Understanding and treating chronic fatigue syndrome

1
Understanding and treating chronic fatigue
syndrome

• Alison Wearden
• Senior Lecturer in Psychology,
• School of Psychological Sciences
• University of Manchester.
• Principal Investigator the FINE Trial
• alison.wearden_at_manchester.ac.uk

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What is chronic fatigue syndrome?

• Severe, long-lasting (more than 6 months) fatigue
  which is unexplained by any medical condition
• Other symptoms are usually present
• Diagnosed on basis of symptoms and history
• Several sets of diagnostic criteria exist
• A controversial condition!

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Evolving diagnostic criteria

• First modern diagnostic criteria 1988
• Since then, several further sets
• Restrictive versus inclusive?
• Early criteria specified more symptoms but did
  not seem to define a more homogenous group
• More symptoms associated with more psychiatric
  morbidity/psychological distress
• Katon Russo (1992), Arch. Int Med, 152, 1604-9.

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CFS diagnostic criteria

• Original CDC (Holmes et al 1988)
• Current CDC (Fukuda et al 1994)
• UK, Oxford (Sharpe et al 1991)
• London ME (National Task Force, 1994)
• Canadian (Carruthers et al. 2003)

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CFS and ME

• ME myalgic encephalomyelitis OR myalgic
  encephalitis
• Debate as to whether they are the same thing
• Lumpers and splitters
• ME different from CFS?
• Extent to which CFS distinguishable from other
  functional somatic syndromes?
• Wessely White, Br J Psychiat 200418595-96

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Fukuda inclusion criteria

• Self-reported persistent or relapsing fatigue
• of new and definite onset
• at least 6 months duration
• not the result of ongoing exertion
• does not improve with rest
• results in substantial reduction in previous
  levels of occupational, educational, social or
  personal activities

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Plus four or more of the following symptoms

• Self-reported concentration problems resulting in
  substantial reduction in previous activity levels
• Sore throat
• Tender neck or armpit lymph nodes
• Muscle pain
• Multi-joint pain without inflammation
• Headache of new type, pattern or severity
• Unrefreshing sleep
• Post-exertional malaise lasting gt 1 day

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Fukuda exclusion criteria

• Any active medical condition of which fatigue is
  a symptom (asthma, hypothyroid)
• Any unresolved previous medical condition
• History/current
• severe depression with psychotic/melancholic
  features
• bipolar/schizophrenia /dementia/delusional
  disorders
• anorexia/bulimia nervosa
• alcohol or substance abuse
• Severe obesity

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NOT excluded

• Depressive or anxiety disorders (e.g. dysthymia,
  phobias, generalised anxiety)
• Other medically unexplained conditions (e.g.
  irritable bowel syndrome, fibromyalgia)
• Isolated and unexplained test results which are
  not sufficient to suggest an alternative medical
  explanation
• Fukuda et al. (1994) Ann Intern Med, 121,953-959

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• Oxford criteria differ from Fukuda mainly in that
  fatigue must
• be the principal complaint
• affect physical and mental function
• No requirement for additional symptoms
• List of exclusions also includes organic brain
  disease
• Sharpe et al., 1991, J R Soc Med, 84, 118-121

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The nature and measurement of fatigue

• Fatigue a universal experience
• Multiple components
• Subjective feelings of fatigue (physical, mental,
  phenomenologically complex.....)
• Observable performance decrements
• Context and duration of fatigue

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Subjective vs observable fatigue

• Measures of subjective fatigue are self-report
• Often no 11 correspondence between subjective
  feelings and observable decrements
• Subjective does not mean not real or
  imaginary!!!

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A continuum of fatigue?

• Pawlikowska et al., 1994, Br Med J, 308, 763-6
• 15000 UK adults in the community
• Fatigue scale 11 items, scores 0-33
• Fatigue is not something you have or dont have
  it is something you have to some degree
• In CFS, fatigue is chronic, not relieved by rest,
  and not explained by the usual factors

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From Pawlikowsa et al., 1994.
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Prevalence of CFS?

• Prevalence estimates vary depending on diagnostic
  criteria used, who is sampled, and how.
• 1988 CDC criteria retrospectively applied,
  community sample 0.01 (Price et al., 1992)
• Oxford criteria, UK postal survey, 0.6 (Lawrie
  et al., 1995)
• Fukuda criteria, UK primary care, 2.6

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Prevalence in primary care?

• UK, patients attending GP surgery
• CF 11.6 CF no psych Dx 4.1
• CFS 1.2-2.6 CFS no psych Dx 0.5-0.7
• These figures generally higher than GP reports of
  CFS
• Presenting problem may not be fatigue
• Note that fatigue associated with psychiatric
  disorder
• Wessely et al., 1997, Am J Pub Health871449-55

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Who is fatigued?

• Walker et al., (1993) J Gen Intern Med 8436-40.
• Household sample
• Fatigue associated with
• being a woman
• never having been married
• fewer years of education
• What about social class?

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Health Lifestyle surveyCox et al.,
1987Percentage of people feeling tired all the
time during the previous month
female male
Professional, managers 27.0 17.9
Other non-manual 29.1 17.8
Skilled manual 29.2 18.6
Semi- and un-skilled manual 33.8 22.0
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• So fatigue shows a slight social gradient whereby
  people of lower socio-economic status are more
  likely to be fatigued
• What about CFS?
• Yuppie flu an illness affecting middle class,
  middle aged women?

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Conclusions from CFS/ME report

• A population prevalence of at least 0.2-0.4
• Commonest age of onset is early twenties to
  mid-forties
• In children commonest age of onset 13-15
• CFS/ME about twice as common in women than men
• Affects all social classes similarly
• Affects all ethnic groups
• (Report to the Chief Medical Officer of
  Independent CFS/ME Working Group, 2002)

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Data taken from Euba et al., 1996, Br J
Psychiatry, 168121-6People with a diagnosis of
CFS in UK tertiary and primary care
Tertiary Primary
women 68 82
social class 1 36 3
previous psychiatric diagnosis 21 74
psychological attribution 7 58
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Is CFS a serious illness?

• CFS compared with 6 other patient groups and
  population norms, using SF-36
• CFS patients scored far lower on all scales than
  general population
• CFS patients more functionally impaired than
  acute MI patients, Type II diabetes or
  hypertension
• CFS patients more emotionally distressed and
  impaired than all patients (including MS, CHF)
  except depressed patients
• (Komaroff et al (1996) Am J Med101281-9)

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Prognosis of CFS?

• Untreated, prognosis for adults is poor
• 54-94 children recover over several years
• Adults with CFS by case criteria - 10 recover
  fully in 3 years
• Adults with CF (not CFS) 40 recover
• (Joyce et al., 1997, Q J Med90223-233)
• Recent systematic review no more optimistic....

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Cairns Hotopf, Occupational Medicine,
20055520-31

• 28 articles included in systematic review
• Median full recovery rate was 5 (0-31)
• Median improvement rate was 40 (8-63)
• Return to work highest figure was 30
• Predictors of good response less severe
  fatigue, belief in control over symptoms, not
  attributing to physical cause.

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Associations of fatigue

• Fatigue is associated with distress
• CFS is associated with other medically
  unexplained conditions
• CFS also associated with psychiatric diagnoses

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Fatigue and distressFrom Pawlikowska et al
(1994), BMJ 308763-6
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CFS and other medically unexplained conditions

• CFS patients have elevated life-time and current
  rates of
• irritable bowel syndrome
• food intolerance
• fibromyalgia
• these conditions are all symptomatically defined,
  share common key symptoms
• Aaron Buchwald (2001) Ann Int Med134(2)S868-81

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CFS psychiatric disorder

• 40-70 CFS patients in specialist clinics have a
  diagnosable psychiatric disorder, mainly
  depression, also anxiety disorders
• (David, 1991, Br Med Bull, 47966-88)

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Do people become depressed or distressed as a
result of CFS?
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• (Data on previous slide extracted from Wessely,
  Hotopf and Sharpe (1998) Chronic Fatigue and its
  Syndromes, OUP, p227)
• the statement that a CFS patient has a
  depressive illness is merely a statement about
  their symptoms. It has no causal implications.
  Kendell, 1991, Lancet.
• What other possible causal explanations have
  been considered?

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CFS and viruses

• Early research suggested CFS results from
  persistent viral infection, e.g. Epstein-Barr
  virus, herpes viruses, enteroviruses (e.g. polio)
• no viral specificity (same illness after
  different infections)
• selected samples of CFS patients?
• current opinion - no convincing evidence that CFS
  is due to persistent viral infection

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Does CFS occur more often after (viral) infection?

• Need prospective studies to answer question, as
  recall bias in retrospective studies
• Minor infections do not pre-dispose (Wessely et
  al., 1995, Lancet, 3451333-8)
• Increased risk of fatigue syndromes after
  glandular fever (x5), hepatitis, meningitis
• Infection as a trigger

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CFS and immune dysfunction

• The cytokine hypothesis
• Suggestion that there may be low levels of NK
  cells in CFS not well supported by the evidence
• Recent systematic review suggested that there is
  no consistent pattern of immunological
  abnormality
• (Lyall, Peakman Wessely, J Psychosom Res,
  20035579-90)
• Scant evidence for change in immune function as
  patients improve clinically more research needed

34
CFS, muscles and activity levels

• fewer mitochondria, reduced oxygen transport,
  post-exercise lactic acid in some studies
• other studies have found near-normal aerobic
  capacity, normal muscle fucntion and normal
  postexercise lactate concentration
• decreased muscle strength and endurance due to
  de-conditioning after inactivity?
• need sedentary comparisons

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• on exercise testing, CFS patients reach
  subjective exhaustion before physiological many
  dont reach predicted maximum heart rate
• decreased activity tolerance due to central
  mechanisms?
• sub group of very inactive patients
• no simple relationship between activity levels
  and other aspects of illness

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HPA axis

• Suggestion of an altered physiological response
  to chronic stress.
• Most studies show that a proportion (1/3?) of
  patients exhibit mild hypocortisolism, not of
  adrenal origin, and blunted HPA axis responses to
  challenge.
• Cause or consequence?
• Prospective studies suggest that HPA axis changes
  may not be seen early in the illness
• (Cleare, Endocrine Reviews, 200324236-52.)

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Neuroendocrinological changes in CFS - serotonin

• Tests of 5HT reactivity suggest different
  responses in patients with primary diagnosis of
  depression and patients with CFS
• Enhanced serotonergic response in non-depressed
  CFS patients may be inversely related to basal
  cortisol levels

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Cognitive problems

• Concentration problems common, very disabling
• Early work using neuropsychological test
  batteries, found few or mild objective deficits
  but many methodological problems
• CFS patients have difficulty with complex speeded
  tasks
• Cognitive complaints correlated with mood
• Mode of onset?

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The role of illness beliefs

• Some studies have found that illness beliefs
  predict outcome
• Strong belief that illness has a physical cause
  (illness attribution)
• Belief that symptoms are uncontrollable
• Belief that exacerbation of symptoms damage

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CFS and ME

• ME - myalgic encephalomyelitis -
• A medically unexplained, fatiguing condition,
  with many other symptoms
• Regarded as an organic illness for which the
  cause has yet to be found
• In Pawlikowska (1994) study, 38/15000 people in
  the community stated they had ME

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ME vs other fatigue conditions

• From Pawlikowska study, matched
• 38 fatigue cases with ME explanations
• 40 fatigue cases with psychological
  explanations
• 38 fatigue cases with social explanations
• Measures at baseline (T1) 18 mos (T2)
• Who were most fatigued, most disabled, most
  distressed?
• Chalder et al. (1996) Psychol Med,26791-800

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Beliefs and impairment

• ME explanations
• most severely fatigued at T1
• most functionally impaired at T2, but
• least psychologically distressed at both times
• Social explanations
• least fatigued and
• least functionally impaired at follow up
• Beliefs drive vs reflect illness?

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• Beliefs about the cause of the illness have been
  shown to predict natural prognosis and response
  to treatment
• But Deale et al. (1998) showed that patients who
  did well on CBT changed beliefs about the meaning
  of symptoms rather than about the cause of the
  illness

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A cognitive behavioural model of CFS

• CFS is probably best explained in terms of a
  combination of interacting factors
• physiological dysregulation,
• cognitive,
• behavioural,
• emotional
• social
• These can be seen as different levels of
  explanation for the illness

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Predisposing, precipitating and maintaining
factors

• The factors which
• predispose to the development of CFS (e.g.
  previous illness),
• precipitate it (e.g. trauma, infection, overwork,
  stress), and
• maintain it (e.g. lowered activity levels,
  somatic focussing)
• may differ.

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Predisposing factors

• Difficult to study (need prospective studies)
• Some evidence for genetic predisposition
• Childhood experience of illness or illness in
  parents?
• Evidence for personality factors rather mixed and
  weak

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Precipitating factors

• Certain infections (e.g. glandular fever) may act
  as a trigger
• May need a combination of factors (e.g. illness
  episode, plus life events)

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Physiological dysregulation

• The deleterious effects of excessive rest on
  healthy people include
• Cardiovascular deconditioning
• reduced exercise tolerance
• muscle pain (may be delayed) on activity
• weakness, dizziness, postural hypotension
• changes to body temperature regulation
• loss of concentration and motivation

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Cognitive maintaining factors

• Fear of activity doing damage - catastrophic
  beliefs
• focusing on symptoms - hypervigilance - leads to
  increased arousal
• feeling out of control

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Behavioural maintaining factors

• avoiding activity
• doing activity in bursts
• sleeping at irregular times
• excessive resting
• monitoring of bodily symptoms

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Social and emotional factors

• Social
• feeling disbelieved
• unhelpful responses on the part of others
• unhelpful advice (e.g. to rest)
• Emotional
• demoralisation, depression, frustration

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Treatment of CFS

• The majority of treatment trials have been
  carried out in specialist settings
• Types of treatment tried
• pharmacological
• antidepressants
• immunological
• hydrocortisone
• anti-viral/anti-histamine/immunoglobulin

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• behavioural and cognitive-behavioural
• cognitive behaviour therapy (CBT)
• graded exercise therapy (GET)
• pragmatic rehabilitation (PR)
• Systematic review by Whiting et al., (2001),
  JAMA,2861360-8

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Which are the effective treatments?

• CBT most consistently effective treatment
• GET and PR also effective, but GET may be
  unacceptable to patients
• Hydrocortisone may improve some outcomes, but
  adrenal suppression a problem
• Immunoglobulin sometimes beneficial, but risks
• Antidepressants not very helpful (but may be
  useful to treat depression in CFS patients)

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Which outcomes to measure?

• Fatigue
• Physical functioning by self-report and or
  exercise tolerance
• Return to work
• Mood symptoms
• Other symptoms
• Global improvement
• All problematical to some extent

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CBT, GET and pragmatic rehabilitation

• What are the essential components?
• Patient engagement important
• PR frontloading educational approach versus CBT
  - more individualised formulations
• Belief change as consequence of behaviour change
  in GET?
• Activity capacity vs activity tolerance?

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• CBT most effective approach to date
• But shortage of trained CBT therapists
• Many patients cant access specialist services
• Need for readily communicable, generalisable
  treatments, deliverable in primary care

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Principal Investigator Dr. Alison WeardenTrial
manager Dr. Lisa Riste0161 275 2686
fine-trial_at_manchester.ac.ukwww.fine-trial.net
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• Randomised controlled trial of treatments for
  chronic fatigue syndrome / ME
• Patients fulfilling study criteria recruited from
  Primary Care, referred by GP
• Therapists are specially trained general nurses
  with experience of working in primary care (not
  mental health nurses)

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• Patients entering trial are randomly allocated to
  ONE of three interventions
• Nurse led self-help (Pragmatic Rehabilitation)
• Supportive Listening
• Treatment as usual by GP

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• Treatment period 18 weeks
• Pragmatic Rehabilitation and Supportive Listening
  take place in patients own homes
• Assessments by research assistant, in patients
  homes, at weeks
• 0 (pre-treatment)
• 20 (post-treatment)
• 70 (1 year follow up)

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• Study criteria
• Aged 18 and over
• Fulfil Oxford inclusion and exclusion criteria
  (Sharpe et al., 1991)
• Not currently receiving systematic
  psychological/behavioural therapy for CFS/ME
• Not received pragmatic rehabilitation in past
  year
• Currently recruiting in about 40 PCTs
• Recruiting NOW to mid 2007

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• If you come across patients who might be
  interested in entering the FINE Trial, they can
  ask their GPs to refer them
• To refer to trial
• GPs may refer new patients/patients from lists
• Use our checklist to aid diagnosis
• Complete and fax us a referral form
• Referral must come from GP