Dangers of research into chronic fatigue syndrome
BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d3780 (Published 22 June 2011) Cite this as: BMJ 2011;342:d3780
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As a mathematician with ME, I would like to point out that I do not
reject the PACE study. I do however reject its conclusions, and that is
very different.
It has taken me many hours of analysis to come to that conclusion:
the data is complex. However an NNT of 7 or 8 for a heterogeneous group
suggests that a generalised conclusion is inappropriate, particularly when
there is no reliable quantitative assessment to back up the results.
Graham McPhee
Competing interests: No competing interests
Whilst disagreement over diagnostic classification in CFS/ME has
arguably hampered research in this area [1], we suggest that the study of
fatigue in other chronic illnesses may alternatively help our
understanding of fatigue as a symptom complex, and provide pointers as to
its pathophysiology.
For example, we have recently studied fatigue and associated symptoms
in 100 unselected HIV-infected outpatients and compared with 166 healthy
persons, and 74 patients with CFS (as defined by CDC 1994 Fukuda
criteria). We find that half of HIV-infected patients (50/99, 51%) suffer
excessive fatigue [2], and that HIV-infected patients appear to fall into
two relatively binary groups, one significantly fatigued, and one
comparable with healthy persons (see Figure 1, left). Among HIV-infected
patients, we found correlation between fatigue and symptoms of autonomic
dysfunction [3] (r=0.65, p<0.001). This physiological disturbance has
been well demonstrated in CFS as well as in association with fatigue in
other chronic diseases [4 5], although further research is needed to
determine its biological significance.
In terms of biological markers of HIV infection, current or previous
immune function (as determined by CD4 lymphocyte count), or plasma HIV
viral load were not associated with fatigue severity, however duration of
HIV infection was predictive of fatigue in a manner suggestive of
underlying fatigue sub-groups within this population. Thus, most patients
diagnosed with HIV prior to 1998 were fatigued (71%), whereas only a
subset of patients diagnosed after this date were fatigued (45%) (Figure
1, right). Those patients with longstanding HIV-infection and fatigue had a
high frequency of prior exposure to mitochondrially-toxic anti-retroviral
drugs [6], as well as clinical evidence of the metabolic syndrome of anti-
retroviral associated lipodystrophy. This plausibly suggests a metabolic
or mitochondrial contribution to the fatigue seen in the longstanding
patient group. In contrast, these clinical features were not observed in
the more recently diagnosed group, suggesting other biological or
psychosocial factors are important in driving fatigue in these patients.
Future rational strategies in fatigue management are likely to need
to take into account fatigue sub-types, and this approach may potentially
be of benefit in both CFS, and chronic disease-associated fatigue.
Figure 1
1. Hawkes N. Dangers of research into chronic fatigue syndrome. BMJ
2011;342:d3780.
2. Prince MI, James OF, Holland NP, Jones DE. Validation of a fatigue
impact score in primary biliary cirrhosis: towards a standard for clinical
and trial use. J Hepatol 2000;32(3):368-73.
3. Schrezenmaier C, Gehrking JA, Hines SM, Low PA, Benrud-Larson LM,
Sandroni P. Evaluation of orthostatic hypotension: relationship of a new
self-report instrument to laboratory-based measures. Mayo Clin Proc
2005;80(3):330-4.
4. Rowe PC, Calkins H. Neurally mediated hypotension and chronic
fatigue syndrome. Am J Med 1998;105(3A):15S-21S.
5. Flachenecker P, Rufer A, Bihler I, Hippel C, Reiners K, Toyka KV,
et al. Fatigue in MS is related to sympathetic vasomotor dysfunction.
Neurology 2003;61(6):851-3.
6. Payne BA, Wilson IJ, Hateley CA, Horvath R, Santibanez-Koref M,
Samuels DC, et al. Mitochondrial aging is accelerated by anti-retroviral
therapy through the clonal expansion of mtDNA mutations. Nat Genet 2011.
Competing interests: JLN has received funding from ME Research UK and the ME Association
There is an obvious paradox in wanting more research in CFS/ME, but
then rejecting research that one does not like, with claims that it is
unscientific. "Science" is the application of the scientific method, and
the sound rebuttals by both the MRC and Lancet to allegations that the
PACE trial was in some way improper should be proof enough. That cognitive
behavioural therapy (CBT) and graded exercise therapy (GET) have been
shown by the PACE trial to be safe whilst moderately improving outcomes
for CFS/ME would ordinarily be a cause of considerable satisfaction to
both doctors and patients. Certainly it would be so in any other branch of
medicine. Entry criteria to the trial were broad, but subgroup analysis on
more narrowly defined CFS/ME still produced the same results. Whilst these
treatments do not resolve the problem for everyone, undoubtedly they do
benefit some. It is precisely for these reasons that we have trials, in
which treatments and outcomes can be standardised. By all means let us
have research into other aspects of this condition, but let us also
acknowledge the good intentions of researchers and doctors involved in all
aspects of this field.
Competing interests: Specialist medical care doctor, PACE trial;Member of guideline development group for National Institute of Health and Clinical Excellence (NICE) CFS/ME guidelines
The behavior of these pressure groups is a social phenomenon with
strong features of a religion. We need help from social
sciences to understand this phenomenon which we also see in religious
homeopaths as I described already in 2009:
(http://www.aerzteblatt.de/v4/archiv/artikel.asp?src=suche&p=Hom%F6opathi...)
Those homeopaths seduce Public Bodies in the same way far beyond the
principles of Common Sense and Enlightenment.
Competing interests: No competing interests
Nigel Hawke describes, CFS/ME as "a common condition, and very
debilitating . . . Patients are incapacitated for years, unable to move,
sometimes bed ridden and fed through a tube." (1)
And yet the NICE panel concluded, "Our report, based on a solid
review of the evidence, was that graded exercise and cognitive behavioural
therapy were the best, indeed only, treatments." (1)
For how many years has CBT and GET been "the best, indeed only,
treatment" for such a debilitating illness?
Has even a single bedridden patient participated in a study of the
effectiveness of CBT or GET?
If the "only treatments" for CFS/ME were not tested on the most
disabled sufferers, did the NICE panel conclude that these patients are
unworthy of treatment? Does this attitude apply to the baffling,
primarily psychosomatic, predominantly female affliction, anorexia
nervosa? Do the guidelines for that condition overlook the need for
treatment of the very sickest patients?
Hawke quotes Crawley; "Ninety four per cent of children get better,
while only a third of adults do". (1) That is a markedly different
outcome for two age groups. Do doctors over-diagnose CFS/ME in children?
What other conditions are handled well by children? Doesn't the young
brain cope better with a number of viral infections? What percentage of
adult sufferers are the children (6%) who did not recover?
Phil Parker (2,3) is one of many practitioners who claim to have
developed an expensive treatment that is effective for a sweeping
assortment of conditions. On his website (2) Parker describes Lightning
Process as "a powerful, non medical tool that is tailored to help people
who are stuck in their life or health". On a quick visit to Parker's
websites, (2,3) without leaving the first page, I found claims LP is
effective for: CFS/ME, fibromyalgia, chronic pain, MS, IBS, digestive
issues, food/chemical intolerances, weight loss, eating disorders,
addiction, depression, phobias/anxiety/stress, low self esteem, OCD, (2)
lupus, ADHD, sleep disorders, migraine, bipolar II (3). A promotional
testimonial from a patient with Bipolar II states, "What was so
transformative for me on the LP seminar was simply learning that you have
a choice, that when manic or depressed symptoms arise, you don't have to
accept and experience them, that they aren't random external things
happening to you, but reactions which can be altered." (3)
The 'decline effect' (4) in replication studies, especially studies
in the behavioural sciences, caused Jonathon Schooler to suggest
researchers need to improve both rigour and transparency of studies,
"Every researcher should have to spell out, in advance, how many subjects
they're going to use, and what exactly they're testing, and what
constitutes a sufficient level of proof". (4) Ad hoc changes were made to
the outcome parameters of the PACE trial, (5) which favoured the authors'
strong a-priori assumptions. Ninety four percent of the subjects in
Crawley's study are likely to recover with or without LP. The study will
need utmost transparency and rigour if it is to provide worthwhile data.
The CFS/ME online community is not unique. Self-diagnosis and online
peer group-directed treatment is common for numerous conditions, both real
and imagined. Some of the dialogue is appalling for its naivety and
brashness, with all the inherent dangers of overconfidence. However, only
a few extremists condone extreme behaviour towards doctors and scientists.
The need for X-ray of mail etc is appalling, but to condemn an entire
group for the reprehensible actions of a few is bigotry.
(1) Hawkes N. Dangers of research into chronic fatigue syndrome. BMJ
2011; 342:d3780
(2) Phil Parker Lightning Process
http://www.lightningprocess.com/Landing/
(3) Phil Parker Lightning Process
http://www.lightningprocess.com/Other-Conditions-Home/
(4) Lehrer J. The Truth Wears Off. The New Yorker 2010; Dec 13
http://www.newyorker.com/reporting/2010/12/13/101213fa_fact_lehrer?curre...
(5) Stouten B, Goudsmit EM, Riley N. 2011 Correspondence on 'The PACE
trial in chronic fatigue syndrome'. The Lancet. 377 (9780): 1832-1833
doi:10.1016/S0140-6736(11)60685-5
http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(11)60685-
5/fulltext
Competing interests: No competing interests
I wonder if there is evidence from both sides of the debate within
Hawkes' article (1), and the associated commentary by Cornes (2), of some
of the underlying difficulties and misunderstandings that continue to fuel
this debate?
In a, perhaps understandable but not justifiable, defence against the
abuse received by Wessely for his work on chronic fatigue syndrome,
Wessely states - "They have personality problems". This to me reads as a
reference towards Personality Disorder, a diagnosis sometimes used in a
pejorative sense by mental health staff referring to a group of
individuals who frequently require support from mental health services,
but raise more than average levels of disagreement amongst staff. (3)
In his at times insightful commentary Cornes refers to an illness
being "in some way psychosomatic" adding the comments "Am I making this
up? Am I really sick?". His statement likely refers to the Somatoform
disorders - a World Health Organisation recognised disease within the
International Classification of Diseases (ICD 10 F45-), excluding in this
case Hypochondriacal disorder (F45.2). Somatoform disorders are an
important category, accounting for a large proportion of general practice
consultations (4). Insight into these conditions is highly variable (5),
however patients will experience symptoms that to them are
indistinguishable from those caused by a medically explained stimulus, and
therefore are "real" to the sufferer.
This ongoing dialogue between sufferers and clinicians seems to
highlight the stigma experienced by those with a mental illness (6), that
in someway their symptoms are not real or that if they respond to
psychological therapy, such as cognitive behavioural therapy, they were
not ill. And yet, there is some emerging evidence that cognitive
behavioural therapy may be of benefit in reducing repeat events in
coronary heart disease, and there can hardly be a more "organic" pathology
then that? (7)
(1) Hawkes N. Dangers of research into chronic fatigue syndrome BMJ
2011;342:d3780.
(2) Cornes O. Commentary: Living with CMS/ME BMJ 2011;342:d3836.
(3) Markham D. Attitudes towards patients with a diagnosis of
"borderline personality disorder": Social rejection and dangerousness. J
Ment Health. 2003;12(6):595-612.
(4) Burton C. Beyond somatisation: a review of the understanding and
treatment of medically unexplained physical symptoms (MUPS). The British
Journal of General Practice. 2003.
(5) Dwamena FC, Lyles JS, Frankel RM, Smith RC. In their own words:
qualitative study of high-utilising primary care patients with medically
unexplained symptoms. BMC Fam Pract. 2009;10(1):67.
(6) Dinos S, Stevens S, Serfaty M, Weich S. Stigma: the feelings and
experiences of 46 people with mental illness: qualitative study. The
British Journal of Psychiatry. 2004;184:176-181.
(7) Gulliksson M, Burell G, Vessby B, et al. Randomized Controlled
Trial of Cognitive Behavioral Therapy vs Standard Treatment to Prevent
Recurrent Cardiovascular Events in Patients With Coronary Heart Disease.
Archives of Internal Medicine. 2011;171(2):134-140.
Competing interests: No competing interests
I'm sure that Peter White and Simon Wesselly must
be at least as disappointed with the PACE results as anyone. The
improvement in self perceived levels of fatigue, though modest, appears
genuine enough. They must have been bitterly disappointed that the
patients showed no objective improvements despite such a rigorous
application of CBT. I would submit however that this would not appear to
be the fault of Simon Wesselly or Peter White. It seems clear that the
original protocol was changed and the initial objective end points
removed. This is clearly unsatisfactory for both psychiatrists and
patients, as the inclusion of these end points would have settled the
debate once and for all.
The problem appears to be reflective of a much wider phenomenan which
has developed in Psychiatry and the sciences since the second world war.
There appears to have been a virtual breakdown in communication between
the two philosophical school. Psychiatry has not imported any discoveries
from neuroscience and the latter discipline rejects the proposals of
psychiatry. A classic example was the interaction between the deputy
editor of the BMJ and the panel of scientists in the recent Invest in ME
conference in London. The lady, who was obviously committed to her cause,
volunteered to help the scientists design studies using statistical
methodology favoured by the BMJ. She was obviously not aware that
scientists had been using such methodology before such practices entered
the field of medicine. It would be such a shame if such a genuine offer
to help was intrepreted as an insult. I feel she was undeservedly
lampooned for this perceived gaff. The response of the panel however must
be applauded. Instead of ascribing the worst possible intentions to the
lady's words, they sat smiling and displayed the tolerant attitude that
promises much for future collaboration. When she attends next year to
discuss the adoption of scientific methodology, which can (given time and
willingness) lead to a cure for this devastating illness, let us hope that
mutual tolerance and open communication prevails.
I feel that sufferers of ME/cfs would be wiser to focus on
deficiencies in study methodology than on personalities. If psychiatrists
wish to avoid criticisms then they would be wise to adopt the scientific
method in its entirety. They would then be immune from accusations of
bias. The use of objective measurements and designing studies to attempt
to disprove their belief, that the cause of the illness is a psychological
one, would quickly dispel anger and suspicion within the patient
community.
Competing interests: No competing interests
"The campaign has gained new life since the publication in March in
the Lancet of the PACE trial, a comparison of four treatments for CFS that
concluded, to the fury of the campaigners, that cognitive behavioural
therapy and graded exercise therapy can be effective."
Show me one piece of evidence that campaigners are furious because
the PACE trial showed moderate benefit for some participants with GET and
CBT. This assertion is nonsense. The outcome of the PACE Trial is almost
exactly as expected by every well-informed doctor, researcher and patient
who is familiar with similar previous research. If anything, the results
support those who are fed-up with repetitive psychological /
rehabilitative research into CFS.
If Nigel Hawkes read the Lancet publication of the PACE Trial results
he will be aware that GET and CBT achieved 'improvement' or 'recovery' for
only 15% more participants than in the Control Group; and that is using
benchmarks for 'improvement' and 'recovery' that are very low. So low, in
fact, that it has been claimed that some meeting the criteria used for
'recovered' would actually still be sufficiently impaired to be accepted
as a participant in the PACE Trial.
The legitimate anger of campaigners is about the highly dubious
design and execution of the PACE Trial
(See:http://www.meassociation.org.uk/?p=6181) and the morally questionable
manipulation of the media which then trumpeted the results as though a
cure had been found.
The BMJ article appears to be another example of such manipulation.
Competing interests: Disabled by Myalgic Ecephalomyelitis
Please listen to us!
Nasim Marie Jafry: 'No one is saying psychiatric illness is not real'
:
Dear Joss Bray, This is not about psychiatric illness being less real or
less important than physical illness.This is about patients with
neurological illness being inappropriately labelled as mentally ill....
...And the oft-quoted body and mind being inextricably linked is not the
issue here. Patients with ME are angry and frightened because we are not
being listened to. That is all. And it can so easily be remedied.
Kelly Latta: 'A molehill' :
The opinion that these patients prefer to have a severe neuroimmune
disease over psychosocial therapies, therapies that are no more effective
than in any in other organic disease, merely serves to marginalize such
patients further. Would patients with AIDS, MS, Parkinson's Disease, or
Alzheimers disease be willing to settle for "moderately effective"
tertiary treatments?
Andrew J. Kewley: 'If there was more than scraps of research, we
wouldn't need to fight' :
For a case in point, Dr Leonard Jason, a psychologist at DePaul University
in Chicago is popular with patients, despite publishing clinical studies
on CBT and research on psychosocial risk factors in CFS. I believe the
difference is that he does not overstate the benefits of CBT/GET and he
has consistently advocated for significant increases in biomedical
research.
May Iren Kapelrud: 'What would a psychiatrist do?' :
But when people protest and they come with relevant and constructive
arguments, then I wish Wessely openminded would listen and try to
understand us. He may very well be a good psychiatrist to my knowledge,
but I don't believe he has understood CFS/ME! This is the reason for the
complaints by CFS/ME patients, and there's quite a lot of people who
disagree with him! In Norway we are many!
Louise Gunn: 'CFS is not a diagnosis. It is a socially constructed
metaphor' :
The situation is made worse by the fact that Simon Wessely's diagnostic
methodology, which is used in UK government sponsored trials, such as
PACE, excludes patients with CFS 2, and includes people with CFS 1 and
people with clinical depression.
Katherine M Wimhurst: 'Response to Nigel Hawkes' article about
research into CFS, 22nd June 2011' :
And while I cannot condone 'hate mail', responses of ME patients to the
somatoform model cannot be understood without addressing the prejudice,
disbelief and neglect that many have suffered as a consequence of that
model.
Linda Crowhurst: 'Who are the real victims ?' :
Patients who have read my articles know that I believe that ME may not be
the same illness as CFS and that the former may be perpetuated by an
infection or abnormal reaction to infection. I've never supported any of
the current psychiatric theories and prefer more flexible, pragmatic
interventions than graded exercise and CBT as described in the literature
on ME/CFS.
Jane Clout: 'Dangers of research into chronic fatigue syndrome and
ME' :
I wholeheartedly agree that the only definition that reliably diagnoses
myalgic encephalomyelitis is the Canadian Consensus (5,6), all others
currently in use conflate the neurological disease with depression and
idiopathic fatigue, a fact that has been perhaps the greatest obstacle to
clarity in the search for understanding of, and effective treatment for,
the discrete disease Myalgic Encephalomyelitis.
Ian T. McLachlan: 'Dangers of not challenging research into chronic
fatigue syndrome' :
...The BMJ therefore should see their role as one of lessening the gap
between such figures and the people they are there to serve. The fact that
it has not happened in this instance only serves to feed into the very
concerns being raised within the article and cast doubt as to the real
motives behind such a publication.
Linda Crowhurst: 'Who are the real victims ?' :
And all because of a quite inappropriate focus on therapy.
Surely it is time for is the BMJ to start raising some serious medical
issues about the most isolated, negated and neglected, severely physically
ill patients in the UK and stop publishing a biased psychiatric
representation of ME ?
Barbara Greene: 'Re:If only life was so simple' :
The situation in England is unbearable for patients with the psychiatrists
thinking they understand M.E. and denying biomedical treatment to
patients.
Andrew J. Kewley: 'If there was more than scraps of research, we
wouldn't need to fight' :
...For example, when you compare the research funding for CFS by the
National Institutes of Health in the USA [1], with studies on societal
economic costs [2] and level of disability, a certain disease ranks at the
bottom of the list: Chronic Fatigue Syndrome.
Competing interests: No competing interests
Re:Can we learn from researching chronic fatigue in chronic illness - the case of HIV?
Would addition of another group - one that experiences paradoxical
arousal - be worthwhile (in future studies)?
Regina Casper's team propose, "that behavioral activation and arousal
represent core symptoms unique and specific to AN [Anorexia Nervosa]." (1)
When reading Casper's paper I was stuck by the similarity of the
effects of semi-starvation to symptoms experienced by people with CFS/ME.
Quote from Casper's paper:
Aspen, a wilderness traveler attempting to survive on an energy
deficient diet, described the behavioral effects of semi-starvation: "we
moved slowly, as if in a dream. It took a long time to get anything done.
We were indecisive and spiritless--no longer able to think clearly, to
act, to choose." In striking contrast, emaciated AN patients display
normal, occasionally high energy and activity levels and tenacious
motivation."
(1) Casper RC. The 'drive for activity' and "restlessness" in
anorexia nervosa: Potential pathways. J Affect Disord 2006; 92(1):99-107
Competing interests: No competing interests