Journal of Infection (x99I) z3, 263-269
B i o p s y c h o s o c i a l aspects o f c h r o n i c fatigue s y n d r o m e (myalgic encephalomyelitis) J. D. I. Yeomans* and S. P. Conwayt * Department of Psychiatry, Roundhay Wing, St James's University Hospital, Beckett St, Leeds LS9 7 TF and t Department of Infectious Diseases, Seacroft Hospital, York Road, Leeds LSI4 6UH, U.K. Accepted for publication 28 May I99I Summary Fifteen patients, with a primary complaint of chronic fatigue, were referred to a physician by their general practitioners. Psychological distress, measured by simple psychiatric rating scales was common, but specific psychiatric diagnoses, derived from a comprehensive diagnostic interview, occurred less frequently. One questionnaire (Montgomery-Asberg depression rating scale) found emotional distress in 93 %, but the diagnostic instrument (Present State Examination) suggested depressive syndromes in only two patients (I3 %). There were significant occupational difficulties in 87 %. No consistently abnormal indices of biochemical or immunological function were found, nor evidence of acute or chronic infection. Chronic fatigue syndrome (CFS) is associated with physical, psychological and social distress. The illness cannot be defined using just one of these dimensions. Such a unilateral approach has resulted in unnecessary controversy over the nature of the 'real' core of CFS. A problemoriented approach, recognising the multi-factorial and overlapping cause and effect issues in CFS, may be of more benefit to patients.
Introduction Chronic fatigue syndrome (CFS), also known as post-infectious fatigue syndrome and myalgic encephalomyelitis, is characterised by severe generalised fatigue, easy fatigability, muscle weakness, myalgia and emotional and cognitive changes. T h e pathogenesis of this illness is unknown, but recent studies have implicated Epstein-Barr virus infection, 1' 2 persistent infection by enteroviruses such as Coxsackie B viruses a'4 and immunological defects. 5-8 Other studies have implicated psychiatric conditions. 9'1° T h e r e has been particular emphasis on the prevalence of depressive illnesses, although anxiety states also occur. 1~-1~ Kendell ~4 has recently commented on the overlap between CFS and psychiatric disorders. This overlap exists between many disorders often thought of as either predominantly psychological or physical. For example, he noted that both depression and myocardial infarction may be precipitated by stressful events and that depression is associated with immunological change. He concluded that no fundamental distinction could be drawn between depression and other kinds of 'organic' illness. David et al., ~5 argued for greater sensitivity in the appreciation of how social factors influence the presentation and outcome of fatiguing illnesses. T h e authors of both these papers implied that traditional concepts of disease classification may create an unnecessary barrier to the understanding of CFS, and presented oi63-4453/9I/o6o263 +o7 $03.00/o
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the case for a balanced approach acknowledging the interaction of physical, psychological and social factors. T h e lack of a case definition for C F S limited early research into the condition. In I988, the Centers for Disease Control in Atlanta proposed an operational definition for C F S ~6 which excluded patients with chronic psychiatric diseases. This made it impossible to use in an assessment of psychiatric morbidity. A small modification, subsequently proposed by some of its original authors, ~7 allowed the inclusion of such patients and brought the criteria for C F S into line with those of a British working party at Green College, O x f o r d ) 8 In contrast to the efforts made to define CFS, there has been less emphasis on the importance of defining the psychiatric syndromes which are thought to overlap it. In particular, little attention has been paid to the level of definition. Standard operational criteria for depression such as those of the American psychiatric classification system, D S M - I I I - R f l 9 have been suggested as appropriate, is However, under this system, a miserable person who manages to work despite poor concentration and lack of sleep may receive the same diagnosis of 'major depressive episode' as someone confined to hospital tormented by guilt and suicidal desires. This is too broad a category to use in a non-psychiatric setting without an accompanying indication of severity. Psychiatric case definition is central to a psychiatrist's work and deserves careful attention in discussions of C F S with medical colleagues. Aims
This study aimed to investigate biological, psychiatric and occupational status in patients who had been selected by virtue of their referral to an infectious diseases clinic by general practitioners. It was hoped that this would avoid selection biases favouring the presence of psychiatric illness as might occur with selection by self-referral, specialised fatigue clinics or specialised tertiary referral centres. 1~'~ Method
Details of I5 consecutive fatigued patients were obtained from the out-patient clinic of a consultant physician specialising in infectious disease. Patients were referred by their general practitioners because of a history suggesting postinfectious fatigue, chronic fatigue or myalgic encephalomyelitis. Medical assessment comprised history, examination and the following investigations: full blood count, plasma viscosity, urea and electrolytes, liver and thyroid function tests, I g G I, 2, 3 and 4, IgA, IgM, serological testing for infections with Epstein-Barr virus (EBV), Toxoplasma, Brucella, Coxsackie B viruses I-6, Influenza viruses A and B, Adenovirus, Chlamydia, Coxiella, Mycoplasma, Respiratory Syncytial Virus, and Cytomegalovirus, B-ceU and T-cell n u m b e r s and helper suppressor T-cell ratio. Psychiatric assessment included two standardised questionnaires: the Hospital Anxiety and Depression Scale (HAD), 2° and the M o n t g o m e r y - A s b e r g Depression Rating Scale (MADRS), 21 and a diagnostic interview, the Present State Examination (PSE). 22 T h e M A D R S is a set of IO items, rated by the interviewer, and each item is given one of six severity ratings, according to brief rules. T h e r e is a total score
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of 60. A score of 7-I 9 has been suggested to represent mild depression 23 and so a low threshold of seven was used to define positive cases. T h e H A D rates depression and anxiety on two separate scales, each with a maximum score of 2i. A score of I I or greater gives a positive result. It is a brief, self-report questionnaire requiring the subject to tick one of four responses (scoring o-3) to I4 statements. Both the M A D R S and the H A D have been designed to reduce false positive ratings due to physical symptoms and are thus appropriate for use in CFS. T h e PSE is a comprehensive structured psychiatric interview. Interviewers should have a psychiatric background and complete a training course in its use. T h e r e is an extensive glossary which describes how each symptom and sign should be rated. T h e accompanying computer program produces psychiatric diagnoses and a rating of the level of importance of each diagnosis called the index of definition (ID) which ranges from I-8. An ID of six or above indicates a considerable likelihood of psychiatric illness, and lower values suggest proportionately less certainty about the diagnosis. Background data and employment details were also collected. Results
Patients came from the region of north and west Yorkshire and included residents of rural, suburban, and inner city areas. T h e mean age of patients was 30"4 years (range I5-57). T e n of the I5 were female. T h e mean duration of illness was 24 months (range 6--6o). Forty-seven per cent reported an acute, infective like onset. Sixty per cent were cases o f ' chronic fatigue syndrome' as operationally defined by Holmes et al., 16 and modified by Komaroff et al. ~7 All had 6 or more months' history of acquired, persistent fatigue causing severe impairment of daily activities. AU patients had CFS as defined by Sharpe et al. TM T h e r e was no history of previous psychiatric illness requiring treatment during adult life though three patients had histories of school refusal and one had a life-long bird phobia. Ninety-three per cent of patients reported a new emotional disturbance since the onset of their illness, particularly tearfulness when tired. Ninety three per cent had a M A D R S rating of 7 + (mild depression). Thirty-three per cent had a positive (I I + ) rating on the H A D depression scale, and 27 ~/o had a positive rating on the anxiety scale. A single item on the H A D depression scale refers to 'feeling slowed down'. Not surprisingly this was cited by all patients. When this single item was removed from analysis, no patient retained a rating of depression. This emphasised the importance of possible false positive diagnoses of depression on the basis of somatic symptoms, particularly since the H A D is designed to avoid this problem. Thirteen per cent (two patients) received a PSE diagnosis of depression (ICD-9 3oo.4") with an index of definition (ID) of six. None received a higher ID. A further four patients (27 ~/o) received threshold diagnoses of depression (one patient) or phobic illness (three patients) with an ID of five. At the time of psychiatric assessment, 87 % patients had evidence of past, but not recent, EBV infection, with full and normal EBV antibody responses. * ICD-9 3oo.4 is the code for depressive neurosis in the International Classification of Diseases, ninth revisionfl8 The PSE computer program, Catego, is designed to produce diagnoses compatible with this classification which is the major system used by U.K. psychiatrists.
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T w e n t y per cent of patients showed initial elevated titres to Coxsackie B viruses greater than Io24, reflecting possible recent infection, which dropped to lower static titres, indicating no chronic or relapsing infection. One patient had evidence of past exposure to T o x o p l a s m a gondii. Forty per cent of patients had T-cell helper/suppressor ratios below the laboratory normal range (I'5-2"4). One had an increased ratio. T h e meaning of these results in a minority of patients is unclear. T h e y may reflect infection with a 'trigger' virus or recent infection with another virus. T h e y could also be paraphenomena of a psychiatric condition or simply a non-specific finding. No significant abnormalities in IgA, I g M , I g G or I g G subclass levels were detected. T w o male patients had mild, non-specific, elevations of alanine transaminase, but otherwise biochemistry, haematology, and thyroid function were normal in all cases. All I5 subjects had been in employment prior to the onset of their illness (including two in full-time education). There was a range of occupations, divided fairly equally between blue and white-collar jobs. Only I3 % were in full time work at assessment. Forty per cent worked part-time when they felt well-enough and 47 % had been off work for an average of 5"6 months. (For the majority it had been their own decision to stop work, but one patient had been dismissed after poor attendance.) Most patients were distressed by the lack of support they felt they received from their doctors. T h e y wanted more discussion and advice about prognosis and therapeutic alternatives. Forty-seven per cent were using 'alternative' therapies, such as homeopathy, spiritual healing and special diets. T w e n t y seven per cent were having some form of counselling or psychotherapy. Although 67 % felt psychological factors might have contributed to their illness, the main cause was felt to be an infection by 33 %, physical illness by 2o %, work related stress by I3 % and a mystery by 33 %. Discussion
Wessely and Powel113 found the total psychiatric morbidity in C F S was 72 ~/o, while M e n u et el., ~ found the prevalence to be 56 %. Estimates of depressive illness range from 67 % by Taerk et el., 9 to 46 % by Kroenke et el. n and to 2I % by Hickie et el. 1°. This study finds a variable prevalence depending on the criteria used. T h e M o n t g o m e r y - A s b e r g Depression Rating Scale used with a low threshold (7 for a range of 0-60) found all but one patient to score positively. It is likely that with such a low threshold the scores represented non-specific psychiatric distress and not clear syndromes of depression. T h e Hospital Anxiety and Depression Scale found fewer positive cases of depression, and when a single somatic symptom, feeling 'slowed d o w n ' , was removed from analysis, no patients retained a positive score. This emphasised the ease with which psychiatric rating scales may lead to false positive diagnoses in patients with physical symptoms. T h e Present State Examination made a diagnosis (i.e. index of definition greater than or equal to 6) of depression in two patients (I3 %). This diagnosis is relevant to psychiatric practice because the level of case definition is compatible with that found in psychiatric populations. In other words a psychiatrist might have recognised
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a depressive syndrome in those two C F S patients which was similar to that of depressed patients attending a psychiatric out-patient clinic. T h e four patients with diagnoses at a lower level of definition however would perhaps have been recognised in primary care as having non-specific distress or partial clinical syndromes. Mayou and H a w t o n 24 reviewed psychiatric studies in general hospital outpatient clinics. T h e y found consistent evidence for considerable psychiatric morbidity in physically ill patients from a range of psychiatric research instruments similar to those used in this study. T h e prevalence of affective (mood) disorder was I 5 - 5 I %. T w o studies had used the Present State Examination and found the prevalence of affective disorder was 29 % in a gynaecology clinic and 32 % in a pain clinic. However, the authors of this review felt that the measurements often over-estimated the prevalence of affective disorder in the general hospital. It is possible that studies of C F S have had a similar tendency to over-estimate the prevalence of depression. T h e important message to non-psychiatrists is that in C F S , research diagnoses or ratings of psychiatric illness need to be carefully interpreted. It cannot be assumed that a research instrument always gives a valid result which would coincide closely with clinical assessment. T h e results of any of the individual research instruments in this study could have been presented singly to give quite different impressions of psychiatric morbitidy in CFS. A consensus of the results suggests a wide range of psychiatric problems from minor distress to syndromes similar to those seen in psychiatric out-patients, and finds most C F S patients to be at the milder end of this spectrum. T h e r e was no evidence from this study of a consistent pathological abnormality with the chronic fatigue syndrome. Although many patients had evidence of previous exposure to pathogenic organisms, this does not indicate a causal link. M a n y people have been exposed to these organisms without developing C F S , and C F S patients may have the same level of exposure as unaffected individuals. 25 Some patients had unusual T 4 / T 8 lymphocyte ratios, but in the absence of clear immunological disturbance, the importance of this finding is uncertain. T h e r e are as yet no satisfactory biological markers to aid in the diagnosis of CFS. T h e absence of such markers has been interpreted as support for a psychogenic aetiology in CFS. This cross-sectional study does not attempt to attribute cause, and cannot contribute to debate in that area, but it does emphasise that psychological distress is c o m m o n and disabling. More importantly this study highlights the variability of prevalence rates of psychiatric conditions depending on the form of assessment. F u r t h e r m o r e , it is suggested that C F S patients are more likely to suffer non-specific psychiatric distress than the typical psychiatric syndromes seen in psychiatric out-patient clinics. White 26 has suggested that if well-recognised psychiatric syndromes appear in the context of C F S , then it is appropriate to treat t h e m as usual. It is important to diagnose such syndromes correctly and this study suggests that questionnaires alone may over-emphasise specific psychiatric syndromes rather than non-specific distress. Routine use of questionnaires, as suggested by Ho-Yen, 27 should be combined with clinical assessment.
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T h e r e was a h i g h p r e v a l e n c e o f o c c u p a t i o n a l h a n d i c a p in this g r o u p . M a n y w e r e o u t o f w o r k a n d o t h e r s h a d m a d e c h a n g e s to t h e i r w o r k p a t t e r n . W e c o n c l u d e t h a t t h e m u l t i - f a c t o r i a l a p p r o a c h to C F S r e c o m m e n d e d b y D a v i d et al., 15 is likely to b e m o r e p r o f i t a b l e t h a n a c o n t i n u e d s e a r c h f o r t h e ' t r u e ' o r g a n i c or f u n c t i o n a l c o r e o f t h e disease. C h r o n i c f a t i g u e s y n d r o m e is difficult to u n d e r s t a n d in t e r m s o f a single p a t h o l o g y . T h e r e is n o b i o l o g i c a l m a r k e r f o r this d i s e a s e w h i c h p r o d u c e s p h y s i c a l d i s t r e s s , o v e r l a p s d e p r e s s i o n ( p a r t i c u l a r l y w h e n l o w t h r e s h o l d s f o r t h a t d i a g n o s i s are set), a n d is a s s o c i a t e d w i t h o c c u p a t i o n a l h a n d i c a p . H o w e v e r , d o c t o r s h a v e a r a n g e o f skills to h e l p p a t i e n t s w i t h biological, p s y c h o l o g i c a l , a n d social p r o b l e m s . T h e s e c a n b e u s e d to h e l p p a t i e n t s w i t h C F S d e p e n d i n g o n i n d i v i d u a l n e e d . I t is u n n e c e s s a r y a n d i n d e e d u n p r o d u c t i v e to f o r c e p a t i e n t s i n t o u n s u i t a b l e d i a g n o s t i c c a t e g o r i e s as a c o n d i t i o n f o r t r e a t m e n t . I t m a y b e m o r e p r o d u c t i v e at p r e s e n t to define p r o b l e m s w i t h p a t i e n t s a n d h e l p to p l a n p r o b l e m - s o l v i n g m e a s u r e s w i t h t h e m . References I. Straus SE, Tosata G, Armstrong G e t al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern IVied I985; IOZ: 7-I6. 2. Jones JF, Ray CG, Minnich L e t al. Evidence for active Epstein-Barr virus infection in patients with persistent unexplained illness : elevated early antigen antibodies. Ann Intern IVied I985; xoz: I - 7. 3- Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase, ff R Soc Med I988 ; 8z : 326-329. 4. Yousef GE, Mann GF, Smith D G et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet I988; i: I46-I5 o. 5- Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. IVied ff ~lust r989; x5I: I22-I24. 6. Cheney PR, Dorman SE, Bell DS. Interleukin-2 and the chronic fatigue syndrome (Letter). Ann Intern ivied I989; IIO: 32i. 7. Komaroff AL, Geiger AM, Wormsley S. IgG subclass deficiencies in chronic fatigue syndrome (Letter). Lancet I988; i: I288-I289. 8. Behan PO, Behan WM, Bell EJ. The postviral fatigue syndrome---an analysis of the findings in 50 cases. J Infect I985 ; xo : 2I 1-222. 9. Taerk GS, Toner BB, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int ff Psychiatry Med r987; I7 (I): 49-56. Io. Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with the chronic fatigue syndrome. Br ff Psychiatry I99O; x56, 534-54o. I I. Kroenke K, Wood DR, Mangelsdorff AD, Meier NJ, Powell JB. Chronic fatigue in primary care. J A m Med Assoc I988; z6o (7): 929-934 • r2. Manu P, Matthews DA, Lane TJ. The mental health of patients with a chief complaint of chronic fatigue.//rch Intern Med 1988; I48 : 2213-2217. I3. Wessely S, Powell R. Fatigue syndromes: a comparison of chronic 'postviral' fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry I989; 5z : 94o-948. I4. Kendell RE. Chronic fatigue, viruses, and depression. Lancet I99I ; 337: I6O-I62. r 5. David AS, Wessely S, Pelosi AJ. Postviral fatigue syndrome: time for a new approach. Br IVied J I988; 296: 696-699. I6. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med I988 ; Io8: 387-389I7. Komaroff AL, Straus SE, Gantz NM. The chronic fatigue syndrome. Ann Intern IVied x989; Ixo (5): 4o7-408. I8. Sharpe MC, Archard LC, Banatvala JE, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med I99I ; 84: I I 8 - I 2 I .
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I9. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, revised 3rd ed. (DSM-III-R). Washington: American Psychiatric Association, I987. 20. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand I983; 67: 361-37o. 2r. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry I979; x34: 382-389. 22. Wing JK, Cooper JE, Sartorius N. The measurement and classification of psychiatric syndromes. Cambridge: Cambridge University Press, I974. 23. Snaith RP, Harrop FM, Newby DA et al. Grade scores of the Montgomery-Asberg depression and the clinical anxiety scales. Br J Psychiatry r986; I48: 599--6oi. 24. Mayou R, Hawton K. Psychiatric disorder in the general hospital. Br ff Psychiatry I986; *49 : r72-I9o. 25. Miller NA, Carmichael HA, Calder BD et al. Antibody to coxsackie B virus in diagnosing postviral fatigue syndrome. Br Med J I99X; 3o2: I4o--I43. 26. White P. Fatigue syndrome : neurasthenia revived. Br Med ,7 I989; 298 : 1I99-I 120. 27. Ho-YenDO. Patient management ofpost-viral fatigue syndrome. BrffGenPract r99o;4o: 37-39. ~8. World Health Organization. Mental disorders : glossary and guide to their classification in accordance with the ninth revision of the international classification of diseases. Geneva: World Health Organization, I978.
B i o p s y c h o s o c i a l aspects o f c h r o n i c fatigue s y n d r o m e (myalgic encephalomyelitis) J. D. I. Yeomans* and S. P. Conwayt * Department of Psychiatry, Roundhay Wing, St James's University Hospital, Beckett St, Leeds LS9 7 TF and t Department of Infectious Diseases, Seacroft Hospital, York Road, Leeds LSI4 6UH, U.K. Accepted for publication 28 May I99I Summary Fifteen patients, with a primary complaint of chronic fatigue, were referred to a physician by their general practitioners. Psychological distress, measured by simple psychiatric rating scales was common, but specific psychiatric diagnoses, derived from a comprehensive diagnostic interview, occurred less frequently. One questionnaire (Montgomery-Asberg depression rating scale) found emotional distress in 93 %, but the diagnostic instrument (Present State Examination) suggested depressive syndromes in only two patients (I3 %). There were significant occupational difficulties in 87 %. No consistently abnormal indices of biochemical or immunological function were found, nor evidence of acute or chronic infection. Chronic fatigue syndrome (CFS) is associated with physical, psychological and social distress. The illness cannot be defined using just one of these dimensions. Such a unilateral approach has resulted in unnecessary controversy over the nature of the 'real' core of CFS. A problemoriented approach, recognising the multi-factorial and overlapping cause and effect issues in CFS, may be of more benefit to patients.
Introduction Chronic fatigue syndrome (CFS), also known as post-infectious fatigue syndrome and myalgic encephalomyelitis, is characterised by severe generalised fatigue, easy fatigability, muscle weakness, myalgia and emotional and cognitive changes. T h e pathogenesis of this illness is unknown, but recent studies have implicated Epstein-Barr virus infection, 1' 2 persistent infection by enteroviruses such as Coxsackie B viruses a'4 and immunological defects. 5-8 Other studies have implicated psychiatric conditions. 9'1° T h e r e has been particular emphasis on the prevalence of depressive illnesses, although anxiety states also occur. 1~-1~ Kendell ~4 has recently commented on the overlap between CFS and psychiatric disorders. This overlap exists between many disorders often thought of as either predominantly psychological or physical. For example, he noted that both depression and myocardial infarction may be precipitated by stressful events and that depression is associated with immunological change. He concluded that no fundamental distinction could be drawn between depression and other kinds of 'organic' illness. David et al., ~5 argued for greater sensitivity in the appreciation of how social factors influence the presentation and outcome of fatiguing illnesses. T h e authors of both these papers implied that traditional concepts of disease classification may create an unnecessary barrier to the understanding of CFS, and presented oi63-4453/9I/o6o263 +o7 $03.00/o
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the case for a balanced approach acknowledging the interaction of physical, psychological and social factors. T h e lack of a case definition for C F S limited early research into the condition. In I988, the Centers for Disease Control in Atlanta proposed an operational definition for C F S ~6 which excluded patients with chronic psychiatric diseases. This made it impossible to use in an assessment of psychiatric morbidity. A small modification, subsequently proposed by some of its original authors, ~7 allowed the inclusion of such patients and brought the criteria for C F S into line with those of a British working party at Green College, O x f o r d ) 8 In contrast to the efforts made to define CFS, there has been less emphasis on the importance of defining the psychiatric syndromes which are thought to overlap it. In particular, little attention has been paid to the level of definition. Standard operational criteria for depression such as those of the American psychiatric classification system, D S M - I I I - R f l 9 have been suggested as appropriate, is However, under this system, a miserable person who manages to work despite poor concentration and lack of sleep may receive the same diagnosis of 'major depressive episode' as someone confined to hospital tormented by guilt and suicidal desires. This is too broad a category to use in a non-psychiatric setting without an accompanying indication of severity. Psychiatric case definition is central to a psychiatrist's work and deserves careful attention in discussions of C F S with medical colleagues. Aims
This study aimed to investigate biological, psychiatric and occupational status in patients who had been selected by virtue of their referral to an infectious diseases clinic by general practitioners. It was hoped that this would avoid selection biases favouring the presence of psychiatric illness as might occur with selection by self-referral, specialised fatigue clinics or specialised tertiary referral centres. 1~'~ Method
Details of I5 consecutive fatigued patients were obtained from the out-patient clinic of a consultant physician specialising in infectious disease. Patients were referred by their general practitioners because of a history suggesting postinfectious fatigue, chronic fatigue or myalgic encephalomyelitis. Medical assessment comprised history, examination and the following investigations: full blood count, plasma viscosity, urea and electrolytes, liver and thyroid function tests, I g G I, 2, 3 and 4, IgA, IgM, serological testing for infections with Epstein-Barr virus (EBV), Toxoplasma, Brucella, Coxsackie B viruses I-6, Influenza viruses A and B, Adenovirus, Chlamydia, Coxiella, Mycoplasma, Respiratory Syncytial Virus, and Cytomegalovirus, B-ceU and T-cell n u m b e r s and helper suppressor T-cell ratio. Psychiatric assessment included two standardised questionnaires: the Hospital Anxiety and Depression Scale (HAD), 2° and the M o n t g o m e r y - A s b e r g Depression Rating Scale (MADRS), 21 and a diagnostic interview, the Present State Examination (PSE). 22 T h e M A D R S is a set of IO items, rated by the interviewer, and each item is given one of six severity ratings, according to brief rules. T h e r e is a total score
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of 60. A score of 7-I 9 has been suggested to represent mild depression 23 and so a low threshold of seven was used to define positive cases. T h e H A D rates depression and anxiety on two separate scales, each with a maximum score of 2i. A score of I I or greater gives a positive result. It is a brief, self-report questionnaire requiring the subject to tick one of four responses (scoring o-3) to I4 statements. Both the M A D R S and the H A D have been designed to reduce false positive ratings due to physical symptoms and are thus appropriate for use in CFS. T h e PSE is a comprehensive structured psychiatric interview. Interviewers should have a psychiatric background and complete a training course in its use. T h e r e is an extensive glossary which describes how each symptom and sign should be rated. T h e accompanying computer program produces psychiatric diagnoses and a rating of the level of importance of each diagnosis called the index of definition (ID) which ranges from I-8. An ID of six or above indicates a considerable likelihood of psychiatric illness, and lower values suggest proportionately less certainty about the diagnosis. Background data and employment details were also collected. Results
Patients came from the region of north and west Yorkshire and included residents of rural, suburban, and inner city areas. T h e mean age of patients was 30"4 years (range I5-57). T e n of the I5 were female. T h e mean duration of illness was 24 months (range 6--6o). Forty-seven per cent reported an acute, infective like onset. Sixty per cent were cases o f ' chronic fatigue syndrome' as operationally defined by Holmes et al., 16 and modified by Komaroff et al. ~7 All had 6 or more months' history of acquired, persistent fatigue causing severe impairment of daily activities. AU patients had CFS as defined by Sharpe et al. TM T h e r e was no history of previous psychiatric illness requiring treatment during adult life though three patients had histories of school refusal and one had a life-long bird phobia. Ninety-three per cent of patients reported a new emotional disturbance since the onset of their illness, particularly tearfulness when tired. Ninety three per cent had a M A D R S rating of 7 + (mild depression). Thirty-three per cent had a positive (I I + ) rating on the H A D depression scale, and 27 ~/o had a positive rating on the anxiety scale. A single item on the H A D depression scale refers to 'feeling slowed down'. Not surprisingly this was cited by all patients. When this single item was removed from analysis, no patient retained a rating of depression. This emphasised the importance of possible false positive diagnoses of depression on the basis of somatic symptoms, particularly since the H A D is designed to avoid this problem. Thirteen per cent (two patients) received a PSE diagnosis of depression (ICD-9 3oo.4") with an index of definition (ID) of six. None received a higher ID. A further four patients (27 ~/o) received threshold diagnoses of depression (one patient) or phobic illness (three patients) with an ID of five. At the time of psychiatric assessment, 87 % patients had evidence of past, but not recent, EBV infection, with full and normal EBV antibody responses. * ICD-9 3oo.4 is the code for depressive neurosis in the International Classification of Diseases, ninth revisionfl8 The PSE computer program, Catego, is designed to produce diagnoses compatible with this classification which is the major system used by U.K. psychiatrists.
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A N D S. P. C O N W A Y
T w e n t y per cent of patients showed initial elevated titres to Coxsackie B viruses greater than Io24, reflecting possible recent infection, which dropped to lower static titres, indicating no chronic or relapsing infection. One patient had evidence of past exposure to T o x o p l a s m a gondii. Forty per cent of patients had T-cell helper/suppressor ratios below the laboratory normal range (I'5-2"4). One had an increased ratio. T h e meaning of these results in a minority of patients is unclear. T h e y may reflect infection with a 'trigger' virus or recent infection with another virus. T h e y could also be paraphenomena of a psychiatric condition or simply a non-specific finding. No significant abnormalities in IgA, I g M , I g G or I g G subclass levels were detected. T w o male patients had mild, non-specific, elevations of alanine transaminase, but otherwise biochemistry, haematology, and thyroid function were normal in all cases. All I5 subjects had been in employment prior to the onset of their illness (including two in full-time education). There was a range of occupations, divided fairly equally between blue and white-collar jobs. Only I3 % were in full time work at assessment. Forty per cent worked part-time when they felt well-enough and 47 % had been off work for an average of 5"6 months. (For the majority it had been their own decision to stop work, but one patient had been dismissed after poor attendance.) Most patients were distressed by the lack of support they felt they received from their doctors. T h e y wanted more discussion and advice about prognosis and therapeutic alternatives. Forty-seven per cent were using 'alternative' therapies, such as homeopathy, spiritual healing and special diets. T w e n t y seven per cent were having some form of counselling or psychotherapy. Although 67 % felt psychological factors might have contributed to their illness, the main cause was felt to be an infection by 33 %, physical illness by 2o %, work related stress by I3 % and a mystery by 33 %. Discussion
Wessely and Powel113 found the total psychiatric morbidity in C F S was 72 ~/o, while M e n u et el., ~ found the prevalence to be 56 %. Estimates of depressive illness range from 67 % by Taerk et el., 9 to 46 % by Kroenke et el. n and to 2I % by Hickie et el. 1°. This study finds a variable prevalence depending on the criteria used. T h e M o n t g o m e r y - A s b e r g Depression Rating Scale used with a low threshold (7 for a range of 0-60) found all but one patient to score positively. It is likely that with such a low threshold the scores represented non-specific psychiatric distress and not clear syndromes of depression. T h e Hospital Anxiety and Depression Scale found fewer positive cases of depression, and when a single somatic symptom, feeling 'slowed d o w n ' , was removed from analysis, no patients retained a positive score. This emphasised the ease with which psychiatric rating scales may lead to false positive diagnoses in patients with physical symptoms. T h e Present State Examination made a diagnosis (i.e. index of definition greater than or equal to 6) of depression in two patients (I3 %). This diagnosis is relevant to psychiatric practice because the level of case definition is compatible with that found in psychiatric populations. In other words a psychiatrist might have recognised
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a depressive syndrome in those two C F S patients which was similar to that of depressed patients attending a psychiatric out-patient clinic. T h e four patients with diagnoses at a lower level of definition however would perhaps have been recognised in primary care as having non-specific distress or partial clinical syndromes. Mayou and H a w t o n 24 reviewed psychiatric studies in general hospital outpatient clinics. T h e y found consistent evidence for considerable psychiatric morbidity in physically ill patients from a range of psychiatric research instruments similar to those used in this study. T h e prevalence of affective (mood) disorder was I 5 - 5 I %. T w o studies had used the Present State Examination and found the prevalence of affective disorder was 29 % in a gynaecology clinic and 32 % in a pain clinic. However, the authors of this review felt that the measurements often over-estimated the prevalence of affective disorder in the general hospital. It is possible that studies of C F S have had a similar tendency to over-estimate the prevalence of depression. T h e important message to non-psychiatrists is that in C F S , research diagnoses or ratings of psychiatric illness need to be carefully interpreted. It cannot be assumed that a research instrument always gives a valid result which would coincide closely with clinical assessment. T h e results of any of the individual research instruments in this study could have been presented singly to give quite different impressions of psychiatric morbitidy in CFS. A consensus of the results suggests a wide range of psychiatric problems from minor distress to syndromes similar to those seen in psychiatric out-patients, and finds most C F S patients to be at the milder end of this spectrum. T h e r e was no evidence from this study of a consistent pathological abnormality with the chronic fatigue syndrome. Although many patients had evidence of previous exposure to pathogenic organisms, this does not indicate a causal link. M a n y people have been exposed to these organisms without developing C F S , and C F S patients may have the same level of exposure as unaffected individuals. 25 Some patients had unusual T 4 / T 8 lymphocyte ratios, but in the absence of clear immunological disturbance, the importance of this finding is uncertain. T h e r e are as yet no satisfactory biological markers to aid in the diagnosis of CFS. T h e absence of such markers has been interpreted as support for a psychogenic aetiology in CFS. This cross-sectional study does not attempt to attribute cause, and cannot contribute to debate in that area, but it does emphasise that psychological distress is c o m m o n and disabling. More importantly this study highlights the variability of prevalence rates of psychiatric conditions depending on the form of assessment. F u r t h e r m o r e , it is suggested that C F S patients are more likely to suffer non-specific psychiatric distress than the typical psychiatric syndromes seen in psychiatric out-patient clinics. White 26 has suggested that if well-recognised psychiatric syndromes appear in the context of C F S , then it is appropriate to treat t h e m as usual. It is important to diagnose such syndromes correctly and this study suggests that questionnaires alone may over-emphasise specific psychiatric syndromes rather than non-specific distress. Routine use of questionnaires, as suggested by Ho-Yen, 27 should be combined with clinical assessment.
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T h e r e was a h i g h p r e v a l e n c e o f o c c u p a t i o n a l h a n d i c a p in this g r o u p . M a n y w e r e o u t o f w o r k a n d o t h e r s h a d m a d e c h a n g e s to t h e i r w o r k p a t t e r n . W e c o n c l u d e t h a t t h e m u l t i - f a c t o r i a l a p p r o a c h to C F S r e c o m m e n d e d b y D a v i d et al., 15 is likely to b e m o r e p r o f i t a b l e t h a n a c o n t i n u e d s e a r c h f o r t h e ' t r u e ' o r g a n i c or f u n c t i o n a l c o r e o f t h e disease. C h r o n i c f a t i g u e s y n d r o m e is difficult to u n d e r s t a n d in t e r m s o f a single p a t h o l o g y . T h e r e is n o b i o l o g i c a l m a r k e r f o r this d i s e a s e w h i c h p r o d u c e s p h y s i c a l d i s t r e s s , o v e r l a p s d e p r e s s i o n ( p a r t i c u l a r l y w h e n l o w t h r e s h o l d s f o r t h a t d i a g n o s i s are set), a n d is a s s o c i a t e d w i t h o c c u p a t i o n a l h a n d i c a p . H o w e v e r , d o c t o r s h a v e a r a n g e o f skills to h e l p p a t i e n t s w i t h biological, p s y c h o l o g i c a l , a n d social p r o b l e m s . T h e s e c a n b e u s e d to h e l p p a t i e n t s w i t h C F S d e p e n d i n g o n i n d i v i d u a l n e e d . I t is u n n e c e s s a r y a n d i n d e e d u n p r o d u c t i v e to f o r c e p a t i e n t s i n t o u n s u i t a b l e d i a g n o s t i c c a t e g o r i e s as a c o n d i t i o n f o r t r e a t m e n t . I t m a y b e m o r e p r o d u c t i v e at p r e s e n t to define p r o b l e m s w i t h p a t i e n t s a n d h e l p to p l a n p r o b l e m - s o l v i n g m e a s u r e s w i t h t h e m . References I. Straus SE, Tosata G, Armstrong G e t al. Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection. Ann Intern IVied I985; IOZ: 7-I6. 2. Jones JF, Ray CG, Minnich L e t al. Evidence for active Epstein-Barr virus infection in patients with persistent unexplained illness : elevated early antigen antibodies. Ann Intern IVied I985; xoz: I - 7. 3- Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome: persistence of enterovirus RNA in muscle and elevated creatine kinase, ff R Soc Med I988 ; 8z : 326-329. 4. Yousef GE, Mann GF, Smith D G et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet I988; i: I46-I5 o. 5- Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. IVied ff ~lust r989; x5I: I22-I24. 6. Cheney PR, Dorman SE, Bell DS. Interleukin-2 and the chronic fatigue syndrome (Letter). Ann Intern ivied I989; IIO: 32i. 7. Komaroff AL, Geiger AM, Wormsley S. IgG subclass deficiencies in chronic fatigue syndrome (Letter). Lancet I988; i: I288-I289. 8. Behan PO, Behan WM, Bell EJ. The postviral fatigue syndrome---an analysis of the findings in 50 cases. J Infect I985 ; xo : 2I 1-222. 9. Taerk GS, Toner BB, Salit IE, Garfinkel PE, Ozersky S. Depression in patients with neuromyasthenia (benign myalgic encephalomyelitis). Int ff Psychiatry Med r987; I7 (I): 49-56. Io. Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with the chronic fatigue syndrome. Br ff Psychiatry I99O; x56, 534-54o. I I. Kroenke K, Wood DR, Mangelsdorff AD, Meier NJ, Powell JB. Chronic fatigue in primary care. J A m Med Assoc I988; z6o (7): 929-934 • r2. Manu P, Matthews DA, Lane TJ. The mental health of patients with a chief complaint of chronic fatigue.//rch Intern Med 1988; I48 : 2213-2217. I3. Wessely S, Powell R. Fatigue syndromes: a comparison of chronic 'postviral' fatigue with neuromuscular and affective disorders. J Neurol Neurosurg Psychiatry I989; 5z : 94o-948. I4. Kendell RE. Chronic fatigue, viruses, and depression. Lancet I99I ; 337: I6O-I62. r 5. David AS, Wessely S, Pelosi AJ. Postviral fatigue syndrome: time for a new approach. Br IVied J I988; 296: 696-699. I6. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med I988 ; Io8: 387-389I7. Komaroff AL, Straus SE, Gantz NM. The chronic fatigue syndrome. Ann Intern IVied x989; Ixo (5): 4o7-408. I8. Sharpe MC, Archard LC, Banatvala JE, et al. A report--chronic fatigue syndrome: guidelines for research. J R Soc Med I99I ; 84: I I 8 - I 2 I .
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I9. American Psychiatric Association. Diagnostic and statistical manual of mental disorders, revised 3rd ed. (DSM-III-R). Washington: American Psychiatric Association, I987. 20. Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand I983; 67: 361-37o. 2r. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. Br J Psychiatry I979; x34: 382-389. 22. Wing JK, Cooper JE, Sartorius N. The measurement and classification of psychiatric syndromes. Cambridge: Cambridge University Press, I974. 23. Snaith RP, Harrop FM, Newby DA et al. Grade scores of the Montgomery-Asberg depression and the clinical anxiety scales. Br J Psychiatry r986; I48: 599--6oi. 24. Mayou R, Hawton K. Psychiatric disorder in the general hospital. Br ff Psychiatry I986; *49 : r72-I9o. 25. Miller NA, Carmichael HA, Calder BD et al. Antibody to coxsackie B virus in diagnosing postviral fatigue syndrome. Br Med J I99X; 3o2: I4o--I43. 26. White P. Fatigue syndrome : neurasthenia revived. Br Med ,7 I989; 298 : 1I99-I 120. 27. Ho-YenDO. Patient management ofpost-viral fatigue syndrome. BrffGenPract r99o;4o: 37-39. ~8. World Health Organization. Mental disorders : glossary and guide to their classification in accordance with the ninth revision of the international classification of diseases. Geneva: World Health Organization, I978.
