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An Assessment of the Chronic Fatigue Syndrome
Clinical Practice Guidelines
by Craig Ellis Consumer Health Forum Representative - May, 2002
This document explains my personal position in relation to the published version
of the Australian CFS Clinical Practice Guidelines. It explains why I decided
finally to give the guidelines my qualified support with cautious acceptance of
the management strategies advocated therein.
I am no longer a Consumers' Health Forum representative on the Royal
Australasian College of Physicians working group set up to produce the CFS
Clinical Guidelines. My comments in no way reflect any policy of, or endorsement
by, these or any other organisations.
I present this document simply as a statement of the processes undertaken during
my consideration of the pre-and post-publication guidelines.
The result of problems on the various sides of the debate concerning the
guidelines has seen the alienation of the very people in the CFS community who
invested the time and effort to make submissions and contribute to the process.
Some people have been angered while others, disillusioned. A cynical distrust
now permeates some people’s views of the guidelines and the Working Group. This
outcome was unnecessary and could have been avoided, or at least reduced; by all
parties, notwithstanding the working group management, State CFS Societies and
members of ME/CFS Association of Australia Inc.
However, whilst such an observation is easy made in hindsight, such an ideal
situation was never achieved. I believe it is now time for us all to move on
from the continual and often harmful negativity so evident during the past seven
years. It is my belief that the guidelines validate Chronic Fatigue Syndrome as
a severe illness while providing a useful, if imperfect, example of scientific
evidence-based content and a process upon which others may build, change or
rectify.
Introduction
This document explains my position in relation to the published version of the
Australian CFS Clinical Practice Guidelines.1 For many weeks prior to their
public release, I weighed-up the contents, effects of, and opinions about, the
guidelines. This time included many conversations with people whom I judged to
have been relatively objective and long-time observers of the guideline-forming
process. I finally decided to give the guidelines my qualified support. This
included cautious acceptance of the management strategies advocated therein. I
could not see that the guidelines would cause more harm than the good such an
educative document would provide. Despite the hard work of all those who
contributed to them, it is my hope that the guidelines will have a short life!
By that I mean that future research will provide the answers to the many
questions inherent in these guidelines; thus making revision a definite and
more-than-welcome necessity.
I am indebted to Jim Oakley (one-time President and honorary life-member of the
ME/CFS Society of Victoria) for his primary work on this document, for the
initial idea of an assessment model, and for allowing me, so generously, to
adapt his work to my own purposes.
In order to review the Guidelines as objectively as possible, a three-part
assessment guide was devised. First, questions were grouped in four levels of
priority. These lists of questions are not meant to be exhaustive, but
indicative of the concerns of people with CFS. Secondly, answers to these
questions provided a rationale for an interpretation, judgment or assessment of
the Guidelines. Thirdly, an assessment is provided which is partly based on
experience, knowledge and information provided by CFS health consumers in the
guideline-forming process (for example see: Ellis, C.T. A CFS Health Consumer
Perspective 1997).
The highest (most important) priority for assessment is assigned to issues
classified in Level 1. The lowest (least important) priority is assigned to
issues classified in Level 4.
I do not share the philosophy that events of the past will necessarily or
directly affect people's actions or life-situations of the future. This
philosophy negates the concept of "free will" and one's ability to make
independent decisions. Nor do I subscribe to a much-touted theory that the
guidelines can be blamed for any malpractice of medical practitioners, or
subsequent harm by them of people with CFS. These particular biases of the
writer are stated in order to enhance the
underlying premise of this document, in agreement with the guidelines,
"…that evidence-based clinical practice involves not only use of the best
available research
evidence, but also exercise of the practitioner's clinical judgment, taking
account of individual
patient preferences." 1
LEVEL 1
Questions that determine Level 1 Priority for assessment:
Will the guidelines cause genuine harm to people with CFS?
Will the guidelines benefit people with CFS and be of assistance to their
doctors?
A Rationale for giving Level 1 Priority for assessment:
The physicians' maxim is, 'First do no harm', and so it should be with the
guidelines. A determination had to be made whether genuine harm could come to
people with CFS as a result of methods of diagnosis or management advocated, or
as a result of any other statements made in the guidelines. This was a top
priority in assessing the document.
The whole purpose of the guidelines is to assist people with CFS by instructing
their doctors in appropriate methods of diagnosing and managing the illness, and
by educating doctors about different aspects of the illness. If the guidelines
do not benefit people with CFS in this way their publication has been a waste of
time, effort and taxpayers' money.
Therefore, the issue of benefit is also included in the top level of priority.
An Assessment of the Level 1 Priority - Benefit
I believe the guidelines will significantly help doctors in the diagnosis and
management of CFS, and give them a much better appreciation of many other
aspects of the illness. Whilst conservative in nature, the chapter on diagnosis
is in line with international practice and recommendations. Taken as a whole,
the management strategies (including pharmacological interventions) - if
implemented according to the guidelines - will definitely be of benefit to some,
even
many, people with CFS
An Assessment of the Level 1 Priority - Harm
In the view of CFS health consumers who made submissions to the Working Group,
the greatest potential for harm arising from the use of the guidelines lies in
the application of the management strategies of graded exercise therapy (GET),
cognitive behaviour therapy (CBT) and sleep management.
In addressing the first two of these, I note that the guidelines:
Stresses the need for a collaborative approach between the patient and doctor.
Advocates a strategy individualised according to the patient's level of
disability and personal preferences, and subsequently modified according to the
response of the patient to treatment.
Advises that new activities should be stopped before they produce a significant
exacerbation of symptoms.
Provides three different conceptual frameworks for management that can be
utilised according to the preferences of the patient and the expertise of the
doctor.
Promotes the concept of self-monitoring of key symptoms and associated
disability.
Acknowledges most of the limitations of the available evidence. This includes
the fact that in published papers, improvement with CBT/GET has not been
observed in all patients or in all studies. It also includes the fact that it is
difficult to extrapolate the results to patients with more severe disability;
and that many studies have significant refusal and dropout rates, which may
reflect on the acceptability of the treatment regimens.
In assessing the appropriateness of CBT/GET as presented in the guidelines, one
must acknowledge that these therapies are now firmly on the agenda for the
management of CFS, not just in Australia but in other countries as well. In 2001
a major systematic review was published in the Journal of the American Medical
Association, which evaluated published trials for CFS, and concluded that:
"Interventions that have shown promising results include CBT and GET." 2
This review was a combination of two conducted independently by the University
of York in England and the University of Texas in the USA. Given the growing
evidence base, I concur with the statements in the guidelines that CBT/GET "may
be effective for some people with CFS."
The main issue to consider was whether the implementation of these management
strategies according to the methods described in the guidelines would cause
genuine harm to people with CFS, or to a subgroup of people with CFS. I believe
that, given the points noted above, there are enough safeguards in place to
protect people with CFS from genuine harm when these therapies are administered
in accordance with the content and intent of the guidelines. I believe that
"genuine harm" would mean anything more severe than a minor/moderate
exacerbation of symptoms for a couple of days at most. It is, therefore,
reasonable for the guidelines to state that "sustained improvements are rarely
achieved without some setbacks and exacerbations of symptoms along the way."
Minor exacerbations cannot be defined as "genuine harm."
The use of CBT/GET appears to be accepted even by researchers who have a firm
belief in the
pathophysiological basis of the illness. In relation to CFS, Professor Anthony
Komaroff of Harvard Medical School - an internationally respected researcher,
and his co-authors, who have spent many years studying the pathology of CFS -
have said that:
"Cognitive behavioural therapy should be used on an individual basis if
possible. A consistent pattern of living - including work, rest, sleep and
physical activity - should be applied, and a slow increase of daily activities
introduced. It should be explained that even a slow increase in physical
exercise can cause an exacerbation of symptoms, but often these subside with
time and there is improvement." 3
and
"Recently, cognitive behaviour therapy has been shown in randomised, controlled
trials to be an
acceptable, effective treatment for CFS; of importance is the fact that
improvements are sustained
and continue over 6-12 months of follow-up." 4
People with CFS can face years - even decades - of illness, and many endure an
incredible amount of suffering.
Apart from the physical and psychological effects of the illness itself, other
factors such as financial difficulties and relationship problems resulting from
the illness can cause further hardship. If anything can help to alleviate this
suffering, it should be considered as an important management option. At
present, the limited amount of available research evidence supports the use of
CBT/GET above any other treatment strategy for people with CFS.
It is pointless waiting for medical research to find a pharmacological 'cure' or
significant treatment for most people with CFS because this is likely to take at
least another ten years (or longer) based on the current inadequate funding
levels and the small number of researchers studying the illness. Biomedical
research into CFS needs to be encouraged and promoted as a matter of real
importance and urgency, but the development of an effective treatment is
necessarily a
medium to long term goal. This is of little comfort to people with CFS who need
help now.
When there is no cure, the ideal situation for anyone with a chronic disease is
to experience just the disease itself without all the accumulated stresses and
problems that compound the difficulty of managing the condition. Factors such as
social isolation and loss of confidence are not trivial in the context of
long-term disability; similarly, the adverse pathophysiological consequences of
extended periods of inactivity cannot be dismissed lightly. This is why the
guidelines state that
"... people with CFS should be encouraged to adopt the widest possible view of
the medical, physical, and psychological management strategies to assist in
coping with the illness."1
The non-pharmacological management strategies advocated in the guidelines
address issues that are common to chronic illness. That is, issues that are
overlaid on the disease process itself. For example, exercise - graded or
non-graded - has been shown to be helpful for at least some people in several
chronic diseases that are associated with severe fatigue and other symptoms well
known to people with CFS. These diseases include post-polio syndrome, rheumatoid
arthritis, multiple sclerosis and FIBROMYALGIA.
A controversial issue is the potential for graded exercise programs to cause
harm to people with CFS, particularly those at the more severe end of the
disability spectrum. Recently, media attention focussed on a young man with CFS
who was advised by his doctor to undertake half an hour of vigorous walking each
day. He tried to comply with this program but his condition deteriorated
significantly.
This was obviously not a graded exercise program. The approach taken by this
doctor falls well outside the approach advocated in the guidelines (which were
not available in their present form when these unfortunate circumstances
occurred). Mistreatment could still occur, even now that the revised guidelines
have been published!
The real issue is whether the problem lies with the guidelines themselves, or
with individual practitioners who do not follow the recommendations in the
guidelines. For example, with just about any prescription drug it is possible to
harm people by giving them a dose that is higher than that recommended. The
approach taken in our society is not to ban medical drugs because of their
potential for harm if misused, but to deal specifically with those doctors who
do not comply with recommended dosage levels.
If graded exercise programs are misused or misinterpreted by some doctors, the
problem clearly lies with those doctors and not with the guidelines. The
guidelines do recommend a cautious approach and do discuss limitations in the
available evidence. The focus should be on those doctors who abuse the therapy,
as it would be if any other form of medical malpractice had been inflicted on a
patient.
In reality, it is a futile exercise to try and eliminate graded exercise from
the CFS agenda. A much more constructive approach is to educate doctors and
patients about its appropriate use in a primary care setting.
The issue of sleep management is not particularly well covered in the
guidelines. However, the guidelines now properly acknowledge that evidence for
the effectiveness of sleep management strategies in CFS is lacking, and just
provide suggestions based on what has been found to be helpful in other
illnesses. The guidelines are now trying to be helpful rather than dogmatic. I
believe that if the content and intent of the guidelines are followed, the
implementation of the sleep management strategies will not cause genuine harm to
people with CFS. The acknowledged lack of evidence means that doctors and
patients who try different sleep management strategies
cannot justifiably have pre-determined expectations of what the outcome should
be. If, by cutting out daytime naps, a patient's condition deteriorates to the
extent that there is more than a short term, minor exacerbation of symptoms,
there is no basis in the guidelines for the doctor to insist that this strategy
should be maintained in the hope of improvement in the future.
Thus, my overall conclusion is that the CBT/GET/sleep management strategies
contained in the guidelines are now presented in such a way that, if implemented
according to the guidelines, should not cause genuine harm to some people with
CFS. I acknowledge the subjectivity of these judgments. Some people may feel
that there are definitely not adequate safeguards in place to prevent harm from
coming to people with CFS. There is no 'right' or 'wrong' answer here.
As with many areas of life, different people have different levels of comfort
when faced with uncertainties. One cannot pretend to know what every
individual's experience with these therapies will be. There is an important role
for CFS Societies in monitoring feedback from their members about the use and
abuse of these therapies in general practice.
I believe that the published version of the guidelines falls within the lower
end of the range of acceptable approaches to the management of CFS. What is
being advocated is a new approach to managing CFS in general practice, and it
necessarily entails some uncertainties; hence my attitude to the management
strategies is one of 'cautious acceptance'.
As for the rest of the document, I do not believe it contains anything that
could cause genuine harm to people with CFS. While some statements in the
guidelines may portray people with CFS somewhat inaccurately, their impact is
likely to be small in the overall context of the document.
LEVEL 2
Questions that determine Level 2 Priority for assessment:
a) Do the guidelines address issues of importance to people with CFS?
Do they treat CFS as a serious illness?
Do they treat people with CFS with respect and empathy?
Do they treat CFS as a medical illness, a psychological illness, or something in
between?
Do they adequately describe CFS as experienced by the patient?
Do they encourage a cooperative and supportive patient-doctor relationship?
Are the management strategies advocated presented in such a way that they are of
practical use?
Are the management strategies advocated presented with appropriate cautions
about the uncertainties in the evidence and the potential harmful effects of the
treatments?
Are day-to-day problems, as experienced by people with CFS, adequately
acknowledged?
Is the feedback provided by consumers to the Working Group reflected in the
guidelines?
Overall, are people with CFS given a 'fair go'?
b) Do the guidelines address issues of importance to doctors?
Are major issues such as diagnosis and management adequately addressed?
Is the scope of the document appropriate?
Is the presentation of the document user-friendly?
Are the guidelines comprehensive?
Are they well referenced?
Are they up to date?
Are strategies presented to help facilitate a beneficial doctor-patient
relationship?
c) Are major themes or groups of tables in the guidelines presented accurately,
fairly and reasonably?
A Rationale of Level 2 Priority for assessment:
The second level of priority includes typical issues that are important to
people with CFS, and to doctors, respectively. These are the aspects of the
guidelines that are particularly relevant to each of these groups. The answers
to the questions will determine how each group perceives the guidelines. Again,
this list of questions is not meant to be exhaustive, but indicative.
There are also some major themes which run through the guidelines, and one
significant grouping of Tables, which I have included in Level 2 because of the
potential they have to influence readers.
An Assessment of Level 2 Priority issues:
Previously the question 'Do the guidelines address issues of importance to
people with CFS?' was asked. I believe, the answer is a qualified 'yes'.
However, some of the issues I listed for assessment are not covered adequately.
For example, the guidelines do not describe CFS adequately and as experienced by
the patient. Only core symptoms are discussed. There is no acknowledgment that
fatigue is not necessarily the most disabling or most distressing symptom. The
feedback provided by consumers to the Working Group has only been incorporated
partially into the guidelines. Overall, I believe that the guidelines do a
satisfactory job of addressing
the major issues of concern to the majority of people with CFS in the general
population.
Regarding the question 'Do the guidelines address issues of importance to
doctors?', my agreement is more emphatic. This opinion has been gained from
reading the feedback provided by medical colleges and societies, and by
individual clinicians and researchers, to the Working Group after the release of
the first and second drafts.
Most of the respondents rated the format and scope of the document as good or
very good. The major focus of the guidelines is on diagnosis and management, and
this should be of significant assistance to doctors.
Furthermore, the guidelines are reasonably well referenced, and they are up to
date: 181 (34%) of the 528 papers in the list of references were published after
the release of the first draft, that is, in 1998 or later. The guidelines also
emphasise the need for a beneficial patient-doctor relationship and provide some
guidance to doctors on how to facilitate this. Overall, the guidelines may be
received well by doctors who are, after all, the target audience.
Major Themes: One of the major themes running through the guidelines is that
fatigue states occur on a continuum, and it is only those at the more severe end
of the continuum who would receive a diagnosis of CFS. This is one way of
looking at it, although there are other ways of interpreting the diversity in
illness severity and duration. Not all fatigue states may be part of the same
pathophysiological continuum as CFS; no one knows yet. Therefore, this theme is
not
'wrong', but it may reflect the views or biases of those on the Working Group.
Groups of Tables: Tables 1.3 to 1.6 are where the medical research findings are
summarised. While there are some omissions from these tables (e.g. research into
erythrocyte deformation, the aerobic capacity of people with CFS, and the
possible role of some microbial agents such as parvovirus B19 in causing the
illness), they nonetheless provide a very good summary and will give doctors and
other readers a rapid appreciation of the current state of research findings.
These tables reflect the often-contradictory findings that are reported by
different CFS research groups.
The statements and comments contained in these tables are consistent with major
reviews of the biology of CFS presented in the medical literature. For example,
consider the following quotations relating to CFS made in one review 3:
"[The link between infections and CFS remains uncertain."
"These studies indirectly suggest the presence of a chronic viral infection, but
are far from constituting proof of such infection."
"So far, no microbes have been isolated and correlated to symptoms."
"Although not specific for CFS, depressed NK cell function has been consistently
seen. The clinical
implications of this finding remain uncertain."
"Other markers of immune activation also have been found…It is not clear that
these abnormalities have any relationship to the symptoms reported by patients
with CFS."…………
"Thus, there is considerable evidence of abnormalities in the CNS, particularly
the limbic system, in patients with CFS. The aetiology of the abnormalities, and
their relationship to the symptoms of CFS, remains obscure."
These statements were made in a November 1999 review co-authored by Professor
Anthony Komaroff Like those in the guidelines, the comments in this review
reflect the uncertain significance associated with many pathophysiological
findings in CFS. This does not mean that there is not a pathophysiological
basis to CFS, but simply that the research is 'work in progress' and it is too
early to draw firm conclusions about the exact nature of the pathophysiological
processes responsible for making people sick.
Another example of this is found in the paper by Professor Kenny De Meirleir and
colleagues published in the American Journal of Medicine. This study examined
the distribution of 2-5A binding proteins in the cells of people with CFS and
controls. The findings are very interesting and warrant further research;
however, the authors note in their paper that:
"The biological significance of these 2-5A binding protein in patients with
chronic fatigue syndrome
is not known." 5
Overall, I give the guidelines at least a satisfactory rating for Level 2
priority issues.
LEVEL 3
Questions that determine Level 3 Priority for assessment:
Are individual paragraphs, statements and tables in the guidelines accurate,
fair and reasonable? Are they supported by appropriate references?
A Rationale for Level 3 Priority assessment:
There are instances in the guidelines where individual statements or paragraphs
may not be accurate, fair or reasonable. When these occur in isolation (i.e.
they are not part of themes running through the guidelines), I have given them a
Level 3 priority. They are still important, but they do occur in isolation and
their impact on the reader is likely to be limited.
An Assessment of Level 3 Priority issues:
The majority of paragraphs, statements and tables in the guidelines are
accurate, fair, and reasonable. Some are not. These have been documented in
submissions received by the Working Group and are Level 3 issues: individual
statements or isolated paragraphs, which are either biased, inaccurate or
misrepresentative. In my view, the Level 3 issues alone are not of sufficient
importance or impact to cause me to withdraw support for the guidelines.
LEVEL 4
Questions that determine Level 4 Priority for assessment:
Are the referencing and proofreading accurate and complete?
Was the process of developing the guidelines appropriate?
A Rationale for Level 4 Priority issues:
Here I have placed minor issues such as referencing and proofreading. These do
need to be accurate and complete, and therefore should be included in an overall
assessment of the guidelines. However, even if the referencing and proofreading
are poor, the impact on doctors and people with CFS is likely to be small. I
believe this justifies the low priority ranking.
In addition, in Level 4 process issues, such as the functioning of the Working
Group, have been considered as well as the relationship and information flow
between the Working Group and other stakeholders such as patient groups and
clinicians.
There are two main reasons why I have given a Level 4 ranking to process issues.
Firstly, one doubts that even if all aspects of the process of
guideline-formation had been conducted impeccably, with perfect consultation
with stakeholders, adherence to a timetable and so on, the contents of the final
guidelines would have been significantly different from the final product. There
has been much input, which has influenced the contents of the guidelines.
These include the literature review conducted by members of the Working Group;
the personal views and knowledge of the members of the Working Group; and the
written submissions received by the Working Group, amongst others. Concerns were
conveyed to the Working Group via submissions, letters, telephone conversations,
the CHF representative, and media publicity. There is absolutely no doubt that,
even with the controversial process that was actually followed, the Working
Group was fully informed about the concerns of people with CFS and some
clinicians in relation to the contents of the two public drafts.
Whatever process had been followed by the Working Group, cognitive behaviour
therapy and graded exercise would still be included as management strategies in
the final document. The chapter on diagnosis would essentially be the same. Only
minor aspects of the guidelines may have been different if the process had been
different. For example wording, expression, table inclusions etc.
Secondly, for ranking process issues in Level 4, for the overwhelming majority
of people with CFS, and for the overwhelming majority of doctors, the process by
which the final guidelines were completed is of no relevance. It is only the
contents of the guidelines that will affect them or be of interest to them.
If the results of overseas epidemiological studies are applicable in Australia,
then it can be expected that between 40,000 and 140,000 Australians will meet
research criteria for CFS at any one time. An even greater number of people will
have idiopathic chronic fatigue, and these people will also come under the
influence of the guidelines.
However, the number of submissions received by the Working Group from CFS health
consumers (patient organisations and individuals) in response to the release of
the first draft was only about 200 (and about 70 from health professionals and
their organisations). Even if every member of every patient organisation falling
under the umbrella of the ME/CFS Association of Australia was keenly interested
in the guidelines and the process by which they were developed, this would
amount to 7,000-8,000 people at most. It is, therefore, clear that the
overwhelming majority of people with CFS had little or no interest in the
guidelines-formation process and would
not have contributed to this process.
An Assessment of Level 4 Priority issues:
The proofreading, referencing and presentation of the guidelines are fine. In
contrast, the guideline-development process had many problems. For example, to
name a few, overall time of the project (over six years) was too long, the
project was "on hold" for two years and "momentum" was lost. There were only
three face-to-face working group meetings and two teleconference calls. Working
group contact and debate was very limited, with often-unrealistic timetable
demands
for written CFS health consumer responses.
The result of these problems has been the alienation of the very people in the
CFS community who invested the time and effort to make submissions and
contribute to the process. Some people have been angered while others,
disillusioned.
A cynical distrust now permeates some people's views of the guidelines and the
Working Group. This outcome was unnecessary and should have been avoided.
Qualifications
Because there are aspects of the guidelines that could be improved
significantly, it is difficult to give them unqualified support. The following
points represent my major concerns with the published version of the document:
Discussion of the spectrum of severity of CFS, and the symptoms that may be
associated with the illness, is poor. This will not necessarily affect the
process of diagnosing CFS, but doctors may be confronted with symptoms they do
not associate with CFS, which could cause unnecessary confusion. It would have
been more helpful if the guidelines contained a table detailing the outcomes of
CBT/GET trials. This would have allowed both doctor and person with CFS to make
better-informed decisions about the effectiveness, relevance and appropriate use
of these therapies. The detection and treatment of neurally mediated
hypertension could have legitimately been discussed in Chapter 3, and would have
potentially given GPs another avenue by which to help some of their CFS
patients. Treatment options other than fludrocortisone do exist.
Far more CFS health consumer "evidence," as provided in written submissions
could have been included. This inadequacy calls into question the interpretation
and use of the National Health and Medical Research Council's "levels of
evidence" as required in evidence-based guidelines. CFS health consumer
experience can often be seen to be ahead of research projects and agenda. Such
experience needs to be treated more seriously. Other suitable formats within the
guidelines could have been used to enable their expression. It could also be
used to pre-empt
suitable research projects.
Overall Assessment
The guidelines receive at least a satisfactory grade for the issues listed as
Level 1 and Level 2 priorities, as discussed previously. For Level 3 priority
issues I believe some problems still exist, but in the overall context of the
guidelines these problems are generally minor (but annoying nonetheless). For
Level 4 priority issues, the guidelines receive an unsatisfactory grade owing to
problems with the guideline-development process. However, as I discussed above,
the
impact of the process on the content of the guidelines - and thus on the
overwhelming majority of people with CFS - is very limited.
Craig Ellis B.A., B.S.W. (Hons), Cert. E.F.M., Cert. Adv. Eng.
June 2002
Consumer Health Forum representative, December 1996 - June 2002
Member, CFS Guidelines Working Group, December 1996 - May 2002
Member, ME/CFS Society of Victoria Inc.
References
1. The Royal Australasian College of Physicians CFS guideline working group,
Chronic Fatigue Syndrome Clinical Practice Guidelines - 2002, The Medical
Journal
of Australia, Supplement, 6 May 2002, Vol. 176.
2. Whiting P, Bagnall A-M, Snowdon AJ et al. Interventions for the Treatment and
Management of Chronic Fatigue Syndrome. A Systematic Review. JAMA 2001; 286:
1360-1368.
3. Evengard B, Schacterle RS, Komaroff AL. Chronic fatigue syndrome: new
insights and old ignorance. Journal of Internal Medicine 1999; 246(5): 455-469.
4. Komaroff AL, Buchwald DS. Chronic Fatigue Syndrome: An Update. Annu. Rev.
Med. 1998; 49: 1-13.
5. De Meirleir K, Bisbal C, Campine I et al. A 37 kDa 2-5A Binding Protein as a
Potential Biochemical Marker for Chronic Fatigue Syndrome. Am J Med. 2000; 108:
99-105.
Craig Ellis (2002) All Rights Reserved (Reprint with Permission)
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