J7ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:617-621

Chronic fatigue syndrome: a follow up study

D Bonner, M Ron, T Chalder, S Butler, S Wessely

AbstractForty-six of 47 patients diagnosed as

having chronic fatigue and offered treat-ment four years previously were followedup. Twenty-nine patients were inter-viewed, three patients refused an inter-view, and information on the remaiing

14 was obtained from their general prac-titioners. All the instruments used atinterview had been used in the initialstudy. The long-term prognosis forpatients with chronic fatigue syndromewho have initially responded to treat-ment is good. Spontaneous recovery inthose who declined or who did not bene-fit from treatment is unlikely. Patientswho continue to fulfil the criteria forchronic fatigue syndrome four yearsafter they were initially diagnosed are

likely to have had more somaticdisorders, to have been more fatigued,and to have had a previous psychiatrichistory when they were initially assessed.

Neurol Neurosurg Psychiatry 1994;57:617-621)

Maudsley Hospital,London, UKD BonnerNational Hospital forNeurology andNeurosurgery,London, UKM Ron

Department ofPsychologicalMedicine, King'sCollege Hospital,London, UKT ChalderS WesselyThe York Clinic, Guy'sand St Thomas'sHospital Trust,London, UKS ButlerCorrespondence to:Dr Bonner, MaudsleyHospital, Denmark Hill,London SE5 8AZ, UK.Received 23 February 1993and in revised form20 August 1993.Accepted 28 September 1993

Over the past decade much attention hasbeen focused on the syndrome variouslydescribed as myalgic encephalomyelitis, post-viral fatigue syndrome, and latterly chronicfatigue syndrome. This plethora of names

and the frequency of descriptions is testamentto the confusion surrounding the syndrome.The term chronic fatigue syndrome has beenproposed to describe disabling fatigue ofat least six months' duration of uncertainaetiology. 1-3 The cause of the syndromeremains to be determined, but there is a

complex interaction between biological andpsychological substrates.A series of studies has shown that between

50 and 80% of subjects with chronic fatiguesyndrome seen in specialist centres or pri-mary care settings fulfil criteria for psychiatricdisorders.49 Although reports of chronicfatigue can be found as far back as 1869 withBeard's description of neurasthenia or ner-

vous exhaustion,'0 systematic studies of thedisorder have only been undertaken in thepast few years and therefore informationabout the natural history and the effects oftreatment is limited. Anecdotal reports of a

large series suggested an extremely gloomynatural history." A follow up study of sub-jects seen at an infectious disease clinic was

only slightly more optimistic,'2 as mostpatients remained symptomatic two to four

years after assessment. Treatment was notoffered in either of these studies.

In this study we followed up a group ofpatients seen at the National Hospital forNeurology and Neurosurgery four years pre-viously who had been diagnosed as havingchronic fatigue.6 These patients were initiallyassessed before the current criteria forchronic fatigue syndrome became available,but most would have satisfied the criteriaretrospectively; only two patients wereexcluded because of a life-long history offatigue (that is, no definite onset).

These 47 patients were initially offeredtreatment in an open, uncontrolled trial usingcognitive behaviour therapy. Antidepressantswere offered to those patients who fulfilleddiagnostic criteria for depression."3 Treatmentfollowed cognitive behavioural principlesderived from work on the management ofchronic pain but adapted for the particularproblems of chronic fatigue syndrome.'4 15We decided to follow up this group of

patients to determine if treatment gains weremaintained, what happened to those whorefused treatment, and to elucidate furtherthe role of psychiatric morbidity in the prog-nosis of chronic fatigue syndrome.

Subjects and methodsSUBJECTSForty-six of the 47 subjects who took part inthe original study were contacted by post fouryears later. The case notes of the remainingpatient could not be traced. Those who didnot respond to the initial letter were sent asecond. Thirty-two (70%) patients responded(18 women, 14 men).Of those who responded, 29 (91%) agreed

to be interviewed. Nine (28%) were seen athome, 11 (34%) at the National Hospital forNeurology and Neurosurgery, and nine wereinterviewed by telephone. The general practi-tioners of the 14 patients who did notrespond were contacted by telephone toobtain information about their physical andmental health during the follow up period.

INSTRUMENTSThree questionnaires were sent by post whenthe patients were initially contacted. One wasa fatigue questionnaire modified from thatdevised for the previous study.616 Scoresranged from 0 to 10; the higher the score thegreater the fatigue. The results of the initialfatigue questionnaires were corrected to makethe index scores and follow up scores directly

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comparable. The other two questionnaireswere the General Health Questionnaire-(GHQ-1 2)'7 and the Hospital Anxiety andDepression (HAD) Questionnaire.'8

At follow up patients were classified as stillhaving chronic fatigue syndrome if they ful-filled the following criteria: (a) scoring above4 on the fatigue questionnaire; (b) beingfatigued for six months or more; and (c) feel-ing fatigued more than 50% of the time.These criteria are based on guidelines set outby Sharpe et aP in their recommendations fora working case definition of chronic fatiguesyndrome.

At the interview the following instrumentswere used: (a) the schedule for affective dis-order and schizophrenia (SADS).19 This is a

standardised psychiatric interview developedto provide current and lifetime research diag-nostic criteria (RDC) diagnoses. (b) TheBeck depression inventory (BDI).20 (c) Themodified somatic discomforts questionnaire.2'This consists of a list of 17 common symp-toms which are rated on a three-point scale(1-3) indicating whether they were a slightproblem (1), a moderate problem (2), or a

severe problem (3). (d) A self-assessmentscale of functional impairment.22 This recordsfunctional disability and consists of fourvisual analogue scales covering ability towork, home management, and social and pri-vate leisure activities. Patients were askedhow much their problems affected their func-tioning in each of these designated areas. Thescores of the four visual analogue ratings offunctional impairment were summed andtreated as a single variable, labelled 'impair-ment index' (range 0-8). All these measures

had been used in the previous study.'3 (c)Self-rated global improvement. Subjects were

also asked to rate their overall improvementsince the initial assessment on a percentagescale, taking 0% as the point they felt mostfatigued and with 100% implying completerecovery.

STATISTICS

Statistical procedures were performed usingthe Statistical Package for Social Scientists(SPSS).23 Non-parametric statistics used were

the Mann-Whitney U test and the x2 test. Allsignificance testing was two-tailed.

ResultsThere was no significant difference betweenthe respondents and non-respondents in age,sex, age at onset of fatigue, duration offatigue, severity of depression, or the presenceof a previous psychiatric history at indexassessment.The mean age at follow up of the 29

patients who were interviewed was 41 years(range 23-64). Their mean age at the onset offatigue was 33-8 years (range 17-57-5) andthey had had the symptom of fatigue for a

mean of 3-2 years (range 0 5-10) when theywere initially assessed.

Twenty two (76%) of these patients hadaccepted treatment when first seen and of

these 17 had successfully completed it. Threepatients discontinued treatment- and twopatients felt no benefit at the completion oftreatment. Seven of the patients seen at fol-low up had refused treatment when initiallyassessed.

SELF-RATED GLOBAL IMPROVEMENTThe 29 subjects were divided into twogroups: group 1-those who felt no or only a

slight improvement (< 50% score on the self-rated global improvement scale) (13patients); and group II-those who felt theyhad recovered or almost recovered (> 50%score on the self-rated global improvementscale) (16 patients). Table 1 summarisesthese findings.Of the 13 subjects who reported little or no

improvement, 11 fulfilled RDC criteria for a

current psychiatric diagnosis of depressionand had the same diagnosis when assessed forthe initial study. Their reported level of func-tional impairment at follow up (mean 20-2,range 8-30) was not significantly changedfrom the initial assessment (mean 20-57,range 13-31). Subjects were impaired in allthe areas assessed. Eight patients in thisgroup had been unable to return to worksince becoming fatigued and two had beenhousebound since the onset of their fatiguesymptoms six and seven years previously.Eight subjects currently fulfilled the criteriafor chronic fatigue syndrome.Of the 16 subjects who felt they had recov-

ered or almost recovered only one fulfilled thecriteria for a psychiatric diagnosis. Thispatient was diagnosed as having postpartumdepression after childbirth six months previ-ously. The functional impairment of subjectsin this group was minimal at follow up (mean2-78, range 0-11). At the initial assessmentthere was no significant difference in func-tional impairment between the two groups.Two patients in this group continued to fulfilthe criteria for chronic fatigue.

CHRONIC FATIGUE SYNDROME

Ten (34%) of 29 patients interviewed contin-ued to fulfil the criteria for chronic fatiguesyndrome at the four year follow up. Ofthese, seven also had an RDC psychiatricdiagnosis (major depression in five and minordepression in two) and this contrasted withonly five of the 19 without chronic fatiguesyndrome. The diagnoses in this group were

Table 1 Self-rated global improvement.numbers ofpatients or questionaire score

Values given are

No or little Improvedlimprovement recovered(< 50%1o) (> 50%)(n = 13) (n = 16)

Psychiatric disorder atfollow up 11 (11) 1 (13)(at index interview)

CFS at follow up* 8 2Completed treatment 6 14

Functional impairmentscore at follow upt 20-2 (8-30) 2-78 (0-11)

*CFS = Chronic fatigue syndrome.tMean (range).

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somatisation disorder (two patients), majordepression (one patient), minor depression(one patient) and anxiety disorder (onepatient). The difference between the groupsis statistically significant (p < 0-05). Table 2reports other differences between the twogroups. Thus patients in the group with per-sisting chronic fatigue syndrome had a greaterfunctional impairment, experienced greatersomatic discomfort and had higher scores foranxiety and depression.The ratings obtained during the initial

assessment by those who fulfilled the criteriafor chronic fatigue syndrome at follow upwere compared with those of the rest of thegroup to ascertain possible differences ofprognostic value (see table 3).

There was no difference in age of onset,sex, or duration of fatigue at index assessmentbetween the two groups, nor was there anydifference in the severity of depression asassessed by their BDI and HAD scores.Those who continue to have chronic fatiguesyndrome at follow up, however, saw them-selves as experiencing greater somatic dis-comfort and had significantly greater fatiguescores at the index assessment.A change in the nature of the symptoms

appeared to have taken place during the fol-low up period. Only five of the 10 patientswho continue to fulfil the criteria for chronicfatigue syndrome felt that their current disor-der was fatigue. Two patients felt that it waslow mood, two reported poor concentration,and one patient felt it was recurrent chestpain due to angina. In contrast, at the initial

Table 2 Physical and psychiatric morbidity in patients with chronic fatigue syndrome:follow up rating

Mean (95% confidence interval) score atfollow up

CFS atfollow up No CFS atfollow up(n = 10)* (n = 19)t

Impairment index 21-5 (16-9 to 26-1) 5-9 (2-5 to 9-3tGHQ 5-7 (3-6 to 77) 1-8 (0 5 to 3-1)tBDI 8-7 (5-0 to 12-4) 3-0 (0-5 to 5-0)tHAD 18-9 (13 6 to 24-2) 7-7 (4-3 to 1 14)*Somatic discomfort

questionnaire 19 5 (13 9 to 25 1) 6-7 (3-5 to 9 9)t

Abbreviations: CFS = Chronic fatigue syndrome; GHQ = General Health Questionnaire; BDI= Beck Depression Inventory; and HAD = Hospital Anxiety and Depression scale.*Seven patients fulfilled the RDC diagnosis at follow up.tFive patients fulfilled the RDC diagnosis at follow up; p < 0-05 (j test).t p < 0-01; Mann-Whitney U test.

Table 3 Initial ratings and outcome offatigue

Mean (95% confidence limit) value at initial interviewCFS at follow up No CFS atfollow(n = 10) up (n = 19)

Age at onset of CFS (years) 324 (25-7 to 39-1) 34.9 (31-3 to 38-5)Duration of fatigue (years) 3-2 (1-5 to 4-9) 3-2 (2-0 to 4 4)Fatigue score 9-5 (8-9 to 10) 8-6 (8-0 to 9.2)*Impairment index score 22-8 (19-0 to 26-6) 19 3 (16 to 22-6)GHQ score 7-3 (4-7 to 9*9) 7.4 (5-8 to 90)BDI score 12-3 (7-0 to 17-6) 7-3 (5-3 to 9 3)HAD score 21 (16-9 to 25-1) 16 4 (12-4 to 20-4)Somatic discomfort

questionnaire score 22-3 (20-1 to 24 5) 16 (12-3 to 19.7)*No with past psychiatric

history 7 3tNo completed treatment 5 13

Abbreviations: CFS = Chronic fatigue syndrome; GHQ = General Health Questionnaire; BDI= Beck Depression Inventory; and HAD = Hospital Anxiety and Depression scale.f p < 0-01; Mann-Whitney U test.*p < 0-05; Mann Whitney U test. tp < 0-01; y2 test.

assessment fatigue was the most prominentdisorder in all of these subjects.

TREATMENT OUTCOMEOf the 22 patients who accepted treatment 17were reported to be improved at the comple-tion of treatment. After four years thisimprovement was sustained in 14 patients asdetermined by their self-rated global improve-ment scores. Two of the three patients whorelapsed have had recent admissions to a psy-chiatric ward for depression. All three arecurrently attending psychiatric outpatientclinics and are receiving antidepressants. Ofthe five patients who did not successfullycomplete treatment none had spontaneouslyimproved at the four year follow up. Seven ofthe patients seen at follow up had refusedtreatment; of these two had made a sponta-neous recovery.

ILLNESS ATTRIBUTIONAll subjects interviewed at follow up wereasked about their illness attribution-whetherthey believed that the cause of their illnesswas physical, mainly physical, or whether itwas psychological or mainly psychological.Nine of the 10 patients with chronic fatiguesyndrome attributed their illness to a physicalcause, but so did 12 of the 19 patients with-out chronic fatigue syndrome. This differencedid not reach statistical significance.

PHYSICAL AND PSYCHIATRIC MORBIDITY INNON-RESPONDENTSThe general practitioners of all the 14 non-respondents were contacted. Six (43%) sub-jects were reported to be well physically andmentally when last seen by their general prac-titioner. All of these had successfully com-pleted treatment. Four patients were reportedto be still unwell and visiting their generalpractitioners every three to four months withfatigue as their main disorder. Two of themwere wheelchair bound when first seen andremained so. All of these had refused treat-ment when initially seen. One patient had anRDC diagnosis of major depression and threehad a diagnosis of somatisation disorder wheninitially assessed. One patient had recentlybeen seen at the National Hospital forNeurology and Neurosurgery for a disabilityallowance appraisal. Her original diagnosis ofsomatisation disorder had been changed toone of hysterical conversion disorder. In fourcases the general practitioners had not seenthe patients for several years and could notgive information. In one of these the generalpractitioner had asked for the patient to beremoved from his practice because of non-compliance with treatment. The patient wasstill confined to a wheelchair when the gen-eral practitioner last saw him two years previ-ously.When the general practitioner reports of

the patients' current status were taken as evi-dence of the presence/absence of fatigue therewas a significant association between comple-tion of treatment and the absence of chronicfatigue syndrome at follow up. Thus from

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patient and general practitioner reports atfour years, 20 (87%) of the 23 patients whosuccessfully completed treatment remainedwell, whereas only two (13%) of the 16 whorefused or did not complete treatment hadmade a spontaneous recovery.

DiscussionWe acknowledge several shortcomings in thisstudy. The number of subjects seen at followup was smaller than in the original study andin the initial study the treatment group wasuncontrolled and therefore non-blind andnon-randomised. Nevertheless it is hopedthat the findings presented here will shedsome light on the long-term prognosis ofchronic fatigue syndrome and the long-termeffects of treatment of a kind which is nowcommonly used in these patients.

Patients were reassessed four years afterthey had been seen at the National Hospitalfor Neurology and Neurosurgery and diag-nosed as having chronic fatigue. In the initialfollow up"3 70% of the group who acceptedtreatment described themselves as 'better' or'much better' when treatment was completedand at three months this had been sustained.Follow up at four years continues to showthat treatment benefits are being maintained.There was a trend for the initial treatmentresponse to be associated with the continuedabsence of chronic fatigue syndrome at fouryears. This reached conventional statisticalsignificance when general practitioner assess-ments of current functioning were included.We therefore conclude that there is a strongassociation between successful completion oftreatment and the absence of functional dis-ability at the four year follow up.Those patients who continued to be

impaired at follow up had marked functionaldisabilities resulting in long-term unemploy-ment and continuing costs to their health ser-vices. The issue of disability payments forpatients with chronic fatigue syndrome is cur-rently receiving attention and is the subject ofcontroversy. Our results highlight the long-term benefits that may result from treatment.As treatment in the original study was non-random and all patients were offered cogni-tive behaviour therapy, with only those whowere considered to be depressed offered anti-depressants, we are unable to discuss the rela-tive merits of cognitive behaviour therapyversus treatment with antidepressants. A ran-domised controlled trial of cognitive behav-iour therapy by two of the authors (TC andSW) is nearing completion, however, and it ishoped that more information on this subjectwill soon be available.One of the salient findings of our study is

that at four years just over one third of oursample continues to fulfill the criteria forchronic fatigue syndrome. This is similar tothe findings of Sharpe et al.24 In their studythese workers followed up a group of 144patients seen in an infectious disease clinicwith a major disorder of fatigue of at least sixweeks' duration. No treatment was offered.

They found that a third of patients remainedimpaired at two to four years compared with73% followed up at six weeks to six monthsafter the initial assessment. Although ourtreated outcome is similar to that of Sharpe etal, it should be emphasised that the NationalHospital for Neurology and Neurosurgery is atertiary referral centre and more severelyaffected patients who have not responded toother methods of treatment are likely to bereferred. Also patients in the study of Wesselyet a16 reported fatigue for a substantiallylonger period of time (more than six monthscompared with more than six weeks). Otherfollow up studies have been conducted overshorter periods and indicate greater morbidityin the short term. Thus Petersen andSchenck25 did not observe complete recoveryin any of their series of 62 patients over oneyear and Valdini et al26 in a primary care set-ting reported an improvement in only a quar-ter of their sample at one year. Neither ofthese studies offered treatment. Although it isclear that the proportion of patients impaireddoes decrease with time, we have shown thattreatment produced the improvement earlyand this improvement was maintained overtime.The prognosis of severe chronic fatigue

syndrome appears to be associated with psy-chiatric morbidity and in particular depres-sion. Eight of the nine patients in our serieswho had a current RDC diagnosis of depres-sion fulfilled the criteria for current chronicfatigue syndrome; on the other hand, thethree patients who had RDC diagnoses otherthan depression did not have chronic fatiguesyndrome.

In descriptive terms many of the symptomsthat are accompanied by chronic fatigue syn-drome are similar to those of depression. Ithas been suggested that severe chronic fatiguesyndrome and severe depression are largelyindistinguishable in their symptom profiles.27Several reviews have discussed these dilem-mas828 and it remains difficult to disentanglethe "cause and effect" conundrum associatingthe two. It has been postulated that in somepatients persistent fatigue may be initiated byan acute viral infection with its usual symp-toms of transient lassitude and malaise, whichare then perpetuated in the psychologicallyvulnerable by relevant psychological factors.'9Another possibility is that patients who fulfillthe criteria for chronic fatigue syndrome havea psychiatric illness which predominantlymanifests as fatigue. In favour of this is thefact that many depressed patients often reportphysical symptoms similar to those of chronicfatigue syndrome. The presence of a psychi-atric disorder before the presentation offatigue would be consistent with this.The presence of a psychiatric diagnosis

before and after the development of fatiguesuggests that for some patients fatigue is anintegral part of depression. This association,however, is by no means clear cut, as not allpatients with chronic fatigue syndrome have apsychiatric diagnosis, nor is the presence of aprevious psychiatric diagnosis uniformly pre-

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sent in patients presenting with fatigue. Manydiseases are aetiologically complex andchronic fatigue syndrome would not beunique in this respect. It is probable that it isnot a disorder with a single specific cause butthe outcome of interacting processes at bio-logical and psychological levels. This wouldfavour treatment approaches aimed at thepsychiatric disturbance as well as dealing withthe specific behavioural aspects of fatigue.

Attribution of illness to a physical cause

does not appear to be as important a prog-

nostic factor in the long term. Butleret al'3found that a poor response to treatment was

significantly associated with attribution to a

physical cause. Although there was a trendfor this to be so at the four year follow up thisfinding was not statistically significant, andthose who had a good response to treatmentdid not change their attribution over theyears. In other words patients still believedthey had had post-viral fatigue syndrome/chronic fatigue syndrome/myalgic encephalo-myelitis even after their recovery. In contrast

with Sharpe et a124 we found no associationbetween membership of the myaglicencephalomyelitis association and continuingmorbidity at follow up. In our series onlythree of those interviewed were active mem-

bers of the myalgic encephalomyelitis associa-tion at four year follow up.

We also found in this series that there was

no evidence for neurological or physical ill-ness developing over four years. New diag-noses were entirely psychiatric; however,some patients developed new somatoformdisorders, one patient now being labelled as

having conversion hysteria, another unex-

plained chest pain. Patients with multipleunexplained somatic symptoms are known to

change attributed labels over time. It hasbeen noted how patients with chronic disor-ders have switched to the label of myalgicencephalomyelitis over time,'0 whereas PottsS and Bass C (unpublished data), in a long-term follow up study of patients with severe

chest pain and normal coronary arteries, havenoted how some have now acquired the labelof myalgic encephalomyelitis. In our study wenoted a two-way traffic. A further area of con-cern was that only half of those who fulfilledthe diagnostic criteria for depression were

receiving any treatment at follow up. Indeed,perhaps the most disturbing aspect of thisstudy is that the morbidity of those whorefused treatment appears to be high. Thismay indicate that the presence of severe

somatic symptoms deflects doctors' attentionand many patients who fulfill diagnosticcriteria for treatment go untreated. Future

studies or treatment should concentrate onthis group who otherwise appear to have abad prognosis.

Dr MA Ron is partly supported by the SCARFE Trust.

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