wouldn't think of once they recognise it as an uncontrolled trial. As
it is only an e-letter, I didn't make much/any effort to be eloquent
and didn't show it to others before submitting it - I just wanted to
get a few points across. Tom https://twitter.com/TomKindlon]
http://bmjopen.bmj.com/content/1/2/e000252.full/reply#bmjopen_el_156
Uncontrolled study proves little about value of therapy received
This paper (1) includes data on two separate (but related) issues: (i)
the prevalence of diagnosed and undiagnosed Chronic Fatigue
Syndrome/Myalgic Encephalomyelitis ("CFS/ME") (NICE criteria (2)) in
children aged 11-16 and (ii) information on how they fared when they
received therapy at the CFS clinic. The relative rigour that is
brought to the first set of data may mean some may miss that many
questions remain about the therapeutic data, which I will now attempt
to elucidate.
Ideally what one would want to know is whether there would have been
any difference in outcomes if the children had been neither diagnosed
nor treated. The criteria used, the NICE criteria (2), which require
fatigue and one other symptom for three months or more, are relatively
broad - most other criteria for ME and/or CFS are stricter i.e. they
require more symptoms (3-9). A systematic review looking at the
prognosis of chronic fatigue and chronic fatigue syndrome found that
as the criteria got more stringent, the prognosis worsened (10). A
Dutch natural course study found that less fatigue improved the
prognosis of CFS (11). A US team noted that CFS patients with higher
levels of physical functioning were more likely to report recovery at
follow-up (12). This suggests the possibility that the group diagnosed
because of the surveillance, who had less severe fatigue and better
physical functioning, might have a better prognosis than clinic
attenders i.e. data from the latter should not necessarily be
extrapolated to the former without adjustment for their less severe
illness. The prognosis for many adolescents with CFS is good (13-14).
However, despite these difficulties in estimating the prognosis of
patients if they had been given neither a diagnosis nor treatment, I'm
inclined to think it is better to give a diagnosis based on existing
data. A Centers for Disease Control and Prevention (CDC) study
suggested that a delayed diagnosis appeared to be a risk factor for
poor prognosis, prompting them to launch a multi-million dollar
awareness and education campaign aimed at both clinicians and the
general public (15). A study in the UK found that a longer time to
diagnosis significantly increased the chances that a person would be
severely affected [i.e. it compared those who were mildly affected and
those who were severely affected (omitting those who could not easily
be classified in either group) and found, even after adjustments, that
the time to diagnosis was greater for the severely affected group than
the more mildly affected group] (16).
So the more important question in my mind is the value, or otherwise,
of therapy received. Unfortunately we don't get that much quantitative
data on this. We are told information about children being "fully
recovered" without information about how this was defined or indeed
who decided they were fully recovered (e.g. clinician, parent,
children or a combination of individuals?). An important aspect of
this is the number of time points that were used. "CFS/ME" is
well-known for often having a relapsing and remitting course,
something the CDC found in one of their longitudinal studies (17).
Another CDC CFS paper reported (in a study where recovery was
self-defined) "at 6 months from first reported recovery, 57% (26/46)
of these patients reported that they continued to consider themselves
recovered from their fatiguing illness, 28% (13/46) reported a return
of their fatigue, and 15% (7/46) had incomplete data on fatigue status
following their report of initial recovery" (18). A US paediatrician
followed some of his ME/CFS patients into adulthood. In one study, ten
persons who considered themselves "recovered" or "nearly recovered"
(at the time of the assessment) were given questionnaires to assess
health status and compared to healthy adults (19). Half of the
"recovered" subjects would be considered ill with CFS based upon the
disability requirements of the CDC empiric definition of CFS (a broad
definition) (20), and all "recovered" subjects had significant somatic
symptoms.
The question of whether patients should be treated, or whether simply
diagnosing at this time might be better, is important given the
therapies in question: Graded Exercise Therapy (GET) and Cognitive
Behaviour Therapy (CBT). I recently published a paper (21) looking at
the reporting of harms for GET and CBT (and in particular the form of
CBT based on scheduling graded activity, the form recommended by the
NICE guidelines to which the clinic adheres (22)). Reporting of harms
in RCTs of these therapies has been recognised as being poor by
Cochrane Reviews on both therapies along with the systematic review on
which the NICE guidelines were based (22- 25). As they are
non-pharmacological interventions, no yellow card facility exists for
reporting adverse events. In this scenario, data from surveys may be
particularly important: a review of 10 surveys I collated found 51% of
survey respondents (range 28-82%, n=4338, 8 surveys) reported that GET
worsened their health while 20% of respondents (range 7-38%, n=1808, 5
surveys) reported similar results for CBT (21). This should raise
serious questions about the use of these therapies, particularly on
individuals who haven't presented themselves to their doctors but have
been picked up by surveillance.
As I said, the information on efficacy in this study (1) is far from
ideal given it's uncontrolled. The authors claim the "PACE trial
provided strong evidence that these treatments are moderately
effective in adults" (1,26). However, this statement is based on
subjective outcome measures and previous studies of therapies testing
graded activity protocols for CFS have shown that, despite reporting
improvements over a control group (27), or over time (28), individuals
may not have improved when activity (as measured by actometers) are
used as the outcome measure. If one looks at the most objective
measure of functioning that has so far been reported in the PACE
Trial, the 6 minute walk test (6MWT), there was no difference between
the CBT and control group (26). Following adjustment, the GET group
did increase by 35 metres over the control group but a final result of
only 379m is more like the result of a spavined older adult than the
644m that population norms predict for the participants in the PACE
Trial (adults of average age 39 year old adults, 77% of whom are
female) (21,26).
So, in conclusion, I'm inclined to believe this study suggests the
need for a greater awareness of how prevalent "CFS/ME" can be amongst
adolescents. However, whether they should then routinely be treated
with CBT and/or GET is still open for debate.
References:
(1) Crawley EM, Emond AM, Sterne JA. Unidentified Chronic Fatigue
Syndrome/myalgic encephalomyelitis (CFS/ME) is a major cause of school
absence: surveillance outcomes from school-based clinics. BMJ Open.
2011 Dec 12;1(2):e000252. Print 2011.
(2) NICE. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or
Encephalopathy); Diagnosis and Management. CG53. London: National
Institute for Health and Clinical Excellence (NICE), 2007.
(3) Carruthers B, Jain A, de Meirleir K, Peterson D, Klimas N, Lemer
A, et al.: Myalgic encephalomyelitis/chronic fatigue syndrome:
clinical working case definition, diagnostic and treatment protocols.
J Chronic Fatigue Syndrome 2003;11(1):7-33
(4) Jason LA, Bell DS, Rowe K, Van Hoof ELS, Jordan K, Lapp C, Gurwitt
A, Miike T, Torres-Harding S, De Meirleir K. & IACFS. A pediatric case
definition for ME/CFS. J Chronic Fatigue Syndr. 2006;13(2/3):1-44.
(5) Fukuda K, Straus SE, Hickie I, Sharpe MC, Dobbins JG, Komaroff A.
The chronic fatigue syndrome: A comprehensive approach to its
definition and study. Annals of Internal Medicine. 1994;121:953-959.
(6) Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a
working case definition. Ann Intern Med. 1988 Mar;108(3):387-9.
(7) Jason LA, Evans M, Porter N, et al. The development of a revised
Canadian Myalgic Encephalomyelitis-Chronic Fatigue Syndrome case
definition. American Journal of Biochemistry and Biotechnology.
2010:6;120 -135.
(8) Carruthers BM, van de Sande MI, De Meirleir KL, Klimas NG,
Broderick G, Mitchell T, Staines D, Powles AC, Speight N, Vallings R,
Bateman L, Baumgarten-Austrheim B, Bell DS, Carlo-Stella N, Chia J,
Darragh A, Jo D, Lewis D, Light AR, Marshall-Gradisbik S, Mena I,
Mikovits JA, Miwa K, Murovska M, Pall ML, Stevens S. Myalgic
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Evans M, Brown M. Myalgic Encephalomyelitis: Case definitions.
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(10) Joyce J, Hotopf M, Wessely S. The prognosis of chronic fatigue
and chronic fatigue syndrome: a systematic review. QJM. 1997
Mar;90(3):223 -33.
(11) Vercoulen JH, Swanink CM, Fennis JF, Galama JM, van der Meer JW,
Bleijenberg G. Prognosis in chronic fatigue syndrome: a prospective
study on the natural course. J Neurol Neurosurg Psychiatry. 1996
May;60(5):489- 94.
(12) Pheley AM, Melby D, Schenck C, Mandel J, Peterson PK: Can we
predict recovery in chronic fatigue syndrome? Minnesota Medicine 1999,
82(11):52-6.
(13) Rimes KA, Goodman R, Hotopf M, Wessely S, Meltzer H, Chalder T.
Incidence, prognosis, and risk factors for fatigue and chronic fatigue
syndrome in adolescents: a prospective community study. Pediatrics.
2007 Mar;119(3):e603-9.
(14) Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic
fatigue syndrome after infectious mononucleosis in adolescents.
Pediatrics. 2009 Jul;124(1):189-93.
(15) Reyes M, Nisenbaum R, Hoaglin DC, Unger ER, Emmons C, Randall B,
Stewart G, Abbey S, Jones JF, Gantz N, Minden S, Reeves WC. Prevalence
and incidence of chronic fatigue syndrome in Wichita, Kansas. Archives
of Internal Medicine 2003;163:1530-1536.
(16) Pheby D, Saffron L. Risk Factors for Severe ME/CFS. Biology and
Medicine. 2009;1:50-74.
(17) Nisenbaum R, Jones JF, Unger ER, Reyes M, Reeves WC. A
population-based study of the clinical course of chronic fatigue
syndrome. Health Qual Life Outcomes. 2003 Oct 3;1:49.
(18) Reyes M, Dobbin JG, Nisenbaum R, Subedar N, Randall B, Reeves WC:
Chronic fatigue syndrome progression and self-defined recovery:
evidence from CDC surveillance system. Journal of Chronic Fatigue
Syndrome 1999 5(1):17-27.
(19) Bell DS, Bell DE. Definition of recovery in Chronic Fatigue
Syndrome. The Journal of IiME. 2010. 4 (1) 23-27
(20) Reeves WC, Wagner D, Nisenbaum R, Jones JF, Gurbaxani B, Solomon
L, Papanicolaou DA, Unger ER, Vernon SD, Heim C. Chronic fatigue
syndrome- -a clinically empirical approach to its definition and
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(21) Kindlon T. Reporting of Harms Associated with Graded Exercise
Therapy and Cognitive Behavioural Therapy in Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome. Bulletin of the IACFS/ME.
2011;19(2):59-111.
http://www.iacfsme.org/BULLETINFALL2011/Fall2011KindlonHarmsPaperABSTRACT/tabid/501/Default.aspx
(22) NICE. Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or
Encephalopathy); Diagnosis and Management. CG53. London: National
Institute for Health and Clinical Excellence (NICE), 2007.
(23) Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour
therapy for chronic fatigue syndrome in adults. Cochrane Database Syst
Rev. 2008;(3):CD001027.
(24) Edmonds M, McGuire H, Price J. Exercise therapy for chronic
fatigue syndrome. Cochrane Database Syst Rev. 2004;(3):CD003200.
(25) Chambers D, Bagnall AM, Hempel S, Forbes C. Interventions for the
treatment, management and rehabilitation of patients with chronic
fatigue syndrome/myalgic encephalomyelitis: an updated systematic
review. J R Soc Med. 2006;99:506-20. Review.
(26) White P, Goldsmith K, Johnson A, et al. Comparison of adaptive
pacing therapy, cognitive behaviour therapy, graded exercise therapy,
and specialist medical care for chronic fatigue syndrome (PACE): a
randomised trial. Lancet 2011;377:823e36.
(27) Wiborg JF, Knoop H, Stulemeijer M, Prins JB, Bleijenberg G. How
does cognitive behaviour therapy reduce fatigue in patients with
chronic fatigue syndrome? The role of physical activity. Psychol Med.
2010;40:1281 -1287.
(28) Friedberg F, Sohl S. Cognitive-behavior therapy in chronic
fatigue syndrome: is improvement related to increased physical
activity? J Clin Psychol. 2009;65:423-42.
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