Prepared for health professionals andmembers of The ME Association by

Dr Charles Shepherd MB BSMedical Advisor, The ME Association

Dr Abhijit Chaudhuri DM MD MRCPClinical Senior Lecturer in Neurology

Consultant NeurologistInstitute of Neurological Sciences

University of Glasgow

ME/CFS/PVFSAn exploration of the key clinical issues

ME/CFS/PVFSAn exploration of the key clinical issues

Prepared for health professionals andmembers of The ME Association by

Dr Charles Shepherd MB BSMedical Advisor, The ME Association

Dr Abhijit Chaudhuri DM MD MRCPClinical Senior Lecturer in NeurologyConsultant NeurologistInstitute of Neurological SciencesUniversity of Glasgow

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Introduction

Nomenclature

Research based definitions

Epidemiology

Pathoaetiology5:1 Role of infection5:2 Immunology5:3 Muscle studies5:4 Central nervous system involvement5:5 Ion channels, resting energy expenditure and Syndrome X5:6 Psychiatric co-morbidity5:7 Sleep disturbance

Diagnostic Assessment6:1 When to consider making a diagnosis of ME/CFS

6:2 Onset: how does ME/CFS usually start?

6:3 Taking a clinical history

6:4 Symptoms

6:5 Physical examination

6:6 Investigations6:7 Mental health assessment

Management7:1 Who should manage people with ME/CFS?

7:2 Pharmacological treatments

7:3 Non-pharmacological treatments

7:4 Complementary treatments

7:5 Other management issues

Prognosis

Severely affected patients

Children and Adolescents

Information for Patients

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2.

3.

4.

5.

6.

7.

8.

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11.

CONTENTS

Nomenclature A disease of many names

� ME (myalgic encephalomyelitis) is a namewhich was originally introduced in a Lanceteditorial (Leading Article, 1956) to describepeople with the illness who had been admittedto London’s Royal Free Hospital during 1955.Clinically, myalgic was used to refer to thecharacteristic muscle symptoms;encephalomyelitis to the brain symptoms.Pathologically, encephalomyelitis indicatesinflammation within the brain and spinal cord –pathology for which there is now very limitedevidence (Schwartz et al 1994).

� CFS (chronic fatigue syndrome) is the namecurrently favoured by the medical professionbecause it makes no firm assumption aboutcause. Two major criticisms of CFS as a nameare that it fails to reflect the severity of the illnessand it has become a convenient label for anyonewith unexplained fatigue. It should also benoted that CFS as currently defined in section 3is designed to select homogeneous groups ofpatients for research purposes and is notintended for the routine clinical assessment ofwhat is a very heterogeneous group of patients.

� PVFS (post-viral fatigue syndrome) wasintroduced during the 1980s as a description forpatients who could clearly trace the onset oftheir illness back to a viral infection. Research based definitions

A number of consensus-driven, criterion-baseddefinitions for CFS have now been agreed uponand published. The definition produced by the USCenters for Disease Control (Fukada et al 1994)is used widely for research purposes but it has anumber of defects (eg the requirement forsymptoms to be present for six months before adiagnosis can be made) that limit its use in clinicalpractice.

IntroductionMost doctors now accept that ME/CFS/PVFS is a genuine and disabling illness. The WorldHealth Organisation classifies ME as a disease of the central nervous system (reference:International Classification of Diseases 10, G93.3) and the Department of Health officiallyrecognises it to be a ‘debilitating and distressing condition’ (reference: House of Commonsdebate, 13/11/91, Hansard col 582W). However, disagreements and uncertainties remain –especially over nomenclature, causation and the most appropriate forms of management.

Having accepted the inaccuracy of the termencephalomyelitis, The ME Association plansto substitute the word encephalomyelitis withencephalopathy, meaning an abnormality ofbrain function. We believe thatencephalopathy is now the most appropriatedescription for the various central nervoussystem abnormalities (ie hypothalamic,autonomic and cognitive dysfunction;cerebral hypoperfusion) that have beenreported in the research literature (see section5:4).

The debate about nomenclature is ongoingand The ME Association will also continueto use the term ME/CFS in its literature inaccordance with its restated charitable objectthat is ‘to offer relief to persons of all ageswith ME/CFS through the provision ofinformation and to further education in allaspects of the illness and to support researchand to publish the useful results of suchresearch’. In America, the Department ofHealth and Human Services has established aName Change Workgroup with the remit ofexploring options surrounding a possiblechange in name.

The current situation

The term encephalomyelitis is no longer anappropriate or accurate pathologicalexplanation for what may be happeningwithin the nervous system in this illness. It now appears that alterations in brainchemicals and hormones, with autonomicdysfunction, provide a more rationalexplanation for many of the key symptoms.

2.

3.

ME/CFS/PVFS 1

1.

2 ME/CFS/PVFS An exploration of the key clinical issues

5.

Epidemiology Who contracts ME/CFS?

A small number of epidemiological studies,mainly based on the CDC diagnostic criteria, havebeen carried out in America, Australia and the UK.One recently published community-based survey(Jason et al 1999) – which involved a sample of28,673 adults – found that 4.2 per thousand hadCDC defined CFS.

Results from other published epidemiologicalstudies indicate:

� A prevalence figure of at least two per thousandof the adult population (ie around 150,000people in the UK or between three and six

cases on the average general practitioner list).

� That all age groups are affected although onsetis rare below the age of seven and above theage of 60.

� The most common age of onset is between mid-teens and mid- forties.

� A slight female:male predominance, which is asyet unexplained.

� ME/CFS affects all social classes and ethnicgroups.

PathoaetiologyRelevant research findings

ME/CFS is an heterogeneous disorder, not only fromthe point of view of clinical presentation, but alsofrom the contribution made by various differentfactors which may be involved in the perpetuationof symptoms.

5:1 Role of infection

Although ME/CFS is precipitated frequently by aviral infection, there is no really convincingevidence to indicate that persistent systemicinfection – viral or bacterial – is responsible for theperpetuation of symptoms. However, it should benoted that ME/CFS symptoms are very similar tothose of post-polio syndrome (Bruno et al 1995)and that viral injury to excitable tissues such asmuscle and nerve has the potential to alter theircritical metabolic functions. These include ionchannel transport, mitochondrial function, and theresponse to circulating neurotransmitters andneurohormones – alterations which are capable ofpersisting well after apparent recovery from aprecipitating infection (Oldstone 1989).

Disruption in immune responses in ME/CFS mayalso allow the reactivation of common latentviruses such as Epstein-Barr and HHV6, as well aspreventing the effective clearance of endemicviruses (eg enteroviruses).

It has recently been suggested that there may bedysregulation of the interferon-induced 2-5Asynthetase and protein kinase R antiviral pathwaysin ME/CFS (Suhadolnik et al 1997). Thesepreliminary findings need to be replicated inbetter studies which include more appropriatecontrols (ie those with a recent viral infection),before any firm conclusions can be drawn.

4.

Table 1

CDC Criteria

1) Clinically evaluated, unexplained,persistent or relapsing chronic fatigue thatis of new or definite onset (has not beenlifelong); is not the result of ongoingexertion; is not substantially relieved byrest; and results in substantial reduction inprevious levels of occupational,educational, social, or personal activities;and

2) the concurrent occurrence of four ormore of the following symptoms, all ofwhich must have persisted or recurredduring six or more months of illness andmust not have predated the fatigue:

� Self-reported impairment in short-termmemory or concentration severeenough to cause a substantialreduction in previous levels ofoccupational, educational, social orpersonal activities

� Sore throat

� Tender cervical or axillary lymph nodes

� Muscle pain

� Headaches of a new type, pattern orseverity

� Unrefreshing sleep

� Post-exertional malaise lasting morethan twenty-four hours

� Multi joint pain without joint swellingor redness

5:2 Immunology

Two basic problems with immune function havebeen reported. First is evidence of immuneactivation as demonstrated by modest elevation ofnumbers of activated T lymphocytes, particularlycytotoxic T cells, as well as elevations incirculating cytokines in some studies. Second ispoor cellular function with low natural killer cellcytology (NKCC), poor lymphocytic response tomitogens in culture and immunoglobulindeficiencies, often involving IgG1 and IgG3.Some studies have also found an increasedincidence of autoantibodies in ME/CFS patients.

These findings tend to have a waxing and waningpattern that is consistent with episodic immunedysfunction. A frequently proposed hypothesis isthat the immune dysfunction is triggered by aninfection, or some other form of antigenicchallenge. The immune dysfunction then persistsas a result of neuroendocrine abnormalities (iehypocortisolaemia), physiological dysfunction,and/or activation of latent viral infection (ieEpstein-Barr virus).

None of the abnormalities so far reported aresufficiently marked or consistent to make themuseful for either routine clinical assessment ordiagnostic purposes.

For a recent review of immunological dysfunctionin ME/CFS see Patarca-Montero et al 2000.

5:3 Muscle studies

A variety of muscle abnormalities have beenreported, some of which are not consistent withthe theory that muscle symptoms in ME/CFS aresimply due to inactivity (Lane 2000). Objectiveevidence of post-exercise fatigue has recentlybeen demonstrated using repetitive isometricquadriceps exercise testing (Paul et al 1999).Oxidative defects in muscle energy metabolism –as demonstrated by magnetic resonancespectroscopy – may be due to impaired bloodflow to the exercising muscles, as a result ofdysregulated autonomic control (McCully andNatelson 1999).

5:4 Central nervous system involvement

Accumulated research evidence suggests thatcentral mechanisms are far more important in theproduction of mental and physical fatigue inME/CFS than peripheral (muscular) abnormalities.These central mechanisms may in fact involve thebasal ganglia (Chaudhuri and Behan 2000) –areas of the brain which are extremely sensitive to

pro-inflammatory cytokines and direct viralinvasion. Basal ganglia are also considered to bethe key neural integrator for motor andmotivational aspects of higher cortical and limbicactivities.

� Autonomic dysfunction and neurally-mediated hypotension

Several studies have demonstrated thatdisturbances in the autonomic regulation ofcardiovascular reflexes can be found in asubgroup of ME/CFS patients (Bou-Holaigah et al1995). Neurally-mediated hypotension (NMH)can be induced by tilt-table testing, whichinvolves a patient lying on a table and then tiltingthe table upright to 70 degrees for 45 minuteswhilst the heart rate and blood pressure arecontinually monitored. Patients with NMHdevelop low blood pressure under theseconditions as well as presyncopal symptoms suchas nausea, sweating and light-headedness.Although the use of fludrocortisone has beenrecommended as a form of treatment for ME/CFSpatients with proven NMH, the results of two

ME/CFS/PVFS 3

How ME/CFS may be affecting thebrain and central nervous system

Source: Living with ME, Charles Shepherd, Vermilion, 1999

clinical trials (Peterson et al 1988; Rowe et al2001) have failed to demonstrate any benefits.

� Hypothalamic dysfunction

Key symptoms such as fatigue, sleep disorder anddisturbed thermoregulation are all consistent withhypothalamic dysfunction. Disturbances inhypothalamic function in ME/CFS are supportedby several studies which have examined thehypothalamic-pituitary-axis control of cortisolproduction and the way in which arginine-vasopressin controls water metabolism (Bakheit etal 1993). The most consistent finding relates todisturbances in the hypothalamic-pituitary-adrenal axis, ie hypocortisolaemia (Demitrack etal 1991) and adrenal gland atrophy (Scott et al1999), which may be the result of lowering ofcentral corticotropin-releasing hormone levels(Altemus et al 2001).

� Neurotransmitters

Evidence of abnormalities in neurotransmitterfunction, particularly involving serotonin,acetylcholine and dopamine, comes from anumber of published studies.

Growth hormone (GH) secretion from the anteriorpituitary is augmented by acetylcholine, andpyridostigmine has been used as a probe tostimulate acetylcholine-mediated growthhormone release. When given pyridostigmine,ME/CFS patients (as well as those with a similarsyndrome following organophosphate pesticideexposure) show an exaggerated response(Chaudhuri et al 1997). Acetylcholinesupersensitivity has also been observed in a studywhich assessed the skin microcirculation inME/CFS patients (Spence et al 2000) – a findingwhich may be related to symptoms that involvevascular integrity.

Prolactin release from the anterior pituitary isunder the inhibitory control of dopamine, and isstimulated by serotonin. Buspirone, an indirectserotonin agonist, produces an exaggeratedserotonin-mediated release of prolactin in ME/CFSpatients when compared to healthy controls andthose with depression (Bakheit et al 1992).

� Neuroimaging

Evidence of regional cerebral hypoperfusion usingSPECT (single-photon emission tomography) scanshas been reported in a number of studies. Ofparticular interest is a finding of brain stemhypoperfusion (Costa et al 1995) which has notbeen found in patients with any other medical or

psychiatric condition. MRI (magnetic resonanceimaging) scans have demonstrated white matterabnormalities that may be consistent with aprevious infection involving the central nervoussystem (Lange et al 1999).

Further evidence of subtle neuropathology comesfrom a more recent study which has demonstratedenlargement of cerebral ventricular volumes(Lange et al 2001).

� Psychological testing

More than twenty different studies on variousaspects of cognitive dysfunction in ME/CFS havenow been published. They confirm that thefrequently reported clinical observations ofproblems with memory, concentration andattention span (particularly the ability to processincoming information) are genuine and cannotsimply be explained by the presence of co-existentpsychiatric disorders such as depression (DeLucaet al 1997). For a recent review ofneuropsychological functioning in ME/CFS seeMichiels and Cluydts 2001. (See also section 5:6on p5).

5:5 Ion channels, resting energyexpenditure and Syndrome X

It has recently been proposed that dysfunctionalion channels may be a key abnormality in thecellular pathogenesis of ME/CFS (Chaudhuri et al2000). This is related to the fact that an ME/CFS-like syndrome develops after ciguatera fishpoisoning (Pearn 1997) and ciguatoxin is a potentinhibitor of neuronal sodium channel activity.Changes in neuronal ion channel function couldaccount for the altered neuroendocrine functionsso far reported in ME/CFS as well as helping toexplain the fluctuation in fatigue and othersymptoms which are a key feature of the illness.

Resting energy expenditure (REE) is the energyexpended by an awake, alert subject in the post-absorptive state. It accounts for between 60% and90% of total energy expenditure. A significant risein REE is found in ME/CFS patients whencompared to controls (Watson et al 1998), and as30% of REE is expended to maintain physiologicalion gradients in normal health, a cell membranedefect causing ion leakage will increase the REE.Higher levels of REE are also found in patientswith sarcoidosis who have profound fatigue.

Ion channel dysfunction may also help to explainthe basis of Syndrome X – an unusual cardiaccondition which appears to be associated withME/CFS (See also section 6:4 p6).

4 ME/CFS/PVFS An exploration of the key clinical issues

5:6 Psychiatric co-morbidity

Research in this area has tended to concentrate onthe incidence of co-existent psychiatric disorders,the possible role of abnormal illness behaviourand the value of CBT (cognitive behaviourtherapy) as a form of treatment. Whilst somestudies have reported relatively high rates of co-morbid depression (Wessely and Powell 1989),others have found levels which are very similar tothose in other chronic medical conditions (Shanksand Ho-Yen 1995). The way in which abnormalillness behaviour and illness attributions(particularly about cause) may be perpetuating ill-health and disability in some ME/CFS patientsremains a contentious issue (Deale et al 1998).

The overlap of ME/CFS symptoms and psychiatricdisorders such as depression can result in patientsbeing misdiagnosed and given inappropriatepsychiatric labels. In fact, one study carried outby psychiatrists (Deale and Wessely 2000) foundthat 68% of a sample of 68 patients attending theirME/CFS clinic had been misdiagnosed as having apsychiatric illness, and in most cases there was noevidence of any previous or current psychiatricdisorder (see section 6:7 p7).

5:7 Sleep disturbance

ME/CFS patients complain commonly ofhypersomnia in the initial stages of their illness.This is then followed by a general decrease insleep efficiency once the illness enters a morechronic stage. Reported sleep disturbancesinclude difficulty in initiating sleep, frequentwakening during the night and vivid dreams.Periodic jerking limb movements and ‘restlesslegs’ are also quite frequently reported.

A variety of anomalies in normal sleep patternhave been reported, including changes in alphanon-rapid eye movement (Moldofsky 1989),which may be acting as perpetuating factors. Onerecent study concluded that there was very littleevidence to support the hypothesis that ME/CFSpatients with a concurrent diagnosis of anxiety,depression or somatisation disorder have anymore sleep disorders than those with nopsychiatric disorder (Morris et al 1997). So itappears that sleep disorder in ME/CFS may be anintegral part of the disease process.

Whatever the cause, sleep disturbance is onesymptom which the physician should always aimto identify and manage (see also section 7:2 p9).

Diagnostic assessment

6:1 When to consider making adiagnosis of ME/CFS

A period of debility frequently follows many acuteinfections. However, when this persists beyond afew weeks in a previously healthy individual,consideration should be given to making adiagnosis of a post-infectious fatigue state as thereis a considerable amount of anecdotal evidenceto suggest that appropriate management (ie rest,followed by convalescence and a gradual returnto normal activities) at this stage can play a role inreducing long-term morbidity.

Where symptoms persist beyond two or threemonths, and the person concerned has beenunable to resume his normal way of life, thenserious consideration should be given towardsmaking a diagnosis of ME/CFS. This shouldinclude baseline investigations, as well as otherinvestigations if particular symptoms (ieneurological, rheumatological, gastrointestinal)are more prominent than would normally beexpected in someone with ME/CFS (see alsosection 6:6 p7). The differential diagnosis ofME/CFS is considered in more detail in Table 2p8.

Patients who present with ME/CFS-like symptomsshould be treated with compassion and carefullyevaluated. They seldom look as ill as they feel,and so friends, family, employers and evendoctors may have doubts about whether they aregenuinely ill.

6:2 Onset: how does ME/CFS usuallystart?

� Some form of viral infection (eg flu-like illness,glandular fever, tonsillitis, meningitis,encephalitis, hepatitis) is the most commonprecipitating factor.

� Less common triggers include vaccinations (eghepatitis B), toxins (eg ciguatera poisoning),pesticide exposure (organophosphates) andmajor stressful events.

� In a minority there is no clear precipitatingfactor and the onset may be more insidious.

6:3 Taking a clinical history

With a diagnosis of ME/CFS being made largelyon a patient’s clinical history, questions shouldaddress:

ME/CFS/PVFS 5

6.

� Previous medical and psychiatric illness.

� Previous operations and blood transfusions (? possibility of hepatitis C infection).

� Occupational history including exposure tochemicals, solvents and pesticides.

� Possible precipitating events (eg infections,vaccinations, toxins, severe stress, trauma orsurgery, athletic overtraining).

� Clinical features (eg weight loss, prominentarthralgia, transient neurological events) whichindicate that other possible diagnosticexplanations need to be pursued.

� Social history (? possibility of HIV infection)

� Family history (? other members with anME/CFS-like illness).

Establishing a clear picture of the effects ofME/CFS on a patient’s lifestyle is important whenit comes to management and benefit entitlement.Questions should therefore be asked aboutemployment, education, family responsibilitiesand the degree of functional impairment that isoccurring.

6:4 Symptoms

Predominant symptoms in one patient may bequite different to those seen in other ME/CFSpatients. Some are affected predominantly bymobility problems whereas others find problemswith cognitive functioning or pain to be far moredisabling.

However, the core symptom of ME/CFS is fatigue,which usually affects both physical and mentalfunctioning. One of the most striking features ofthis fatigue is the way in which patients describehow even minor amounts of physical exertion canproduce a marked exacerbation in musclefatigue/pain etc, often accompanied by severalother symptoms. It may then take days or evenweeks after such a relapse before they return to amore ‘normal’ level of activity.

Key symptoms for making a diagnosis of ME/CFSare:

� Exercise-induced muscle fatigue.

� Post-exertional malaise: a delayed onset ofsymptoms following exertion.

� Myalgia (present in varying degrees in up to75% of patients) and fasciculations, includingblepharospasm.

� Cognitive dysfunction: problems with short-

term memory, concentration and attention span(especially affecting visuospatial tasks) andanomia (difficulty in naming common objects)or dysnomia (the inability to give objects acorrect name). Cognitive dysfunction alone isoften severe enough to cause a substantialreduction in previous levels of occupational,educational, personal and social activities.

� A general feeling of on-going flu-like malaise.

Other symptoms which are consistent with adiagnosis of ME/CFS include:

� Dysequilibrium and orthostatic intolerance:feelings of unsteadiness are more frequentlyreported than vertigo.

� Autonomic dysfunction: particularly affectingcirculation (postural hypotension andorthostatic tachycardia) and thermoregulation(night sweats, hypersensitivity to temperatureextremes).

� Sleep disturbance: non-refreshing patternwhich can include both hypersomnia (early inthe illness), reversal of sleep rhythm (especiallyin children) and insomnia.

� Sensory disturbances: paraesthesiae andsometimes hemisensory pain or dysaesthesia.

� Hyperacusis and/or photophobia.

� Arthralgia but not including swelling, rednessor joint deformity.

� Digestive symptoms: nausea and motilitydisturbances.

� Alcohol intolerance.

� Recurrent sore throats and tender cervical oraxillary lymph nodes.

� Headaches of new type, pattern or severity.

The symptoms follow a characteristic pattern ofboth variability (often throughout the course of aday) and chronicity. Patients will often describehow they experience ‘good days’ and ‘bad days’with fluctuations in severity being influenced byphysical activity, stress, infections andtemperature excesses.

There also appears to be an increased incidence ofSyndrome X (anginal-type chest pain with normalcoronary arteriogram but abnormal thallium 201SPECT scan results) and a tendency to developallergic conditions (Straus et al 1988) as the illnessbecomes chronic.

6 ME/CFS/PVFS An exploration of the key clinical issues

6:5 Physical examination

Although this is usually unremarkable, a fullphysical examination is mandatory to excludeother possible diagnoses.

Tests of balance and vestibular function (egRomberg and Fukuda) should be carried out inpatients who complain of dysequilibrium. Thismay be due to vestibular dysfunction (Ash-Bernalet al 1995).

6:6 Investigations

The diagnosis of ME/CFS should essentially bemade on the typical pattern of symptoms, with theexclusion of other possible conditions that canpresent with fatigue and general ill health.

Anyone who is suspected of having ME/CFSshould have the following routine investigations:

� ESR or acute phase protein changes (eg CRP).

� Haemoglobin.

� White cell count and differential. NB: Minorabnormalities may be present, especially duringthe early stages of the illness.

� Routine biochemistry screen (urea, electrolytes,calcium etc)

� Liver and thyroid function. NB: There is anincreased incidence of Gilbert’s disease inME/CFS (Cleary and White 1993).

� Creatine kinase (CK).

� Antibodies to gliadin or endomysium to screenfor coeliac disease (Skowera et al, 2001). NB:check serum IgA concentrations as well.

� Urinalyses for protein, blood, sugar.

Significant abnormalities in any of the aboveroutine investigations indicate that otherdiagnostic explanations need to be pursued.

Further selected tests may also be appropriate insome circumstances:

� Autonomic function tests (eg tilt-table testing) ifautonomic symptoms, syncope or posturalhypotension are prominent.

� Infectious disease screening if there is apossibility of chlamydia (Chia and Chia 1999),Epstein-Barr, HIV, hepatitis B/C, Lyme disease,mycoplasma, Q Fever etc..

� MRI brain scan if multiple sclerosis isconsidered possible.

� Muscle biopsy if CK raised.

� Rheumatology screen and autoantibodies ifarthralgia is prominent. Also considerscreening for infections which can causearthralgia and fatigue (ie borrelia, brucella,campylobacter, cytomegalovirus, parvovirus,shigella and yersinia).

� Serum oestradiol and FSH if there is asignificant premenstrual exacerbation ofsymptoms (Studd and Panay, 1996).

� Short synacthen (ACTH) test if plasma orurinary cortisol is low and symptoms aresuggestive of Addison’s disease (hypotension,low serum sodium and raised potassium)

Tests which cannot be recommended in normalcircumstances:

� Assessment of antiviral pathways* such asRNase L (Suhadolnik et al 1997).

� EMG studies.

� Functional neuroimaging (eg PET or SPECTscans) – the only indications are for researchpurposes.

� Neuroendocrine challenge tests (eg buspirone-induced prolactin test)

� Urinary markers* (eg CFSUM)

� Screening for coxsackie antibodies (Miller et al1991) or evidence of reactivation of HHV-6infection.

Some of these investigations will revealabnormalities (eg hypocortisolaemia, exaggeratedprolactin response to buspirone challenge) whichare consistent with the diagnosis of ME/CFS.However, their value in routine clinicalassessment is very limited as results are unlikely toinfluence practical management decisions.

( * The presence of specific urinary markers andabnormalities in antiviral pathways is beingassessed in research studies financed by The MEAssociation 2000/2001).

6:7 Mental health assessment

About a quarter of all patients with ME/CFS willexperience true clinical depression (as opposed tojust feeling ‘fed up’) during the course of theirillness. The explanation probably involves acombination of endogenous (ie disturbances inneurotransmitters) and reactive (ie psychologicaldistress associated with problems connected towork, education, doctors, benefits, familycommitments etc) factors. A comprehensivemental health assessment, possibly involving

ME/CFS/PVFS 7

questionnaires, should be carried out for patientswho have co-existent psychiatric/psychologicalsymptoms.

It should, however, be noted, that results frommental health questionnaires need to be viewedwith caution (Farmer et al 1996) and that formaltests of neuropsychological function seldomreflect the degree of impairment reported by these

patients. And as already pointed out in section5:6, a significant number of people with ME/CFSare being given inappropriate psychiatricdiagnoses by their doctors.

8 ME/CFS/PVFS An exploration of the key clinical issues

Table 2

Differential diagnosisAlthough extensive and elaborate investigations are seldom required, other causes ofchronic fatigue must be considered where the history is atypical. Also remember that‘new’ symptoms should not be ascribed automatically to ME/CFS.

CARDIOVASCULAR MALIGNANCYValve disease and claudication Hodgkin’s lymphoma

ENDOCRINE AND METABOLIC NEUROMUSCULARAddison’s disease Multiple sclerosisFluid Retention Syndrome Myasthenia gravisHypothyroidism Parkinson’s diseasePituitary tumour Rare myopathiesThyrotoxicosisHaemochromatosis PSYCHIATRICHypercalcaemia Anxiety +/- hyperventilationHyponatraemia Depression

Post Traumatic Stress DisorderSomatisation

GASTROINTESTINALCoeliac diseaseCrohn’s disease RESPIRATORYFood allergy SarcoidosisIrritable bowel syndrome Tuberculosis

HAEMATOLOGICAL RHEUMATOLOGICALAnaemia Fibromyalgia

Sjogren’s syndromeSystemic lupus erythematosus

INFECTIONSBrucellosisGiardia MISCELLANEOUSHepatitis B or C Alcohol or drug abuseHIV AllergiesLeptospirosis hardjo Organophosphate pesticidesLyme disease Sick building syndromeParvovirus Sleep apnoea Post-polio syndrome NarcolepsyToxocara (children) Various prescribed drugsToxoplasmosis

Management

7:1 Who should manage patients withME/CFS?

Provided the diagnosis is not in doubt, themanagement of early straightforward cases ofME/CFS should be carried out by generalpractitioners and other members of the primaryhealthcare team. During the early stages (ie thefirst six months) this will involve givingappropriate advice about lifestyle modification,providing symptomatic relief through the carefuluse of drugs, and dealing with problems whichmay arise relating to employment, benefits andsocial support.

If the illness becomes more chronic and/or severe,consideration should be given towards referringthe patient to a hospital specialist who isgenuinely interested and informed about ME/CFS.In some parts of the UK (eg Dorset and Norfolk),multidisciplinary ME/CFS clinics are beingestablished which permit easy access tooccupational therapists, psychologists and otherhealth professionals who may be able to play auseful role in the management of more difficultcases. Unfortunately, there are still many parts ofthe UK where general practitioners are unable tolocate a single hospital consultant with thenecessary expertise.

There are also a small number of tertiary referralcentres where in-patient facilities and researchinto ME/CFS is being carried out. One such unit isthe National ME Centre, Harold Wood Hospital,Romford, Essex RM3 9AR. NHS referrals for eitherout-patient or in-patient assessment are acceptedfrom throughout the UK. For further informationtelephone 01708 378050.

7:2 Pharmacological treatments

A variety of drug treatments have been advocatedfor people with ME/CFS, but few have beensubjected to well organised, randomisedcontrolled trials (RCTs). At present, there is nosingle drug treatment that has been found to begenerally effective in the majority of patients.However, there are a number of drugs which havebeen shown to be helpful in relieving symptomssuch as myalgia and sleep disturbance.

People with ME/CFS are often more sensitive to theside-effects of drugs, particularly antidepressants,anaesthetics and those which act on dopaminergictransmission (eg metoclopramide/Maxalon). Cons-equently, it is often desirable to commence at a

low dose, followed by gradual increases over aperiod of weeks when it comes to the use ofantidepressant medication in particular.

Allergy TreatmentsThese should be directed at specific allergies thathave been identified by reliable forms of allergytesting. There is no evidence from clinical trialsto show that anti-allergy drugs such as terfenadine(Steinberg et al 1996) are of any benefit – unless aspecific allergy has been confirmed.

AnalgesicsWhen conventional first line analgesics (egaspirin, paracetamol, NSAIDs) prove ineffective,it may be appropriate to prescribe a low dailydose (ie 10mg or 25mg) of amitriptyline.Anticonvulsants such as gabapentin/Neurontinand carbamazepine/Tegretol may be helpful incases of more severe nerve pain that fail torespond to ordinary analgesics (Anon. Drug andTherapeutics Bulletin, 2000). Difficult casesshould be referred to a hospital pain clinic foradvice.

AntibioticsThere are anecdotal reports of patients improvingfollowing the use of antibiotics. Possibleexplanations include the way in which someantibiotics have immunomodulatory effects andthe fact that some of these individuals may havehad a persisting infection (eg Lyme disease orchlamydia) which responded to antibiotictherapy. Even so, there is no justification atpresent for the speculative use of prolongedcourses of one or more antibiotics.

AntidepressantsA low dose of a sedating tricyclic antidepressant(eg 10mg or 25mg of amitriptyline taken beforebedtime) may be helpful in the relief of myalgia orinsomnia. Anyone who has co-existent clinicaldepression should be treated with a full course ofan appropriate antidepressant or [possibly] StJohn’s Wort.

Research studies indicate that there may bedisturbances in the brain chemical transmitterserotonin in ME/CFS. However, the only largeRCT (Vercoulen et al 1996) to assess the use of anSSRI (fluoxetine/Prozac) found no significantbenefit.

Moclobemide/Manerix, a monoamine oxidaseinhibitor, has been reported in an RCT to producesome benefits in key symptoms (Hickie et al 2000).The greatest reduction was found in patients withconcurrent immunological dysfunction.

ME/CFS/PVFS 9

7.

Antifungal DrugsThere is no scientific evidence to support thewidely held view that candida/thrush, a commonfungal infection, is in any way involved in ME/CFS(Dismukes et al 199l). Antifungal drugs such asnystatin should not therefore be prescribed.

AntihypotensivesThe finding that some people with ME/CFS havelow blood pressure/neurally mediatedhypotension has led to the use of drugs such asfludrocortisone, which act by raising the bloodpressure. The only RCTs (Peterson et al 1998 andRowe et al 2001) to assess the value offludrocortisone found no clear benefits.

Antiviral DrugsAlthough viral infections commonly triggerME/CFS, there is conflicting scientific evidenceabout the role of persisting viral infection beingpresent. The only antiviral drug to be assessed in aclinical trial is acyclovir (Straus et al 1988). Nobenefits were found, so this form of interventioncannot be recommended.

AnxiolyticsBenzodiazepines are best avoided because of thereal risks of dependency and problems whenwithdrawal is attempted.

Hydrocortisone and other hormonal treatmentsResearch studies have confirmed a number ofhormonal abnormalities in ME/CFS (eg low levelsof cortisol and DHEA) which may be contributingto symptoms and consequently are amenable totreatment.

� Clinical trials involving low doses ofhydrocortisone have produced conflictingresults. An American RCT (McKenzie et al1998) found no obvious benefit whereas amore recent UK RCT (Cleare et al 1999), whichused a slightly lower dose of hydrocortisone,did produce benefits with no evidence ofsuppression of the adrenal gland’s naturaloutput of cortisol.

� Deficiency of DHEA in ME/CFS has also beenreported but no proper clinical trials have beencarried out into the use of this controversialhormone.

� Oestrogen supplementation may be of value(Studd and Panay 1996) in women who havea premenstrual exacerbation of symptoms withlow levels of serum oestradiol and FSH.

� There is no evidence of disturbed thyroid glandfunction in ME/CFS, and the use of thyroxinesupplementation in people who have normalthyroid function tests is a controversial form of

treatment which carries a number of risks,including the potential complication ofprecipitating an Addisonian crisis in patientswith hypocortisolaemia (Shepherd 1997).

HypnoticsSleep disturbance in ME/CFS is a symptom whichshould always be taken seriously because even fithealthy people cannot function effectively withoutfive hours solid uninterrupted sleep each night.Pharmacological approaches include the use of alow dose of amitriptyline (10 or 25mg a few hoursbefore going to bed) and the cautious use ofhypnotics such as zaleplon/Sonata (helpful forpatients with problems initiating sleep).Anecdotal reports indicate the patients with severesleep problems may find melatonin helpful.Advice on appropriate sleep hygiene measuresshould also be given. (See also section 7:3 p11).

Immunological treatmentsDespite the fact that a number of immunologicalabnormalities have been identified in ME/CFS,there is no clear evidence about the value ofimmunological treatments. None of thesetreatments is readily available on the NHS. Theyshould all be regarded as experimental at present,and not for routine use in ME/CFS patients.

� Ampligen, a very expensive American drug, isclaimed to have both antiviral andimmunomodulatory properties. Benefits havebeen reported in one small trial (Strayer et al1994) and further assessment is currently takingplace in America and Belgium. Ampligen hasnot yet been approved by the American FDA foruse in the treatment of ME/CFS.

� Intravenous injections of immunoglobulin Ghave now been assessed in five RCTs. Threereported benefits (Du Bois 1986; Lloyd et al1990; Rowe 1997) whereas two found no benefit(Peterson et al 1990; Vollmer Conna et al 1997).Some benefit has also been demonstrated onsubgroup analysis in a small trial involving alphainterferon (See and Tilles 1996).

� Inosine pranobex/Imunovir, an immuno-modulatory drug that has a potential to enhancenatural killer cell activity, is currently beingassessed as a possible treatment for ME/CFS.

Irritable bowel symptomatologyThis should be treated with appropriate use ofbulk forming laxatives, antidiarrhoeals,antispasmodics and, if indicated, a trial involvingexclusion of certain foods (eg wheat, citrus fruits,dairy produce) which are implicated in somecases of irritable bowel.

10 ME/CFS/PVFS An exploration of the key clinical issues

Muscle relaxantsCautious use of low doses of drugs such asmethocarbamol/Robaxin may be indicated inpatients who complain of severe muscle spasms.

Supplements� Significant benefits for evening primrose oil

have been reported in one RCT (Behan et al1994) but not in a more recently publishedRCT (Warren et al 1999). Evening primrose oilhas a good safety profile and may be helpful inrelieving arthralgia.

� NADH (nicotinamide adenine dinucleotide) is anatural substance which is known to triggerenergy metabolism at a cellular level throughATP production. A supplement containingNADH (Enada) has been shown to be effectivein one small clinical trial (Forsyth et al 1999).

� Carnitine deficiency has been reported asoccurring in ME/CFS (Majeed et al 1995) andsome patients claim that carnitine supplementshave been helpful. One small RCT (Plioplysand Plioplys 1997) found ‘statisticallysignificant improvement’ in 12 out of 18patients taking a carnitine supplement.

Vestibular dysfunctionVestibular sedatives such as cinnarizine/Stugerontend to be of limited or no value in themanagement of dysequilibrium and other balanceproblems that are frequently reported by ME/CFSpatients (Ash-Bernal et al 1995).

Vitamins and mineralsDeficiencies involving magnesium, (Cox et al1991), folic acid (Jacobson et al 1993) and severalB vitamins (Heap et al 1999) have been reportedas occurring in ME/CFS. However, there is noevidence from clinical trials to indicate thatvitamin and mineral supplementation is of value.Megadosing of vitamins and minerals can, in fact,cause serious harm. The only clear indication forsupplements is in the case of women with ME/CFSwho are contemplating pregnancy. They shouldalways have their folic acid level checked andthen take an appropriate folic acid supplement.

Other possible approaches� A number of other drugs, eg selegeline/Eldepryl,

amantadine/Symmetrel (Plioplys and Plioplys1997; Bowman et al 1997) andmethylphenidate/Ritalin in children, have beenreported to be of benefit in selected ME/CFSpatients. None, however, has been assessed in aclinical trial.

� A preliminary trial into the use of 5-HT3receptor antagonists – tropisetron and

ondansetron – has recently been reported fromGermany (Spath et al 2000). Results indicatethat these drugs, which are normally used totreat nausea and vomiting, and do not havedopamine antagonist properties orextrapyramidal side-effects, may be of value inME/CFS.

� Galanthamine hydrobromide, a selectiveacetylcholinesterase inhibitor, has not beenshown to improve fatigue or cognitiveimpairment in a recently completedmulticentre RCT (results not as yet published).

None of these drugs can as yet be recommendedfor general use in ME/CFS patients.

7:3 Non-pharmacological treatments

Activity management (pacing)This involves trying to achieve the appropriatebalance between periods of activity and rest. Atthe onset of ME/CFS (ie within the first few weeksfollowing a viral infection) a period of rest,possibly bed rest, may be necessary. Ideally, thisshould then be followed by a gradual increase inboth physical and mental activity. It is importantfor patients to establish baselines at which theyfeel comfortable and accept that progress may beboth slow and erratic. Activity levels shouldalways be reduced during a relapse orexacerbation of symptoms.

From the doctor’s point of view, this meansproviding clear guidance on how to set realisticgoals, creating flexible plans to account for day-to-day fluctuations in energy levels andsymptoms, and remaining positive aboutrecovery. Referral to an occupational therapist orphysiotherapist who can design a programmeaimed at appropriate activity management can behelpful for those who are having difficulty withthis crucial aspect of management.

Graded exercise regimes that involve aprogressive increase in physical activity on a day-to-day basis, regardless of how a patient is coping,are not recommended as they are likely to resultin a relapse.

Results from three RCTs (Wearden et al 1998,Powell et al 2001; Fulcher and White 1997) intothe use of graded exercise are frequently used toclaim that rest has no place in the management ofME/CFS. However, the authors of this document(Shepherd and Chaudhuri 2001), believe thatappropriate periods of rest are just as important asgradually trying to increase physical and mentalactivity once the condition has started to stabilise.

ME/CFS/PVFS 11

It should also be noted that an American study (Lapp1997) has now confirmed that inappropriate adviceabout exercise can easily produce a rapid and quitesevere exacerbation of symptoms and that physicaldeconditioning does not appear to be a perpetuatingfactor in the illness (Bazelmans et al 2001).

From the medico-legal point of view, doctors whoprescribe exercise programmes for ME/CFSpatients must do so with just as much care as theywould with a prescription drug

Management of sleep disturbanceDuring the early post-infectious stage of ME/CFSmany patients have hypersomnia, which need notbe interfered with.

Once the phase of hypersomnia starts to diminish,patients should be encouraged to adopt varioussimple sleep hygiene measures which should helpto reduce the chance of other types of sleepdisturbances developing.

� Avoid excessive amounts of caffeine-containingstimulants such as tea, coffee and cola drinks,especially during the evening.

� Afternoon sleeps should be avoided if at allpossible – these should be replaced with aperiod of rest/relaxation if necessary.

� Try to establish a regular routine for waking up,getting up and going to bed at around the sametime.

� Have a soak in a warm bath about half an hourbefore going to bed.

� Make sure the bed and bedroom are not too hotor too cold.

Cognitive behaviour therapy (CBT)This approach may be helpful for a subgroup ofpatients with ME/CFS who are not managing theirlifestyle adjustment in a satisfactory manner. CBTmay also be useful for those with co-existingdepression or where there are difficulties incoping socially or psychologically.

However, it should be noted that clinical trialsinvolving the use of CBT have producedconflicting results (Deale et al 1997; Friedburgand Krupp 1994; Lloyd et al 1993; Prins et al2001; Sharpe et al 1996) and that there are veryfew therapists available who have experience ofdealing with this illness. CBT programmes whichare based on the assumption that ME/CFS isessentially a behaviour problem perpetuated byabnormal illness beliefs and/or behaviour areunlikely to be acceptable or beneficial.

7:4 Complementary treatments

Approaches such as acupuncture and homoeopathymay be worth investigation, but patients should beadvised how to find a reputable practitioner. Otheralternative treatments are far more speculative.There is no evidence to support the use of widelyrecommended anti-candida regimes or takingmegadoses of vitamins or minerals.

7:5 Other management issues

DSS benefitsThe Department of Social Security makes it clearin their Disability Handbook that people withME/CFS are as potentially disabled as those withother chronic conditions and are therefore entitledto apply for a full range of sickness and disabilitybenefits. However, patients often haveconsiderable difficulty in persuading examiningdoctors and lay adjudicators that they aregenuinely ill and unable to safely care forthemselves in the home.

Problems with benefit applications are oftenexacerbated by the way in which written andpractical assessments for Incapacity Benefit andDisabled Living Allowance are badly designed forillnesses such as ME/CFS in which there arefluctuating levels of disability and ill-health. Highlevels of success on appeal suggest that initialapplications are being refused at a higher levelthan is fair. The ME Association can providepatients with information on benefit applicationsand appeal procedures which may be relevant.

Diet and nutritionA well-balanced diet that includes complexcarbohydrates (to help stabilise blood sugar levels)and avoids caffeine should be advised. A goodfluid and adequate salt intake should also beencouraged, especially for those patients whohave symptoms related to hypotension.

Employment and educationA sudden return to full-time employment oreducation is often unrealistic. It may therefore benecessary for the GP to become involved innegotiations aimed at ensuring a more gradual orflexible return to normal activities for those whohave managed to achieve a substantial degree ofrecovery.

Unfortunately, many people with ME/CFS areunable to return to their previousemployment/educational activities or attempt todo so and find that they are unable to perform at asatisfactory level or on a sufficiently regular basis.

12 ME/CFS/PVFS An exploration of the key clinical issues

For those who remain severely unwell and areunable to resume employment, the possibility ofearly retirement on the grounds of ill health mayneed to be considered.

Permanent Health Insurance/Income ProtectionAs with state sickness benefits, some peopleexperience considerable difficulties in successfullyclaiming permanent health insurance/incomeprotection benefits – even where their inability towork is supported by statements from a GP and areputable NHS specialist. Being in receipt ofIncapacity Benefit is no guarantee that a permanenthealth insurance/income protection claim will beaccepted. Patients who become involved indisputes involving insurance companies should beadvised to contact The ME Association for detailedinformation on how to proceed.

Private medical sectorA wide range of investigative procedures andtreatments is available from the private medicalsector. These are often quite costly and theirefficacy is seldom based on any reliable publishedevidence. Patients need to consider carefullywhether such investigations and treatments willbe of any genuine benefit.

Relapse or exacerbation of symptomsPatients need to be aware of those factors whichcan commonly exacerbate symptoms or cause arelapse.

� Alcohol intolerance is extremely common - afactor which is recognised quickly and usuallyaccepted.

� Intercurrent infections invariably produce arapid deterioration and patients may well findthat it then takes several weeks to return to‘normal’ levels of activity.

� Immunisations appear to be capable of bothtriggering the syndrome as well as causing arelapse. A number of cases in health workershave followed hepatitis B vaccination. Whenimmunisation is considered necessary, itshould be arranged at a time when the patientis feeling reasonably well. Travel vaccinesshould not be given immediately beforedeparture if at all possible.

� Surgery and general anaesthetics may again beunavoidable. Routine procedures should, ifpossible, be arranged for a time when the personis well and practical help in the home can easilybe arranged for the post-operative period.

� Temperature extremes should be avoided,although a holiday in a warm sunny climatemay well have its benefits.

Prognosis - what are the chances of recoveringfrom ME/CFS?

Most people with ME/CFS fall into one of fourgroups:

� Those who manage to return to completelynormal health, even though this may take aconsiderable period of time. The percentagefalling into this category is fairly small.

� The majority, who tend to follow a fluctuatingpattern with both good and bad periods ofhealth. Relapses or exacerbations are oftenprecipitated by infections, operations,temperature extremes or stressful events.

� A significant minority remain severely affectedand may require a great deal of practical andsocial support.

� Continued deterioration is unusual in ME/CFS.When this occurs, a detailed medicalassessment is advisable to rule out otherpossible diagnoses.

Several research studies looking at prognosis inME/CFS have now been published (Bombardierand Buchwald 1995; Hinds et al 1993; Sharpe etal 1992; Vercoulen et al 1996; Wilson et al 1994).Results from these studies indicate that ME/CFSoften becomes a chronic and very disablingillness with complete recovery only occurring in asmall minority of cases. The high level of debilityand disability associated with ME/CFS often stemsfrom a combination of symptoms such as fatigue,pain, sleep disturbance, cognitive impairment,and, in some cases, an associated depression.

Studies which have examined functional statusand quality of life measures, (Buchwald et al1996; Komaroff et al 1996; Schweitzer et al1995) also confirm that the scale of impairmentacross a range of physical and mental activitiescan be just as great or greater than is seen in manyother chronic medical conditions.

Severely affected patientsThere are serious deficiencies in the way thatseverely affected ME/CFS patients (ie those whospend a considerable period of time either house,wheelchair or bed bound) are currently managedin both primary and secondary care. Although noreally accurate figures are available, it isestimated that at least 25% of all people with

ME/CFS/PVFS 13

8.

9.

ME/CFS will fall into this category at some stage intheir illness.

Feedback to The ME Association indicates that agreat deal more could be done at a primary carelevel in relation to regular home assessments andinvestigation of new or prominent symptoms;more effective symptom control and painmanagement; involvement of other healthcareprofessionals; practical support from socialservices; and the availability of local respite care.

When it comes to secondary care facilities,feedback indicates that there are very fewhospitals to whom severely affected patients canbe referred - a situation that needs to be addressedwith urgency. And even where facilities exist,more consideration needs to be given to practicalproblems faced by the severely affected whenattending out-patient appointments. The situationis even worse in relation to the provision ofsuitable facilities for in-patient assessment andmanagement.

It should also be noted that very few of theresearch studies into either pathoaetiology ormanagement of ME/CFS have ever involvedseverely affected patients - a fact which should beborne in mind when considering the use ofcontroversial management approaches such asCBT and/or graded exercise in this group ofpatients. The ME Association is currently fundingthe first ever study into factors which may beinvolved in the development of severe ME/CFS.

Children and adolescentsThere is currently very little reliable informationon the prevalence of ME/CFS among children andadolescents, but one study (Dowsett and Colby1997) indicated that it is one of the most commonreasons for long-term absence from school.

Diagnostic assessment of possible ME/CFS in thisage group is very similar to that in adults.However, symptoms such as headaches anddisrupted sleep patterns tend to be moreprominent and there are other diagnoses (eglymphoreticular malignancy, Crohn’s disease)which may need to be excluded by furtherinvestigation in some instances.

Management of children and adolescents is againvery similar to that of adults but with less emphasison the use of drug treatments. Appropriate liaisonwith local education authorities (LEAs), schoolsand teachers, which is aimed at keepingeducation going through the use of home tutorsand part-time attendance, is vital. Children whoare sufficiently unwell to be away from schoolshould generally be under the active care of apaediatrician. It should also be noted that childrenand adolescents with ME/CFS may be eligible forvarious state sickness and disability benefits.

There are a number of registered charities dealingspecifically with children and adolescents withME/CFS. Details can be obtained from The MEAssociation.

Information for patientsThe ME Association provides information topatients, carers and health professionals on allaspects of ME/CFS. Information sheets areavailable on many of the management topicscovered in this booklet.

The ME Association also recommends two self-help guides for patients:

� Living with ME, Dr Charles Shepherd(Vermilion, 1999).

� ME/chronic fatigue syndrome: how to cope, Dr Anne Macintyre (Thorsons, 1998).

ReferencesWith the exception of those related tomanagement, only key medical and scientificreferences are included in this booklet.

14 ME/CFS/PVFS An exploration of the key clinical issues

11.

10.

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BAKHEIT, A M O et al. Abnormal arginine-vasopressin secretion and water metabolism inpatients with post-viral fatigue syndrome. Acta Neurologica Scandinavia, 1993, 87, 234-238.

BAKHEIT, A M O et al. Possible upregulation ofhypothalamic 5-hydroxytryptamine receptors inpatients with post-viral fatigue syndrome. British Medical Journal, 1992, 304, 1010-1012.

BAZELMANS, E et al. Is physical deconditioninga perpetuating factor in chronic fatiguesyndrome? A controlled study on maximalexercise performance and relations with fatigue,impairment and physical activity. Psychological Medicine, 2001, 31, 107-114.

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BEHAN, P et al. Effect on high doses ofessential fatty acids on the postviral fatiguesyndrome. Acta Neurologica Scandinavia,1990, 82, 209-216.

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DEALE, A et al. Illness beliefs and outcome inchronic fatigue syndrome: do patients need tochange their beliefs in order to get better? Journalof Psychosomatic Research, 1998, 45, 77-83.

ME/CFS/PVFS 15

DeLUCA, J et al. Cognitive functioning isimpaired in patients with chronic fatiguesyndrome devoid of psychiatric disease. Journalof Neurology, Neurosurgery and Psychiatry,1997, 62, 151-155.

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DOWSETT, E G and COLBY, J. Long termsickness absence due to ME/CFS in UK schools:an epidemiological study with medical andeducational implications. Journal of ChronicFatigue Syndrome, 1997, 3, 29-42.

Du BOIS, R. Gamma globulin therapy forchronic fatigue mononucleosis syndrome. AIDS Research, 1986, 2 (suppl 1), 191-195.

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FRIEDBERG, F and KRUPP, L B. A comparisonof cognitive behavioural treatment for chronicfatigue syndrome and depression. ClinicalInfectious Diseases, 1994, 18 (Suppl 1), S105-110.

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FULCHER, K Y and WHITE, P D. Randomisedcontrolled trial of graded exercise in patients withchronic fatigue syndrome. British MedicalJournal, 1997, 314, 1647-1652.Correspondence: 315, 947-948.

HEAP, L C et al. Vitamin B status in patientswith chronic fatigue syndrome. Journal of theRoyal Society of Medicine, 1999, 92, 183-185.

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16 ME/CFS/PVFS An exploration of the key clinical issues

MAJEED, T et al. Abnormalities of carnitinemetabolism in chronic fatigue syndrome.European Journal of Neurology, 1995, 2, 425-428.

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SHARPE, M C et al. Follow up of patientspresenting with fatigue to an infectious diseasesclinic. British Medical Journal, 1992, 305, 147-152.

SHEPHERD, C B. Long term treatment is beingused. British Medical Journal 1997, 315, 813-814.

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18 ME/CFS/PVFS An exploration of the key clinical issues

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