34ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:684-689

Analysis of neuropsychological functioning inpatients with chronic fatigue syndrome

Jordan Grafnan, Vicki Schwartz, Janet K Dale, Marten Scheffers, Christine Houser,Stephen E Straus

AbstractMemory impairment dominates the cog-nitive complaints of patients withchronic fatigue syndrome (CFS). TwentyCFS patients were available for studieswith a clinical and experimental batterycomposed ofmemory and cognitive tests.The results on objective testing indicatedthat the CFS patients had some mildmemory impairment, but only on tasksrequiring conceptually driven encodingand retrieval processes. There were noassociations between the nature of theprecipitating illness, self ratings offatigue, physical findings, or laboratorydetermination and objective memoryperformance or self report of memoryfunctioning. These generally negativeresults indicate that memory impair-ment in CFS patients is typically mildand involves memory processes that par-ticipate in conceptualising information.

(3 Neurol Neurosurg Psychiatry 1993;56:684-689)

CognitiveNeuroscience Section,Medical NeurologyBranch, N NDS, NIH,Bethesda, MD 20892,USAJ GrafnanV SchwartzM ScheffersC HouserLaboratory of ClinicalInvestigation, NAID,NIH, Bethesda, MD20892, USAJ K DaleS E StrausCorrespondence to:Dr J Grafman, CognitiveNeuroscience Section,Medical Neurology Branch,NINDS, NIH, Building 10,Room 55209, Bethesda,MD 20892, USA.Received 21 February 1992and in revised form17 June 1992.Accepted 11 August 1992

Medical professionals are frequently requiredto assess and manage patients who complainof chronic fatigue. When associated withpain, sore throat, feverishness, tender lymphnodes, decreased concentration, memoryproblems, and depressed mood in theabsence of a discernible cause, the symptomcomplex is termed the chronic fatigue syn-drome (CFS).1 The lack of uniform physicalor laboratory abnormalities in patients withCFS dictates that the diagnosis is one ofexclusion, and that treatment is empirical.2'In addition, there is a striking overall simi-larity between CFS and the condition longknown as neurasthenia.45

Depression is a prominent feature in manypatients with CFS. While in some it predatesthe illness and may contribute to this syn-drome's immune, somatic, and cognitivefeatures,7-"3 in others, the depressive symp-toms may represent reactions to the debil-itating illness and/or be a co-morbidexpression of constitutional factors that ulti-mately make people susceptible to delayedrecovery from infections or other acutelystressful events.7-9121' This combination offactors has fuelled an unresolved debate as towhether CFS is the reflection of an underly-ing psychiatric disturbance or, instead, is theresult of an ongoing disorder with an infec-tious or immune origin.14-8 Regardless of theoutcome of this debate, qualitative and quan-

titative characterisation of the clinical featuresof CFS would permit better patient classifica-tion and management.Among the least studied features of CFS

are the common complaints of deficits inmemory, cognition, and mood. 19 The goals ofthe present study were to characterise thedimensions of these neuropsychological prob-lems and to determine the degree to whichthey correlate with other clinical and labora-tory measures.

In a pilot study, we administered retro-spective and current period surveys to 54patients who met Center for Disease Controlcriteria for CFS and who were participatingin ongoing research studies at the NationalInstitutes of Health. These patients under-went medical and laboratory evaluations andcompleted self rating forms regarding moodand cognitive functions.20 The results showedthat CFS patients report many symptomsthat are characteristic of depression, and thatthe prevalence and severity of depressivecomplaints reflect the degree of overall illnessand its cognitive features, especially thoseregarding memory, an observation made inan earlier controlled therapeutic trial inpatients such as these.2 We extended theseearlier observations by a detailed assessmentof cognitive complaints in CFS patients andby analysis of their relationship with depres-sive complaints and severity of illness. Ourresults indicated that complaints of memoryimpairment dominate the current and pastreports of patients with CFS. Moreover, theseverity levels of cognitive and mood prob-lems recalled during the worst period of ill-ness correlated highly with the currentcognitive and mood levels. For both the cur-rent and past periods, the level of depressioncorrelated directly with the number andseverity of memory complaints. Importantly,neither the current or recalled complaints ofcognitive and mood problems could be pre-dicted on the basis of any other clinical orlaboratory data accrued.We, therefore, decided to examine CFS

patients with a battery of cognitive and mem-ory tests to determine whether objectivememory and cognitive deficits could bedemonstrated in the light of the survey results.

MethodsSUBJECTSThe first 20 of the survey respondents whosubsequently travelled to the NIH for furtherbiological studies were neuropsychologically

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evaluated. They were compared with 17healthy control subjects matched for age andeducation (see table 1). This subset ofpatients was similar in all respects to thelarger group of patients we surveyed.

MEASURESA set of measures was chosen that wouldevaluate objectively the cognitive complaintsof CFS patients based on the pilot surveystudy. While we focused on memory mea-sures, tests of planning, reaction time andintellectual capacity were also included in thebattery. Two "Tower" planning tasks wereselected because they represent different diffi-culty levels in planning. Thus, this battery notonly measures those domains of cognitionnoted by CFS patients to be taxing, butincludes measures known to be sensitive to"subcortical dementia" such as time percep-tion, response speed, and planning. The fol-lowing battery of tests and scales wasadministered over a total of eight hours ontwo consecutive days of study. A moredetailed description of these tests, exceptwhere noted, is available in Lezak.2'

All patients and controls demonstratedexcellent effort and motivation during theevaluation. All of the patients remarked thatthe examination was tiring for them. Somepatients complained of debilitating fatigueonly on the day following the completion ofthe evaluation.

GENERAL INTELLECTUAL PERFORMANCE1. Wechsler adult intelligence scale revisedThis is a standard intelligence test composedof 11 subtests assessing verbal and non-verbalabilities. Both scale and subtest scores arereported.

TIMING AND REACTION TIME TASKS1. Simple reaction timeSubjects were instructed to press the spacebar on a computer keyboard as quickly aspossible every time a stimulus appeared on acomputer monitor. There were a total of 21trials on this task.

2. Serial reaction time test 22Subjects were instructed to press one of fourkeys that were spatially aligned with one offour positions on a computer monitor.Stimuli would appear at one of the four posi-tions, one at a time, and subjects were topress the key that was underneath the posi-tion where the stimulus would appear asquickly as possible. There were seven blocksof 100 trials each. The first two blocks werecomposed of random presentations, the nextfour blocks were composed of 10 repetitions

Table I Subject characteristics

of a fixed sequence of 10 stimuli, and the lastblock was another random presentation.Familiarity with the task itself should bereflected by a slight decrease in reaction times(RT) across the first two blocks. The furtherexpected decline in RT across blocks three tosix indicates the procedural learning of therepeated sequence. The expected increase inRT on block seven (composed of random tri-als) compared with block six (the last repeatedtrial block) is an indication of visuomotorprocedural learning (the difference score thatwe use subtracts the RT of block seven fromblock six). The RT for blocks one and twoalso represents a choice-RT measure inde-pendent of procedural learning.

3. Time wallSubjects viewed a block falling from the topof a computer monitor at a steady velocity.Half way down the screen the block disap-peared from view behind an opaque mask.Subjects had to press a key when theybelieved the block had reached the bottom ofthe screen. This task measures time percep-

tion based on encoding of the speed of a

visual stimulus.

4. Time clockSubjects saw a circle on a computer monitorand were asked to press a key once every sec-

ond for 60 keypresses. After each keypress,the subject saw a clock hand move 1/60 of thedistance around the circumference of thecircle in a clockwise direction. This task mea-sures elapsed time estimation when the targettime interval (- 1 second) is known.

PROBLEM SOLVING AND PIANNING1. Tower of London23On this simple task of planning and proce-

dural knowledge, subjects were shown a col-lection of three coloured discs placed upon a

set of different sized pegs in a certain patterndefined as the initial state. They were thenshown a card indicating the final state that thediscs should be in. Subjects were then told tomove the discs one at a time until theyreached the final state. Only one disc couldbe moved at a time, there was a limit on howmany discs could be placed on the pegs, andthere was a time limit of two minutes by theend of which a move had to be made. If a vio-lation of any of these rules was made, thesubject was allowed to start over again. Atotal of three attempts per problem was

allowed. Response times were recorded permove.

2. Tower ofHanoi 23

This is a more demanding task than theTower of London but measures similar plan-ning and procedural knowledge skills.Subjects were shown the graphic image of a

collection of five discs placed upon a set ofpegs on a computer screen. From this initialstate, subjects were asked to use the numeri-cal keys on the keyboard to shift discs to dif-ferent pegs in order to reach a final state.Subjects had to solve the problem within two

Controls (N = 17) CFS patients (N = 20)

Age (years) 38-1 (8-9) 37-2 (9-0)Education (years) 15-9 (2 7) 15-5 (2 2)Handedness 100% Right Handed 100% Right HandedSex 9 Women/8 Men 12 Women/8 Men

(Means and standard deviations are shown.)

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minutes. The number correct out of nineproblems was recorded. Each problem had adifferent initial state but a constant finalstate.

3. Twenty questionsSubjects had to identify the correct objectfrom a set of 24 objects by asking questions.Two problems (each with a specific targetobject) are given with the type of question(for example, deductive) asked by the subjectand whether the subject identified the objector not recorded by the test examiner. Thistest measures reasoning ability and questiondevelopment (for example, divergent versusconvergent).

MEMORY1. Wechsler memory scale revisedThis is a standardised test that includes sev-eral subtests which measure short term mem-ory, verbal and non-verbal learning, andimmediate and delayed recall, mental control,and attention.

2. Experimental paired associate test 24Subjects were asked to remember severaltypes of paired items (either word word, wordpicture, picture word, or picture picturepairs); each pair was presented on a card.Subjects were next given a visual cued recalltest using the first item in each pair, followedby a verbal free recall test and an incidentallearning task which required subjects to indi-cate whether each item was presented origi-nally as a picture or a word. This testevaluates structured versus free recall andincidental memory for a stimulus feature.

3. Hasherfrequency monitoring task24Subjects were read a set of words that theywere told to remember. Some of the wordswere repeated up to seven times. Followingthe presentation of this list, subjects wereasked to recall as many of the items as theycould from the original list. Then, subjectswere read all the items from the original listand some items that were never presentedbefore and asked to estimate how many timesthey had heard these words. This test evalu-ates sensitivity to frequency of presentationunder implicit (free recall) and explicit(forced choice) conditions.

4. Story memorySubjects were read two stories and asked torecall as much information as they couldabout each story following its presentation.The number of story idea units recalled wererecorded.

5. WordfluencySubjects were asked to generate words for 90seconds that belonged to various ategories(for example, animals, countries, things youcan buy in supermarkets) or began with aspecific letter (for example, F, A, S).

MOOD STATE AND PHYSICAL CONDITION1. Beck depression inventory'5

This scale was completed by the subject whoindicated the number and severity of symp-toms associated with depression that theywere currently experiencing. A score of 15 orhigher is suggestive of at least a mild depres-sion.

2. Somatisation scaleThis questionnaire is completed by the sub-ject who indicates whether he is currentlyexperiencing unusual symptoms that are typi-cally associated with somatisation.

3. Neurobehavioural rating scaleThis scale is completed by the test examinerand indicates the severity of behaviouralsymptoms (for example, depressed effect)observed by the examiner during the testexamination. The higher the score per behav-ioural symptom, the more severe the symp-tom appears to the observer. There are 29behavioural symptoms scored on this scale.

4. Fatigue scaleSubjects rated their fatigue on an unpub-lished analogue scale developed by the Centerfor Disease Control reflecting the degree offatigue they were experiencing on the day oftesting, the month before the testing, and themonth before their illness.

These scales and questionnaires are usedfor screening purposes only. A psychiatricdiagnosis requires a formal psychiatric inter-view which was not completed on any of thepatients or controls in conjunction with thisevaluation.

STATISTICAL ANALYSESAnalysis of variance was used for mostbetween group comparisons. Posthoc evalua-tions used the Scheffe test. Regression analy-sis was used to determine the effects of age,education, and sex on specific measures.Pearson product moment correlations werecomputed to evaluate the relationshipbetween performance on related cognitivemeasures. The error bars in the figures alwaysrefer to standard deviations.

ResultsGENERAL INTELLECTUAL AND COGNIrIVEFUNCTIONSThere were no significant between group dif-ferences in performance on tests of intelli-gence, reaction time, planning, timeperception, or problem solving, with twoexceptions. The CFS patients demonstratedgreater variability than the controls in thetiming of their tapping on the time clock task(F(1,33) = 4-62, p < 0 03) although the over-all mean tapping times of the CFS patientsand controls were similar. CFS patientssolved more problems than did the controlson the Tower of London task (F(1,33) =4 04, p < 005). On the other hand, CFSpatients tended to make more errors in solv-ing the Tower of London problems (F(1,30)= 7-38, p < 0-01). The essentially normalperformance of CFS patients on these mea-

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Table 2 Wechsler memory scale-revised

Raw scores

Subtests Controls CFS patients

Information 13 94 (0-25) 13 90 (0 31)Mental Control 5 44 (0-73) 5 15 (0 93)Figural Memory 7 38 (1 20) 6-79 (1 08)Logical Memory I 29 06 (5 57) 26 05 (6-92)Logical Memory II 24 38 (6 64) 20-50 (8 10)Visual Paired-Associates I 16-00 (2 73) 14 85 (3 03)Visual Paired-Associates II 5 94 (0-25) 5 70 (0-66)Verbal Paired-Associates I 20 75 (3-53) 20 70 (2-68)Verbal Paired-Associates II 7-69 (0 60) 7 70 (0 57)Visual Reproduction I 36 50 (2 37) 34 00 (3-51)*Visual Reproduction II 33 13 (5 73) 28 50 (6.34)*

The oiily significant differences between groups occurred on the visual reproduction subtest.However, CFS patients generally performed slightly worse than controls on almost all subtests.(Means and standard deviations are shown.)

sures was in accordance with expectations,given that their cognitive complaints primar-ily revolved around memory functions.

MEMORY FUNCTIONSThere were no between group differences onthe digit span task, indicating that short termmemory span was intact in the CFS group.There were also no between group differencesin retrieval of category exemplars suggestingthat at least some aspects of semantic mem-ory search and retrieval were intact. CFSpatients also demonstrated normal reactiontimes and visuomotor procedural learning onthe serial reaction time task.

Despite normal functioning on these mem-ory measures, CFS patients had a signifi-cantly lower score than controls on thegeneral memory index of the Wechsler mem-ory scale (F(1,34) = 5 05, p < 0-03) suggest-ing that some aspects of their current memoryfunctioning were impaired. Specific subtestraw score comparisons (see table 2) revealedthat the CFS patients were only impaired onthe immediate (F(1,34) = 5 94, p < 0 02)and delayed (F(1,34) = 5-15, p < 0.02) visualreproduction subtests which requires the sub-ject to reproduce complex geometric designs.Other subtests requiring attention and orien-tation, immediate and delayed verbal cuedand free recall, and non-verbal recognitionmemory were all performed normally. On twomeasures of free and incidental recall (from

Figure 1 Experimentalpaired associates test. CFSpatients performedsignificantly worse thancontrols only in the cuedrecall condition. (Meansand standard deviationsare shown.)

Experimental Paired-Associates T

a)

cU

X 50-

40-a)

o 30-~0

20-

c 10-a)

O-

*1. | ControlsO CFS Patients

11

Cued-recall Item-recall Pair-recall IncirE

11

Retrieval conditions

est

dental-ecall

III

the experimental paired associates andHasher frequency tasks), CFS patient recalland judgment were similar to those of thecontrols. On the first of two experimentalstories, the CFS patients recalled as manystory idea units as did the controls. However,following the second story, patients recalledsignificantly fewer idea units than did con-trols (F(1,33) = 15-26, p < 0-0004). Further-more, on the experimental paired associatestest (see fig 1), CFS patients recalled fewerwords in the cued retrieval condition than thecontrols (F(1,35) = 4-81, p < 0 03).

Thus, CFS patients appeared to havegenerally normal memory functioning, yet,paradoxically, they demonstrated specific dif-ficulties in recalling information under condi-tions of greater semantic structure (forexample, cued as opposed to free recall andrecall of story propositions as opposed to iso-lated words) and in reproducing geometricdesigns. This is the opposite of the commonfinding in which normal subjects and patientswith various types of central nervous systemimpairments are generally helped by increas-ing stimulus structure (as seen in story mem-ory or cued recall tasks). Correlationalanalysis was not particularly helpful in identi-fying associations between other variables (forexample, age, education, degree of fatigue,mood state) and these unusual memorydeficits in the CFS patients although verbalIQ was significantly correlated with the num-ber of propositions retrieved on story two (r =0 46), suggesting that the general verbal skillsof these patients were partially responsible fortheir poorer performance.

MOOD STATE AND EFFORTThere was no difference in the number ofdepressive symptoms reported by the CFSpatients and controls on the Beck depressioninventory. Scores from an examiner ratingscale showed that about a quarter of the CFSpatients demonstrated mild to moderatelyimpaired attention and memory during theevaluation. As expected, CFS patientsreported being significantly more fatigued onthe day of testing than controls (F(1,30) =46-37, p < 0-0001) and their fatigue on thetesting day was compatible with their generallevel of fatigue throughout the illness.However, there were no differences betweenthe level of pre-illness fatigue in the CFSpatients and the current level of fatigue in thecontrols. Furthermore, there was no relation-ship between any of these fatigue measuresand cognitive performance in the CFS group.

This series of tests demonstrated, then,that CFS patients have selective deficits inmemory processing arising against a back-ground of relatively normal cognitive func-tioning. Curiously, they had greater problemsrecalling material when the material orretrieval measure was the most structured.There was no relationship between perfor-mance on these specific memory measuresand mood state, fatigue level, age, or educa-tion although verbal intelligence was corre-lated with story memory performance.

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DiscussionThe cumulative results of the pilot and neu-

ropsychological studies indicate that reportsof memory impairment dominate the currentand past cognitive complaints of patients withCFS. For both the current and past periods,the level of depression correlated directly withthe number and severity of memory com-

plaints. Importantly, neither the current or

recalled complaints of cognitive or moodproblems could be predicted on the basis ofany other clinical or laboratory data accrued.On objective neuropsychological testing, we

found only a few, selective memory deficits inthe CFS patients consistent with their pri-mary complaints on the survey. However,performance on objective memory tests was

not correlated with scores on the Beckdepression inventory (which were generallywithin normal limits on the day of testing).Had we tested patients who were more

acutely ill (for example, bedridden patients),we might have observed more severe andwidespread cognitive deficits. However, theseverity of complaints in our patient cohortwas typical of that usually published, was suf-ficient to permit a diagnosis of CFS accordingto CDC criteria, and sufficient to render twothirds of them vocationally disabled.'4 2630 It istrue that the mean scores of the CFS patientgroup, while not significantly different fromthe controls on most measures, were gener-

ally slightly lower than the controls.Nevertheless, it is not obvious that this mod-est difference could fully explain the extent ofCFS patient distress over their cognitive andmemory functions. Thus, we can concludewith reasonable certainty that the cognitiveabilities of CFS patients are generally intact.

There are a few caveats to our findings.Firstly, not all 54 of the respondents in thepilot study were available for cognitive stud-ies. It is possible that those patients who didnot complete the survey, and in particularthose who did not travel to our laboratoriesfor cognitive testing, were the more seriouslydisabled patients. Yet two thirds of the par-

ticipants in the cognitive study, as in the pilotstudy, were vocationally disabled owing totheir chronic fatigue.

Secondly, the Beck depression inventory,while being an excellent self rating index ofdepression, cannot substitute for a carefulpsychiatric examination and diagnosis."Nevertheless, we believe that true depressivesymptomatology based on emotional ratherthan physical symptoms was measured on thesurveys. The emotional status scale scores,which reflected the frequency of crying, agita-tion, and similar behaviours, correlated highlywith the Beck depression scale scores.

Furthermore, the present finding of a highprevelance of depression is consistent withearlier findings of structured psychiatric inter-

views conducted in our, and other groups of,CFS patients.89'2 Even though we found a

strong relationship between elevated depres-sive symptomatology and memory com-

plaints, other factors such as degree of fatiguemay also predict memory complaints.

Thirdly, although we found no strong rela-tion between biological measures and currentcomplaints of cognitive problems or moodstate abnormalities, we cannot rule out such arelationship. A stronger relation might havebeen found had we conducted the survey andthe medical assessments concurrently. On theother hand, abnormal physical findings areunusual, routine laboratory tests are typicallynormal, and immunoglobulin levels and viralantibody titres have proved to be remarkablystable over periods of a year or longer in thissyndrome.2 It is entirely possible that moresophisticated immunological or neuroen-docrine tests-for example, not conductedhere, would show variation in accord with thesymptoms, although objective markers of dis-ease severity, such as these, have yet to beidentified and confirmed.33 34

CFS patients complain consistently ofconcentration and memory problems,particularly memory for recently presentedinformation.'429 For example, some patientsreport severe impairment when required todescribe a film or television show previouslyviewed, when recalling conversations fromearlier in the day, remembering appoint-ments, or recognising the faces of peoplerecently introduced to them. This level ofseverity of memory deficits is typical ofpatients who have suffered a moderate closedhead injury. There has been only one otherpublished peer reviewed neuropsychologicalstudy of CFS that has used a wide range ofobjective tests to assess the degree of memoryimpairment as reported by CFS patients inour pilot study35 (but also see the studies byAltay and Smith3637). The results of thosestudies were similar to ours and the authorsdescribed their patients as demonstrating adiscrete deterioration of short-term mem-ory.5 While the results of our study indicatethat CFS patients experience some impair-ment on selective measures of memory; theseverity of this impairment is relatively mildand inconsistent with the severity of com-plaints on the self report survey. We areunable to identify the cause(s) of the mildmemory deficit at present.

Both infections and depression may causea decrease in cognitive effort.'8'9 Such adecrease in effort can affect the encoding andrecall of new information. Thus, memoryproblems that result from infection and theinflammatory responses to it could be exacer-bated by a concurrent depression.40The findings in this study reinforce the

importance of formally testing the memoryand mood state symptoms in patients withCFS, since these will be among their mostprominent complaints. The fact that thesesymptoms and deficits appear grossly inde-pendent of routine indices of illness severityand fatigue41 42 and, at least in the pilot surveyconducted here, are highly intercorrelated,further complicates the diagnostic examina-tion of CFS patients and of illuminating thepathogenesis of CFS.13 43-46

Regardless of the basis for the cognitiveand emotional complaints and mild memory

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impairment in CFS patients, these symptomscause considerable distress.'9 With the back-ground provided by this study and a recentlycompleted parallel study of selective attentionin CFS, in which patients were shown to havenormal visual attentional processes butslowed response execution,47 we have devel-oped a more focused testing protocol forcontinued prospective and objective measure-ment of neuropsychological complaints inCS48 49CFS.4 9

1 Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatiguesyndrome: a working case definition. Ann Intern Med1988;108:387-9.

2 Straus SE, et al. Acyclovir treatment of the chronic fatiguesyndrome: lack of efficacy in a placebo-controlled trial.N EnglJMed 1988;319:1692-8.

3 Gold D, Bowden R, Sixbey J, et al. Chronic fatigue: aprospective clinical and virologic study. JAMA 1990;264:48-53.

4 Gosling FG. Before Freud: neuroasthenia and the AmericanMedical Community, 1870-1910. Urbana, Illinois:University of Illinois Press, 1987.

5 Abbey SE, Garfinkel PE. Neurasthenia and chronicfatigue syndrome: the role of culture in the making of adiagnosis. Am _J Psychiatry 1991;148:1638-46.

6 Mechanic D. Social psychologic factors affecting the pre-sentation of bodily complaints. N Engl Jf Med 1972;286:1132-9.

7 Hickie I, Lloyd A, Wakefield D, et al. The psychiatric sta-tus of patients with the chronic fatigue syndrome. Br JPsychiatry 1990;156:534-40.

8 Manu P, Lane TJ, Matthews DA. The frequency ofchronic fatigue syndrome in patients with symptoms ofpersistent fatigue. Ann Intern Med 1988;109:554-6.

9 Abbey SE, Garfinkel PE. Chronic fatigue syndrome andthe psychiatrist. Can 7 Psychiatry 1990;35:625-33.

10 Cohen S, Williamson GM. Stress and infectious disease.Psychol Bull 1991;109:5-24.

11 Cohen S, Tyrrell DAJ, Smith AP. Psychological stress andsusceptibility to the common cold. N Engl Jf Med1991;325:606-12.

12 Kranzler HR, Manu P, Hesselbrock V, et al. Substanceuse disorders in patients with chronic fatigue. HospComm Psychiatry 1991;42:924-8.

13 Wessely S. Chronic fatigue syndrome. _J Neurol NeurosurgPsychiatry 1991;54:669-71.

14 Straus S. The chronic mononucleosis syndrome. Jf InfectDis 1988;157:405-12.

15 Edelstein H, Knight RT. Epstein-Barr virus causingencephalitis in an elderly woman. SMJ 1989;82: 1192-3.

16 Ray C. Chronic fatigue syndrome and depression: concep-tual and methodological ambiguities. Psychol Med199 1;21: 1-9.

17 Powell R, Dolan R, Wessely S. Attributions and self-esteem in depression and chronic fatigue syndrome.7 Psychosom Res 1990;34:665-73.

18 Yabuki S, Kazahaya Y, Kubonishi I. Epstein-Barr virusantibodies in neurological diseases. Folia PsychiatryNeurolJap 1985;39:85-93.

19 Grafman J, Johnson RJ, Scheffers M. Cognitive andmood-state changes in patients with chronic fatigue syn-drome. Rev Infect Dis 1991;13(Suppl 1):S45-52.

20 Bennett-Levy J, Powell GE. The subjective memory ques-tionnaire (SMQ): an investigation into the self-reportingof real-life memory skills. Br J Soc Clin Psychol 1980;19:177-88.

21 Lezak M. Neuropsychological assessment. 2nd ed. NewYork: Oxford University Press, 1983.

22 Grafman J, Weingarmner H, Newhouse P, et al. Implicitlearning in patients with Alzheimer's disease.Pharmacopsychiatry 1990;23:94-101.

23 Grafman J, Litvan I, Massaquoi S, et al. Cognitiveplanning deficit in patients with cerebellar atrophy.

Neurology 1992;42:1493-6.24 Grafman J, Rao S, Bemardin L, et al. Automatic memory

processes in patients with multiple sclerosis. Arch Neurol199 1;48:1072-5.

25 Beck AT. Beck depression inventory: Manual. San Antonio,Texas: Psychological Corporation, 1987.

26 Holland R. Chronic fatigue syndrome. Can Med Ass J1989;141:375.

27 Holmes GP, Kaplan JE, Stewart JA, et al. A cluster ofpatients with a chronic mononucleosis-like syndrome:is Epstein-Barr virus the cause? JAMA 1987;257:2297-302.

28 Katz BZ, Andiman WA. Chronic fatigue syndrome.J Pediatr 1988;113:944-7.

29 Straus SE, Tosato G, Armstrong G, et al. Persisting illnessand fatigue in adults with evidence of Epstein-Barr virusinfection. Ann Intern Med 1985;102:7-16.

30 Jones JF, Ray CG, Minnich LL, et al. Evidence of activeEpstein-Barr virus infection in patients with persistent,unexplained illnesses: elevated anti-early antigen anti-bodies. Ann Intern Med 1985;102:1-7.

31 Wells KB, et al. Detection of depressive disorder forpatients receiving prepaid or fee-for-service care: resultsfrom the medical outcomes study. JAMA, 1989;262:3298-302.

32 Kreusi MJP, Dale J, Straus SE. Psychiatric diagnoses inpatients who have chronic fatigue syndrome. J ClinPsychiatr 1989;50:53-6.

33 Klimas NG, Salvato FR, Morgan R, et al. Immunologicabnormalities in chronic fatigue syndrome. Y ClinMicrobiol 1990;28:1403-10.

34 Demitrack MA, Dale JK, Straus SE, et al. Evidence forimpaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome.J Clin Endocrin Metabol 199 1;73:1224-34.

35 Riccio M, Thompson C, Wilson B, et al. Neuro-psychological and psychiatric abnormalities in myalgicencephalomyelitis: a preliminary report. Br Y ClinPsychol 1992;31:111-20.

36 Altay HT, Abbey SE, Toner BB, et al. The neuropsycho-logical dimensions of postinfectious neuromyasthenia(chronic fatigue syndrome): a preliminary report. Int YPsychiatry Med 1990;20:141-9.

37 Smith A. Cognitive changes in myalgic encephalomyelitis.In: Jenkins R, Mowbray JF, eds. Post-viral fatigue syn-drome. New York: Wiley, 1991: 179-94.

38 Smith AP, Tyrrell DAJ, Al-Nalib W, et al. Effects andafter-effects of the common cold and influenza onhuman performance. Neuropsychobiology 1989;21:90-3.

39 Weingartner H, Silberman E. Cognitive changes indepression. In: Post R, Ballenger J, eds. Neurobiology ofmood disorders. Baltimore: Williams and Wilkins, 1987.

40 Blakely AA, Howard RC, Sosich RM, et al. Psychiatricsymptoms, personality, and ways of coping in chronicfatigue syndrome. Psychol Med 1991;21:347-62.

41 Monks J. Experiencing symptoms in chronic illness:fatigue in multiple sclerosis. Int Disabil Studies 1989;11:78-83.

42 White PD. Fatigue and chronic fatigue syndromes. In:Bass CM, ed. Somatization: physical symptoms andpsychological illness. London: Blackwell ScientificPublications, 1990:104-40.

43 Imboden JB, Canter A, Leighton EC. Convalescence fromInfluenza. Arch Intern Med 1961;108:393-9.

44 Cluff LE. Medical aspects of delayed convalescence. RevInfect Dis 1991;13(Suppl 1):S138-40.

45 Kasl SV, Evans AS, Niederman JC. Psychosocial risk fac-tors in the development of infectious mononucleosis.Psychosom Med 1979;41:445-66.

46 Kiecolt-Glaser JK, Kennedy S, Malkoff S, et al. Maritaldiscord and immunity in males. Psychosom Med 1988;50:213-29.

47 Scheffers M, Johson Jr R, Grafman J, et al. Attention andshort-term memory in chronic fatigue syndromepatients: an event-related potential analysis. Neurology[in press].

48 Schluederberg A, Straus SE, Grufferman S. Considera-tions in the design of studies of chronic fatigue syn-drome. RID 1991;13(Suppl 1):S1-S140.

49 Sharpe MC, Archard LC, Banatvala JE, et al. A report-chronic fatigue syndrome: guidelines for research. J RSoc Med 1991;84:118-21.

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