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by Ted Shaw
Living with chronic fatigue syndrome can be very difficult, not only because of the debilitating symptoms, but also because of the lack of knowledge about the cause of the disease and the lack of support from the medical community. Many people have found it necessary to seek help from several doctors before finding one that will make a diagnosis and provide advice. Scepticism about CFS is common amongst doctors and this view has permeated through to the general public and to the families of those with the illness. Consequently, those with CFS not only have to deal with the illness itself, but also with the doubt and disbelief of those dear to them.
The Clinical Practice Guidelines present a unique opportunity for both the clinicians and the patients. This is an opportunity for the medical community to set the record straight - to explain that the illness has a wide spectrum of severity and that it can be profoundly debilitating and even dangerous. For those with CFS, it is an opportunity to have their illness validated, to be acknowledged as being worthy of understanding and empathy from family and friends.
We, the combined consumer groups and individuals with CFS, have trusted in the Working Group, the people who have been chosen to explain this illness to the medical professionals. We trusted them to present a fair picture of the illness, one that genuinely reflects the many aspects of CFS. We trusted them to accurately interpret the research that’s been done on the disease. We trusted them to provide soundly-based recommendations for treatments. We also trusted them to provide accurate information for the institutions which are critical to people with CFS, such as insurance companies, superannuation boards, the department of social security and the departments of health. Regretfully, with the publication of the Draft Guidelines, the Working Group has shown that it is unworthy of this trust. The characterisation of CFS depicted in the Guidelines is one which the great majority of those with the disease won’t recognise. The Guidelines do not present a true and fair picture of the illness. We believe strongly that the interpretation of the research is inaccurate and unjustifiably skewed towards a psychological view of the illness, thus resulting in treatment recommendations which are highly inappropriate. For us, the Guidelines represent an opportunity gone begging. Instead of producing a set of Guidelines that would lead to a better understanding and insight into the disease, the Working Group has published a document that will increase the misconceptions about CFS, making it more difficult to obtain understanding from the medical community, families and the general public.
The Working Group is commended for acknowledging the considerable suffering and disability caused by CFS and accurately comparing the distress involved to the difficulties accompanying multiple sclerosis and rheumatoid arthritis. Since finding a clinician that will diagnose the illness and provide empathetic support is often extremely difficult for many people with this illness, we welcome the importance given to providing a definite diagnosis and accepting the reality of the patients’ suffering as the basis for good clinical care.
Also welcomed is the recommendation for the clinician to display a "non-judgemental style". We suggest that the Guidelines also point out the benefits of a collaborative relationship between the doctor and patient. In an idiosyncratic and little understood illness like CFS, the traditional hierarchical doctor/patient relationship, akin to that of "expert" and novice, is a great hindrance to communication. Much can be gained by the clinician adopting a team approach to the management of the illness, especially when empiric treatments are required.
The denial of benefits to people with CFS by superannuation boards and insurance companies is a major concern, as is the need for continued access to disability benefits, social security and educational assistance. It is therefore pleasing to see the Guidelines recommend that the doctor should be prepared to act as an advocate for the patients in their negotiations with the institutions involved.
However, the Working Groups’ emphasis on cognitive behavioural therapy (CBT), and the statements that suggest that maladaptive illness beliefs prolong the complaint (both of which imply strongly that CFS is a primarily a psychological problem) will make it much more DIFFICULT for anyone with CFS to qualify for superannuation benefits, disability claims or social security benefits. In this respect the Draft Guidelines create immense difficulties for those with this disease. We strongly believe that the emphasis on CBT is not justified by the research and that it has the potential to violate the first, most basic requirement of medical care: to do no harm.
In recent years, some of those researchers who are attempting to show that CFS is primarily psychological have answered their critics by suggesting that the concept of the physical/mental model is outmoded. They suggest that the criticism of their work is unwarranted due to the scientific truth that all mental activity is based on organic, chemical changes. They state also that the sciences of psychoneuroendocrinology and psychoneuroimmunology have demonstrated the inappropriateness of the physical/mental paradigm by highlighting the intricate interconnectivity amongst the nervous, endocrine and immune systems. We would point out that there is more than scientific truth involved. There is the political truth - that the benefits provided to those with an illness that has an established physical basis, like multiple sclerosis, are MUCH different to the benefits provided to someone with a psychological problem. Insurance companies and governments are spending large amounts of money attempting to show that CFS is a psychological illness in an attempt to cut costs. The Royal Colleges report instigated by the British Government is an obvious example. It is disingenuous to argue that the physical/mental dichotomy is superfluous when our health, social security and insurance institutions are so solidly wedded to this distinction.
In addition, the Guidelines state in the Physical Activity Section of this chapter that those with the illness should not make the mistake of putting off physical activity in the early stages of the illness. We strongly disagree with this and suggest that the emphasis should be placed on obtaining as much REST as possible in the early stages. The greatest danger does not come from inactivity, but from overexertion, which could greatly exacerbate and needlessly prolong the illness. Shepherd and Macintyre1 state, "Definitions of the chronic fatigue syndrome state that symptoms must have been present for at least six months before a diagnosis can be made. As a result no research study has been done into the most appropriate advice regarding rest and activity during the first few months of this illness. Until this has been done, our guidelines will continue to advise an initial period of rest followed by a gradual increase in activity."
The Guidelines state, "Graded exercise programs have been shown to be safe for people with CFS, and can improve both aerobic capacity and functional status." This statement is irresponsible and should be heavily qualified to say that it is true for only a small subset of those with CFS and that those at the early stage of illness should approach graded exercise with great caution. Specific criticisms of the research underpinning the Guideline’s approach to exercise will be provided later in this submission.
Central to our disagreement regarding exercise is the assumption by the Working Group that it is incorrect illness beliefs causing the inactivity in people with CFS. They state, "initial avoidance of physical activity may lead to longer-term avoidance of all activity." This is not an accurate description of the illness or one which most people with CFS will recognise. The great majority of those with CFS are as active as possible and are functioning at the upper level of their energy limit. The greatest problem is not inactivity, but overexertion.
Our predicament is accurately portrayed by Friedberg and Krupp2, "Our impression is that many of our patients were already performing near or at their activity ceiling. A graduated activity schedule beginning at their current behavioral baseline would have quickly exceeded their threshhold for setbacks and relapses. Behavioral schedules are more appropriate for depressed patients without CFS, for whom increasing activity produces unequivocal physical and psychological benefits."
A major concern is that in both the charts and the text of this chapter, the terms "chronic fatigue" and "chronic fatigue syndrome" are intermixed, creating the impression that there is little difference between them. For example, under the heading, "What is CFS?", a paragraph describing chronic fatigue is inserted suggesting that two-thirds of people with chronic fatigue will have another medical or psychiatric disorder that accounts for it. Many readers will believe this statement refers to CFS. In fact, this intermixing of CF and CFS is common throughout the Guidelines. Also, there is no attempt to explain the important differences between CF and CFS. Buchwald et al.3, one of the studies cited in this section, details the large difference between the two conditions, stating that, "Although chronic fatigue is a widespread symptom in the community, unexplained debilitating fatigue of at least 6 months duration is considerably less common." The paper estimated the number of CFS cases per 100,000 to be between 98 and 267, whereas the number of cases of CF was estimated to be 2316 per 100,000.
We believe that the Guidelines should strive to reduce the confusion between the two conditions, not exacerbate it by intermixing the terms as if the distinction was unimportant. It needs to be pointed out that anyone who complains of tiredness for a few weeks can be said to be suffering from chronic fatigue, whereas the diagnosis of CFS can only be made after 6 months of fatigue that substantially reduces the level of activity of the individual and after the confirmation of 4 out of 8 symptoms listed in the 1994 case definition.
The Working Group is to be commended for pointing out the differences between the symptoms of CFS and depression, correctly stating that people with CFS suffer more from irritation and frustration than from the profound sadness, self-reproach, guilt, loss of motivation and loss of pleasure that is found in depression.
We would add that most of those with CFS are as busy and active as their fatigue permits. Individuals with CFS tend to be "engaged" , eager to participate but enormously frustrated that their fatigue places such profound limits to their activities. Loss of motivation is certainly not a feature of the illness, which strongly underscores again the fallacy of the theory that it is maladaptive illness beliefs that limit physical activity.
Although the Guidelines briefly acknowledge the large overlap of symptoms between somatisation disorder and CFS, we feel that more should be said about the inappropriateness of diagnosing somatisation disorder in illnesses such as CFS that have an unknown aetiology. Our major concern is the danger of diagnosing somatisation disorder in those with severe CFS.
Johnson, DeLuca and Natelson4 have shown that during psychological assessment, the attitude of the interviewer towards CFS determines whether the symptoms will be classified as physical or psychiatric, showing clearly that the diagnosis of somatisation disorder is highly subjective. They state, "Whether or not symptoms of CFS are considered medically caused will strongly affect the incidence of SD [somatisation disorder] within the CFS population. Because arguments exist as to whether CFS is an organic disease or an emotional disorder, chances for inconsistencies in diagnosis are high. If the examiner recognizes that the patient’s CFS symptoms indicate a physical illness, the diagnosis of SD may not be made. Conversely, if the examiner does not consider CFS a medical illness, the patient’s symptom endorsement may lead to the diagnosis of SD." They found that changing the attribution of the symptoms using the Diagnostic Interview Schedule (DIS) from organic to psychiatric made a large difference in the prevalence rate of somatization disorder - from 0% to 98%. They concluded, "The diagnosis of SD is of limited use in populations in which the etiology of the illness has not been established."
In relation to somatisation disorder, the Guidelines state, "A long-standing history of frequent medical investigation and treatment for unexplained physical symptoms, persistent fear of medical ill-health despite adequate assessment, preoccupation with unusual physical explanations of illness, and persistent rejection of the potential relevance of psychosocial factors may suggest the diagnosis [of somatisation disorder].
This description of someone requiring frequent medical investigation and having more symptoms than usual also fits closely those with severe CFS. Indeed, in one of the references cited, Hickie et al.5, the authors suggest that those with severe CFS, with numerous and severe symptoms, are BY DEFINITION suffering from somatisation disorder. This poses a diabolical problem for those severely affected individuals (who will have more than the usual number of symptoms) seeking medical assistance, as they will be seen as having a psychological rather than physical problem.
Although the Guidelines acknowledge the difficulties in diagnosing somatisation disorder, we urge the Working Group to elaborate more fully on the dangers of this diagnosis to those with severe symptoms.
We offer this quote from Ian Hickie6 in 1990. It’s a reply to Dr Simon Wessely:
"Dr Wessely’s final statement that the patient’s belief in the physical nature of their condition is clinically more important than either concurrent immunological or psychiatric disorder must surely represent his own point of view and one which, like all others, requires empirical evaluation. Whenever patients with non-specific physical complaints fail to demonstrate evidence of a known disorder, psychiatric evaluation is likely to follow. Often this is appropriate. As has been demonstrated in patients with myasthenia gravis, however, such patients are often mislabelled by psychiatrists as "somatisers" until the actual nature of the disorder is later revealed. To avoid that pitfall, psychiatric diagnoses should be restricted to the identification of ‘typical’ disorders in patients with positive features of psychological disturbance. More doubtful notions such as ‘somatisation’ should not be invoked haphazardly to conceal a lack of basic knowledge."
In addition, it is disappointing to find in these Guidelines inappropriate references and studies with little scientific merit.
A paper by Gold et al.7 is cited five times in the Guidelines. This paper is one of the most publically discredited papers in the history of CFS. Gold and colleagues performed virologic, immunologic and psychiatric studies on 26 CFS patients. The paper’s publication in the Journal of the American Medical Association was announced by a media release stating that the study provided evidence that CFS is caused by depression. There was an uproar within the CFS research community. Paul Cheney, a respected researcher, wrote an open letter to the JAMA editors8 which stated, "After reading your article by Gold and colleagues concerning chronic fatigue, I am quite certain that this study has made almost no contribution to our understanding of severe and disabling fatigue." Cheney pointed out that the study used depression as a selection criteria, making their conclusion that, "the patients had a high amount of distress on standardized psychological tests" a rather unsurprising one. The paper itself admitted that only 6 of the patients met the CDC criteria for CFS, and half of the patients were working full time, making the sample unrepresentative.
The Guidelines cite the Gold paper as Level II evidence (second highest rating) that reactivation of Epstein-Barr Virus replication is not increased in CFS patients. However, Cheney points out that only a small percentage of the patients in the Gold study had abnormal EBV titers, stating, "Since most patients had essentially normal EBV titers, it is not surprising that EBV culture attempts and hybridization data were unremarkable and no different than controls."
A further criticism is that the authors of the Gold paper make a number of gross generalisations from the sparse amount of their own data and cite an inordinate number of references (often not the most relevant) to bolster these conclusions. Cheney concluded, "Gold’s study has little scientific merit and its appearance in your journal says a great deal more about the bio-politics of JAMA editors and Harborview Medical Clinic than the real scientific concerns of this pressing clinical issue."
Also of great concern are the exaggerated rates of depression quoted in the Guidelines. Under the heading, "Does chronic fatigue overlap with other illnesses?" the Guidelines state, "Up to two-thirds of adults with CFS have either a prior, or concurrent, diagnosis of major depression...By comparison, the lifetime rate of comparable depressive disorders in the general community is 15%-25%..." This paragraph is very misleading. As members of the Working Group know, the two-thirds figure for lifetime depression in those with CFS is not credible. The Working Group is well aware that the problem in measuring depression in CFS is the same as that encountered in assessing somatisation disorder. Taylor and Jason9, in a study that properly controlled for the physical symptoms of CFS, found a lifetime prevalence of major depression of 28% in CFS patients.
The main issue in the study of depression in CFS is that if the symptoms of CFS are considered "medically unexplained" by the interviewer, they will be coded as evidence of a psychiatric disorder. Taylor and Jason9 have shown clearly that the biases of the interviewer using the Diagnostic Interview Schedule (DIS) determine to a large degree the prevalence rates in CFS for lifetime psychiatric disorders, major depression and somatisation disorder. They have also shown that the DIS will produce considerably larger scores of psychiatric illnesses than the Structured Clinical Interview for the DSM-III-R (SCID). In reviewing the rates of psychiatric illness found in studies of CFS, they state, "prevalence rates for total lifetime psychiatric disorders that occurred before, during, or after the onset of chronic fatigue range from 24.5% to 85.7%. With respect to specific diagnoses, rates have ranged from 12.5% to 76.5% for major depression, and from 0% to 28% for somatization disorder." Given the difficulties of objective measurement and the large range of scores the studies have produced, it serves no purpose to quote in the Guidelines a figure such as "two-thirds for lifetime depression in CFS".
The following papers are cited by the Working Group to show that depression is common in CFS:
1. Taerk et al.10 tested 24 patients with "neuromyasthenia" using the Diagnostic Interview Schedule (DIS). In their attribution of symptoms, they made no allowance for the common symptoms of CFS, attributing each of the physical symptoms as evidence of psychiatric illness and found a 67% rate of major depression. The citing of this paper is inappropriate.
2. The Manu et al.11 study required a person to be tired for 50% of the time for the past one month to qualify as a subject. Only 8% of the subjects were unemployed. They studied 100 people using the DIS and made no allowance in the attribution of symptoms for the common symptoms of CFS. Assigning a psychiatric category to each of the physical symptoms of CFS, they found that a psychiatric diagnosis accounted for 64% of those reporting fatigue, stating, "our findings suggest that chronic fatigue is an expression of somatization ...associated, in the majority of our patient, with three distinct psychiatric conditions: mood disorders, somatoform disorders, and anxiety disorders." The fallacy of these conclusions is self-evident. This is also an inappropriate reference.
3. Kruesi et al.12 studied 28 CFS patients who met the 1988 CDC criteria. This study attempted to make an allowance for the common symptoms of CFS in the attribution of symptoms. The lifetime prevalence of major depressive episodes in this study was 54%. This figure, although lower than other studies, is still high. Two things that could account for this is firstly, the use of the DIS - Taylor and Jason9 showed that the DIS consistently gives a higher psychiatric diagnosis than did the SCID. Also, it is likely that Kruesi et al. only made allowance for those symptoms listed in the 1988 CDC criteria, attributing the other physical symptoms experienced by the CFS patients to psychiatric causes.
4. Wessely and Powell 13 studied 47 patients with fatigue of at least 6 months duration and partially controlled for the symptoms of CFS in the attribution of symptoms by not listing fatigue as a psychiatric diagnosis. However, all other symptoms common to CFS were coded as psychiatric. This paper found a 47% rate of major depression. This is also not an appropriate reference.
5. The deficiencies of the Gold et al. 7 paper, cited here to justify the Guidelines’ attempt to associate CFS with depression, have been discussed.
6. Hickie et al. 14 studied 48 patients meeting strict criteria for CFS using the Structured Clinical Interview for the DSM-III-R (SCID) and found a 46% rate of lifetime depression.
7. The citing of the Buchwald et al. 1995 3 paper is inexplicable as the study produced no information regarding depression.
Since much of the depression in CFS can be seen as a consequence of having a long-term illness, a more appropriate and useful measure of depression in CFS is that of the rate of depression in CFS patients before they became ill. Hickie et al.14 found that the rate of premorbid depression in CFS patients was no greater than that in the general community. We believe that the guidelines should have discussed the inappropriateness of assigning a psychiatric diagnosis such as depression to the symptoms of CFS and should have also explained the misleading nature of many of the studies linking depression to CFS.
The basic assumptions underpinning the Guidelines are alluded to in the paragraph headed, "What drawbacks can occur as a consequence of a diagnosis of CFS?" The Guidelines state, "Inappropriately linking simple biomedical notions of disease (e.g., infection or poisoning) with complex forms of ill-health (notably chronic fatigue) may create artificial concepts such as a ‘chronic viral infection’ and ‘chronic immune deficiency’. Such concepts may then actively promote ill-health, life-time disability or third party responsibility...Such overly simplistic notions tend to minimise the important roles of social and psychological factors in determining the course of chronic ill-health."
The premise of the Guidelines is that CFS is a post-infectious behavioural and interpretive disorder that is initiated by a viral infection or other stressor that causes the victim to believe that the illness continues on after the acute infectious stage and to imagine that the symptoms are severe and damaging. This belief supposedly creates a fear of exercise which then leads to prolonged inactivity and deconditioning, the supposed cause of many of the symptoms.
Attributing the cause of the illness to a viral infection or other physical cause is seen as the leading indicator of this behavioural problem, which is thought to be perpetuated by physicians who mistakenly assign a physical rather than psychological diagnosis to the illness. The cure for this interpretative disorder is believed to be cognitive behavioural therapy, which attempts to treat the faulty view of the illness, remove the fear of physical activity and instigate graded exercise programs to overcome the effects of deconditioning. In adopting this view of the illness, the Working Group demeans everyone concerned. It is insulting to those with the illness, many with swollen glands, severe headaches, sore throats, cardiac problems, difficulty with swallowing, severe cognitive problems, severe pain, visual and auditory abnormalities, food and chemical sensitivities, seizures, ataxia (loss of muscle co-ordination) and paresis (partial paralysis).
It is insulting to the many doctors who don’t view the illness as a behavioural problem to advise them that diagnosing CFS "may create or perpetuate myths about aetiology, natural history and treatment rationales which can themselves increase disability." Many of those with the illness would have been ill for months and unaware of what complaint they might have before finding a doctor that could provide a diagnosis, making the suggestion that it was the doctors’ behaviour and the provision of a diagnosis that were instrumental in prolonging the illness nonsensical.
This suggestion, that the diagnosis of CFS by a doctor could prolong the illness, will cause doctors to be even more reluctant to make a diagnosis, making it even more difficult for those who already find it necessary to go from doctor to doctor in an effort to find one that will provide an insight into the illness. In what other illness can it be said that providing a diagnosis will actually exacerbate the illness? This suggestion is highly objectionable.
At the heart of this view is a cynical distrust of the patient, a disbelief of the accounts of pain and fatigue. No amount of superficial "empathy" can mask this distrust. The Guideline’s proposals are a recipe for condescension and paternalism, suggesting that the doctor say to the patient, "Yes, we understand your illness and empathize, but you must realise that your pain and fatigue are subjective (imaginary) and will be alleviated by a few sessions with a psychologist and graded exercise."
These appear to be the "New Age" Guidelines - the solution to the complaint lies in simply changing our view of the illness. If true, this should be great news for those with other illnesses as well, like AIDS or cancer.
Under the heading, "What factors may delay recovery?" it is extremely disappointing that the Guidelines don’t mention the most important factor in delaying recovery: overexertion. Also not mentioned is the importance of protecting a person with CFS from unnecessary stress and the need to obtain adequate rest.
The Guidelines’ emphasis in this section on the person’s belief system and the doctor’s behaviour rather than on the need for the person with CFS to heed the body’s signal of fatigue, which in all other illnesses would be seen as a warning to seek rest, illustrates clearly that the Guidelines, as written, are at risk of being irrelevant and potentially dangerous to those with this illness. The dangers of overexertion, stress and inadequate rest, which can cause a relapse lasting months and exacerbate symptoms dramatically, need to be much more fully acknowledged if the document is to be credible.
CFS can have a devastating effect on children, affecting their self-image, social life and school studies. Yet the specific needs of children with CFS are not once mentioned in the Guidelines. This is an inexcusable omission. More than any other group, children need to have their illness validated and their special needs acknowledged. One would think that such topics as the use home tutoring or distance education, appropriate palliative measures, advice on alleviating social isolation and methods by which schools might accommodate a child with CFS by minimising the need to climb stairs or walk long distances between buildings would be a minimum requirement for a document purporting to provide guidelines on CFS.
We disagree strongly with the importance the Guidelines attach to the use of cognitive behavioural therapy (CBT) and graded exercise for CFS. CBT has been used in the past as a coping strategy to assist those with a chronic illness (e.g. chronic pain) to live more comfortably with their disability. But the Guidelines go much further than suggesting the use of CBT as a coping strategy. It is put forward as an "effective treatment" or curative measure. Sharpe15 states, "Though the results tell us little about the aetiology of the chronic fatigue syndrome, they show that a return to normal functioning (albeit often with continuing fatigue) is possible in most cases." We believe the Guidelines greatly exaggerate the usefulness of CBT in chronic fatigue syndrome.
The evidence for CBT in CFS is conflicting. Two studies, Lloyd et al.16 and Friedberg and Krupp2 found that CBT was not effective. This fact alone disqualifies CBT from being awarded the Level I rating that was assigned to it by the Working Group. A Level I rating requires CONSISTENT evidence obtained from MORE than two independent studies. CBT, by the Guideline’s own criteria, doesn’t qualify for a Level I rating. The Working Group attempts to circumvent this issue by including Fulcher and White’s paper17 on graded exercise as CBT. However, this stretches the definition of CBT beyond its breaking point. Fulcher and White’s paper was strictly an exercise regime, with no psychological intervention whatsoever. No attempt was made to change the patients’ attitudes towards the illness, no request was made of the patient to consider psychological or social factors, no attempts were made to reduce "perfectionism" or self criticism and no attempt was made to adopt a "problem solving" approach with interpersonal and occupational difficulties. Simple, graded exercise cannot be considered to be CBT. We therefore request the Working Group to downgrade CBT to its rightful rating of III-4 (conflicting evidence obtained from two or more well-designed and controlled studies).
Another point concerning CBT is that none of the papers cited as evidence for CBT describe significant improvement of the symptoms of CFS, although the Deale paper claims to have reduced fatigue. One has to question the relevance of a set of Guidelines that places its first priority on a treatment that has little or no effect on such common symptoms as headaches, severe pain, cognitive difficulties, food and chemical sensitivities, cardiac abnormalities and neurally mediated hypotension.
Also, all three of the studies cited in the Guidelines to justify the use of CBT, Sharpe et al. 15, Deale et al 18 and Fulcher and White 17, must be viewed with a healthy scepticism, as the subjects in these three papers seem to be carefully selected to include only the very moderately disabled, creating a group that is unrepresentative of the illness. In only one of the three papers, the Deale study, did the subjects fulfill the criteria for the 1994 CDC Case Definition.
In the Sharpe15 study, The mean Karnofsky score for those qualifying as subjects was 71 before treatment. A score of 80 is considered normal functioning. Gibbons, Macintyre and Richards19 report that the 143 patients involved in the "Case History Research on ME would have scored between 30-60 on the Karnofsky Performance Scale. In a study of Ampligen involving 92 subjects with CFS20, the average Karnofsky score was about 50. This illustrates the very modest disability of Sharpe’s subjects. It was not a representative group of CFS patients.
Sharpe studied 60 people with CFS. He used the Oxford criteria22, which doesn’t exclude those with major depression nor does it require any specific physical symptoms other than fatigue of six months duration. Jason et al.21 state, "It is conceivable that included within the Sharpe et al. sample were individuals with moderate fatigue caused primarily by depression and other psychological factors rather than CFS (at study onset 67% of the sample has an anxiety or depressive diagnosis and 10% had a somatization disorder)."
Sharpe and colleagues make much of the 10 point improvement that was found in the Karnofsky score of 73% of the subjects after CBT. However, when Lloyd et al.16 in a 1993 paper on CBT found that the CFS subjects receiving CBT increased their Karnofsky scores from 71.5 to 80, they stated the result was "insignificant" as the finding wasn’t supported by increases in other measures such as the Profile of Mood States and the number of hours spend in nonsedentary activities. We think the same judgement should be applied to Sharpe’s study.
Deale et al.18 states that his 60 patients fulfilled the Sharpe 199122 and the Fukuda 199423 criteria. A surprisingly large number of CFS patients were declared ineligible for the study; the 60 being chosen from 142 assessed CFS patients. Thirty subjects were given CBT and 30 were provided with relaxation therapy. The report states that at 6-month follow-up, 19 of the patients receiving CBT and 5 of those receiving relaxation were improved. They comment, "The combined improvement in physical functioning and fatigue was such that by final follow-up 15 cognitive behavior therapy patients and two relaxation patients no longer fulfilled the diagnostic criteria for chronic fatigue syndrome." The suggestion is that CBT has effectively cured 50% of the CFS subjects. However, 28% of those that received CBT were unchanged or worse at the trials end. Also, the final average on the fatigue scale for those receiving CBT was 4.1. A score of 4.0 indicates excessive fatigue.
In the "Treatment Procedures", the Deale study discusses the exercise regime and states, "Patients were encouraged to persevere with their targets and not to reduce them on a bad day or exceed them on a good day." This is dangerous advice and a sure recipe for serious relapse. It is worth re-quoting Friedberg and Krupp’s2 statement, "Our impression is that many of our patients were already performing near or at their activity ceiling. A graduated activity schedule beginning at their current behavioral baseline would have quickly exceeded their threshhold for setbacks and relapses. Behavioral schedules are more appropriate for depressed patients without CFS, for whom increasing activity produces unequivocal physical and psychological benefits."
We believe the claims by Deale et al. about the benefits of CBT should be viewed with great caution.
Fulcher and White17 studied the use of graded exercise on 66 CFS patients. They screened 167 CFS patients, an abnormally large number of people, to find the 66 subjects. Their selection criteria was unique. They used the Oxford criteria then screened out all those with a psychiatric or sleep disorder. Sleep disorder is extremely common in CFS, so much so that it is found in EVERY case definition. With no psychiatric or sleep disorders, the people chosen for this study were a very select group indeed. Commenting on the group of subjects in this study, Dr Alan Franklin stated24, "To most doctors dealing regularly with patients with the chronic fatigue syndrome, such patients are a small proportion, perhaps a tenth, of the total and would probably exclude most children."
Fulcher and white seem to take an exceptionally narrow view of the illness, stating that the fatigue associated with CFS may be caused by deconditioning, sleep deprivation or psychological distress. They don’t consider the possibility of an infectious agent or a biochemical abnormality.
The exercise treatment used in this study is worth repeating in its entirety, as it shows the uniqueness of this group:
"Patients attended weekly for 12 weeks of supervised treatment and the next week’s exercise prescription. All laboratory sessions were supervised by an exercise physiologist using basic principles of exercise prescription, which adapted for the patient’s current capacity. Home exercise was prescribed on at least five days a week, with initial sessions lasting between five and 15 minutes at an intensity of 40% of peak oxygen consumption (roughly 50% of the maximum recorded heart rate). The daily exercise prescription was increased by one or two minutes (negotiated with the patient each week) up to a maximum of 30 minutes. The intensity of exercise was then increased to a maximum of 60% of peak oxygen consumption. Patients were given ambulatory heart rate monitors to ensure that they reached but did not exceed target heart rates. The main exercise was walking, but patients were encouraged to take other modes of exercise, such as cycling and swimming. Patients were advised not to exceed prescribed exercise during a good phase. If patients complained of increased fatigue, they were advised to continue at the same level of exercise for an extra week and increase when the fatigue had lessened."
It is a major concern that the Working Group believes that the majority of people with CFS would be able to undertake this exercise regimen without experiencing a serious relapse. Lapp25 found that one 8 to 10 minute test of maximal exercise is enough to bring on a relapse. He asked 31 CFS patients to record their symptoms on an integer scale starting 3 weeks prior until 12 days after the maximal exercise testing. They used a braked bicycle in which the work of peddling increased steadily with time. The subjects reached maximum oxygen consumption in 8 to 10 minutes. 23 of the subjects (74%) experienced worsening fatigue and 8 (26%) stayed about the same after the effort. None improved. The average relapse lasted 8.82 days, although this score may be low as 22% were in relapse when the study ended at 12 days. They also found changes in lymph pain, sleep quality, joint and muscle pain, headache and sore throat.
It should also be noted that exercise is one of the precipitating factors of neurally mediated hypotension, a condition closely associated with CFS. NMH is discussed later in this submission. We believe that the results of the Fulcher and White paper, which found that graded exercise is beneficial to those with CFS, must be viewed with great caution due to the select group of subjects.
In view of the deficiencies described, we don’t feel the papers cited to justify the use of CBT are of sufficiently high scientific merit to justify the high priority given to this treatment in the Guidelines.
In the Guideline’s evaluation of treatment trials, Ampligen is given a very low rating. The drug is characterised as, "not recommended, unrepresentative patient group, further studies indicated, limited treatment benefit and no replication study". One paper, Strayer 199420 is listed in the Guidelines’ bibliography. There have actually been two trials of Ampligen. Strayer and colleagues also published a smaller study in 199526. We disagree strongly with the Guideline’s evaluation of this drug.
The Strayer 1994 study was a randomised, placebo controlled, double-blind study of 92 CFS patients meeting the 1988 case definition. 800 mgs per week of Ampligen were provided as an intravenous infusion to each of the 45 subjects in the Ampligen group. The equivalent amount of saline was given to the placebo group.
The Karnofsky score, a measure of functional status, averaged 51 in the Ampligen group at the beginning of the study, indicating that the group was more severely disabled than the average CFS group, justifying the Guideline’s evaluation of the group as being "unrepresentative". However, the fact that the group was severely disabled makes the improvement seen with Ampligen all the more noteworthy.
The results of the 24 week trial showed that the Ampligen group’s average Karnofsky score increased 20% from 51 to 61. The perceived cognitive deficit as measured by the Symptom Checklist 90-R (SCL-90-R) was reduced by 27%. Duration of treadmill testing performance increased by 10%. The Activities of Daily Living (ADL) measure increased 23%. The drug was tolerated well by the subjects with few adverse effects. As the group was quite severely disabled, the 10 point improvement in the Karnofsky score, while modest, meant a dramatic improvement in the functional status and lifestyle of these patients.
The effect of the drug on the 45 patients was so pronounced that HEM, the makers of the drug, decided to end the trial after 24 weeks, rather than at the end of the planned 48 weeks. The improvement in the Ampligen patients was such that it was making it difficult to keep the study blinded. Stopping the supply of Ampligen had a profound impact on the 45 patients. Hillary Johnson, author of "Osler’s Web"27, described the effect of stopping the infusions on the 45 patients:
"With the premature end of the trial, the forty-five victims of the disease who had received the drug were cut adrift. Many of them had been restored from total disability to a degree of ability that had eluded them for years, and when the Ampligen was withdrawn, they noticed their intellectual clarity and physical strength slipping after as few as ten days. By the third and fourth week off the drug, patients who had been confined to wheelchairs before they entered the trial were returned to their wheelchairs; almost everyone was again housebound."
One sufferer told a journalist, ‘It’s like somebody turned on a light and I could see, and then they turned it off again." Seventeen of the patients subsequently sued HEM in an attempt to obtain a continued supply of Ampligen.
Ward Karns, who has had CFS since 1987, was patient 034 in the Strayer 1994 study. He said this about his experience with Ampligen:
"I received Ampligen for 6 months (9/90-4/91) and for 12 months (1/92-1/93). Ampligen was efficacious for everyone I knew receiving it. The following are the documented improvements for me while taking Ampligen: 1. My productive hours per day improved from about 3 or 4 to approximately 7 to 9, 2. IQ improved from 124 to greater than 134, 3. Alpha Interferon, which is produced when viruses invade cells, decreased from 460 to less than one (extraordinarily high to normal), 4. T4-Lymphocyte numbers increased from 846 to 1817, 5. T8-Lymphocyte numbers increased from 414 to 674, 6. B-Lymphocyte numbers increased from 188 to 401, 7. Natural Killer Cell numbers increased from 14% to 34%, 8. Natural Killer Cell activity increased from 7.4% to 8.4%, 9. Ability to perform pre-selected tasks improved from 59% to 71%.
My pain reduced to the point that I realized I had a hernia which had not been recognized due to groin lymph node pain and swelling caused by CFS. After 4 months of receiving Ampligen I could exercise without exacerbation of my CFS symptoms. I was not able to do so before receiving Ampligen despite years of trying to gradually increase my exercise capacity.
Other CFS symptoms that improved while I received Ampligen vastly increased my quality of life. These are a few examples. Short term working memory, hand to eye coordination, and my cognition improved. I could dial a phone number the first time, rather than the three to four times it took due to memory loss, or because of inadvertently pressing wrong keys. Short term memory improvement enabled me to cook without burning food or forget to turn off burners, draw bath water without flooding the house, and not lose my car in parking lots.
I was considerably more efficient in completing tasks because I was not constantly losing my train of thought. I was able to read without continuously going back to reread sections of paragraphs I forgot. My increase in coordination and cognition made it easier and more pleasurable to walk and drive because it required significantly less concentration and vigilance not to fall or have an accident. Visual acuity fluctuations diminished. I could tolerate a larger range of ambient temperatures without becoming uncomfortable. The frequency and intensity of my headaches lessened. Spontaneous bruising on my body stopped so there was less tenderness. Dryness and irritation of eyes, nose, and mouth declined. Stiffness and soreness of joints was reduced.
My heightened health, ability, and dependable mental and physical stamina made planning and participation in daily events a great deal more successful and enjoyable."
Strayer 199526 also studied a smaller group of 15 CFS patients that met the 1988 CDC criteria in an open-label (unblinded) study of Ampligen. The mean Karnofsky score was 47 at baseline. The amount of Ampligen was initially 400 mg per week then increased to 800 mg per week. Some patients were subsequently increased to 1200 mg per week.
The Karnofsky scores in this study increased from an average of 47 to 67 after 12 weeks of Ampligen therapy. The average reached 80 by 24 weeks and 85 by 60 weeks. A score of 80 describes a person capable of normal activity with effort.
The patients tested at baseline in the Ampligen study for giant cell formation all tested positive. It’s known that Human Herpesvirus-6 (HHV-6) infection produces giant blood mononuclear cells. The study states, "The frequency of virus-producing giant cells in blood mononuclear cell cultures was reduced during the Ampligen treatment in 50% of the patients at 8 weeks and 77% at 16 weeks...At 28 weeks, all the patients tested demonstrated a reduction in giant cells with an average reduced giant cell score of 83%."
Exercise tolerance was measured by oxygen uptake and duration of treadmill testing. Both measures increased throughout the 24 weeks of testing. The patients’ scores on the Wechler Memory Scale increased 23% after 16 weeks and 54% after 24 weeks of Ampligen therapy.
In a separate study of the 15 patients taking part in the Ampligen trial, Suhadolnik et al.28 found that prior to treatment, the intracellular antiviral pathway, 2-5 synthetase/RNaseL, was activated (upregulated) in CFS patients. They also found evidence of reactivated infection with HHV-6. The authors state, "Our results show that Ampligen has biological activity in CFS, as evidenced by the restoration of the 2-5 synthetase/RNaseL system towards normal. This conclusion is supported by clinical improvements during Ampligen therapy, which are being reported separately." Commenting on the decrease in giant cell formation, they state, "This decrease could be due to the direct inhibition of viral reactivation. Thus the finding that treatment with Ampligen downregulates an already upregulated pathway strengthens the argument that this dsRNA drug may have antiviral properties in vivo."
It is obvious that the effects of Ampligen on the CFS patients was dramatic. The increase of the average Karnofsky scores from 47 to 85 are extraordinary. The statements of those involved in the studies and the fact that 17 people sued HEM in order to continue the supply of the drug are testimony to it’s efficacy. All the major symptoms seem to be significantly alleviated by the use of the drug.
These studies speak volumes about the nature of CFS. The next question to be asked is: how can CFS be primarily a psychological illness when a single drug has such a dramatic, systemic effect on the illness?
The Guidelines also address the issue of sleep problems, which are common in CFS. The Guidelines’ advice for improving sleep consists of: 1. Restricting the sleep period to about eight night-time hours. 2. Avoiding stimulants during the evening period. 3. Reducing or abolishing daytime naps. 4. Promoting daytime physical and mental activity.
This may be sound advice for a healthy person but for someone with CFS it’s counterproductive. We would remind the working group that this is an illness of exhaustion, for which there is only one cure: rest. Restricting night-time sleep to ANY set time places a limit on those ingredients most necessary for the recovery of energy. The same holds true for the advice to reduce or abolish daytime naps. The level of exhaustion is such that there is often no alternative but to rest and sleep. The final advice, to promote daytime physical and mental activity, suggests an ignorance of the illness that is disturbing. The greatest hindrance to recovery is overexertion. The very nature of the illness requires that those with CFS function at or near the upper limit of available energy levels. If there is one rule for survival it is to rest when overly tired. Those with CFS have learned from long experience that breaking this rule is the surest way to bring on a relapse that can last for months. This advice again increases the likelihood that the Guidelines will lack relevance to those with this illness.
It is disappointing to see the statement, "Premorbid and concurrent depression are common in people with CFS," headlined in the box at the beginning of this chapter.
Premorbid depression has been shown to be no more prevalent in those with CFS than is found in the general community14. As discussed previously, inappropriate attribution of the common physical symptoms of CFS to psychiatric diagnoses has been a feature in many of the studies on CFS and depression, making their findings less than credible.
It would have been appropriate for the Working Group to emphasize the differences between CFS and depression by discussing in detail the study by Demitrack et al.29, who found that cortisol levels in CFS were lower than normal when the adrenal cortex was stimulated by ACTH. This is the opposite response from that of clinically depressed patients.
It is also disappointing that in the evaluation of evidence for immunological factors in the pathophysiology of CFS, the Guidelines state that there has been no consensus on the pattern and prevalence of immunological disturbance in people with CFS. This is misleading as there are two immune system abnormalities found consistently in CFS research - evidence of an activated immune system and low Natural Killer function.
In relation to immune system activation, the Guidelines cite 9 references to justify the statement that "Despite numerous studies there is no consensus on the pattern and prevalence of changes in peripheral blood lymphocyte subpopulations or activation status." There is actually a considerable degree of consensus amongst this group in relation to activation status. The only paper that was cite that did not find evidence of immune activation was Peakman M, Deale A, et al.
Other papers that found evidence of immune activation that are not cited in the Guidelines are:
1. Bates DW, et al. 199530. They concluded, "The immunologic abnormalities are in accord with a growing body of evidence suggesting chronic, low-level activation of the immune system in chronic fatigue syndrome.
2. Suhadonik RJ, et al. 199428, who concluded, "The upregulated 2-5A pathway in CFS before therapy is consistent with an activated immune state and a role for persistent viral infection in the pathogenesis of CFS."
3. Hilgers A, et al. 199631 who concluded, "Together with other results, the data confirm the hypothesis that a reduced or unstable immune control or delayed immune reaction to persisting viruses or bacterial intracellular pathogens, possibly triggered by common infections or other environmental factors, can lead to a chronic neuroimmune activation state and auto-immune disorders."
4. Buchwald D, et al. 199732 who concluded, "Our findings that levels of several markers were significantly correlated points to a subset of patients with immune system activation."
The Guidelines state that reduced lymphoctye proliferation and natural killer cell cytotoxicity are common findings in CFS research but are nonspecific, meaning that other illnesses, including depression, may be the cause.
In regards to Natural Killer Cell activity, we would like to bring one paper to the attention of the Working Group. In the CFS literature, there are very few papers that find a strong correlation between the measurement of one abnormality and the overall symptom severity of CFS. Ojo-Amaize 199433 measured the degree of Natural Killer Cell activity in 20 CFS patients and compared it to the degree of symptom severity found in the patients. He found that the activity of NK cells in the CFS patients was abnormally low. He also found that lower scores of NK activity were related to high symptom severity. The authors concluded, "...the fact that NK cell activity decreases with the increased severity and duration of certain clinical variables suggests that measurement of NK cell function could be potentially useful for stratification of patients and possibly for monitoring therapy for and/or the progression of CFIDS."
We would also like to mention an important paper by Lutgendorf et al.34, not cited in the Guidelines. This study investigated immunity (including lymphocyte proliferation) and cognitive ability in 65 CFS patients. Importantly, the study controlled for depression. Its exclusion from the Guidelines is inexplicable. The study found that lymphocyte proliferation was much lower in those with higher cognitive difficulties. Neopterin levels (evidence of immune activation) correlated well with cognitive difficulties, and were higher than normal. These findings were also valid when depression was isolated as a variable. The authors stated,
"we found that independent of depression, blastogenic responses were significantly dampened and neopterin levels were significantly elevated as a function of greater cognitive difficulties. This suggests that the presence of cognitive difficulties experienced by CFS patients may be linked to specific abnormalities in the immune system which cannot be explained solely by mood disturbances or other depressive features."
We also believe that the paper on Neurally Mediated Hypotension, by Issam Bou-Holaigah et al.35 , requires specific attention. This condition, involving severe light-headedness or fainting when changing from a sitting or horizontal position to standing upright, also can involve such symptoms as diaphoresis (acute perspiration), nausea, abdominal discomfort, blurred vision, and pallor. Using an upright tilt table test, this study found that an abnormal response was evident in 22 of 23 CFS patients. It should be noted that factors known to precipitate NMH are prolonged standing, a warm environment, EXERCISE, and stressful situations. Nine patients reported complete or nearly complete resolution of CFS symptoms after therapy with increased intake of salt, fludrocortisone, ß-adrenergic blocking agents and disopyramide, alone or in combination. Since 23 of 24 patients were found to have NMH, we suggest that the condition be included as part of the screening of CFS patients and that the treatments for NMH be considered for further evaluation. The authors concluded:
"The findings of this study document a close link between neurally mediated hypotension and the chronic fatigue syndrome. Evidence for this association comes from the extensive overlap in symptoms and exacerbating features between the two conditions, the almost uniform provocation of neurally mediated hypotension and uniform exacerbation of symptoms in chronic fatigue syndrome patients during upright tilt, and the improvement in symptoms of chronic fatigue syndrome in association with therapy directed at neurally mediated hypotension."
We welcome the acknowledgement that neurocognitive performance in people with CFS is impaired.
Previously mentioned in this submission is the fact that very few studies on CFS provide evidence of an abnormality that correlates strongly with symptom severity. However, a group of important papers from the University of Newcastle36 have shown evidence of urinary metabolites associated with CFS, the concentrations of which correlate very well with the severity of the symptoms of CFS.
They have also extended this work to show that the pattern of the presence and concentrations of these metabolites in individuals correlates with the particular set of symptoms that are experienced.37, 38 This work is ground-breaking and deserves sympathetic treatment and special emphasis in the Guidelines.
Another body of research, completely ignored in the Guidelines, deserves special mention for its insight into an intracellular antiviral pathway in association with CFS and for it’s potential to provide a diagnostic marker for the illness.
Suhadolnik et al.28 have found that two of the enzymes of the 2-5A synthetase/RNaseL antiviral pathway , bioactive 2-5A and RNaseL, were found in increased quantities in patients with CFS, indicating an activated immune state. The 2-5A synthetase/RNaseL pathway is part of the antiviral defence mechanism of mammalian cells and is activated mainly by viral infection. The authors state:
"The upregulation of the 2-5A synthetase/RNaseL pathway described here has several striking features. First, 2-5A synthetase is present predominantly in the activated form in PBMC [peripheral blood mononuclear cells] extracts from individuals with CFS but not in those from controls. Second, this activated 2-5A synthetase produces intracellular concentrations of bioactive 2-5A that are elevated by up to 220 fold. Third, this bioactive 2-5A results in a marked elevation in the activity of RNaseL, the terminal functional enzyme of this antiviral pathway. This pathway phenotype could result from chronic overstimulation due to chronic viral reactivation. "
Suhaldonik et al.39, in a paper entitled, "Biochemical evidence for a novel low molecular weight 2-5A-dependent RNaseL in chronic fatigue syndrome", found evidence that in CFS patients, the 2-5A synthetase/RNaseL antiviral pathway is not only activated, but also is dysfunctional in the sense that some of the enzymes involved in the process are of lower than normal molecular weight. This dysfunction may be unique to CFS, which could ultimately lead to a diagnostic marker.
We would also like to bring to the attention of the Working Group three important recent papers that associate cardiac abnormalities with CFS. In a cohort of 67 CFS patients, Lerner et al.40, using Holter monitoring, found abnormal T-wave inversions in 61% of the subjects. He found abnormal T-wave flattenings in 96% of the patients. The authors concluded, "This study confirms our earlier report that CFS patients uniformly have abnormal oscillating T-wave flattenings and T-wave inversions by Holter monitoring." They added, "At light and electron microscopic review, eight of the nine patients with right ventricular endomyocardial biopsies had cardiomyopathic changes. One patient had inflammatory myocarditis." In the second study, Lerner et al.41, tested 18 CFS patients with abnormal T-wave results by Holter monitor, high Human Cytomegalovirus titers and low Epstein-Barr virus titers. None of the 18 patients could work or function normally. He treated this group with Ganciclovir, giving intravenous infusions for 30 days. Six months after treatment, 13 patients had improved dramatically and returned to their premorbid activity. The characteristics of those in the group that didn’t improve were lower titers to HCMV and higher titers to EBV than the group that improved.
The third paper by Lerner et al.42, entitled "A unified theory of the cause of chronic fatigue syndrome" proposes that CFS is an infection of the heart by either Human Cytomegalovirus or Epstein-Barr virus or both. They suggest, "EBV and/or HCMV nucleic acids are present in myofibers (myoctyes) of cardiac tissues of these CFS patients and that they are detectable by PCR or in situ hybridization techniques." In order to detect the virus in the heart, a biopsy must be performed. They also suggest the use of antiviral drugs such as acyclovir, ganciclovir, foscarnet and interferon, stating, "To be sure, no antiviral drug is active in vitro vs. any latent, nonpermissive persistent herpesvirus infection. However, implicit in this unified hypothesis is the assumption that low-level, continuing, infectious herpesvirus multiplication is occurring in susceptible B cells (EBV) and epithelial cells (EBV), and/or in tissue macrophages (HCMV) and cardiac myoctyes (EBV and HCMV)...Eradication of productive virus infection by an effective antiviral drug might inhibit the slowly active, persisting pathologic process we hypothesize."
We disagree strongly with the cynical way in which the Working Group misrepresented the quotes from the consumer submissions. Instead of using the quotes to support the sentiments expressed by the consumer, they were taken out of context and used to support specific points made in the Guidelines, many of which were directly contradictory to the consumers’ viewpoint expressed in the Consumer Perspective. This reprehensible use of consumer input shows a callous disregard towards those that made the effort to voice their views.
For example, this quote from page 9 of the Consumer Perspective was made in the context of describing the difficulties of living with CFS: "One consequence of being chronically ill for years at a time is the isolation. As much as you try, it is very hard to keep up the old friendships from school, work and uni. People move on, but I have not been able to go out and socialise like before." However, this quote was placed adjacent to the statements describing CBT and the need for psychosocial rehabilitation strategies, creating the impression that the quote was indicative of a psychological problem.
We request that the views expressed in the submissions be presented in the Guidelines in a fashion that is in keeping with the original sentiment intended by the consumer. We also request that the placement of the quotes be approved by the consumer representative.
We also object to the fact that Joan Rothery was heavily involved in the compiling and summarising of the submissions without knowledge of the consumers. Although Joan Rothery was the original consumer representative, she resigned when it became apparent that her appointment did not have widespread consumer approval. As consumers, we assumed that Craig Ellis was our sole representative. We had no knowledge of Joan Rothery’s involvement, illustrating again the contemptuous attitude of the Working Group towards the consumers.
In summary, we make the following points:
For our last word on the Guidelines, we quote from the letter written by the editorial staff of The Lancet in response to the Royal Colleges report. 43 "Psychiatry has won the day for now. A decade hence, when an organic cause for at least some cases of CFS may have emerged, it would be tempting to ask the committee to reconvene. We believe that the report was haphazardly set-up, biased, and inconclusive, and is of little help to patients or their physicians."
1. Shepherd C, Macintyre A. Graded exercise in chronic fatigue syndrome: Patients
should have initial period of rest before gradual increase in activity. British Medical
Journal 1997; 315: 947.
2. Friedberg F, Krupp LB. A comparison of cognitive behavioural treatment for chronic
fatigue syndrome and primary depression. Clinical Infectious Diseases 1994; 18 Suppl 1:
S105-S110.
3. Buchwald D, Umali P, Umali J, et al. Chronic fatigue and the chronic fatigue syndrome:
prevalence in a Pacific Northwest health care system. Annals of Internal Medicine 1995;
123: 81-88.
4. Johnson SK, DeLuca J, Natelson BH. Assessing somatization disorder in the chronic
fatigue syndrome. Psychosomatic Medicine 1996; 58: 50-57.
5. Hickie I, Lloyd A, Hadzi-Pavlovic D, et al. Can the chronic fatigue syndrome be defined
by distinct clinical features? Psychological Medicine 1995; 25: 925-935.
6. Hicke I. Parker G. Chronic fatigue syndrome [Letter] British Journal of Psychiatry
1990; 157: 449-450.
7. Gold D, Bowden R, Sixbey J, et al. Chronic fatigue. A prospective clinical and
virologic study. Journal of the American Medical Association 1990; 264: 48-53.
8. Cheney PR. A letter: to JAMA editor. CFIDS Chronicle 1990; Spring: 146.
9. Taylor RR, Jason LA. Comparing the DIS with the SCID: chronic fatigue syndrome and
psychiatric comorbidity. Paper presented at the AACFS conference: San Francisco 1994.
10. Taerk GS, Toner BB, Salit IE, et al. Depression in patients with neuromyasthenia
(benign myalgic encephalomyelitis). International Journal of Psychiatric Medicine 1987;
17: 49-56.
11. Manu P, Matthews D, Lane TJ. The mental health of patients with a chief complaint of
chronic fatigue: a prospective evaluation and follow-up. Archives of Internal Medicine
1988; 148: 2213-2217.
12. Kruesi MJP, Dale J, Straus SE, Psychiatric diagnoses in patients who have chronic
fatigue syndrome. Journal of Clinical Psychiatry 1989; 50: 53-56.
13. Wessely S, Powell R. Fatigue syndromes: a comparison of chronic "postviral"
fatigue with neuromuscular and affective disorders. Journal of Neurology, Neurosurgery and
Psychiatry 1989; 52: 940-948.
14. Hickie I, Lloyd A, Wakefield D, Parker G. The psychiatric status of patients with the
chronic fatigue syndrome. British Journal of Psychiatry 1990; 156: 534-540.
15. Sharpe M, Hawton K, Simkin S, et al. Cognitive behaviour therapy for the chronic
fatigue syndrome: a randomised controlled trial. British Medical Journal 1996; 312: 22-26.
16. Lloyd AR, Hickie I, Brockman A, et al. Immunologic and psychologic therapy for
patients with chronic fatigue syndrome: a double-blind, placebo-controlled trial. American
Journal of Medicine 1993; 94: 197-203.
17. Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with
the chronic fatigue syndrome. British Medical Journal 1997; 314: 1647-1652.
18. Deale A, Chalder T, Marks I, Wessely S. Cognitive behaviour therapy for chronic
fatigue syndrome: a randomised controlled trial. American Journal of Psychiatry 1997; 154:
408-414.
19. Gibbons R, Macintyre A, Richards C. Cognitive behaviour therapy for the chronic
fatigue syndrome [Letter]. British Medical Journal 1996; 312: 1096.
20. Strayer DR, Carter WA, Brodsky I, et al. A controlled clinical trial with a
specifically configured RNA drug, poly(I)åpoly(C12U), in chronic fatigue syndrome.
Clinical Infectious Diseases 1994; 18 Suppl 1: S88-S95.
21. Jason LA, Richman JA, Friedberg F, et al. Politics, science and the emergence of a new
disease. American Psychologist 1997; 52(9): 973-983.
22. Sharpe MC, Archard LC, Banatvala JE, et al. A report - chronic fatigue syndrome:
guidelines for research. The Royal Society of Medicine 1991; 84: 118-121.
23. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive
approach to its definition and study. Annals of Internal Medicine 1994; 121: 953-959.
24. Franklin AJ. Graded exercise in chronic fatigue syndrome. British Medical Journal
1997; 315: 947.
25. Lapp CW. Exercise limits in chronic fatigue syndrome. American Journal of Medicine
1997; 103(1): 83-84.
26. Strayer DR, Carter W, et al. Long term improvements in patients with chronic fatigue
syndrome treated with Ampligen. Journal of Chronic Fatigue Syndrome 1995; 1(1): 35-53. 27.
Johnson H. Osler’s Web: Inside the labyrinth of the chronic fatigue syndrome
epidemic. Crown Publishers, Inc. 1996. 28. Suhadolnik RJ, Reichenbach NL, et al.
Upregulation of the 2-5A synthetase RNase L antiviral pathway associated with chronic
fatigue syndrome. Clinical Infectious Diseases 1994; 18 (Suppl 1): S96-S104.
29. Demitrack MA, Dale JK, Straus SE, et al. Impaired activation of the
hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. Journal of
Clinical Endocrinology and Metabolism 1991; 73: 1224-1234.
30. Bates DW, Buchwald D, Lee J, et al. Clinical laboratory test findings in patients with
chronic fatigue syndrome. Archives of Internal Medicine 1995; 155(1): 97-103.
31. Hilgers A, Frank J. Chronic fatigue Syndrome: evaluation of a 30 criteria-score and
correlation with immune activation. Journal of Chronic fatigue syndrome 1996; 2(4): 35-47.
32. Buchwald D, Wener MH, Pearlman T, Kith P. Markers of inflammation and immune
activation in chronic fatigue and chronic fatigue syndrome. Journal of Rheumatology 1997;
24(2): 372-376.
33. Ojo-Amaize EA, Conley EJ, Peter JB. Decreased natural killer cell activity is
associated with severity of chronic fatigue immune dysfunction syndrome. Clinical
Infectious Diseases 1994; 18(1): S157-S159.
34. Lutgendorf S, Klimas NG, Antoni M, Brickman A, Fletcher MA. Relationships of cognitive
difficulties to immune measures, depression and illness burden in CFS. Journal of Chronic
Fatigue Syndrome 1995; 1(2): 23-41.
35. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated
hypotension and the chronic fatigue syndrome. Journal of the American Medical Association
1995; 274: 961-967.
36. McGregor NR, Dunstan HR, Zerbes M, Butt HL, Roberts TK, Klineberg IJ. Preliminary
investigation of a molecular basis to chronic fatigue syndrome. Biochemical and Molecular
Medicine 1996; 57: 73-80.
37. McGregor N, Dunstan H, et al. Preliminary determination of the association between
symptom expression and urinary metabolites in subjects with chronic fatigue syndrome.
Biochemical and Molecular Medicine 1996; 58: 85-92.
38. McGregor N, Dunstan H, Butt H, Roberts T, et al. A preliminary assessment of the
association of SCL-90-R psychological inventory responses with changes in urinary
metabolites in patients with chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome
1997; 3(1): 17-37.
39. Suhadolnik RJ, Peterson DL, O’Brien K, Cheney PR. Biochemical evidence for a
novel low molecular weight 2-5A-dependent RNaseL in chronic fatigue syndrome. Journal of
Interferon and Cytokine Research 1997; 17(7): 377-85.
40. Lerner AM, Goldstein J, Chang CH, Zervos M, Fitzgerald JT, et al. Cardiac Involvement
in patients with chronic fatigue syndrome as documented with Holter and biopsy data in
Birmingham, Michigan, 1991-1993. Infectious Diseases in Clinical Practice 1997; 6: 327-33.
41. Lerner AM, Zervos M, Dworkin HJ, Chang CH, Fitzgerald JT, Goldstein J. et al. New
cardiomyopathy: pilot study of intravenous ganciclovir in a subset of the chronic fatigue
syndrome. Infectious Diseases in Clinical Practice 1997; 6(2): 110-117.
42. Lerner AM, Zervos M, Dworkin HJ, Chang CH, O’Neill W. A unified theory of the
cause of chronic fatigue syndrome. Infectious Diseases in Clinical Practice 1997; 6:
239-43.
43. Editorial staff of The Lancet. Frustrating survey of chronic fatigue [Editorial].
Lancet 1996; 348: 971.
Ted Shaw 1998
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