50ournal ofNeurology, Neurosurgery, and Psychiatry 1996;60:504-509

Chronic fatigue and minor psychiatric morbidityafter viral meningitis: a controlled study

Matthew Hotopf, Norman Noah, Simon Wessely

Institute of Psychiatry,Denmark Hill,London, UKM HotopfS WesselyKing's College SchoolofMedicine andDentistry, London, UKN NoahS WesselyCorrespondence to:Dr M Hotopf, Departmentof Psychological Medicine,Institute of Psychiatry, 103Denmark Hill, London, SE58AZ, UK.

Received 31 January 1995and in final revised from1 September 1995Accepted 4 September 1995

AbstractObjective-To test the hypotheses thatpatients exposed to viral meningitis wouldbe at an increased risk of developingchronic fatigue syndrome and would havean excess of neurological symptoms andphysical impairment.Methods-Eighty three patients were fol-lowed up 6-24 months after viral meningi-tis and a postal questionnaire was used tocompare outcome with 76 controls whohad had non-enteroviral, non-CNS viralinfections.Results-For the 159 patients and con-trols the prevalence of chronic fatiguesyndrome was 12-6%, a rate higher thanpreviously reported from primary careattenders, suggesting that moderate tosevere viral infections may play a part inthe aetiology ofsome fatigue states. Thosewith a history of meningitis showed aslight, non-significant increase in preva-lence of chronic fatigue syndrome (OR1-4; 95% CI 0.5-3.6) which disappearedwhen logistic regression analysis was usedto correct for age, sex, and duration offollow up (OR 1-0; 95% CI 0 3-2 8).Controls showed marginally higher psy-chiatric morbidity measured on the gen-eral health questionnaire-12 (adjusted OR0-6; 95% CI 0-3-1.3). Both groups hadsimilar rates of neurological symptomsand physical impairment. The best pre-dictor of chronic fatigue was a prolongedduration of time off work after the illness(OR 4-93, 95% CI 1-3-18-8). The best pre-dictor of severe chronic fatigue syndromediagnosed by Center for Disease Controlcriteria was past psychiatric illness (OR7-82, 95% CI 1-8-34.3). Duration of viralillness, as defined by days in hospital, didnot predict chronic fatigue syndrome.Conclusions-(l) The prevalence ofchronic fatigue syndrome is higher thanexpected for the range of viral illnessesexamined; (2) enteroviral infection isunlikely to be a specific risk factor for itsdevelopment; (3) onset of chronic fatiguesyndrome after a viral infection is pre-dicted by psychiatric morbidity and pro-longed convalescence, rather than by theseverity of the viral illness itself.

(J Neurol Neurosurg Psychiatry 1 996;60:504-509)

Keywords: chronic fatigue syndrome; viral meningitis;psychiatric morbidity

Viral meningitis is usually considered to be abenign illness. It is most commonly causednow by enteroviruses, as mumps hasdecreased in incidence.' Enteroviral infectionhas been suggested as a cause of fatigue andchronic fatigue syndrome, sometimes calledpostviral fatigue syndrome or myalgicencephalomyelitis (ME). A range of serologicaland viral markers of infection in patients hasbeen examined in case-control studies. Earlyresults suggested a relation between thesemarkers of infection and current symptoms.2 7These studies have been criticised8 for theiruse of inappropriate control groups, and selec-tion and ascertainment biases. More recentstudies, which have overcome these method-ological problems, suggest that the relation isless compelling than previously thought,9 '3although one well conducted study found evi-dence for a relation.'4One problem is the difficulty of defining

exposure given the frequency of enteroviralinfections in the community. We hypothesisedthat if enteroviral infection is a true risk factorfor chronic fatigue syndrome, then this effectwill be strongest in a sample of patientsexposed to enteroviral infection of the CNS.Patients with viral meningitis represent such asample: in the United Kingdom enterovirusesare the commonest cause of viral meningitis.'5If enteroviruses cause chronic fatigue syn-drome we would expect patients recoveringfrom viral meningitis to be at increased risk ofabnormal fatigue. Viral meningitis is also saidto be benign and without neurological seque-lae and this was also examined in this study.

There are two large studies that followed uppatients with viral meningitis. Lepow et all6 inan uncontrolled study found that two thirds ofpatients were at risk of fatigue, headaches, andclumsiness three months after the illness, butthe impression was of recovery at one year,although follow up was incomplete. Muller etal'7 traced 238 patients with aseptic meningitisand followed them up for two to 12 years.They could detect no difference between theirmental health and that of healthy controls.These two studies did not aim to examinepatients specifically for fatigue; nor did theyuse standardised assessments of symptoms.The aims of this study were: (a) to examine

whether patients with viral meningitis are atgreater risk of subsequent chronic fatigue syn-drome, psychiatric morbidity, and neurologi-cal complications than a control group ofpatients who had non-enteroviral, non-CNS,viral illnesses; (b) to attempt to find predictorsof fatigue and psychological symptoms.

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MethodsCASE SELECTIONCases were identified from four virology labo-ratories and from the records of a hospital spe-cialising in infectious diseases. Theserepresented a mix of urban and rural popula-tions. In the virology laboratories records ofsamples of CSF in the routine day books over

the previous two years (July 1 99 1-June 1993)were used to identify patients, whose hospitalcase notes were then obtained and examined.For cases at the infectious diseases hospital thedisease cards (which document by diseaseeach admission to the hospital) were used toidentify cases of viral meningitis and the rele-vant case notes were then checked.

In all cases the following inclusion criteriawere met: age 16-65; a clinical diagnosis ofacute onset meningitis (characterised bypyrexia, headache, photophobia, and neckstiffness) leading to admission to hospital;spontaneous resolution of symptoms; evidenceof lymphocytic meningitis as defined by lym-phocytes in the CSF (> 8 per cm3). Caseswere excluded if there was any evidence of a

bacterial or other non-viral cause of themeningitis from microscopy and culture of theCSF. Further exclusion criteria included seri-ous medical illnesses, which would be a poten-tial cause of fatigue, and patients with a historyof psychosis, substance misuse, or eating dis-order. Other psychiatric disorders were notexcluded. Cases with illness that had appearedin the context of recent travel outside Europeand North America were also excluded.Finally, cases were excluded if there was a

clinical suspicion or definite confirmation ofHIV infection.

CONTROL SELECTION

Controls were identified from one virologylaboratory and the infectious diseases hospital.Those identified from the laboratory were

proved cases of self limiting viral infectionswhich the laboratory had identified from sam-ples other than chronic fatigue syndrome.From this information hospital casenotes or

general practice records were examined.Controls were identified from the infectiousdiseases hospital using the disease cards andcasenotes. Inclusion criteria were of self limit-ing viral illness which had led to admission tohospital or consultation with a general practi-tioner in the past two years in patients aged16-65 years. Exclusion criteria were as for thepatients. Viral illnesses characterised by persis-tent pathology-such as hepatitis B, enterovi-

Table 1 Definition offatigue states

Chronic fatigue syndrome Chronic fatigue syndrome +Chronic fatigue (Green College) (CDC)

* Score > 4 on fatigue * As for chronic fatigue * As for chronic fatiguequestionnaire syndrome

Plus Plus* Present > 6 months *Present 50% of the time *Four of the following* No medical illness or major *Causes functional impairment symptoms: new headache;mental illness to explain fatigue *Both mental and physical post exertional malaise;

symptoms of fatigue memory/concentrationdifficulties myalgia; sorethroat; lymphadenopathy;polyarthralgia, andunrefreshing sleep

ral infections, and infectious mononucleosis(which has been shown to be a risk factor forfatigue'8) were also excluded. Controls withany evidence of "meningism" (nuchal rigidityand photophobia) or a history of lumbar punc-ture during the acute illness were excluded.

CASE NOTE INFORMATIONFor all subjects, case notes or hospital dis-charge summaries were examined to gatherbaseline sociodemographic information anddetails regarding current and past physical andpsychiatric illness. Information on the natureof the illness leading to admission to hospitalwas also collected on a checklist of symptomsand signs. Investigations performed in hospitalwere recorded as well as any information onthe clinical state of the patient at discharge.

POSTAL SURVEYA questionnaire was designed to elicit sociode-mographic details and information regardingmedical and psychiatric history and serviceuse. Current psychiatric health was measuredusing the general health questionnaire- 12(GHQ-12)19 and the Beck depression inven-tory.20 Fatigue was measured on a validatedquestionnaire used in several studies ofchronic fatigue and chronic fatigue syn-drome.21 Somatic symptoms were identifiedon a checklist of 32 symptoms. Finally, func-tional impairment and quality of life wereassessed on the medical outcome survey shortform (SF-36) scored according to predeter-mined thresholds.22 Table 1 gives the defini-tions of the different fatigue syndromes.Chronic fatigue syndrome is defined accordingto the Green College criteria23 or to the Centerfor Disease Control (CDC) criteria (chronicfatigue syndrome +).24

ResultsOf 255 eligible patients, 159 (62%)responded. Of the remainder, 49 had changedaddress and could not be traced. If these wereremoved from the sample the response ratewas 77%. The remaining non-responderseither failed to return a questionnaire despitereminders or retumed the questionnaireuncompleted. There were no differencesbetween responders and non-responders interms of age and sex. A similar proportion ofpersons in each group responded. Of theresponders, there were 76 controls and 83patients. Table 2 gives a description of thediagnoses of control subjects.

Table 2 Diagnoses for the 76 controls

Diagnosis No (%)

Hepatitis A 25 (32-8)Epstein-Barr virus hepatitis 2 (2 6%)Adenovirus 6 (7-9)Measles 1 (13)Chickenpox 20 (26 3)Influenza 4 (5-3)Unknown: URTI 13 (17 1)Unknown: rash 2 (2-6)Unknown: gastroenteritis 2 (2 6)

URTI = upper respiratory tract infection.

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DEMOGRAPHIC CHARACTERISTICSThere were no significant differences betweenthose exposed to viral meningitis and controlsin terms of age (32 v 31 years), home owner-

ship (56% v 51% own home), duration of stayin hospital (5 9 days v 4 9 days), and maritalstatus (55% v 45% married or cohabiting).Cases of viral meningitis were more likely tobe female (64% v 46%, x = 5-08, ldf, P =0 02), and to have taken more time off workafter the illness (49 days v 30 days, U = 2115,z = -2-13, P = 0 03 (Mann-Whitney U test)).The duration of follow up was also longer inpatients who were followed up for a mean of18 months compared with 13 for the controls(U= 1965, z = -4 00, P = 0.0001). The dura-tion of follow up and sex differences are likelyto confound the results of other outcome vari-ables. Nine of the control subjects were notadmitted to hospital but were treated by theirgeneral practitioner.

OUTCOME VARIABLESFatigue and psychiatric outcomeTable 3 shows the outcome for cases and con-

trols. Cases of viral meningitis were not atincreased risk of chronic fatigue, chronicfatigue syndrome, or chronic fatigue syndrome+. There was no increase in risk of depressionas measured by the BDI, or emotional distresson the GHQ-12. To control for the potentialconfounding variables of age, sex, and dura-tion of follow up, a forced entry logistic regres-sion analysis was performed. Again no

differences could be detected in outcomebetween cases and controls. These outcomeswere no different if the controls who had notbeen admitted to hospital were excluded fromthe analysis.

Physical symptoms and impairmentsCases and controls did not differ in their score

on the checklist of 32 possible symptoms(mean number for cases 7 4 and 9 0 for con-trols, t = 1 10, 154 df, P = 0 27). To assesswhether the cases were at greater risk of neu-

rological symptoms total scores on the eightneurological symptoms (headaches, tremor,tingling in the arms and tingling in the legs,double vision, light headedness, increased sen-

sitivity to noise, and increased sensitivity tolight) were compared. Again no excess ofsymptomatology was found (1 *8 v 2- 1 neuro-

logical symptoms for cases and controlsrespectively: t = 1-41, 155 df, P = 0-16).Impairment measured on the six subscales ofthe SF-36 showed no differences betweencases and controls in any area of functioning(table 4). This finding was not changed whenodds ratios were adjusted for age, sex, andduration of follow up using logistic regressionanalysis.

FACTORS PREDICTIVE OF CHRONIC FATIGUE,CHRONIC FATIGUE SYNDROME, AND CHRONICFATIGUE SYNDROME +We went on to examine the features of thosewe identified with chronic fatigue, chronicfatigue syndrome, and chronic fatigue syn-drome +. These three conditions representgradations of severity along the range offatigue so it is not surprising that there weremore cases of chronic fatigue (36) than ofchronic fatigue syndrome (20) and chronicfatigue syndrome + (11). For all three diag-noses there were no differences between casesand healthy controls in terms of age, sex distri-bution, duration of follow up, or duration ofstay in hospital. Table 5 summarises the maindifferences between those with chronic fatiguesyndrome and those who were well at followup. These results are similar for chronicfatigue and chronicMore cases had used

fatigue syndrome +.services for emotional

Table 3 Outcome for cases of viral meningitis and other viral illness controls

Cases Controls 95% CIfor(n = 83) (n = 76) X2 Pvalue OR 95% CI adj OR adj OR

Chronic fatigue 21 15 0-62 0-43 1-35 0-6-2-9 1 13 0-5-2-6(25%) (20%)

Chronic fatigue syndrome 12 8 0 47 0-49 1-39 0-5-3-6 0-96 0-3-2-8(14%) (10%)

Chronic fatigue syndrome + 8 3 1 93 0-16 2-55 0-6-10-0 1-78 0-4-8-0(10%) (4%)

Case on GHQ 39 37 0-15 0-15 0-88 0-4-1-6 0-64 0-31-1-34(3/4) (48%) (51%)

Case on BDI 11 17 2-82 0 09 0-49 0-4-2 3 0-78 0-14-1 01(12/13) (13%) (24%)

OR = Odds ratio; adj OR = adjusted odds ratio.

Table 4 Impairment on SF-36 atfollow up

Cases Control 95% CIfor(n = 83) (n = 76) X2 P value OR 95% CI adj OR adj OR

Psychological 31 30 0-17 0-67 0 87 0-5-1-7 0 79 0 4-1 7impairment (38%) (41%)

Pain 24 20 0-04 0-83 1-08 0-5-2-2 1-02 0-5-2-2(29%) (28%)

Perception of illness 43 39 0-02 0-88 0 95 0-5-1-8 1 20 0-6-2-5(54%) (55%)

Physical impairment 45 41 0-06 0 79 0-92 0-1-1-7 1-14 0-5-2-4(55%) (57%)

Role 21 15 0-48 049 1-31 0-6-2-8 1-68 0-7-40fumction (26%) (21%)

impairmentSocial impairment 4 9 2-7 0-1 0 37 0-1-1-3 0-28 0 1-1 1

(5%) (11%)OR = Odds ratio; adj OR = adjusted odds ratio.

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Table 5 Characteristics ofpatients with chronic fatigue syndrome

Chronic Non-chronicfatigue fatiguesyndrome syndrome(n = 20) (n = 139) Statistic P value OR (95% CI)

Age (y (SD)) 34-1 (11 1) 31-8 (10-4) *z = - 0-76 0 44Females (%) 13 (65) 74 (54) X2 = 0-85 0-36 1-58

1 df (0-6-4 2)Duration of stayin hospital 5-4 (3 5) 5-4 (5-1) *z = -0 5 0-64

(days (SD))Time taken off work (days 62-6 (99-1) 37-3 (63 4) *z = - 1 42 0-15

(SD))Duration offollowup 172 (6-3) 15-5 (7-7) *z= - 114 0-25

(months (SD))Psychiatrichistory(%) 11 (55) 29 (21) X2 = 10 5 0-001 3 05

1 df (1 2-8-1)Depression on BDI (%) 9 (35) 20 (13) X2= 7-24 0 007 3-77

1 df (14-10 4)Distress on GHQ-12 (%) 16 (80) 60 (44) x2 = 8-81 0 003 5 00

1 df (16-157)

*Mann-Whitney U test.

Table 6 Adjusted odds ratios after logistic regression analysis to accountfor potential confounding variables, age, sex,and duration offollow up

Chronic fatigue Chronic fatigueChronic fatigue syndrome syndrome +

Psychiatric history P = 0-55 P = 0-02 P = 0 006OR = 1-33 OR = 3-58 OR = 7-82(0-5-3 4) (1-2-10-6) (1-8-34 3)

Prolonged convalescence P = 0-002 P = 0-02 P = 0 12OR = 4-85 OR = 4-93 OR = 3-8(1-8-11 7) (1-3-18 8) (0-7-20 9)

Values in parentheses are 95% CI.

problems and this relation became stronger asthe severity of fatigue increased. Those withchronic fatigue and chronic fatigue syndromehad had a longer convalescence than thosewithout fatigue states, but this difference didnot maintain statistical significance in thosewith chronic fatigue syndrome +. Finally,those with fatigue states were more likely to bein psychological distress as measured on theGHQ-12 and to have depression as measuredon the BDI.

LOGISTIC REGRESSIONTo disentangle the potentially confoundingvariables of sex, duration of follow up, age,previous service use for emotional problems,and prolonged time offwork after viral illness, aforced entry logistic regression analysis wasperformed. Prolonged time off work wascoded as above and below median (21 days)taken off work after the viral illness. Thisallowed odds ratios (ORs) for the risk offatigue states if an individual had had a psychi-atric history or prolonged convalescence.Psychiatric history was no longer a statisticallysignificant association with chronic fatigue,but was associated with chronic fatigue syn-drome and chronic fatigue syndrome +.Prolonged convalescence was associated withchronic fatigue and chronic fatigue syndrome.Table 6 shows the adjusted ORs for these riskfactors.

DiscussionThere were three main findings in this study.Firstly, there were no statistically significantdifferences in outcome between the group whohad viral meningitis compared with other viralinfections. This suggests that there is little to

support enterovirus infection as a specific riskfactor for chronic fatigue syndrome. Secondly,the prevalence of chronic fatigue syndrome forthe sample as a whole was considerably higherthan that seen in primary care samples.Thirdly, the variables which best predictchronic fatigue syndrome at follow up are pre-vious psychiatric morbidity and a prolongedconvalescence.

These findings must be interpreted withcare. This was a postal survey and a responserate of 77% leaves the results open to responsebias, although no differences between respon-ders and non-responders could be identified.The sample sizes used limit the statisticalpower of this study, and it is possible thatsmall but significant differences between thetwo groups could have been missed. The rarityof adult viral meningitis makes it expensiveand impractical to perform large scaleprospective studies except after an epidemic.

There are also demographic differencesbetween the two groups. There was an excessof women among the cases. We would haveexpected a higher rate of psychiatric disorderand fatigue among women so this potentialconfounder is likely to push the results towarda positive finding (an excess of fatigue amongthose exposed to viral meningitis). The othermain difference was that the duration of followup was longer in the viral meningitis group.This potential confounder should work in theopposite direction-that is, to increase the levelof morbidity among the controls, who wouldbe at an earlier stage of their convalescence.Our analyses suggest that these potential con-founders are not powerful-there was noexcess of fatigue among the female respondersand the cases of fatigue identified were at asimilar stage in their convalescence to those

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who were well. When these potential con-founders were adjusted for by logistic regres-sion analysis the lack of association betweenviral meningitis and subsequent fatigueremained.The morbidity in the group as a whole was

high. The prevalence of chronic fatigue syn-drome was higher than that of previous sur-veys using the same instruments in primarycare. For example, Wessely et aP1 found that9 9% and 1*3% of patients presenting to pri-mary care with any viral infection had chronicfatigue or chronic fatigue syndrome respec-tively when followed up for six months afterinfection. These rates did not differ from thosein the comparison group of patients presentingin primary care for other reasons. Our esti-mates for chronic fatigue syndrome (12-6%)were considerably higher and we will examinepossible reasons for this finding.

It may be that all the viral illnesses studiedact directly to cause chronic fatigue syndrome.For example, there is now some evidence thathepatitis A may cause chronic fatigue.26Unfortunately, without a control group admit-ted to hospital for non-viral illness it is impos-sible to test this hypothesis. However, thereare two findings which are against this view:(1) there was no relation between the durationof initial admission to hospital, which may beused as a proxy measure of severity andfatigue; and (2) there was no relation betweenduration of follow up and fatigue. If exposureto severe viral infection on its own was respon-sible for these high rates of fatigue, those whowere early in their convalescence would beexpected to be most severely affected.The increased rates of chronic fatigue and

chronic fatigue syndrome could have been dueto bias. With a response rate of 77%, responsebias is not a sufficient explanation, but mayplay a part, because those with fatigue may bemore inclined to respond. Selection bias is analternative explanation: the processes whichled to admission of these patients to hospitalmay have contributed to their increased preva-lence of chronic fatigue syndrome on followup. Most patients with a viral infection are notadmitted to hospital. This would apply to theinfections seen among controls-for example,influenza and chickenpox. No studies areavailable on the admission rates for viralmeningitis; however, there are degrees ofseverity for the illness, ranging from asympto-matic cases to the full syndrome of meningi-tis'5 and it is reasonable to suppose that aproportion of patients with viral meningitis donot consult or are not diagnosed as such.There is some support for this explanationfrom a prospective study of consulting behav-iour after influenza infection.27 The attack ratefor clinically evident infection with Asianinfluenza in the 1957 pandemic was increasedalmost threefold in high scorers on theMinnesota multiphasic personality inventory.This increase applied to clinically evident ill-ness, not actual disease, as shown by a rise inantibody titres. This explanation is unlikely tofully account for the rates of chronic fatiguesyndrome that we detected.

Assuming that the result of high levels ofchronic fatigue syndrome are not due to biasor confounding, it is necessary to construct amodel to bring our other findings together.Previous service use for emotional disorderand a prolonged period of time off work afterthe viral illness were associated with chronicfatigue syndrome. These variables are notindependent. Logistic regression analysisshowed that prolonged convalescence was apredictor for chronic fatigue and chronicfatigue syndrome. A history of previous con-sultation for psychiatric disorder predictedchronic fatigue syndrome and chronic fatiguesyndrome +.The finding that prolonged convalescence is

a risk factor for chronic fatigue syndromecould be interpreted in two ways. Firstly, thosewho had a more serious viral illness would bemore likely both to have a longer time off workand be more prone to chronic fatigue syn-drome. This explanation must be balancedagainst the finding that the duration of stay inhospital, which is predominantly a doctor ledassessment of severity, is no greater in thosewho later developed chronic fatigue syndrome.Secondly, duration of time off work is a mea-sure of the patient's assessment of his or hersymptoms and is more sensitive to thepatient's illness behaviour, which may in turnbe associated with chronic fatigue syndrome.

Could a better understanding of the patho-genesis of fatigue be gleaned from these find-ings? Prolonged time off work after a viralinfection may be the principle mechanism offatigue. Previous studies have found that bedrest or prolonged convalescence is a predictorof fatigue and subjective symptoms in infec-tious mononucleosis'8 28 and postvaccinial (yel-low fever) illness.29 Further, there is evidenceto suggest that poor prognosis in establishedchronic fatigue syndrome may relate to limit-ing exercise and changing or leaving employ-ment.30 The deconditioning caused by suchchanges may be responsible for fatigue.The relation between psychiatric morbidity

and chronic fatigue syndrome is well estab-lished8 and in a prospective study one of themost powerful predictors of chronic fatigueand chronic fatigue syndrome after a viralinfection was a high score on the GHQ-12.25Psychiatric morbidity is also an indicator ofpoor prognosis of chronic fatigue syn-drome.3' 33 There is good evidence that psychi-atric morbidity is an important determinant offunctional recovery from other illnesses forexample, recovery after myocardial infarction34and back pain.35 Previous psychiatric morbid-ity might be a risk factor by leading to pro-longed convalescence, or alternatively may actdirectly due to the considerable overlapbetween depression, anxiety, and fatigue.

Subsequent research should aim to com-pare recovery from a range of infectious andnon-infectious physical illnesses with prospec-tive information on psychiatric morbidity andchanges in behaviour after acute illnesses. Inthis way it may be possible to predict those atrisk of a poor outcome after physical illness,and to plan early interventions.

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MH was supported by a grant from the Wellcome Trust. Wethank Professor Banatvala, Dr F Nicholson, ProfessorCarmichael, Dr S Sutherland, and Dr B Bannister for theiradvice and assistance in identifying subjects.

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