limited data from RCTs provide insufficient evidence about the effects of

corticosteroids in people with chronic fatigue syndrome. Any benefit from

low dose glucocorticoids seems to be short lived, and higher doses are

associated with adverse effects.

Benefits

We found no systematic review. Versus placebo: We found three placebo

controlled RCTs in people with chronic fatigue syndrome. One, a crossover

RCT of fluorocortisone in 20 people, measured outcomes as change in symptom

severity on a visual analogue scale, and functional status (using the

SF-36).[16] It found no significant difference between active treatment and

placebo, though the number of participants may have been too small to detect

a difference. The two other trials evaluated hydrocortisone. One compared

hydrocortisone 25-35 mg daily with placebo in 65 people and found a greater

improvement in a self rated scale of " wellness " in the treatment group.

However, other self rating scales did not show significant benefit.[17] The

other study used a lower dose of hydrocortisone (5 or 10 mg daily) in 32

people and found short term improvement in fatigue. Nine people (28%) taking

hydrocortisone improved, as measured by a self report fatigue scale,

compared with three (9%) taking placebo. The benefit rapidly attenuated when

treatment was stopped.[18]

Harms

The study using the higher doses of hydrocortisone found that 12 people

(40%) receiving active treatment experienced adrenal suppression.[17] Minor

adverse effects were reported in up to 10% of people in the other

studies)[16 18]

Comment

The trials used different reasons for their choice of active treatment. The

use of fluorocortisone, a mineralocorticoid, was based on the hypothesis

that chronic fatigue syndrome is associated with neurally mediated

hypotension.[19] The use of hydrocortisone in the other trials was based on

evidence of underactivity of the hypothalamic-pituitary-adrenocortical axis

in some people with the syndrome.[20]

Option: Exercise

Two RCTs have found that a graded exercise programme can substantially

improve measures of fatigue and physical functioning for people with chronic

fatigue syndrome.

Benefits

We found no systematic review. We found two RCTs. The first compared aerobic

exercise with flexibility training (control intervention) in 66 people.[21]

The programmes involved individual weekly sessions over 12 weeks, with the

exercise group building up their level of activity to 30 minutes exercise a

day with a maximum energy expenditure of 60% of maximum oxygen consumption

([VO.sub.2] max). With the self rated clinical global impression scales used

as an outcome measure, 55% of the aerobic exercise group reported feeling

much better or very much better compared with 27% of the flexibility

training group (P = 0.05). Significantly better outcomes were also reported

as measured by physical fatigue and levels of physical functioning on the

SF-36. The flexibility training group crossed over to aerobic exercise at

the end of the trial, and significant improvements from baseline were found.

The second trial randomised 136 people with chronic fatigue syndrome to one

of four groups: exercise plus fluoxetine; exercise plus placebo;

appointments plus fluoxetine; and appointments plus placebo.[13] The

exercise group undertook graded aerobic exercise for 20 minutes three times

a week up to an energy expenditure of 75% of [VO.sub.2] max. Exercise was

associated with significant improvements in fatigue and functional work

capacity. This trial was complicated by a high withdrawal rate, particularly

in the exercise groups (37% v 22% in the appointment groups), but the

differences remained significant after intention to treat analysis.

Harms

Adverse effects of exercise were not reported in either trial, and we found

no evidence that exercise is harmful in people with chronic fatigue

syndrome. However, experience suggests that exacerbation of symptoms may

result from overambitious or overhasty attempts at exercise. These can be

reduced by cautious setting of targets and providing information about the

cause of possible symptoms after exertion.

Comment

None.

Option: Prolonged rest

We found no evidence that prolonged rest is an effective treatment for

chronic fatigue syndrome. We found considerable indirect evidence suggesting

that prolonged rest may be harmful.

Benefits

We found no systematic reviews or RCTs.

Harms

We found no direct evidence of harmful effects of rest in people with

chronic fatigue syndrome. However, we found observational evidence

suggesting that prolonged inactivity may perpetuate or worsen fatigue and

its associated symptoms in both healthy volunteers[22] and in people

recovering from viral illness.[23]

Comment

None.

Option: Dietary supplements

One small RCT found limited evidence of benefit from magnesium injections.

Two small RCTs of oral evening primrose oil found mixed results.

Benefits

We found no systematic review. Magnesium: We found one RCT comparing

intramuscular injections of magnesium with placebo in people with chronic

fatigue syndrome over a six week period.[24] This trial found important

benefits with magnesium: 12/15 of the treatment group improved compared with

3/17 of the placebo group. Evening primrose oil: We found two RCTs comparing

evening primrose oil with placebo in people with a diagnosis of postviral

fatigue syndrome or chronic fatigue syndrome, only one of which found

significant benefit. One RGT compared evening primrose oil (4 g orally per

day) with placebo in 63 people with a diagnosis of postviral fatigue

syndrome.[25] At three months, 85% of the people receiving active treatment

had improved compared with 17% on placebo. However, a further three month

trial found no significant difference between evening primrose oil (4 g

orally per day) and placebo in 50 people with chronic fatigue syndrome

(using the Oxford diagnostic criteria).[26]

Harms

These trials reported no adverse effects.

Comment

Subsequent studies have failed to find a deficiency of magnesium in people

with chronic fatigue syndrome.[27-29] The difference in outcome for the

studies of evening primrose oil may be partly explained by participant

selection; the second study used currently accepted diagnostic criteria.[26]

Also, whereas the first study used liquid paraffin as a placebo,[25] the

second study used sunflower oil, which is better tolerated and less likely

to affect the placebo response adversely.[26]

Option: Immunotherapy

Four small RCTs of IgG in people with chronic fatigue syndrome found only

limited benefit and considerable adverse effects. RCTs of other forms of

immunotherapy have found no evidence of a benefit over placebo.

Benefits

We found no systematic review. IgG: We found four RCTs comparing IgG with

placebo. In the first, 30 patients were given either intravenous IgG (1

g/kg) or albumin (placebo) every 30 days.[30] After six months no

differences were found in measures of fatigue or physical and social

functioning. A similar study randomised 49 patients to three infusions of

either intravenous IgG (2 g/kg) or placebo (a maltose solution).[31]

Treatment was given monthly. Ten of the 23 immunoglobulin recipients

improved in terms of a physician rated assessment of symptoms and

disability, compared with three of 26 placebo recipients. The studies

differed in that the second study used twice the dose of IgG, did not

require that participants fulfilled the operational criteria for chronic

fatigue syndrome, and made no assessments of them during the study, waiting

until three months after completion.[31] A subsequent attempt by the same

group to replicate the results was unsuccessful.[32] A further trial

compared IgG (1 g/kg) with placebo in 71 adolescents (age 11-18 years).[33]

Three infusions were given one month apart. There was a significant

difference between the active treatment and control groups in mean

functional outcome determined by taking the mean of clinician ratings from

four areas of the participants' activities. However, both groups showed

significant improvements from baseline, continuing to the six month

post-treatment assessment. Other immunotherapies: We found one RCT comparing

interferon alfa with placebo (n = 30).[34] In this study, improvement was

found only on subgroup analysis. Other RCTs have found no significant

advantage over controls from dialysable leucocyte extract (in a factorial

design with cognitive behavioural therapy)[35] or terfenadine.[36]

Harms

Considerable adverse effects (gastrointestinal complaints, headaches,

arthralgia, and worsening fatigue) were reported with IgG in up to 82% of

trial participants.[30] Adverse effects were also notable with alpha

interferon, and two of 13 participants on active treatment developed

neutropenia.[34]

Comment

None.

Option: Cognitive behavioural therapy

A systematic review of RCTs has found that cognitive behavioural therapy

administered by highly skilled therapists in specialist centres is an

effective intervention for people with chronic fatigue syndrome, with a

number needed to treat (NNT) of 2. The generalisability of this finding to

less specialised settings is likely to be limited.

Benefits

We found one systematic review, updated in August 1998, which identified 13

RCTs of cognitive behavioural therapy in people with chronic fatigue

syndrome.[37] Three trials met the reviewers' inclusion criteria (all

participants fulfilled diagnostic criteria for chronic fatigue syndrome, use

of adequate randomisation, and use of controls).[35 38 39] The earliest

study in 90 people used the Australian diagnostic criteria and evaluated

cognitive behavioural therapy and immunotherapy, using a factorial

design.[35] The comparison group received standard medical care. Cognitive

behavioural therapy was given every two weeks for six sessions lasting 30-60

minutes each. Treatment involved encouraging participants to exercise at

home and feel less helpless. There was no significant difference in outcomes

between cognitive behavioural therapy and standard care when the Karnofsky

scale and symptom report on a visual analogue scale were used. The second

study used the Oxford diagnostic criteria and compared cognitive behavioural

therapy with normal general practice care in 60 people attending a secondary

care centre.[38] The active treatment consisted of a cognitive behavioural

assessment, followed by 16 weekly sessions of behavioural experiments,

problem solving activity, and re-evaluation of thoughts and beliefs

inhibiting return to normal functioning. At 12 months, on the Karnofsky

scale, 73% of those receiving cognitive behavioural therapy were improved

compared with 27% receiving standard care. The relative benefit increase was

175% (95% confidence interval 54% to 432%), with two people needing to be

treated with cognitive behavioural therapy for one patient to achieve normal

functioning (NNT 2;2 to 53. This study was replicated in the third study in

60 people attending a different secondary care centre.[39] The cognitive

behavioural therapy was given in 13 weekly sessions, and the control

patients received relaxation therapy. Outcome was assessed by using the

medical outcomes survey short form. A good outcome was found in 63% of those

treated with cognitive behavioural therapy compared with 17% receiving

relaxation therapy. The relative benefit increase was 270% (137% to 531%)

with a NNT of 2 (1 to 7). In both the second and third studies, improvement

continued over 6-12 months' follow up.[38 39]

Harms

No harmful effects were reported.

Comment

The disappointing results of the Australian study may have been because the

therapy was less intense and no attempts at cognitive reappraisal were

offered, and because routine care was itself reasonably effective.[35] The

conflict between the differing illness models for the two active treatments

being evaluated, cognitive behavioural therapy and immunotherapy, may also

have had an impact on effectiveness. The Australian diagnostic criteria are

no longer widely used. The other two studies took place in centres with

highly skilled cognitive behavioural therapists.[38 39] The generalisability

of their positive results to settings outside specialist centres remains

uncertain. A large Dutch RCT (G Bleijenberg, personal communication) and a

British RCT based in primary care (L Ridsdale et al, personal communication)

are due to report shortly.

Option: Oral nicotinamide adenine dinucleotide

One small RCT found evidence of limited benefit from oral nicotinamide

adenine dinucleotide.

Benefits

We found no systematic review. We found one RCT using a crossover design,

which compared nicotinamide adenine dinucleotide (NADH) 10 mg a day and

placebo over four weeks.[40] Of the 33 people with chronic fatigue syndrome

who completed the study, 26 were included in the analysis. On a symptom

rating scale, 8/26 receiving the study drug attained a 10% improvement,

compared with 2/26 receiving placebo.

Harms

Minor adverse effects (loss of appetite, dyspepsia, flatulence) were

reported with the study drug but did not lead to stopping treatment.

Comment

The rationale for this treatment is that NADH facilitates generation of ATP,

which may be depleted in chronic fatigure syndrome.[40] The authors plan to

conduct a further study using greater numbers.

We thank Clinical Evidence musclosketal disorders advisers: Troels Mork

Hansen, Herlev, Denmark, and Stothard, Middlesbrough, UK.

Competing interests: None declared.

Interventions

Beneficial:

Exercise

Cognitive behavioural therapy

Unknown effectiveness:

Corticosteroids

Antidepressants

Dietary supplements

Oral nicotinamide adenine dinucleotide (NADH)

Unlikely to be beneficial:

Immunotherapy

Likely to be ineffective or harmful:

Prolonged rest

Diagnostic criteria for chronic fatigue syndrome

Centers for Disease Control, Oxford[2]

1994[1]

Diagnostic criteria

Clinically evaluated, medically Severe, disabling fatigue of at

unexplained fatigue of at least least six months' duration

six months' duration that is: that:

* of new onset * affects both physical and

* not a result of ongoing mental functioning

exertion * was present for more than

* not substantially alleviated 50% of the time

by rest

* a substantial reduction in

previous levels of activity

The occurrence of four or more Other symptoms, particularly

of the following symptoms: myalgia and sleep and mood

* subjective memory impairment disturbance, may be present

* tender lymph nodes

* muscle pain

* joint pain

* headache

* unrefreshing sleep

* postexertional malaise

(>24 hours)

Exclusion criteria

Active, unresolved, or suspected Active, unresolved, or suspected

disease likely to cause fatigue disease likely to cause fatigue

Psychotic, melancholic or Psychotic, melancholic or

bipolar depression (but not bipolar depression (but not

uncomplicated major depression) uncomplicated major depression)

Psychotic disorders Psychotic disorders

Dementia Dementia

Anorexia or bulimia nervosa Anorexia or bulimia nervosa

Alcohol misuse or other

substance misuse

Severe obesity

Summary points

Though we found limited data from RCTs providing insufficient evidence to

support the use of antidepressants in people with chronic fatigue syndrome,

antidepressants may be useful in treating associated depression, insomnia,

or myalgia

We found limited data from RCTs providing insufficient evidence to support

the use of corticosteroids in people with chronic fatigue syndrome; any

benefit from low dose glucocorticoid treatment seems to be short lived, and

higher doses are associated with adverse effects

Two RCTs have found that a graded exercise programme can produce substantial

improvements in measures of fatigue and physical functioning for people with

chronic fatigue syndrome

We found no evidence that prolonged rest is an effective treatment for

chronic fatigue syndrome, and indirect evidence that prolonged rest may be

harmful

Limited data from small RCTs provide no clear evidence of benefit from

magnesium injections or oral evening primrose oil in people with chronic

fatigue syndrome

Four small RCTs of IgG in people with chronic fatigue syndrome found only

limited benefit and adverse effects; other forms of immunotherapy have no

advantage over placebo

A systematic review of RCTs has found that cognitive behavioural therapy

administered by highly skilled therapists in specialist centres is effective

in people with chronic fatigue syndrome

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