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CLOSE ANALYSIS OF A LARGE PUBLISHED COHORT TRIAL INTO FATIGUE SYNDROMES AND MOOD DISORDERS THAT OCCUR AFTER DOCUMENTED VIRAL INFECTION

 

D.P. Sampson, BSc (Hons), MSc, MBPsychS

 

 

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ABSTRACT

This paper presents a close analysis of a large published cohort trial into predictors (risk factors) for developing a fatigue syndrome or mood disorder following either infectious mononucleosis or an upper respiratory tract infection - White et al (16). Critically, in addition to utilising broad based definitions of ME/CFS, such as the Oxford and CDC CFS criteria, White et al also utilise a further definition, Empirical Fatigue Syndrome, which excludes current psychiatric illness. This provides important additional insights into the results, leading to conclusions which are materially different to those that the author draws, in relation to the inherent validity of broad based definitions of CFS and in relation to the significance of deconditioning as a perpetuating factor in this illness.

Examination of the data shows that the highest risk factor for developing a non-psychiatrically defined Fatigue Syndrome (i.e. Empirical Fatigue Syndrome), even 6 months later, is documented clinical evidence of viral infection (infectious mononucleosis) not previous psychiatric morbidity. Furthermore under the Empirical definition, no significant correlation exists between bed rest at onset and subsequent development of a fatigue syndrome; this suggests that deconditioning is not an important perpetuating factor under this definition.

Conversely, wider definitions of ME/CFS that do not exclude individuals with psychological/psychiatric reasons for their fatigue (such as the Oxford and CDC criteria) reduce the importance of clinical factors (infectious mononucleosis) and increase the importance of  factors such as G.P. attendance in year before onset, mood disorder at 2 months and past psychiatric illness, which are consistent predictors of subsequent mood disorder quite independently of the existence or otherwise of a fatigue syndrome.

This analysis and the original data in the White et al. paper strongly calls into question the validity of broad based definitions of ME/CFS, such as the Oxford (and to lesser extent CDC) criteria. This is in large part due to the clear inclusion within such criteria of significant numbers of patients with primarily mood disorder/psychiatric illness in addition to those with ME/CFS.

Keywords: chronic fatigue syndrome, deconditioning, mood disorder, infectious mononucleosis.

 

INTRODUCTION
An increasing body of scientific literature suggests that the illness ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) is primarily a physical one (1).

However, a small number of psychiatrists have consistently argued for a “psychosomatic model”. This model is based on the premise that ME/CFS is a form of activity avoidance (2), in which sufferers get caught in a cycle of inactivity and deconditioning, marked by higher rates of both current and past psychiatric disorders, compared with other chronic medical disorders (3). This they have supported on the basis of limited trials demonstrating improvement of subjects using Cognitive Behavioural Therapy and/or Graded Exercise (4,5,6), both of which interestingly are effective treatments for mood disorders/psychiatric illness (7,8).

One of the major problems in researching ME/CFS is that many consensually defined diagnostic criteria, including the American “Centre for Disease Control and Prevention Criteria” (CDC) (9) and those consensually defined by these psychiatrists - the “Oxford” CFS criteria (10) do not clearly separate out or exclude patients with current psychological/psychiatric illness.  In addition to the core symptom of anhedonia, decreased energy and fatigue are common in psychiatric illnesses such as depression (11,12,13), which makes any pertinent conclusions about the fatigue in ME/CFS per se, defined using these criteria very difficult to say the least.

Support for such an explanation comes from studies, which demonstrate a clear correlation/prediction between depression and anxiety scores and treatment outcome (14,15).  This problem is evident in many of the studies that have been used to support the psychosomatic model. A highly relevant illustration of this occurs in the study of White et al. (16).

This study is of great importance, because (a) it is one of the few studies that have looked prospectively at a large number of patients [i.e. before the main onset of ME/CFS] and examined significant risk factors/predictors for developing ME/CFS; and (b) in doing so it uses various diagnostic criteria to identify ME/CFS including both the “Oxford” and “CDC” criteria, but critically it also includes one definition, Empirical Fatigue Syndrome, which excludes current Psychiatric illness.

Despite the clear delineation of fatigue syndromes using these three distinct diagnostic criteria, the White et al. (16) study still asserts that “since our measure of deconditioning predicted a fatigue syndrome, and since reversal of deconditioning in CFS with graded exercise therapy is associated with increased exercise capacity, we suggest that deconditioning is an important maintaining factor for post infectious fatigue. Prevention of post infectious fatigue by an early return to physical activity may be possible…. Since an interactive model of maintaining factors in CFS suggests that certain illness beliefs lead to inactivity, which itself leads to more fatigue, future studies should look for interactions between certain illness beliefs (which we did not measure), personality, inactivity, and deconditioning.”

If ME/CFS is viewed and defined as primarily a psychological disorder and therefore includes a significant proportion of people who have psychiatric disorders but fewer clinical symptoms, then it should be no surprise to find the results are similar to those that you would find with a more general psychological patient group. But this says nothing about what we might describe as “Empirical” ME/CFS sufferers-in White’s study, those for whom the clinical evidence is a significant predictor of ME/CFS symptoms but for whom psychological factors are a poor predictor. In fact one of the treatments most likely to relapse true ME/CFS sufferers has been the inappropriate administration of an activity regime-such as graded exercise; 50.2% of sufferers found this detrimental in one study for which see (17) and the reviews by Van Hoof et al. (18) and Carruthers et al. (1). To this end, the current paper carries out a critical review of the study by White et al. (16).

METHOD
Procedure
The White et al. (16) study examined risk factors amongst 250 primary care patients for developing a mood disorder or a fatigue syndrome following either infectious mononucleosis (118 patients) or an upper respiratory infection (127 patients), documented by bloods etc. until 6 months after clinical onset.

Definitions
Fatigue syndromes were further classified into three categories.  First, Empirically Defined Fatigue Syndrome, which included fatigue present for a minimum of 2 weeks plus two or more core ME/CFS symptoms such as poor concentration, hypersomnia, retardation and excluded all psychiatric illness bar for example simple phobias etc; measured at 1, 2 and 6 months from clinical onset.* Second, the Oxford CFS Criteria (which include fatigue of at least 6 months duration, but do not necessarily require any more minor symptoms and do not exclude pre-existing psychiatric disorders with some exceptions e.g. schizophrenia).  Finally, CDC Fukuda CFS Criteria (which include fatigue of at least 6 months duration, plus four or more minor symptoms e.g. sore throat, muscle pain, etc), are more stringent than Oxford, but still do not clearly exclude many people who may have purely psychosocial, stress or psychiatric reasons for their fatigue (14).

* The average duration of illness in this group at 6 months was at least 4.5 months.



Measures
A wide range of risk factors/predictors were examined based on demographic clinical and laboratory data including age, sex, time spent in bed at onset, fitness, Positive Monospot at onset, EBV IgM titre, cervical lymphadenopathy etc.

Similarly a wide range of psychosocial factors were examined i.e. history of previous psychiatric disorder, anxiety score, record of pre-morbid mood disorder by the general practitioner, mood disorder at 2 months , emotionality etc.

RESULTS
In discussing White’s study, frequent reference will be made to Table 1A, which contains the main results reported in the study. It demonstrates the Relative Risk in numerical terms of demographic, clinical, and psychological factors in predicting a Fatigue Syndrome using the above 3 definitions of ME/CFS.  Relative risk was calculated using the primary data by comparing those with a Fatigue Syndrome against those who were well.  The first 3 columns represent the Empirically Defined Fatigue Syndrome at 1, 2 and 6 months. The fourth and fifth columns represent the Oxford and CDC defined fatigue syndrome respectively, which by definition is of 6 months duration.  The higher the value of the risk factor the more relevant/predictive this factor is found to be in development of a particular Fatigue Syndrome. So for example a value of 4 under “Oxford Defined patients” for GP record of past psychiatric disorder means that this factor is of significant importance in predicting this fatigue syndrome.

The White et al. study had hypothesised that previous psychiatric history/social adversity (both psychosocial factors) would predict all definitions of fatigue syndromes on the basis of the “Psychosomatic” model of ME/CFS. In fact, in the discussion even White et al. noted that neither univariate nor logistic regression analyses supported his original hypothesis that a previous psychiatric history or social adversity would predict the empirically defined syndrome (TABLE 1A).



In fact he states - “Whereas mood disorders were predicted by a pre-morbid psychiatric history, emotional personality, and social adversity, none of these factors predicted having an empirical fatigue syndrome... The consensually defined Oxford and CDC criteria were predicted by a mixture of the factors that predicted the empirical fatigue syndrome and mood disorders… In particular pre-onset primary care attendance and previous mood disorders were predictive of these models” (TABLE 1A).

It also leads him to suggest that the Oxford and CDC criteria for CFS should be used with caution or only with stratification by mood disorders in aetiological studies.

In fact in the White et al. paper the strongest predictions of development of an Empirically Defined Fatigue syndrome at any stage was of a positive Monospot (blood test) for infectious mononucleosis or infectious mononucleosis at onset (TABLE 1A).

There is a noticeable and distinct lack of psychological factors in predicting an Empirical (non-psychiatric) Fatigue Syndrome at 1,2 and 6 months (TABLE 1A). The converse is true for Oxford and to a lesser extent CDC defined fatigue syndromes (TABLE 1A).

In the discussion, White et al. mention that the most likely explanation for the surprising lack of correlation between previous psychiatric morbidity /social adversity and an Empirically Defined Fatigue Syndrome is “That we studied participants in the first 6 months of their illness, whereas most previous studies observed patients several years after onset... This explanation would fit with the hypothesis that psychosocial factors are unimportant in a fatigue syndrome of several months duration, but may become more important with time…” 

This explanation however is not supported by the data. Psychological correlates for the empirical fatigue syndrome were distinctly lacking at 6 months (TABLE 1A) compared with those defined using the Oxford or CDC criteria which already clearly display such psychological correlates at 6 months. In other words a clearly delineated Empirical Fatigue Syndrome can occur independently of a mood disorder (18).

In fact further data from the study support an organic basis for an acute empirical fatigue syndrome at 1 or 2 months.

A number of immunological parameters, which reflected development of an empirically defined fatigue syndrome, were examined including heterophil antibody titres, and CD8 lymphocytes. White et al. interpret this to suggest that in infectious mononucleosis “The importance of the initial heterophil antibody, supported by the association with cervical lymphadenopathy, and the trend towards greater numbers of CD8 lymphocytes close to onset, suggests that an interaction between the initial virus infection and the consequent immune response may have an aetiological role in the acute fatigue syndrome, close to onset. This immune response may be related to release of particular cytokines, which in turn may cause an acute fatigue syndrome, as part of acute sickness behaviour.”  That the lowest correlation between positive monospot/infectious mononucleosis and fatigue syndrome occurred in those meeting the Oxford criteria is not surprising-Oxford does not clearly exclude those with purely psychiatric disorders, in addition to those with a fatigue syndrome (TABLE 1A).

Similarly in the fatigue syndrome as defined by CDC the correlation with previous psychiatric morbidity is of interest for it supports the idea that such criteria also are not sufficiently exclusive (TABLE 1A).

White et al. did find a relationship between initial fatigue and bed rest at onset in Empirical Fatigue Syndrome at 1 or 2 months, which is logical, as the worse you feel during the acute stages of any viral illness the longer you will remain in bed. This tallies in to some extent with basic immunological data.  However and remarkably, at 6 months there was no significant correlation between bed rest at onset and development of an Empirical psychiatrically free Fatigue Syndrome (TABLE 1A).  Conversely, in the Oxford defined group (the most lenient definition of CFS/ME regarding inclusion of those with co-morbid psychological/psychiatric disorders) there was the strongest relationship between initial bed rest and risk of developing a fatigue syndrome-3 times as likely (p<0.001, TABLE 1A).

Interestingly, White et al. noted an interaction between bed rest and emotional personality in the model for Oxford defined CFS, which supports the assertion that the Oxford criteria clearly select people with purely mood disorders or mixed anxiety states/avoidant behaviours, in addition to those with ME/CFS per se, (p<0.01).

CDC defined patients showed some correlation but as with much of the data this fell somewhere between Empirical and Oxford (p<0.05).

This is highly significant in relation to White’s claims. No significant correlation between initial bed rest and development of an empirical fatigue syndrome at 6 months exists.  This suggests that a psychiatrically free empirical ME/CFS has nothing to do with over-resting when first ill.

White et al. also found that physical fitness was also a predictor (negative) of any fatigue syndrome. That is the more unfit the patient the more likely they would have a fatigue syndrome 1,2 or 6 months after an infection (TABLE 1A - the fitness data are highlighted in a box). This is used as an argument for deconditioning being an important perpetuating factor in fatigue syndromes- i.e. the “vicious cycle of inactivity” theory.  However, there is one particularly critical fact; all fitness measurements were made after diagnosis. So, as we have no idea of how fit patients were before they became ill, all we can say is that if you are physically unfit after an infection it is correlated with having a fatigue syndrome. This is not surprising. Even if empirically defined patients do become deconditioned when they have a fatigue syndrome this does not mean that such deconditioning caused their illness.

Even at 1 or 2 months with an acute post infectious mononucleosis fatigue any reduction in fitness does not imply that patients should start exercising to relieve their fatigue especially when the predictive factor of lymphadenopathy (swollen glands) and immunological markers (including absolute numbers of CD8 lymphocytes) are at their strongest.

Any long-term illness will cause some deconditioning but this does not mean that deconditioning is the cause of their illness. It is a result. And loss of fitness is a result; this very study supports such a hypothesis.  In fact White et al. noted negligible change in fitness over the three interviews. This led the researchers to state that fitness (deconditioning) may have been a stable trait that independently predisposed some participants to a fatigue syndrome- the corollary of which is that it is a maintaining factor for such fatigue, which can be thereby remedied by graded exercise.

This is counter-intuitive, as we have no idea of fitness levels prior to illness. It is far more likely to be a marker for illness in general.  We have already seen that bed rest at  onset is predictive of a fatigue syndrome that includes patients with psychiatric illness.  White et al. state that this may well be a marker for subsequent inactivity in Oxford and CDC defined patients.  It may indeed be a marker - but certainly not for deconditioning (or probably inactivity, given the stability of the fitness data over time).  It cannot be a marker for subsequent inactivity because if it were then the Oxford defined group should be even less fit than the other two groups. They are not (FIGURE 1).  It is a marker for psychiatric illness, i.e. anxiety, neurosis, emotionality.  It has nothing at all to do with deconditioning – because in this whole study there was no general relationship between fitness and bed rest at onset (FIGURE 1).  If we look again at the clear relationship between time in bed at onset and leniency with regard to inclusion of psychiatric illness, this is a psychological/psychiatric response in psychological/psychiatric patients.  It has nothing to do with deconditioning but everything to do with emotionality which was marked and strongly correlated with bed rest in Oxford defined patients.  It has nothing to do with ME/CFS per se (FIGURE 1).

This is also confirmed by the observation that if we look at “Fatigue at onset” as a predictor of developing any fatigue syndrome, we find that the only group at 6 months showing a statistically significant effect is the Empirical group; neither Oxford or CDC defined CFS patients show a significant effect at onset.

 

This means that Oxford and CDC patients are spending more time in bed at onset but this is not related to either their fatigue at this time or to their fitness.

Most studies demonstrating deconditioning in CFS/ME to date have unfortunately compared ME/CFS patients to rather active control subjects. Sisto et al. (19) used sedentary controls and found that CFS patients had a low but normal fitness compared with sedentary controls. In a more recent study closely matched neighbourhood controls were employed (20). The latter study found no evidence of deconditioning as a perpetuating factor in ME/CFS.

CFS patients did not have a worse physical fitness compared with controls closely matched for age and sex etc. This emphasises the need for a well-matched control group (20).

If fatigue is perpetuated by deconditioning, one would also expect that an activity programme that increases performance in CFS patients would therefore increase fitness.

The Fulcher & White (6) study demonstrated no relationship between improvement in CFS after an exercise treatment programme and increase of peak aerobic capacity produced by exercise after this programme. As Bazelmans himself notes this finding “adds to the hypothesis that factors other than physical fitness determine a lower level of activity, fatigue and impairment in CFS” (20). Again this provides evidence that undermines the hypothesis that deconditioning plays a central role in ME/CFS or in mood disorders/psychiatric illness for that matter.

In concluding, the White et al. paper, which forms the basis of this critique, reasserts the success that Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET), has in reversing deconditioning and stating that deconditioning is an important factor in maintaining post-infectious fatigue.
This is rather surprising given that the lack of correlation of bed rest at onset with loss of physical fitness argues against deconditioning as a causal factor, and given that “fitness” or as he would say “deconditioning” was only measured after the illness had been diagnosed.

When scanning the extensive tables of data one is struck by the strong correlation between a positive Monospot test and cervical lymphadenopathy (swollen glands), clear signs of viral infection and the risk of development of a fatigue syndrome (Empirical) -four to five times greater with these factors. I have already discussed the limitations of the fitness/deconditioning data which were only initially measured several weeks after the initial infection (TABLE 1A).

Utilising the Oxford or CDC criteria a positive Monospot test or infectious mononucleosis lose effect as predominant factors that predict a fatigue syndrome and the factors of most importance are GP attendance in the year before illness, record of previous psychiatric disorder/treatment, mood disorder at 2 months and emotionality) for the former i.e. (Oxford defined patients), and GP attendance in the year before illness, pre-morbid mood disorder in the two weeks before infection ,mood disorder at 2 months, for CDC defined fatigue syndromes  (TABLE 1A). Also most strongly in Oxford Criteria defined subjects is the relationship between time spent in bed at onset and development of a fatigue syndrome. Already we have moved away from a physical construct of ME/CFS to a psychological one.


Although the data available in the published study is limited, we can see an apparent relationship between leniency of diagnostic criteria and relative importance of a documented viral infection (Monospot or infectious mononucleosis) at onset in predicting a fatigue syndrome (FIGURE 2). Conversely we can also see an increase in importance of mood disorder at 2 months, GP record of previous psychiatric disorder (PPD), or GP attendance in year before onset in predicting more lenient fatigue syndromes that include co-morbid psychiatric illness (FIGURES 3, 4 and 5).

This strongly suggests that the Oxford (and to a lesser extent), CDC Criteria select patients with purely mood disorder/psychiatric illness in addition to those with CFS/ME, whereas the Empirical criteria select patients primarily with a physical illness.


Most critically it is obvious from the data that these definitions do not form a continuum along which one may proceed. It is clear when looking at the marked delineation in risk factors between Empirical (clinical, viral) and Oxford defined CFS (psychosocial) that they are completely different illnesses/conditions.


Indeed it is clear from this study that wider definitions such as the Oxford criteria are in fact a “surrogate“term for mood disorder/psychological illness with fatigue as a symptom, amongst whom may reside patients with an Empirical Fatigue Syndrome.

In the above discussion we took Professor White’s analysis at face value.  However, in arriving at the analysis he makes an “adjustment” to the data sets for Empirical and CDC defined Fatigue Syndromes at 6 months.  Most pertinently of all the author states under statistical analysis that “because there were only 16 cases of the empirical fatigue syndrome at 6 months, we added in the 26 cases of ‘fatigue not otherwise specified’ to reduce type II error. Similarly, we added the 18 cases of ‘idiopathic chronic fatigue’ to the 17 cases of CFS according to the definition of the Centres for Disease Control and Prevention (CDC) found at 6 months. These two categories defined participants with prolonged unexplained abnormal fatigue, but with insufficient accompanying symptoms or disability to qualify for the full syndrome.”


In this context, and most crucially for this study, idiopathic chronic fatigue is classified as a psychiatric illness (listed by the WHO World Health Organisation as a Mental Disorder under section F 48). Similarly it is highly likely that fatigue not otherwise specified i.e. mild non specific fatigue will contain individuals with fatigue of a psychogenic nature.

Such statistical adjustment is disappointing for it clearly distorts the data of 2 critical groups at 6 months and leads to the valid cases being diluted by a higher number of those with milder/insufficient symptoms to meet the criteria being studied. This can be expected to have naturally distorted the findings.  What is clear is that these additions will by definition mask to some extent the fallibility of the Oxford criteria in selecting bona fide “fatigue syndrome”, with their inordinate reliance on psychiatric morbidity in comparison with other fatigue syndrome criteria such as Empirical and to a slightly lesser degree CDC criteria.

Furthermore, it is almost certain that the addition will dampen the strength of the clinical correlates we discussed earlier in Empirical fatigue at 6 months. Conversely, it is inevitable that their addition to the data set will increase the values for psychosocial factors.

We can see the effect of this dampening, in part, by noting the changes between 2 months (where the data has not been adjusted) and 6 months (where it has); in particular, there is a clear reduction of the apparent strength of monospot/infectious mononucleosis in predicting empirical fatigue states from 2 months to 6 months (TABLE 1A), and an increase in apparent psychological morbidity in this group between 2 months and 6 months (TABLE 1A).  If this dilution of the data at 6 months in the group with pure Empirical Fatigue syndrome had not taken place we may well have seen an even more critical relationship between documented viral infection and prediction of a fatigue syndrome in this group. And - which is more disturbing - maybe even an inverse relationship between bed rest and Empirical CFS/ME at this point, i.e. less bed rest was more likely to cause an empirical syndrome.

Similarly the inclusion into the CDC defined criteria of many patients with idiopathic chronic fatigue may support the existence of an empirically defined fatigue syndrome that cannot be explained using psychosocial models as it would certainly have the effect of diluting the correlation between a positive monospot/infectious mononucleosis in CDC defined fatigue syndrome and bolstering the psychiatric morbidity in this group. In any event if we exclude Professor White’s additions of those with undefined fatigue state or idiopathic chronic fatigue then the numbers of patients under each diagnostic criteria would be 16 Empirical subjects, 17 CDC based subjects, and 38 Oxford criteria based subjects.  The significance of this is explained below in the context of looking at Professor White’s data on mood disorders.

White’s study also examined risk factors for the development of a Mood Disorder independently of ME/CFS.  The results from the original Lancet paper are reproduced in the Table 1B below.


Not surprisingly the most significant predictors of a mood disorder are factors such as previous psychiatric history, GP attendance prior to illness, mood disorder at 2 months, emotionality etc. How does this relate to the Fatigue?

Critically only 16 patients with an Empirical Fatigue Syndrome (free from psychological/psychiatric illness) were apparent at 6 months. Using the Oxford criteria, which does not exclude psychological/psychiatric illness in its definition, the number increases to 38 patients.

Now the predictive factors of ME/CFS most important in this Oxford group become GP record of previous psychiatric illness, GP attendance in year before onset, mood disorder at 2 months- all of which are the most significant predictors of a mood disorder at 6 months, quite independently of a Fatigue Syndrome (TABLE 1B). Infectious mononucleosis was not a significant predictor of mood disorder. This clearly suggests that many patients included in wider and vague definitions of ME/CFS (that do not exclude current psychological/psychiatric illness) include large numbers of people with premorbid mood disorder/psychiatric illness that have nothing to do with a fatigue syndrome per se. Again this provides evidence that the core symptom of fatigue in ME/CFS and fatigue in co-morbid mood disorders are separate conditions and should be treated as such.


CONCLUSION
Even if the data and results of the White et al. study are taken at face value, the data do not support many of their conclusions.  Furthermore, material additions to the data set are made for reasons that are inadequately explained and in a way that may dilute the extent of the above bias created by choice of ME/CFS definition.

Firstly, close analysis of the data has shown that following viral infection, the strongest predictor of going on to develop a non-psychiatrically defined Fatigue Syndrome (Empirical), even  6 months later, is documented clinical evidence of specific viral infection (infectious mononucleosis) not previous psychiatric morbidity (TABLE 1A).  Significantly, in these patients, amount of bed rest at onset of infection is not predictive of having a fatigue syndrome 6 months later. This strongly argues that in such individuals exists a CFS/ME which has nothing to do with over-resting/deconditioning and has everything to do with some as yet undetermined physical abnormality.

Conversely, wider definitions of ME/CFS that do not exclude individuals with psychological/psychiatric reasons for their fatigue reduce the importance of clinical factors (infectious mononucleosis) and increase the importance of psychological factors including premorbid mood disorder and pre-existing psychiatric illness, in predicting their subsequent fatigue syndrome. Such factors are consistent predictors of mood disorder quite independently of the existence of a fatigue syndrome. Close analysis of the data shows that this is due to patients with primarily psychological/psychiatric illness being included, in addition to those with ME/CFS.

Secondly, it is obvious that these definitions do not form a continuum. It is clear when looking at the marked delineation in risk factors between Empirical (clinical, viral) and Oxford defined CFS (psychosocial) that they are looking at completely different illnesses/conditions. The heart of the psychosomatic case is that both Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT), which promote graded exercise, are effective treatments for ME/CFS. It is therefore important to consider the evidence on GET.

White’s work is viewed as providing important evidence for this view. But, as shown above, the suggestion that Graded Exercise can help post-infectious ME/CFS is not supported by the data itself in White’s study.  The only other evidence referred to by White et al. in the Lancet article to support the case that exercise may help a Post Infectious Fatigue Syndrome comes from a study conducted 41 years ago (21). But this examined enforced bed rest compared with normal rest/activity as the patient wished, and did not examine graded exercise.

A number of studies have examined the effects of exercise regimes in ME/CFS, reporting improvement with graded exercise (6). The centre reports good results for Graded Exercise. In this context, it is noticeable that 69% of patients attending the outpatient clinic used for the Fulcher and White study thought their illness was psychological (22). Although this latter study claimed to have intentionally excluded patients with primarily a psychiatric illness, 30% of the participants were receiving normal dose antidepressant therapy or low dose tricyclic antidepressant hypnotic medication. Furthermore those with appreciable sleep disturbance (one of the hallmarks of CFS/ME) were excluded (nearly 90% of even CDC defined CFS sufferers reported profound sleep disturbance (23).  Furthermore, Bazelmans (20) has already pointed out that the results of White’s study into Graded Exercise in 1997 “showed that there was no relationship between improvement in CFS after an exercise treatment programme and increase of peak aerobic capacity produced by exercise after this programme. This finding adds to the hypothesis that factors other than physical fitness determine a lower level of activity, fatigue and impairment in CFS”. 

In the other seminal publication by Deale et al. (4) we read that 63% of patients free from psychiatric illness showed improvement. But out of all those who received CBT/Graded Exercise only 9 were not classified as psychological cases.

In summary, the evidence for the beneficial effect of GET in CFS/ME (as defined in a way that is compatible with the Empirical criteria referred to above) is not persuasive.

In contrast, research demonstrating clear improvement of mood disorder/psychological conditions utilising exercise regimes are unequivocal. The following conclusions of the International Society of Sport Psychology (8) are based on examining the research literature regarding depressed and anxious patients: exercise can help reduce state anxiety; exercise can help decrease the level of mild to moderate depression; long-term exercise can help reduce neuroticism and anxiety; exercise may be an adjunct to the professional treatment of severe depression; exercise can help reduce various kinds of stress; exercise can have beneficial emotional effects across all ages for both sexes (p. 201). Plante and Rodin (7) found that exercise has been consistently shown to decrease mild to moderate anxiety, depressive symptoms and stress. Thirlaway and Benton (24) determined that it is participation in physical activity, rather than actual physical fitness that has greater impact on improving mental health.

This strongly suggests that the beneficial effects of graded exercise in CFS patients defined using criteria that include co-morbid psychiatric illness is due to an amelioration of psychological morbidity in patients primarily with such disorder. This is supported by the observation by Jason (14) of a correlation/prediction between depression and anxiety scores and treatment outcome in a CBT/modified activity study in patients defined using the Oxford criteria (5).

Data from studies using graded exercise also support this analysis. Improvement in groups using psychiatrically biased definition is not due to a reversal of deconditioning in such patients (20,25). It is more likely to be due to an amelioration of pre-existing mood disorder/psychiatric illness.

In fact, a study of a small sample of CFS patients without concurrent mood disorder/psychiatric illness found that fatigue, muscle pain, and overall mood did not improve with increased activity which led them to suggest that a “daily activity limit" may exist in this population (26).

Finally, this analysis and the original data in the White et al. paper strongly calls into question the inherent validity of broad based definitions of CFS/ME, such as the Oxford (and to a lesser extent CDC) criteria. If your sample of ME/CFS patients by definition contains large numbers of patients with purely psychiatric reasons for their fatigue quite independently of a fatigue syndrome (including premorbid mood disorder/previous psychiatric illness) then it is hardly surprising to find that psychosocial factors are important – this is tautology. But it tells us little about the fatigue syndrome underlying CFS itself.



FOOTNOTE
Tables 1, 1A and 1B are reprinted from the Lancet, Vol. 358(9297): 1946-1954, White PD et al.: “Predictions and association of fatigue syndromes and mood disorders that occur after infectious mononucleosis” Copyright 2001 with kind permission from Elsevier.

ACKNOWLEDGEMENTS
Jane Colby, F.R.S.A. for help in editing the manuscript.
Dr Charles Jenne, BSc, MSc (Oxon), D.Phil (Cantab)
Professor Paul Willner, BSc, MSc, D.Phil (Oxon)


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(14)  Jason L. (1997). Politics, Science, and the Emergence of a New Disease: The Case of Chronic Fatigue Syndrome, American Psychologist; Vol. 52, No. 9, 973-983.

(15)  Sharpe M.C. (1996). Cognitive behavioural therapy for chronic fatigue syndrome. Paper presented at the biannual meeting of the American Association for Chronic Fatigue Syndrome, San Francisco.

(16)  White P., Thomas J.,’O Kangro H., Bruce-Jones W., Amess J., Crawford D., Grover S., Clare A. (2001); Lancet, Vol. 358, N.9297; pp 1946-1953 Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis.

(17)  Shepherd C. (2001). Pacing and Exercise in Chronic Fatigue Syndrome. Physiotherapy, 87 (8), 395-396

(18)  Van Hoof E. (2003). Cognitive Behavioural Therapy as Cure-All for CFS Journal: Journal of Chronic Fatigue Syndrome, Vol. 11(4), pp. 43-47.

(19)  Sisto S.A., LaManca J., Cordero D.L., Bergen M.T., Ellis S.P., Drastal S., Boda W. L., Tapp W.N. & Natelson B.H. (1996). Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome. American Journal of Medicine 100, 634-640.

(20)  Bazelmans E., Blejenberg G., Van Der Meer J.W.M. and Folgering H. (2001). Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity - Psychological Medicine, 31, 107-114.

(21)  Dalrymple W. (1964) Infectious mononucleosis. Relation of bed rest and activity to prognosis. Postgrad Med, 35:345-9.

(22)  White P., Pinching AJ, Rakib A, Castle M, Hedge B, Priebe S. (2002). A comparison of patients with chronic fatigue syndrome attending separate fatigue clinics based in immunology and psychiatry. Journal:  J R Soc Med, 95(9):440-444.

(23)  De Becker P., McGregor N., De Meirleir K. (2001). A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med., 250(3): 234-40.

(24)  Thirlaway K. & Benton D. (1992). Participation in physical activity and cardiovascular fitness has different effects on mental health and mood. Journal of Psychosomatic Research, 36(7), 657-665.

(25)  Scroop G. C., Burnet R. B. (2004). To exercise or not to exercise in chronic fatigue syndrome? Med J Aust 181 (10), 578-580.

(26)  Black CD, O'Connor P J, McCully KK. (2005). Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med. 4: 10.


 Bulletin of the IACFS/ME. 2010;18(2):44-81. © 2010 IACFS/ME

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CLOSE ANALYSIS OF A LARGE PUBLISHED COHORT TRIAL INTO FATIGUE SYNDROMES AND MOOD DISORDERS THAT OCCUR AFTER DOCUMENTED VIRAL INFECTION

 

D.P. Sampson, BSc (Hons), MSc, MBPsychS

 

 

9 Cherry Tree Road
London N2 9QL
Tel.: +44 208 442 1722
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ABSTRACT

This paper presents a close analysis of a large published cohort trial into predictors (risk factors) for developing a fatigue syndrome or mood disorder following either infectious mononucleosis or an upper respiratory tract infection - White et al (16). Critically, in addition to utilising broad based definitions of ME/CFS, such as the Oxford and CDC CFS criteria, White et al also utilise a further definition, Empirical Fatigue Syndrome, which excludes current psychiatric illness. This provides important additional insights into the results, leading to conclusions which are materially different to those that the author draws, in relation to the inherent validity of broad based definitions of CFS and in relation to the significance of deconditioning as a perpetuating factor in this illness.

Examination of the data shows that the highest risk factor for developing a non-psychiatrically defined Fatigue Syndrome (i.e. Empirical Fatigue Syndrome), even 6 months later, is documented clinical evidence of viral infection (infectious mononucleosis) not previous psychiatric morbidity. Furthermore under the Empirical definition, no significant correlation exists between bed rest at onset and subsequent development of a fatigue syndrome; this suggests that deconditioning is not an important perpetuating factor under this definition.

Conversely, wider definitions of ME/CFS that do not exclude individuals with psychological/psychiatric reasons for their fatigue (such as the Oxford and CDC criteria) reduce the importance of clinical factors (infectious mononucleosis) and increase the importance of  factors such as G.P. attendance in year before onset, mood disorder at 2 months and past psychiatric illness, which are consistent predictors of subsequent mood disorder quite independently of the existence or otherwise of a fatigue syndrome.

This analysis and the original data in the White et al. paper strongly calls into question the validity of broad based definitions of ME/CFS, such as the Oxford (and to lesser extent CDC) criteria. This is in large part due to the clear inclusion within such criteria of significant numbers of patients with primarily mood disorder/psychiatric illness in addition to those with ME/CFS.

Keywords: chronic fatigue syndrome, deconditioning, mood disorder, infectious mononucleosis.

 

INTRODUCTION
An increasing body of scientific literature suggests that the illness ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome) is primarily a physical one (1).

However, a small number of psychiatrists have consistently argued for a “psychosomatic model”. This model is based on the premise that ME/CFS is a form of activity avoidance (2), in which sufferers get caught in a cycle of inactivity and deconditioning, marked by higher rates of both current and past psychiatric disorders, compared with other chronic medical disorders (3). This they have supported on the basis of limited trials demonstrating improvement of subjects using Cognitive Behavioural Therapy and/or Graded Exercise (4,5,6), both of which interestingly are effective treatments for mood disorders/psychiatric illness (7,8).

One of the major problems in researching ME/CFS is that many consensually defined diagnostic criteria, including the American “Centre for Disease Control and Prevention Criteria” (CDC) (9) and those consensually defined by these psychiatrists - the “Oxford” CFS criteria (10) do not clearly separate out or exclude patients with current psychological/psychiatric illness.  In addition to the core symptom of anhedonia, decreased energy and fatigue are common in psychiatric illnesses such as depression (11,12,13), which makes any pertinent conclusions about the fatigue in ME/CFS per se, defined using these criteria very difficult to say the least.

Support for such an explanation comes from studies, which demonstrate a clear correlation/prediction between depression and anxiety scores and treatment outcome (14,15).  This problem is evident in many of the studies that have been used to support the psychosomatic model. A highly relevant illustration of this occurs in the study of White et al. (16).

This study is of great importance, because (a) it is one of the few studies that have looked prospectively at a large number of patients [i.e. before the main onset of ME/CFS] and examined significant risk factors/predictors for developing ME/CFS; and (b) in doing so it uses various diagnostic criteria to identify ME/CFS including both the “Oxford” and “CDC” criteria, but critically it also includes one definition, Empirical Fatigue Syndrome, which excludes current Psychiatric illness.

Despite the clear delineation of fatigue syndromes using these three distinct diagnostic criteria, the White et al. (16) study still asserts that “since our measure of deconditioning predicted a fatigue syndrome, and since reversal of deconditioning in CFS with graded exercise therapy is associated with increased exercise capacity, we suggest that deconditioning is an important maintaining factor for post infectious fatigue. Prevention of post infectious fatigue by an early return to physical activity may be possible…. Since an interactive model of maintaining factors in CFS suggests that certain illness beliefs lead to inactivity, which itself leads to more fatigue, future studies should look for interactions between certain illness beliefs (which we did not measure), personality, inactivity, and deconditioning.”

If ME/CFS is viewed and defined as primarily a psychological disorder and therefore includes a significant proportion of people who have psychiatric disorders but fewer clinical symptoms, then it should be no surprise to find the results are similar to those that you would find with a more general psychological patient group. But this says nothing about what we might describe as “Empirical” ME/CFS sufferers-in White’s study, those for whom the clinical evidence is a significant predictor of ME/CFS symptoms but for whom psychological factors are a poor predictor. In fact one of the treatments most likely to relapse true ME/CFS sufferers has been the inappropriate administration of an activity regime-such as graded exercise; 50.2% of sufferers found this detrimental in one study for which see (17) and the reviews by Van Hoof et al. (18) and Carruthers et al. (1). To this end, the current paper carries out a critical review of the study by White et al. (16).

METHOD
Procedure
The White et al. (16) study examined risk factors amongst 250 primary care patients for developing a mood disorder or a fatigue syndrome following either infectious mononucleosis (118 patients) or an upper respiratory infection (127 patients), documented by bloods etc. until 6 months after clinical onset.

Definitions
Fatigue syndromes were further classified into three categories.  First, Empirically Defined Fatigue Syndrome, which included fatigue present for a minimum of 2 weeks plus two or more core ME/CFS symptoms such as poor concentration, hypersomnia, retardation and excluded all psychiatric illness bar for example simple phobias etc; measured at 1, 2 and 6 months from clinical onset.* Second, the Oxford CFS Criteria (which include fatigue of at least 6 months duration, but do not necessarily require any more minor symptoms and do not exclude pre-existing psychiatric disorders with some exceptions e.g. schizophrenia).  Finally, CDC Fukuda CFS Criteria (which include fatigue of at least 6 months duration, plus four or more minor symptoms e.g. sore throat, muscle pain, etc), are more stringent than Oxford, but still do not clearly exclude many people who may have purely psychosocial, stress or psychiatric reasons for their fatigue (14).

* The average duration of illness in this group at 6 months was at least 4.5 months.



Measures
A wide range of risk factors/predictors were examined based on demographic clinical and laboratory data including age, sex, time spent in bed at onset, fitness, Positive Monospot at onset, EBV IgM titre, cervical lymphadenopathy etc.

Similarly a wide range of psychosocial factors were examined i.e. history of previous psychiatric disorder, anxiety score, record of pre-morbid mood disorder by the general practitioner, mood disorder at 2 months , emotionality etc.

RESULTS
In discussing White’s study, frequent reference will be made to Table 1A, which contains the main results reported in the study. It demonstrates the Relative Risk in numerical terms of demographic, clinical, and psychological factors in predicting a Fatigue Syndrome using the above 3 definitions of ME/CFS.  Relative risk was calculated using the primary data by comparing those with a Fatigue Syndrome against those who were well.  The first 3 columns represent the Empirically Defined Fatigue Syndrome at 1, 2 and 6 months. The fourth and fifth columns represent the Oxford and CDC defined fatigue syndrome respectively, which by definition is of 6 months duration.  The higher the value of the risk factor the more relevant/predictive this factor is found to be in development of a particular Fatigue Syndrome. So for example a value of 4 under “Oxford Defined patients” for GP record of past psychiatric disorder means that this factor is of significant importance in predicting this fatigue syndrome.

The White et al. study had hypothesised that previous psychiatric history/social adversity (both psychosocial factors) would predict all definitions of fatigue syndromes on the basis of the “Psychosomatic” model of ME/CFS. In fact, in the discussion even White et al. noted that neither univariate nor logistic regression analyses supported his original hypothesis that a previous psychiatric history or social adversity would predict the empirically defined syndrome (TABLE 1A).



In fact he states - “Whereas mood disorders were predicted by a pre-morbid psychiatric history, emotional personality, and social adversity, none of these factors predicted having an empirical fatigue syndrome... The consensually defined Oxford and CDC criteria were predicted by a mixture of the factors that predicted the empirical fatigue syndrome and mood disorders… In particular pre-onset primary care attendance and previous mood disorders were predictive of these models” (TABLE 1A).

It also leads him to suggest that the Oxford and CDC criteria for CFS should be used with caution or only with stratification by mood disorders in aetiological studies.

In fact in the White et al. paper the strongest predictions of development of an Empirically Defined Fatigue syndrome at any stage was of a positive Monospot (blood test) for infectious mononucleosis or infectious mononucleosis at onset (TABLE 1A).

There is a noticeable and distinct lack of psychological factors in predicting an Empirical (non-psychiatric) Fatigue Syndrome at 1,2 and 6 months (TABLE 1A). The converse is true for Oxford and to a lesser extent CDC defined fatigue syndromes (TABLE 1A).

In the discussion, White et al. mention that the most likely explanation for the surprising lack of correlation between previous psychiatric morbidity /social adversity and an Empirically Defined Fatigue Syndrome is “That we studied participants in the first 6 months of their illness, whereas most previous studies observed patients several years after onset... This explanation would fit with the hypothesis that psychosocial factors are unimportant in a fatigue syndrome of several months duration, but may become more important with time…” 

This explanation however is not supported by the data. Psychological correlates for the empirical fatigue syndrome were distinctly lacking at 6 months (TABLE 1A) compared with those defined using the Oxford or CDC criteria which already clearly display such psychological correlates at 6 months. In other words a clearly delineated Empirical Fatigue Syndrome can occur independently of a mood disorder (18).

In fact further data from the study support an organic basis for an acute empirical fatigue syndrome at 1 or 2 months.

A number of immunological parameters, which reflected development of an empirically defined fatigue syndrome, were examined including heterophil antibody titres, and CD8 lymphocytes. White et al. interpret this to suggest that in infectious mononucleosis “The importance of the initial heterophil antibody, supported by the association with cervical lymphadenopathy, and the trend towards greater numbers of CD8 lymphocytes close to onset, suggests that an interaction between the initial virus infection and the consequent immune response may have an aetiological role in the acute fatigue syndrome, close to onset. This immune response may be related to release of particular cytokines, which in turn may cause an acute fatigue syndrome, as part of acute sickness behaviour.”  That the lowest correlation between positive monospot/infectious mononucleosis and fatigue syndrome occurred in those meeting the Oxford criteria is not surprising-Oxford does not clearly exclude those with purely psychiatric disorders, in addition to those with a fatigue syndrome (TABLE 1A).

Similarly in the fatigue syndrome as defined by CDC the correlation with previous psychiatric morbidity is of interest for it supports the idea that such criteria also are not sufficiently exclusive (TABLE 1A).

White et al. did find a relationship between initial fatigue and bed rest at onset in Empirical Fatigue Syndrome at 1 or 2 months, which is logical, as the worse you feel during the acute stages of any viral illness the longer you will remain in bed. This tallies in to some extent with basic immunological data.  However and remarkably, at 6 months there was no significant correlation between bed rest at onset and development of an Empirical psychiatrically free Fatigue Syndrome (TABLE 1A).  Conversely, in the Oxford defined group (the most lenient definition of CFS/ME regarding inclusion of those with co-morbid psychological/psychiatric disorders) there was the strongest relationship between initial bed rest and risk of developing a fatigue syndrome-3 times as likely (p<0.001, TABLE 1A).

Interestingly, White et al. noted an interaction between bed rest and emotional personality in the model for Oxford defined CFS, which supports the assertion that the Oxford criteria clearly select people with purely mood disorders or mixed anxiety states/avoidant behaviours, in addition to those with ME/CFS per se, (p<0.01).

CDC defined patients showed some correlation but as with much of the data this fell somewhere between Empirical and Oxford (p<0.05).

This is highly significant in relation to White’s claims. No significant correlation between initial bed rest and development of an empirical fatigue syndrome at 6 months exists.  This suggests that a psychiatrically free empirical ME/CFS has nothing to do with over-resting when first ill.

White et al. also found that physical fitness was also a predictor (negative) of any fatigue syndrome. That is the more unfit the patient the more likely they would have a fatigue syndrome 1,2 or 6 months after an infection (TABLE 1A - the fitness data are highlighted in a box). This is used as an argument for deconditioning being an important perpetuating factor in fatigue syndromes- i.e. the “vicious cycle of inactivity” theory.  However, there is one particularly critical fact; all fitness measurements were made after diagnosis. So, as we have no idea of how fit patients were before they became ill, all we can say is that if you are physically unfit after an infection it is correlated with having a fatigue syndrome. This is not surprising. Even if empirically defined patients do become deconditioned when they have a fatigue syndrome this does not mean that such deconditioning caused their illness.

Even at 1 or 2 months with an acute post infectious mononucleosis fatigue any reduction in fitness does not imply that patients should start exercising to relieve their fatigue especially when the predictive factor of lymphadenopathy (swollen glands) and immunological markers (including absolute numbers of CD8 lymphocytes) are at their strongest.

Any long-term illness will cause some deconditioning but this does not mean that deconditioning is the cause of their illness. It is a result. And loss of fitness is a result; this very study supports such a hypothesis.  In fact White et al. noted negligible change in fitness over the three interviews. This led the researchers to state that fitness (deconditioning) may have been a stable trait that independently predisposed some participants to a fatigue syndrome- the corollary of which is that it is a maintaining factor for such fatigue, which can be thereby remedied by graded exercise.

This is counter-intuitive, as we have no idea of fitness levels prior to illness. It is far more likely to be a marker for illness in general.  We have already seen that bed rest at  onset is predictive of a fatigue syndrome that includes patients with psychiatric illness.  White et al. state that this may well be a marker for subsequent inactivity in Oxford and CDC defined patients.  It may indeed be a marker - but certainly not for deconditioning (or probably inactivity, given the stability of the fitness data over time).  It cannot be a marker for subsequent inactivity because if it were then the Oxford defined group should be even less fit than the other two groups. They are not (FIGURE 1).  It is a marker for psychiatric illness, i.e. anxiety, neurosis, emotionality.  It has nothing at all to do with deconditioning – because in this whole study there was no general relationship between fitness and bed rest at onset (FIGURE 1).  If we look again at the clear relationship between time in bed at onset and leniency with regard to inclusion of psychiatric illness, this is a psychological/psychiatric response in psychological/psychiatric patients.  It has nothing to do with deconditioning but everything to do with emotionality which was marked and strongly correlated with bed rest in Oxford defined patients.  It has nothing to do with ME/CFS per se (FIGURE 1).

This is also confirmed by the observation that if we look at “Fatigue at onset” as a predictor of developing any fatigue syndrome, we find that the only group at 6 months showing a statistically significant effect is the Empirical group; neither Oxford or CDC defined CFS patients show a significant effect at onset.

 

This means that Oxford and CDC patients are spending more time in bed at onset but this is not related to either their fatigue at this time or to their fitness.

Most studies demonstrating deconditioning in CFS/ME to date have unfortunately compared ME/CFS patients to rather active control subjects. Sisto et al. (19) used sedentary controls and found that CFS patients had a low but normal fitness compared with sedentary controls. In a more recent study closely matched neighbourhood controls were employed (20). The latter study found no evidence of deconditioning as a perpetuating factor in ME/CFS.

CFS patients did not have a worse physical fitness compared with controls closely matched for age and sex etc. This emphasises the need for a well-matched control group (20).

If fatigue is perpetuated by deconditioning, one would also expect that an activity programme that increases performance in CFS patients would therefore increase fitness.

The Fulcher & White (6) study demonstrated no relationship between improvement in CFS after an exercise treatment programme and increase of peak aerobic capacity produced by exercise after this programme. As Bazelmans himself notes this finding “adds to the hypothesis that factors other than physical fitness determine a lower level of activity, fatigue and impairment in CFS” (20). Again this provides evidence that undermines the hypothesis that deconditioning plays a central role in ME/CFS or in mood disorders/psychiatric illness for that matter.

In concluding, the White et al. paper, which forms the basis of this critique, reasserts the success that Cognitive Behavioural Therapy (CBT) and Graded Exercise Therapy (GET), has in reversing deconditioning and stating that deconditioning is an important factor in maintaining post-infectious fatigue.
This is rather surprising given that the lack of correlation of bed rest at onset with loss of physical fitness argues against deconditioning as a causal factor, and given that “fitness” or as he would say “deconditioning” was only measured after the illness had been diagnosed.

When scanning the extensive tables of data one is struck by the strong correlation between a positive Monospot test and cervical lymphadenopathy (swollen glands), clear signs of viral infection and the risk of development of a fatigue syndrome (Empirical) -four to five times greater with these factors. I have already discussed the limitations of the fitness/deconditioning data which were only initially measured several weeks after the initial infection (TABLE 1A).

Utilising the Oxford or CDC criteria a positive Monospot test or infectious mononucleosis lose effect as predominant factors that predict a fatigue syndrome and the factors of most importance are GP attendance in the year before illness, record of previous psychiatric disorder/treatment, mood disorder at 2 months and emotionality) for the former i.e. (Oxford defined patients), and GP attendance in the year before illness, pre-morbid mood disorder in the two weeks before infection ,mood disorder at 2 months, for CDC defined fatigue syndromes  (TABLE 1A). Also most strongly in Oxford Criteria defined subjects is the relationship between time spent in bed at onset and development of a fatigue syndrome. Already we have moved away from a physical construct of ME/CFS to a psychological one.


Although the data available in the published study is limited, we can see an apparent relationship between leniency of diagnostic criteria and relative importance of a documented viral infection (Monospot or infectious mononucleosis) at onset in predicting a fatigue syndrome (FIGURE 2). Conversely we can also see an increase in importance of mood disorder at 2 months, GP record of previous psychiatric disorder (PPD), or GP attendance in year before onset in predicting more lenient fatigue syndromes that include co-morbid psychiatric illness (FIGURES 3, 4 and 5).

This strongly suggests that the Oxford (and to a lesser extent), CDC Criteria select patients with purely mood disorder/psychiatric illness in addition to those with CFS/ME, whereas the Empirical criteria select patients primarily with a physical illness.


Most critically it is obvious from the data that these definitions do not form a continuum along which one may proceed. It is clear when looking at the marked delineation in risk factors between Empirical (clinical, viral) and Oxford defined CFS (psychosocial) that they are completely different illnesses/conditions.


Indeed it is clear from this study that wider definitions such as the Oxford criteria are in fact a “surrogate“term for mood disorder/psychological illness with fatigue as a symptom, amongst whom may reside patients with an Empirical Fatigue Syndrome.

In the above discussion we took Professor White’s analysis at face value.  However, in arriving at the analysis he makes an “adjustment” to the data sets for Empirical and CDC defined Fatigue Syndromes at 6 months.  Most pertinently of all the author states under statistical analysis that “because there were only 16 cases of the empirical fatigue syndrome at 6 months, we added in the 26 cases of ‘fatigue not otherwise specified’ to reduce type II error. Similarly, we added the 18 cases of ‘idiopathic chronic fatigue’ to the 17 cases of CFS according to the definition of the Centres for Disease Control and Prevention (CDC) found at 6 months. These two categories defined participants with prolonged unexplained abnormal fatigue, but with insufficient accompanying symptoms or disability to qualify for the full syndrome.”


In this context, and most crucially for this study, idiopathic chronic fatigue is classified as a psychiatric illness (listed by the WHO World Health Organisation as a Mental Disorder under section F 48). Similarly it is highly likely that fatigue not otherwise specified i.e. mild non specific fatigue will contain individuals with fatigue of a psychogenic nature.

Such statistical adjustment is disappointing for it clearly distorts the data of 2 critical groups at 6 months and leads to the valid cases being diluted by a higher number of those with milder/insufficient symptoms to meet the criteria being studied. This can be expected to have naturally distorted the findings.  What is clear is that these additions will by definition mask to some extent the fallibility of the Oxford criteria in selecting bona fide “fatigue syndrome”, with their inordinate reliance on psychiatric morbidity in comparison with other fatigue syndrome criteria such as Empirical and to a slightly lesser degree CDC criteria.

Furthermore, it is almost certain that the addition will dampen the strength of the clinical correlates we discussed earlier in Empirical fatigue at 6 months. Conversely, it is inevitable that their addition to the data set will increase the values for psychosocial factors.

We can see the effect of this dampening, in part, by noting the changes between 2 months (where the data has not been adjusted) and 6 months (where it has); in particular, there is a clear reduction of the apparent strength of monospot/infectious mononucleosis in predicting empirical fatigue states from 2 months to 6 months (TABLE 1A), and an increase in apparent psychological morbidity in this group between 2 months and 6 months (TABLE 1A).  If this dilution of the data at 6 months in the group with pure Empirical Fatigue syndrome had not taken place we may well have seen an even more critical relationship between documented viral infection and prediction of a fatigue syndrome in this group. And - which is more disturbing - maybe even an inverse relationship between bed rest and Empirical CFS/ME at this point, i.e. less bed rest was more likely to cause an empirical syndrome.

Similarly the inclusion into the CDC defined criteria of many patients with idiopathic chronic fatigue may support the existence of an empirically defined fatigue syndrome that cannot be explained using psychosocial models as it would certainly have the effect of diluting the correlation between a positive monospot/infectious mononucleosis in CDC defined fatigue syndrome and bolstering the psychiatric morbidity in this group. In any event if we exclude Professor White’s additions of those with undefined fatigue state or idiopathic chronic fatigue then the numbers of patients under each diagnostic criteria would be 16 Empirical subjects, 17 CDC based subjects, and 38 Oxford criteria based subjects.  The significance of this is explained below in the context of looking at Professor White’s data on mood disorders.

White’s study also examined risk factors for the development of a Mood Disorder independently of ME/CFS.  The results from the original Lancet paper are reproduced in the Table 1B below.


Not surprisingly the most significant predictors of a mood disorder are factors such as previous psychiatric history, GP attendance prior to illness, mood disorder at 2 months, emotionality etc. How does this relate to the Fatigue?

Critically only 16 patients with an Empirical Fatigue Syndrome (free from psychological/psychiatric illness) were apparent at 6 months. Using the Oxford criteria, which does not exclude psychological/psychiatric illness in its definition, the number increases to 38 patients.

Now the predictive factors of ME/CFS most important in this Oxford group become GP record of previous psychiatric illness, GP attendance in year before onset, mood disorder at 2 months- all of which are the most significant predictors of a mood disorder at 6 months, quite independently of a Fatigue Syndrome (TABLE 1B). Infectious mononucleosis was not a significant predictor of mood disorder. This clearly suggests that many patients included in wider and vague definitions of ME/CFS (that do not exclude current psychological/psychiatric illness) include large numbers of people with premorbid mood disorder/psychiatric illness that have nothing to do with a fatigue syndrome per se. Again this provides evidence that the core symptom of fatigue in ME/CFS and fatigue in co-morbid mood disorders are separate conditions and should be treated as such.


CONCLUSION
Even if the data and results of the White et al. study are taken at face value, the data do not support many of their conclusions.  Furthermore, material additions to the data set are made for reasons that are inadequately explained and in a way that may dilute the extent of the above bias created by choice of ME/CFS definition.

Firstly, close analysis of the data has shown that following viral infection, the strongest predictor of going on to develop a non-psychiatrically defined Fatigue Syndrome (Empirical), even  6 months later, is documented clinical evidence of specific viral infection (infectious mononucleosis) not previous psychiatric morbidity (TABLE 1A).  Significantly, in these patients, amount of bed rest at onset of infection is not predictive of having a fatigue syndrome 6 months later. This strongly argues that in such individuals exists a CFS/ME which has nothing to do with over-resting/deconditioning and has everything to do with some as yet undetermined physical abnormality.

Conversely, wider definitions of ME/CFS that do not exclude individuals with psychological/psychiatric reasons for their fatigue reduce the importance of clinical factors (infectious mononucleosis) and increase the importance of psychological factors including premorbid mood disorder and pre-existing psychiatric illness, in predicting their subsequent fatigue syndrome. Such factors are consistent predictors of mood disorder quite independently of the existence of a fatigue syndrome. Close analysis of the data shows that this is due to patients with primarily psychological/psychiatric illness being included, in addition to those with ME/CFS.

Secondly, it is obvious that these definitions do not form a continuum. It is clear when looking at the marked delineation in risk factors between Empirical (clinical, viral) and Oxford defined CFS (psychosocial) that they are looking at completely different illnesses/conditions. The heart of the psychosomatic case is that both Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT), which promote graded exercise, are effective treatments for ME/CFS. It is therefore important to consider the evidence on GET.

White’s work is viewed as providing important evidence for this view. But, as shown above, the suggestion that Graded Exercise can help post-infectious ME/CFS is not supported by the data itself in White’s study.  The only other evidence referred to by White et al. in the Lancet article to support the case that exercise may help a Post Infectious Fatigue Syndrome comes from a study conducted 41 years ago (21). But this examined enforced bed rest compared with normal rest/activity as the patient wished, and did not examine graded exercise.

A number of studies have examined the effects of exercise regimes in ME/CFS, reporting improvement with graded exercise (6). The centre reports good results for Graded Exercise. In this context, it is noticeable that 69% of patients attending the outpatient clinic used for the Fulcher and White study thought their illness was psychological (22). Although this latter study claimed to have intentionally excluded patients with primarily a psychiatric illness, 30% of the participants were receiving normal dose antidepressant therapy or low dose tricyclic antidepressant hypnotic medication. Furthermore those with appreciable sleep disturbance (one of the hallmarks of CFS/ME) were excluded (nearly 90% of even CDC defined CFS sufferers reported profound sleep disturbance (23).  Furthermore, Bazelmans (20) has already pointed out that the results of White’s study into Graded Exercise in 1997 “showed that there was no relationship between improvement in CFS after an exercise treatment programme and increase of peak aerobic capacity produced by exercise after this programme. This finding adds to the hypothesis that factors other than physical fitness determine a lower level of activity, fatigue and impairment in CFS”. 

In the other seminal publication by Deale et al. (4) we read that 63% of patients free from psychiatric illness showed improvement. But out of all those who received CBT/Graded Exercise only 9 were not classified as psychological cases.

In summary, the evidence for the beneficial effect of GET in CFS/ME (as defined in a way that is compatible with the Empirical criteria referred to above) is not persuasive.

In contrast, research demonstrating clear improvement of mood disorder/psychological conditions utilising exercise regimes are unequivocal. The following conclusions of the International Society of Sport Psychology (8) are based on examining the research literature regarding depressed and anxious patients: exercise can help reduce state anxiety; exercise can help decrease the level of mild to moderate depression; long-term exercise can help reduce neuroticism and anxiety; exercise may be an adjunct to the professional treatment of severe depression; exercise can help reduce various kinds of stress; exercise can have beneficial emotional effects across all ages for both sexes (p. 201). Plante and Rodin (7) found that exercise has been consistently shown to decrease mild to moderate anxiety, depressive symptoms and stress. Thirlaway and Benton (24) determined that it is participation in physical activity, rather than actual physical fitness that has greater impact on improving mental health.

This strongly suggests that the beneficial effects of graded exercise in CFS patients defined using criteria that include co-morbid psychiatric illness is due to an amelioration of psychological morbidity in patients primarily with such disorder. This is supported by the observation by Jason (14) of a correlation/prediction between depression and anxiety scores and treatment outcome in a CBT/modified activity study in patients defined using the Oxford criteria (5).

Data from studies using graded exercise also support this analysis. Improvement in groups using psychiatrically biased definition is not due to a reversal of deconditioning in such patients (20,25). It is more likely to be due to an amelioration of pre-existing mood disorder/psychiatric illness.

In fact, a study of a small sample of CFS patients without concurrent mood disorder/psychiatric illness found that fatigue, muscle pain, and overall mood did not improve with increased activity which led them to suggest that a “daily activity limit" may exist in this population (26).

Finally, this analysis and the original data in the White et al. paper strongly calls into question the inherent validity of broad based definitions of CFS/ME, such as the Oxford (and to a lesser extent CDC) criteria. If your sample of ME/CFS patients by definition contains large numbers of patients with purely psychiatric reasons for their fatigue quite independently of a fatigue syndrome (including premorbid mood disorder/previous psychiatric illness) then it is hardly surprising to find that psychosocial factors are important – this is tautology. But it tells us little about the fatigue syndrome underlying CFS itself.



FOOTNOTE
Tables 1, 1A and 1B are reprinted from the Lancet, Vol. 358(9297): 1946-1954, White PD et al.: “Predictions and association of fatigue syndromes and mood disorders that occur after infectious mononucleosis” Copyright 2001 with kind permission from Elsevier.

ACKNOWLEDGEMENTS
Jane Colby, F.R.S.A. for help in editing the manuscript.
Dr Charles Jenne, BSc, MSc (Oxon), D.Phil (Cantab)
Professor Paul Willner, BSc, MSc, D.Phil (Oxon)


REFERENCES
(1)  Carruthers, DeMeirleir, Klimas Carruthers (2003). Canadian ME/CFS Clinical Working Case Definition, Diagnostic and Treatment Protocols; published in the Journal of Chronic Fatigue Syndrome, Volume 11, no.1).

(2)   Prins JB, Bleijenberg G, Bazelmans E, et al. (2001). Cognitive therapy for chronic fatigue syndrome: a multicentre randomized controlled trial. Lancet, 357: 841-847.

(3)  Wessely S. C., Sharpe, M. C. & Hotopf, M. (1998) Chronic Fatigue and its Syndromes. Oxford: Oxford University Press.

(4)  Deale A., Chalder T., Marks I. & Wessely S. (1997). Cognitive behaviour therapy for chronic fatigue syndrome: A randomized controlled trial. American Journal of Psychiatry, 154, 408-414.

(5)  Sharpe M., Hawton K., Simkin S., Surawy C., Hackmann A., Klimes I., Peto T., Warrell D. & Seagroatt V. (1996). Cognitive behaviour therapy for the chronic fatigue syndrome: A randomised controlled trial. British Medical Journal, 312, 22-26.

(6)  Fulcher KY, White PD. (1997). Randomised controlled trial of graded exercise in patients with the chronic fatigue syndrome. BMJ, 314:1647-1652.

(7)  Plante T. G., & Rodin J. (1990). Physical fitness and enhanced psychological health. Current Psychology: Research & Reviews, 9(1), 3-24.

(8)  Singer R. S. (1992). Physical activity and psychological benefits: A position statement of the International Society of Sport Psychology (ISSP). The Sports Psychologist, 6, 199-203.

(9)  Fukuda K., Straus S.E., Hickie I., Sharpe M.C., Dobbins J.G. & Komaroff A. (1994). The chronic fatigue syndrome: A comprehensive approach to its definition and study. Annals of Internal Medicine, 121, 953-959.

(10)  Sharpe M. (1991). ‘A report-chronic fatigue syndrome: guidelines for research’. Journal of the Royal Society of Medicine, 84,118-21.

(11)  Willner P. (1985); Depression: A Psychobiological Synthesis. John Wiley and Sons, London.

(12)  Willner P., Muscat,R., Papp,M. & Sampson,D. (1991) Dopamine, depression and antidepressant drugs. ln Willner,P. & Scheel- Kruger,J. (Eds.) The Mesolimbic Dopamine System: From Motivation to Action. Wiley: Chichester, pp.385-408.

(13)  Sampson,D., Muscat,R. & Willner,P. (1991) Reversal of antidepressant action by dopamine antagonists in an animal  model of depression. Psychopharmacology, 104, 491-495.

(14)  Jason L. (1997). Politics, Science, and the Emergence of a New Disease: The Case of Chronic Fatigue Syndrome, American Psychologist; Vol. 52, No. 9, 973-983.

(15)  Sharpe M.C. (1996). Cognitive behavioural therapy for chronic fatigue syndrome. Paper presented at the biannual meeting of the American Association for Chronic Fatigue Syndrome, San Francisco.

(16)  White P., Thomas J.,’O Kangro H., Bruce-Jones W., Amess J., Crawford D., Grover S., Clare A. (2001); Lancet, Vol. 358, N.9297; pp 1946-1953 Predictions and associations of fatigue syndromes and mood disorders that occur after infectious mononucleosis.

(17)  Shepherd C. (2001). Pacing and Exercise in Chronic Fatigue Syndrome. Physiotherapy, 87 (8), 395-396

(18)  Van Hoof E. (2003). Cognitive Behavioural Therapy as Cure-All for CFS Journal: Journal of Chronic Fatigue Syndrome, Vol. 11(4), pp. 43-47.

(19)  Sisto S.A., LaManca J., Cordero D.L., Bergen M.T., Ellis S.P., Drastal S., Boda W. L., Tapp W.N. & Natelson B.H. (1996). Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome. American Journal of Medicine 100, 634-640.

(20)  Bazelmans E., Blejenberg G., Van Der Meer J.W.M. and Folgering H. (2001). Is physical deconditioning a perpetuating factor in chronic fatigue syndrome? A controlled study on maximal exercise performance and relations with fatigue, impairment and physical activity - Psychological Medicine, 31, 107-114.

(21)  Dalrymple W. (1964) Infectious mononucleosis. Relation of bed rest and activity to prognosis. Postgrad Med, 35:345-9.

(22)  White P., Pinching AJ, Rakib A, Castle M, Hedge B, Priebe S. (2002). A comparison of patients with chronic fatigue syndrome attending separate fatigue clinics based in immunology and psychiatry. Journal:  J R Soc Med, 95(9):440-444.

(23)  De Becker P., McGregor N., De Meirleir K. (2001). A definition-based analysis of symptoms in a large cohort of patients with chronic fatigue syndrome. J Intern Med., 250(3): 234-40.

(24)  Thirlaway K. & Benton D. (1992). Participation in physical activity and cardiovascular fitness has different effects on mental health and mood. Journal of Psychosomatic Research, 36(7), 657-665.

(25)  Scroop G. C., Burnet R. B. (2004). To exercise or not to exercise in chronic fatigue syndrome? Med J Aust 181 (10), 578-580.

(26)  Black CD, O'Connor P J, McCully KK. (2005). Increased daily physical activity and fatigue symptoms in chronic fatigue syndrome. Dyn Med. 4: 10.


 Bulletin of the IACFS/ME. 2010;18(2):44-81. © 2010 IACFS/ME

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