ArticlePDF Available

Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Authors:
Article

Reporting of Harms Associated with Graded Exercise Therapy and Cognitive Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract and Figures

Across different medical fields, authors have placed a greater emphasis on the reporting of efficacy measures than harms in randomised controlled trials (RCTs), particularly of nonpharmacologic interventions. To rectify this situation, the Consolidated Standards of Reporting Trials (CONSORT) group and other researchers have issued guidance to improve the reporting of harms. Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT) based on increasing activity levels are often recommended for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, exercise-related physiological abnormalities have been documented in recent studies and high rates of adverse reactions to exercise have been recorded in a number of patient surveys. Fifty-one percent 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. Using the CONSORT guidelines as a starting point, this paper identifies problems with the reporting of harms in previous RCTs and suggests potential strategies for improvement in the future. Issues involving the heterogeneity of subjects and interventions, tracking of adverse events, trial participants’ compliance to therapies, and measurement of harms using patient-oriented and objective outcome measures are discussed. The recently published PACE (Pacing, graded activity, and cognitive behaviour therapy: a randomised evaluation) trial which explicitly aimed to assess “safety”, as well as effectiveness, is also analysed in detail. Healthcare professionals, researchers and patients need high quality data on harms to appropriately assess the risks versus benefits of CBT and GET.
No caption available
… 
No caption available
… 
Content may be subject to copyright.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((59!
!
Reporting of Harms Associated with Graded Exercise Therapy and Cognitive
Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Tom Kindlon
Information Officer (voluntary position)
Irish ME/CFS Association
PO Box 3075, Dublin 2, Rep. of Ireland
Tel: +353-1-2350965
E-mail: tkindlon@maths.tcd.ie or info@irishmecfs.org
!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((60!
!
ABSTRACT
Across different medical fields, authors have placed a greater emphasis on the reporting of
efficacy measures than harms in randomised controlled trials (RCTs), particularly of
nonpharmacologic interventions. To rectify this situation, the Consolidated Standards of
Reporting Trials (CONSORT) group and other researchers have issued guidance to improve the
reporting of harms. Graded Exercise Therapy (GET) and Cognitive Behavioural Therapy (CBT)
based on increasing activity levels are often recommended for Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, exercise-related
physiological abnormalities have been documented in recent studies and high rates of adverse
reactions to exercise have been recorded in a number of patient surveys. Fifty-one percent 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.
Using the CONSORT guidelines as a starting point, this paper identifies problems with the
reporting of harms in previous RCTs and suggests potential strategies for improvement in the
future. Issues involving the heterogeneity of subjects and interventions, tracking of adverse
events, trial participants’ compliance to therapies, and measurement of harms using patient-
oriented and objective outcome measures are discussed. The recently published PACE (Pacing,
graded activity, and cognitive behaviour therapy: a randomised evaluation) trial which explicitly
aimed to assess “safety”, as well as effectiveness, is also analysed in detail. Healthcare
professionals, researchers and patients need high quality data on harms to appropriately assess
the risks versus benefits of CBT and GET.
!
!
!
!
!
!
!
!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((61!
!
Reporting of Harms Associated with Graded Exercise Therapy and Cognitive
Behavioural Therapy in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
1. Introduction
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is increasingly recognised as
an important worldwide health problem (1,2). Community-based epidemiological studies have
shown it is more prevalent than previously thought and that it affects people of all races and
socioeconomic groups (3-7). Illness intrusiveness is high with patients having poor health-
related quality of life (8,9). Given that average onset is at an age when people should be at their
most productive, its economic impact is substantial with total direct and indirect costs in the
USA estimated at 18.7 to 24 billion dollars annually (10-13). There is a lack of consensus on
many issues, including what causes the illness, what it should be called, how it should be
defined, and whether it is one condition or many (14-31).
One of the most contentious views in the field of ME/CFS is the suggestion that gradual increase
of activity or exercise will substantially improve or even reverse the condition (32-34).
Proponents of Graded Exercise Therapy (GET), Graded Activity Therapy (GAT), and Cognitive
Behavioural Therapy (CBT) programs which involve graded exercise/activity for ME/CFS often
point to the efficacy that has been reported in the literature (35-41). Prior studies suggest that
approximately 40% of those who received CBT experienced lower fatigue levels post-
intervention in contrast to 26% in usual care, while those receiving GET experienced both lower
fatigue levels as well as improved self-rated physical functioning. Although a small number of
trials have shown some benefits over the long term, most of the efficacy data are from trials that
did not involve long-term follow-up (35,36,42-45). Other non-pharmacological interventions
have also been proposed, with some showing efficacy in trials (46-53).
Although RCTs of CBT and GET have generally shown average improvements on the measures
reported (which is not the same as meaning no individual deteriorated on these measures), one
recently published randomised controlled trial (RCT) of a “[m]ultidisciplinary treatment
combining CBT, GET, and pharmacological treatment” found that, at 12 months, there was a
statistically significant decline in physical function compared to baseline when measured by the
Medical Outcomes Study Short-Form questionnaire (SF-36) physical function subscale and that
pain was significantly worse when measured by both the SF-36 bodily pain and the pain subscale
of the Stanford Health Assessment Questionnaire (HAQ) (54). There was also a statistically
significant increase in the total number of the following co-morbidities: fibromyalgia, sicca
syndrome, endometriosis/dysmenorrhea, dysthymia, thyroid dysfunction, multiple chemical
sensitivity, and irritable bowel syndrome.
Many patients, as well as some clinicians and researchers, disagree that CBT and GET should be
routinely recommended at this time believing, amongst other reasons, that safety issues have not
been properly addressed (55). Using a generic definition of “harms”, the harms associated with
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((62!
!
GET (or CBT) could be defined as the “totality of possible adverse consequences of GET (or
CBT)” (56). Breau and colleagues constructed a more detailed definition when looking at harms
in the urological literature (57) that could also be applied: “any undesirable event that occurred
during the trial that had a deleterious impact on morbidity, mortality, quality of life or increase in
the use of resources. Harm could be a primary or secondary outcome and could also be referred
to as adverse event, side effect, complication, toxicity or safety.” The purpose of this paper is to
explore issues of safety for ME/CFS patients in regards to GET and the form of CBT that
involves scheduling increasing activity and/or exercise.
!
2. Exercise and the measurement of the effects of exercise programs
It is well recognised that exercise can have beneficial effects for many in society. Exercise is
recommended not only as an important component of maintaining good health and preventing
disease but also suggested as an adjunct treatment for a host of chronic medical conditions.
However, exercise can also cause harm (58). As Cooper and colleagues note (58), “like
pharmaceutical therapies, prescribing exercise as therapy, an activity that is gaining in
acceptance throughout the medical community, must be predicated on understanding the risks
and benefits of exercise as thoroughly as possible.”
Given the limited understanding of exercise pathophysiology in ME/CFS, it is difficult to
formulate a definition of safe and effective exercise that confers the benefits of being active
without causing harm. The effects of exercise in ME/CFS, although not fully understood, have
been examined in several studies. A number of physiological abnormalities have been detected
with exercise in individuals with ME/CFS (59,60), including metabolic disturbances, modified
gene expression, decreased cognitive reaction times, impaired cellular ion channel functions, and
immune dysfunction. For example, the Pacific Fatigue Laboratory, using the commonly accepted
American Medical Association disability guidelines, found that 48% of 203 CFS subjects would
be classified as moderately to severely impaired based on peak oxygen uptake (VO2 max) during
cardiopulmonary exercise testing (CPET) (61). Furthermore, even among those participants who
were not impaired or mildly impaired during initial testing, repeated testing 24 hours later
yielded, on average, a 22% decline in VO2 max (62). This is unique and significantly different
from other chronic diseases where VO2 max initially can be low but is reproducible on repeated
CPET (61).
In another study, Light and colleagues compared the effect of moderate exercise on patients with
CFS and controls (63). These investigators found that after the exercise, CFS patients showed
enhanced gene expression for receptors detecting muscle metabolites and for both the
sympathetic nervous and immune systems; many of these changes correlated with symptoms of
physical fatigue, mental fatigue, and pain. Given the range of abnormalities that have been found
with exercise in ME/CFS subjects, it would not be unexpected if programs encouraging
increased physical activity resulted in adverse reactions for some patients.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((63!
!
Indeed, observational studies have shown that physical exertion of various intensities can
provoke a diverse array of symptoms in ME/CFS such as fatigue, light-headedness,
muscular/joint pain, cognitive dysfunction, headache, nausea, physical weakness,
trembling/instability, insomnia, and sore throat/glands (64,65). These symptoms are not
uncommon and can last days, if not weeks, for some individuals (65). In 2006, an audit of adult
specialty ME/CFS rehabilitation (CBT/GET) clinics in Belgium (clinics that had been set up
following a request from the Minister of Social Affairs (66)) found that, compared to before
treatment, about one-third of participants reported worsening of their pain, concentration, and
sleep after CBT/GET (67,68).
It should be noted that randomised controlled trials (RCTs) of GET and CBT have tended to
assess fatigue primarily, so it is unclear whether other symptoms have regularly been
exacerbated in such trials. Furthermore, the instruments used to measure fatigue often suffer
from ceiling/floor effects so it is not possible to ascertain whether some participants experienced
a worsening of their fatigue (69-71). Moreover, factor analysis has shown that fatigue in
ME/CFS is multidimensional and so other scales, such as the ME/CFS Fatigue Types
Questionnaire (MFTQ), may be required to capture the different fatigue-related sensations and
symptoms experienced by patients with the condition (72).
3. Direct reports of adverse reactions by patients
3.1. The value of patients’ self-reported data
Generally, in medicine, the documentation of adverse reactions to pharmacologic and non-
pharmacologic treatments has almost entirely been based on reports from researchers and
clinicians. However, Basch has contended that an accurate portrait of patients’ subjective
experiences cannot be obtained from clinicians’ and researchers’ documentation alone: “A
substantial body of evidence [shows that] clinicians systematically downgrade the severity of
patients' symptoms, that patients' self-reports frequently capture side effects that clinicians miss,
and that clinicians' failure to note these symptoms results in the occurrence of preventable
adverse events” (73). Given this information, a system for reporting adverse events to treatments
would ideally involve the collection of data from patients as well as health care professionals.
3.2. Qualitative and quantitative data about harms from GET and CBT
Currently, assessing the harms of non-pharmacologic treatment relies mainly on anecdotal data
(74).
Discourse within the ME/CFS patient community is replete with reports of adverse reactions
from those who undertook exercise programs. Some members of the Irish ME/CFS Association
have reported not just temporary increases in ME/CFS symptoms but also long-term decreased
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((64!
!
levels of functioning. This was explicitly recorded in a United Kingdom 25% ME Group survey
where the authors noted that some participants had made clear that they had not been severely
affected before undertaking a GET program (75). This was echoed in a subsequent survey by the
same group (76):
- "I participated in Graded Exercise therapy via the <name of a ME/CFS specialist unit>.
This lead to a relapse, at home, and made me unable to sit upright for 1 year due to
pressure in my head, and chest pain. I then relapsed and ended up in my local NHS
Hospital in a cardiac care unit."
- "Graded Exercise Therapy worsened me dramatically and I have no doubt had been a
large factor in my being severely affected after 20 years.”
- "I worked with a physiotherapist, who also had no experience of M.E. I began to
seriously deteriorate, and 4 months in, suffered a major relapse. I had a kind of
undiagnosed 'stroke', collapsed, and became incapable of looking after myself. When I
went to the hospital I could walk 100 yd., feed, wash and dress myself. When I left I could
not weight bear at all, had no leg muscles to speak of, and needed two people to transfer
me on and off the toilet and in and out of bed. I had little use of my hands and was totally
bed bound. I could not tolerate sitting upright against the pillows, conversation was
beyond me, and I could barely manage to feed myself by picking up food in my hands --
cutlery was out of the question. Nine years later I have improved, but I'm still bed bound.
One recently published study found that there was a trend for both CBT (p=0.088) and GET
(p=0.02) (received before diagnosis) to be risk factors for severe illness at follow-up (77). In
addition, the risk for a related modality, physiotherapy (p=0.0009), was significant at an α-
threshold of 0.0036. It is important to point out that this was a self-report retrospective survey,
rather than a prospective longitudinal study, and thus has similar limitations to other surveys, as
itemised in section 3.3. Also, the sample sizes were relatively small. Of those reporting therapies
before diagnosis, there were 415 individuals with mild illness and 84 with severe illness (at
follow-up); 18 mild cases and 8 severe cases reported using CBT while 23/11 and 35/20,
respectively, reported receiving GET and physiotherapy.
High rates of adverse reactions following GA/GE programs have consistently been reported in
large patient surveys in various countries over the last two decades (see Table 1) (75, 77-85).
Participants in these surveys were asked about the effect of GET and a myriad of treatment and
management strategies on their health. The data has been pooled in Table 2, with the mean of
worsening for GET/GAT and CBT respectively amounting to 51.24% (range: 28.1-82%) and
19.91% (7.1-38%) of subjects. The percentages of subjects adversely affected in Table 2 are not
low; in comparison, an average of 2.58% (of 5894) subjects reported that “pacing” worsened
their health.
3.3. Limitations of survey data
Some researchers have been dismissive of the survey results, contrasting them with what they
see as the safety that has been proven in RCTs and suggesting the discrepancy might be due to
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((65!
!
improper implementation of GET outside of RCTs. Even if safety had been shown in RCTs,
which is debatable given there appears to be scope for improvement in the reporting of harms
(see sections 4 and 5), it has been observed in other medical domains that outcomes from routine
practice may be more relevant than the “artificial” environment of a clinical trial (86, 87).
Moreover, a subgroup analysis of a GET survey performed by Action for M.E./AYME and
published in 2008 (82) found that there was no statistically significant difference in the rate of
people saying they were made worse from engaging in GET under a “NHS specialist” (31.27%,
111/355) compared to the rest of those reporting such an outcome from GET in another scenario
(33.02%, 70/212).
Secondly, in eight of the surveys, categories of harm have been collapsed into single categories
such as “harmful”, “made worse”, “disimproved with treatment” and “deterioration”. In two of
the surveys, two levels of severity of the harms were available to respondents: “somewhat
worse” and “a lot worse”. Although it is somewhat unsatisfactory to not have more details about
adverse events, participant-rated clinical global impression (CGI) change scores, which use
similar language, have been used as both primary and secondary outcome measures in RCTs of
non-pharmacologic interventions for ME/CFS (44, 49, 88-92). The current survey data and CGI
change scores can be subject to recall and other biases as they are dependent on the participant
having an accurate memory of how they were overall before the therapy and making an accurate
global comparison.
Thirdly, survey respondents may not be representative of all who undertake CBT and GET,
resulting in either an over- or under-estimate of harm. People who have been harmed by GET or
CBT may be more inclined to fill in treatment surveys or join patient groups. Members of
ME/CFS patient groups may also satisfy more restrictive definitions for ME/CFS (which may
correspond with less response to GET/CBT), have been sick for a longer period of time (79, 85),
or be more severely affected. On the other hand, some of the most disabled subset of patients
may not be able to respond to the survey. People who actively seek out support organizations or
fill in surveys may have higher levels of general education (93, 94). Compared to the general
ME/CFS population, these individuals might be less likely to be harmed by a therapy not only
because of cautions about exercise and CBT/GET issued by patient groups but also because they
have the confidence to challenge prevailing ideas about treatment that do not seem to be working
for them.
Fourthly, there may be differences in the content of the therapies received. For example, the first
Cochrane Review of CBT for CFS distinguished between two forms of CBT offered (95):
“The way in which modification of thoughts, beliefs, rest, and activity was attempted was used
to delineate two 'types' of CBT. ‘Type A' attempted to increase activity and reduce rest time in
a systematic manner, independent of symptoms, towards 'normal' levels. 'Type B' attempted to
tailor the patient's rest and activity towards levels which were compatible with the limitations
imposed by the disorder. Therefore, type B CBT did not explicitly attempt to increase the
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((66!
!
patient's physical or psychological capacity beyond improving their ability to 'cope' with their
disabilities.
!
Even within ‘type A’ and ‘type B’ protocols, as well as within GET programs, there can be
heterogeneity in the components of the interventions (e.g., when activity levels should be
decreased, maintained, or increased and by how much; the intensity of the exercise; the
frequency per week, etc.). Consequently, harms-related data from one study may not be fully
applicable to another. In an editorial on the reporting of psychological interventions in general,
Marks highlights how there can be many differences between programs that appear superficially
to be similar (96). Practitioners themselves can alter the program they offer over time. In a
manual published in 2006, the influential team at Radboud University Nijmegen Medical Center
described how their CFS program had changed from the one assessed in an earlier RCT (32,97).
The newer approach involved dividing patients up into two groups, the so-called “relatively
active” and “relatively passive”, and giving different advice to each group. The new protocol for
“relatively passive” patients was quite intense (32): "So, for example, the first day the patient has
six 1-minute walks, the second day six 2-minute walks, the third day six 3-minute walks, and so
on. The aim is a total build-up of 5 minutes a week for each walk a day.” The therapy usually
offered in the UK does not divide patients in this way (41). Exactly what constituted GET or
CBT for each survey respondent was not made explicit. It would have been ideal if we had data
available on the activity/exercise performed by each survey participant; however, as discussed
later in Section 5.4, even data taken from RCTs has generally been of a poor quality in terms of
measuring the actual activity. These differences in focus, type, and execution of GET and CBT
might at least partly explain the wide range of means in Table 2.
Differences in the content of interventions may also explain the large difference in the rate of
harms reported between GET and CBT. So, for example, some therapists may employ the
aforementioned “type B” CBT which does not involve scheduling graded increases in activity.
Also, at least one set of authors have pointed out that many clinicians using CBT principles in
practice “add a host of interventions that are not specific for CBT” (98), for example measures
“target[ing] pain, sleep problems and emotional distress [...] stress management techniques,
experiential group discussions, family support and so on (see e.g. 99 [i.e. Pardaens et al.,
2006]).” Due to there being effectively more interventions involved in the CBT, participants may
focus less on exercise/activity between sessions.
Finally, there may be possible problems with pooling data in this way since there might be some
overlap among surveys (i.e. an individual filled in more than one survey) and since there was
inconsistent wording across surveys. However, looking at absolute figures, if one were to just
combine one of the UK surveys (80) with the Norwegian-language study from Norway that was
published 8 years later (84), there is likely to be very little, if any, overlap. Between the two
surveys, approximately 1100 respondents reported being made worse by a graded exercise
programme.
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((67!
!
Despite these reservations, the consistently high rates and absolute numbers of adverse reactions
coupled with the potentially disabling effects of GET and CBT reported in these surveys are
concerning and need to be investigated more thoroughly.
4. Guidelines for the reporting of RCTs and application to ME/CFS RCTs
4.1. CONSORT randomized controlled trials statements
The CONSORT (Consolidated Standards of Reporting Trials) Group is an international
organization of experts in the methodology of clinical trials that was formed in 1993 due to
concerns regarding inadequate reporting of RCTs. The Group created a 25-item checklist (100)
of essential points that should be included in all publications of RCTs to “enabl[e] readers to
understand a trial's design, conduct, analysis and interpretation, and to assess the validity of its
results.” (101) Specific suggestions from the CONSORT statement include sufficiently detailed
interventions such that it is able to be replicated by other researchers, blinding of participants and
researchers as appropriate, and tracking participant withdrawals. CONSORT is endorsed by over
50% of the core medical journals listed in the Abridged Index Medicus on PubMed (102).
Since publication of the initial CONSORT guidelines, extensions for specific areas have been
prepared, e.g. for acupuncture interventions (103,104) and, more recently, for non-
pharmacologic treatment interventions (105). Reporting in general has been shown to improve
since the publication of CONSORT guidelines with some reviews demonstrating improvements
in particular areas such as weight loss intervention studies and acupuncture (106-109).
4.2. Poor reporting of harms in RCTs, particularly for non-pharmacological interventions
Evidence across various medical domains suggests the reporting of harms in clinical trials has
been especially inadequate and receives less attention than efficacy outcomes (110-113). As one
group of authors noted, “Reporting harms may cause more trouble and discredit than the fame
and glory associated with successful reporting of benefits” (114). Breau also observed that, in
general, “[t]rialists may not evaluate adverse outcomes because they believe the safety of the
intervention has already been established. However, this assumption is often invalid since the
adverse effects of an intervention may differ depending on the indication or population subjected
to treatment” (57).
To help remedy this, the CONSORT group issued a statement extension in 2004 focusing on
harms (56). This extension consisted of a 22-item checklist that researchers should consider in
the process of designing, carrying out, and publishing their studies. The checklist includes
“clarify[ing] how harms-related information was collected”, “list[ing] addressed adverse events
with definitions for each”, and “describ[ing] for each arm the participant withdrawals that are
due to harms and their experiences with the allocated treatment” (56).
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((68!
!
Harms reporting for nonpharmacologic RCTs is generally inferior to that for pharmacologic
RCTs. A study focusing on the reporting of harm in RCTs of mental health interventions found
that no report of nonpharmacologic treatment trials adequately reported harms (115). Another
group of researchers compared the reporting of harm in pharmacologic (n=119) and non-
pharmacologic (n=74) RCTs of treatments for rheumatic disease (74). Pharmacologic treatment
reports included information related to harms more often than nonpharmacologic treatment
reports. This information consisted of collection methods, blinded assessment, reporting of
adverse events, causal relationship between the treatment and adverse events, withdrawals due to
the events, and severity of the events. A greater proportion of the space in the results section was
allocated to harms in pharmacologic than nonpharmacologic treatment reports. These differences
remained with adjustment for sample size, medical area, funding, and multicenter trials. Fewer
than half of the nonpharmacologic treatment trials assessed reported any harm-related data at all.
The authors commented (74):
“Presupposed lower toxicity profiles of nonpharmacologic treatment, such as exercise
therapy, complementary and alternative medicine, and behavioral interventions, could
explain a lower interest in the evaluation of adverse events. However, most therapy entails the
risk for adverse events, including serious events.”
The aforementioned CONSORT statements provide a framework against which to evaluate the
quality of RCTs. Reporting of harms from trials of nonpharmacologic trials should be as
systematic as the reporting recommended for pharmacologic trials.
4.3 Quality of reporting of harms in ME/CFS RCTs
RCTs of CBT and GET for CFS have been found lacking in their reporting of harms by the
Cochrane Collaboration, a multinational independent network of medical professionals,
researchers, and policymakers. For all five RCTs of GET that the Collaboration examined in
2004, no data for adverse effects was documented in any of the trials (36). However, the
CONSORT statement on harms (56) notes that “it is important to report participants who are
non-adherent or lost to follow-up because their actions may reflect their inability to tolerate the
intervention.” Perhaps this may partially explain the finding of a trend for a higher dropout rate
in GET as compared to the control group in the studies assessed in the Cochrane review
(Analysis 1.3). Thus the Cochrane reviewers concluded that (36) “studies of higher quality are
needed that involve different patient groups and settings, and that measure additional outcomes
such as adverse effects, quality of life and cost effectiveness over longer periods of time.”
The Collaboration similarly reviewed RCTs of CBT for CFS in 2000 (95) and performed an
update in 2008 (35). Out of 14 separate RCTs examined, only one had any data to assess patient
acceptability and none of the studies had good quality data related to adverse effects. In the
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((69!
!
“Selective outcome reporting” subsection of “Risk of bias in included studies”, the Collaboration
authors wrote (35): “Whilst Lloyd 1993 collected data concerning the adverse effects of DLE
injection, data referring to adverse effects of psychological treatment was not systematically
presented by any study.” Drop-out rates averaged 16% across studies but definitions for what
constituted “drop-outs” varied and reasons for attrition were not detailed; a third of the studies
had drop-out rates over 20%. The authors finished by asserting that future studies should
incorporate data on adverse effects and acceptability among other outcome measures.
In 2006, a systematic review by Chambers and colleagues of the same set of GET trials and most
of the same CBT studies echoed similar concerns (38), “There is limited evidence about adverse
effects associated with behavioural interventions. Withdrawals from treatment in RCTs suggest
that there may be an issue but the evidence is often difficult to interpret because of poor
reporting.”
5. Considerations for future research
5.1 Recognize heterogeneity of patients with a diagnosis of ME/CFS
A complication in the ME/CFS field is the heterogeneity of patients who might have the
diagnosis of ME or CFS (22,31). Interventions such as GET and CBT may be associated with
lower rates of harms for some groups of patients but with much higher risks for others. Indeed,
the authors of one recent paper recommend that some patients should not participate in GET at
all: “the use of GET in the management of CFS is in serious doubt, and there stands a need to
develop a method of identifying which patients respond poorly to physical exercise and should
be advised to avoid GET” (116).
The various diagnostic criteria for ME and CFS may pick out groups of patients with different
symptomatology, functional impairment and psychiatric comorbidity (117-119). Some criteria
require post-exertional symptoms (23,24,29,30,31); others take a polythetic approach where such
symptoms are optional (25,26). At least one set of criteria do not mention them at all and could
be described as criteria for chronic fatigue (27). There are wide variations in the prevalence rates
for CFS depending on how it is defined. Population studies in the US using the Fukuda criteria
give estimates of 0.2-0.4% (6,7) while the figure for the empiric criteria is 2.5% (28,120). It is
clear from these figures that whether somebody is classified as having CFS largely depends on
the criteria used.
Given that fatigue, cognitive dysfunction and sleep problems can be part of depressive disorders
(121), some fear that some patients who satisfy criteria that do not specify post-exertional
symptoms may have primary depression (122-124). A model that is the basis for CBT trials was
found to adequately represent chronic fatigue secondary to psychiatric conditions but not CFS
(125,126). Moreover, it has been shown that satisfying the Fukuda CFS criteria (25) was the
most powerful predictor of poor response to either GET or CBT in those with fatigue (127).
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((70!
!
Investigators may add specific criteria that may affect the generalisability of results. For
example, one study testing GET for CFS excluded those with “appreciable sleep disturbance”
problems (88) despite the fact that in the region of 90% of those with CFS have such symptoms
with sleep (128,129).
More severely affected patients have often been excluded from trials for ME/CFS. Indeed, a
review reported that "No severely affected patients were included in the studies of GET”, adding
that “the balance between effectiveness and adverse effects of interventions may be different in
more severely affected compared with less severely affected” (38). Some clinicians employ this
factor in their practice, giving different recommendations based on severity. Ho-Yen stated that
he does “not recommend an emphasis on greater activity until a patient feels 80% normal” (130)
while Lerner “prohibits” exercise (131,132) until CFS patients score 7 on his Energy Index Point
Score [meaning a person who does not need to nap during the day, is up from 7AM to 9PM, can
work a sedentary 40-hr/ week job, and do light house-keeping] saying “if you exercise before
that you're going to go backwards" (133).
Some researchers have examined whether certain biological markers might predict the efficacy
of CBT/ GET. Roberts and colleagues found that hypocortisolism predicted a poor response to a
CBT program designed to increase activity levels (134). These results are consistent with
findings reported by Jason and colleagues (135) who found, in a study of four non-
pharmacologic interventions (including CBT and an exercise program), that those with abnormal
baseline cortisol did not improve over time. In a follow-up paper (136), it was reported that
baseline measures including immune function, activity levels, sleep status and past psychiatric
diagnosis significantly differentiated those participants who demonstrated positive change over
time from those who did not. CFS subjects with a dominance of the Type 2 over the Type 1
immune response, as indicated by the patterns of lymphocyte subset distributions, did not
improve over time.
“At risk groups” may not be clearly defined by single variables so multivariate analyses may be
required. A recent exploratory study using latent class regression (LCR) explored the Chalder
Fatigue Questionnaire outcome data from 236 CFS patients as defined by the Oxford criteria (27)
who had received CBT at a specialist CFS clinic in the UK (137). It found that participants could
be divided into 4 classes with one class predicting a poor response to CBT outcomes. We were
not given data on all 38 possible predictors but this class was characterised by more frequent
weight fluctuation, physical shakiness and pain, and had higher anxiety and symptom focusing
scores compared to the other classes (137).
Given how frequently increased physical activity is recommended in healthcare settings, there
should be an added impetus to characterise those who might be at increased risk of harm from
following such recommendations.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((71!
!
5.2. Make detailed instructions of interventions easily accessible
The CONSORT statement on the reporting of RCTs (100) suggests that researchers describe "the
interventions for each group with sufficient details to allow replication, including how and when
they were actually administered." The CONSORT Extension for Trials Assessing
Nonpharmacologic Treatments re-emphasises this (105):
“authors [should] allow interested readers to access the materials they used to standardize
the interventions, either by including a Web appendix with their article or a link to a stable
Web site. Such materials include written manuals, specific guidelines, and materials used to
train care providers to uniformly deliver the intervention.”
Such materials have often not been available when RCTs have been published in the ME/CFS
field. Consequently the programs offered in clinical practice may not be the same as those
assessed in clinical trials and may have different rates of harms associated with them.
As alluded to in section 3.3, Marks has highlighted how there can be many differences between
psychological interventions that can appear superficially to be similar (96). Manuals can be long
and detailed so it can be useful if investigators can summarise the active components of
interventions and contrast them with other therapies being assessed. One example of this is
exemplified in Table 1 (“Shared and distinct activities among treatment groups”) of the Jason et
al. (2007) trial of four non-pharmacologic interventions for CFS (49).
If intervention details are not present, it can be difficult for readers and reviewers to classify
therapies correctly. In the PACE Trial, the GET intervention was guided by the principle that,
“[p]lanned physical activity and not symptoms are used to determine what the participant does”
(33); similarly “[i]t is their planned physical activity, and not their symptoms, that determine
what they are asked to do”(33). In contrast, in adaptive pacing therapy, “activity is planned and
then modified in the light of its effect on symptoms"(33). If one looks at the exercise
prescription used in the Wallman et al. (91,138) study from Australia, it appears perhaps more
like the latter program: “on days when symptoms are worse, patients should either shorten the
session to a time they consider manageable or, if feeling particularly unwell, abandon the session
altogether” (138). Given the low rate of harms reported in the survey data for pacing in contrast
to GET (Table 2), it may be that interventions that involve the principles of pacing may have
lower rates of harms associated with them and should be analysed separately in reviews.
5.3 Develop a system to track adverse effects
Some GET and CBT studies have included general statements, like “no adverse event
attributable to CBT was reported”, or have simply counted the number of subjects who did not
complete a study with scant details (35,38). CONSORT regards “using generic or vague
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((72!
!
statements” as insufficient reporting so both they and others have suggested several strategies to
counter this practice (56, 74, 139).
Researchers should state in the study methods section why harms data were omitted if no data
was collected. For those studies where it will be collected, researchers should contemplate
setting up a system before study initiation to systematically track adverse effects as passive
surveillance of harms (i.e. spontaneous reporting) leads to fewer recorded adverse events than
active surveillance (140). Different methods of ascertainment can produce different reporting
incidences. For example, one study found that patient diaries yielded higher rates of Adverse
Drug Reactions (ADRs) than other forms of assessment (113). Open-ended questions may yield
different information, both quantitatively and qualitatively, than structured questionnaires (141).
If the latter are used, researchers should ideally be ready to make the questionnaire accessible
and to explain why it was selected or how it was constructed.
Pooling of data from various studies is often required to investigate signals of adverse events.
Abstracts should contain the existence of harms-related data (including no adverse events) to
help facilitate appropriate database indexing and information retrieval.
Investigators should also consider: defining adverse events; recording the
nature/frequency/severity of events (and the definition used to define severity); noting whether
an event led to subject withdrawal; stating whether harms appraisement was done blindly and its
timing; making explicit the rationale behind whether or not to attribute an event to an
intervention, and noting who did the attribution. Only if such detailed data collection is
attempted can a complete picture emerge of the benefits versus risks of proposed interventions.
5.4 Monitor intervention implementation and compliance using objective measures of activity
The CONSORT extension for RCTs of non-pharmacological interventions suggests that “details
of the experimental treatment and comparator as they were implemented” be reported. One
example given is of an exercise intervention where not only the mean sessions of exercise
attended by participants are noted but also the minutes exercised (105). The rationale behind this
suggestion is to demonstrate that the interventions are reproducible and were carried out as
intended, without contamination of treatment either by research staff treating participants
unequally and/or with different/ additional unintended protocols or by participants choosing to
treat themselves differently. Furthermore, it has long been recognised that adherence to
medication regimens can be poor; objective tools such as Medication Event Monitoring System
(MEMS) devices have shown that self-reported measures tend to inflate reports of compliance
(142-5). Without data on implementation and adherence, claims that an intervention is safe are
questionable.
There are reasons to believe that compliance to interventions might be problematic. The
distinction between an exercise program and a Graded Exercise (GE)/ Graded Activity (GA)
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((73!
!
program for CFS is that, for the latter, a participant is not supposed to decrease exercise (or
activity) levels based on his or her symptoms. As a GET expert described, "if [after increasing
the intensity or duration of exercise] there has been an increase in symptoms, or any other
adverse effects, they should stay at their current level of exercise for a further week or two, until
the symptoms are back to their previous levels" (146). One has to wonder how many patients
would dutifully comply with counterintuitive instructions to maintain a higher activity level for
7-14 days in the face of new or worsening symptoms. If participants did comply, their level of
activity on completion should increase substantially; however, a review of three studies using
objective measures found only a small increase in total activity levels at assessment subsequent
to treatment, and a similar level of increase was recorded in those who had undertaken no
intervention (147).
Another reason that some might feel measuring compliance is important is that some researchers
have hypothesised that personality factors such as higher “action proneness” (“the extent to
which one is oriented toward direct action and achievement”) might make people vulnerable to
ME/CFS (148,149). Theoretically, this might affect proper adherence to programs with high
“action prone” individuals potentially being more likely to increase activities or exercise
prematurely, leading to exertional symptoms. However, these personality studies were
retrospective, performed after subjects were ill, and thus are subject to recall bias. Additionally,
when the same team actually recorded “action-proneness” levels, using the "Vragenlijst voor
Habituele Actiebereidheid" (Questionnaire for Habitual Action-proneness) (HAB), they found a
score of 17.75 (SD6.21) and 20.23 (SD4.65) in CFS patients before and after a multidisciplinary
group treatment respectively (150). Both these sets of scores are lower than the Dutch norm of a
mean of 29.4 (SD6.5), derived from 316 industrial workers (148). It is thus unclear whether
people with CFS should be seen as having high “action-proneness” or not after they become ill.
It is also unclear whether being “action-prone” would lead to more or fewer adverse reactions
from activity programs: people who are “action prone” might in fact be more compliant with
treatment than the average subject if their interpretation of “action” or “achievement” is to
adhere to therapist recommendations. Nevertheless, for some, given possible concerns about the
theoretical effect of personality factors on compliance, this might be a sufficient reason to seek to
measure the activity that was actually performed.
In general, implementation of Graded Exercise (GE) or Graded Activity (GA) programs by
therapists and adherence to them by patients has not been rigorously assessed. No RCT of such a
therapy for ME/CFS, to my knowledge, has measured the intervention using objective measures
of activity. Some trials have employed participant self-report of activity but several studies have
found that activity questionnaires do not correspond well with objective measures (151-153). As
one set of researchers explained, "the subjective instruments do not measure actual behaviour.
Responses on these instruments appear to be an expression of the patients' views about activity
and may be biased by cognitions concerning illness and disability" (152). In fact, non-ME/CFS
exercise studies have shown that activity interventions can influence participants to overestimate
physical activity when compared to objective measures (154-7). This seems particularly relevant
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((74!
!
in the context of GET and GET-based CBT which are designed to change patients’ attitudes
about activity.
Documenting the type of, intensity of, and frequency of exercise/activity sessions in GE/GA
programs is also needed. When assessing the safety of pharmaceuticals, dosage is important: a
drug may be safe at one dosage but quite dangerous at a higher dosage. There seems to be no
reason to view GE and GA differently. For example, a pilot study by Meyer et al. of high- and
low-intensity exercise for fibromyalgia, a condition that has considerable overlap in
symptomatology with ME/CFS (158,159), required participants to complete and post weekly
activity logs (160). An examination of the returns found very poor compliance with the assigned
exercise programs, leading the researchers to reassign participants to the high- and low- intensity
groups based on the actual activity levels recorded in their logs. Interestingly they found that
there was a difference (p<0.05) between the groups on the Fibromyalgia Impact Questionnaire,
with scores improving from baseline in the low-intensity exercise group but deteriorating in
those who had performed high intensity exercise.
Assessments of the effects of activity in ME/CFS as discussed in Section 2 may involve higher
levels of activity than the intensity of activity and exercise in some GET and CBT programs
(161-172). However, a gentle walking test, where participants with CFS covered on average
558m (0.35 miles) at a reported average speed of 0.9m/s (2 miles/hour), resulted in a statistically
significant worsening of fatigue, pain, sore throat, and general health perception (64). Moreover,
when Van Oosterwijck et al. (2010) assessed a short, self-paced and physiologically limited
exercise bout lasting just 5 minutes on average at a mean workload of only 46 Watts, there was a
worsening of the ME⁄CFS symptom complex post-exercise (173). Given the problems
individuals with ME/CFS have experienced with aerobic programs, one set of clinicians have
suggested exercise needs to be performed at below the anaerobic threshold (174). To be able to
satisfactorily assess any differences in adverse events or outcomes between various programs,
investigators need to collect good information on the activity or exercise performed.
Beyond merely showing compliance with interventions, objective measures can also test the
claims that CBT and GET have been shown to lead to recovery in CFS (175,176) indeed that
recovery should be seen as an achievable goal in months rather than years (177). However, since
we do not have data on patients attempting a normal level of activity in a ME/CFS trial, we do
not know the level of risk associated with patients attempting to achieve such a level of activity.
Given the ceiling of activity (178) that has been recorded in ME/CFS, higher levels of adverse
reactions seem possible at or close to this “dosage” of activity or exercise.
Good quality compliance data could help answer many questions. With non-pharmacologic
interventions such as GET and CBT, objective measures of activity, through use of devices such
as actometers or pedometers, should be utilized to confirm compliance and to assess any increase
that was achieved, e.g. the percentage increase in activity in comparison to baseline levels. There
should be careful documentation of sessions attended as well as type, duration, frequency, and
intensity of activity.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((75!
!
5.5 Evaluate for harms using objective measures
In pharmacologic trials, subjects are monitored for harm not only through interviews, patient
questionnaires, and clinical examinations but also with objective measures such as blood tests
assessing kidney function, liver metabolism, or any other anticipated adverse effects of the
medication. Non-pharmacologic interventions in contexts outside of ME/CFS are also monitored
similarly. During supervised exercise post-heart surgery, healthcare staff ask patients if they have
symptoms such as shortness of breath or chest pain (possible signs of the heart not receiving
adequate oxygen), take patients’ blood pressure/ heart rate regularly, and observe for abnormal
heart rhythms using portable monitors. If symptoms occur or abnormalities are seen, staff might
ask patients to stop exercising or decrease the intensity/ duration of exercise.
The effects of exercise on ME/CFS are not yet fully elucidated to the degree it is in coronary
heart disease but there are existing objective measures that that have been utilized to document
symptoms experienced by ME/CFS subjects with exercise. Aside from using repeated
cardiopulmonary exercise testing to measure fatigue/ energy metabolism as mentioned in section
2, standardized tests such as the CalCap reaction time component and the Stroop Word/Color
Test could be used to monitor for any deterioration in cognitive function (171,179).
Polysomnography could be used to examine changes in sleep patterns. Serum cytokine measures
are another possible avenue to monitor exercise effects: Light recently showed that post-exercise
symptoms (mental fatigue, physical fatigue, pain) in ME/CFS subjects were correlated with
persistently high levels of certain cytokines compared to healthy controls (60). Furthermore, in a
small subset of patients who developed CFS after documented infection with parvovirus B-19
and subsequently treated with intravenous immunoglobulin, Kerr and colleagues
demonstrated that recovery from CFS symptoms including post-exertional malaise correlated
strongly with normalization of cytokine levels (180).
Researchers should consider utilizing these or exploring other objective measures. If specific
objective measures correlating with exercise/ activity-associated symptoms are established, these
could be monitored to determine the intensity, frequency, type, or duration of activity that could
be safely tolerated by an individual with ME/CFS and customized treatment plans could be
constructed.
5.6 Measure non-physical harms / patient-oriented outcomes pertaining to quality of life
Aside from any possible "direct" biological harm from increased activity/exercise, other
"indirect" harms, such as psychological, social, and economic harms (181), are also possible.
The magnitude of a harm can be judged by the effect it has on someone's ability to pursue life
goals and the duration of this interference (182). A distinction can be made between interfering
with minor (e.g. visit a museum, meet friends, vacation, etc.) and major (e.g. attend school,
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((76!
!
work, have children, etc.) life goals. GET and GA-based CBT programs involve large
commitments of time and energy which might interfere with the pursuit of both minor and major
life goals by some participants. Given the post-exertional symptoms that are part of ME/CFS
(59,183), effects may not just be experienced during the activity sessions and since such
programs may not involve an increase in total activity levels, other activities are presumably
being substituted for (184). This could put a strain on individuals with ME/CFS in terms of their
ability to perform other roles, like employee, student, partner, and/or parent.
Even if eventually an increased total activity level was achieved, there is likely to be a transitory
period where a reduced amount of time and energy is available for other aspects of one’s life.
This could potentially lead to increased social isolation and, in particular, the break-down of
relationships (i.e. have a long-term, rather than just temporary, effect). Outside the ME/CFS
arena, it has been recognised that psychosocial treatments can have negative effects on family
functioning (185).
In terms of education, a student's academic performance could suffer due to the cognitive
problems which can occur post-exercise (171,179): they might underperform or fail exams, or
simply fall too far behind and drop out.
In the employment realm, an employee might lose their job because an employer was not
satisfied with their performance. In Belgium, an audit of five rehabilitation centres for CFS that
involved CBT and GET (66-68) found that the average hours working decreased at conclusion
and at follow-up six months later compared to the start. In addition, more people (10%)
decreased the number of hours they worked than increased (6%). In fact, when one notes that
only 27% were employed before the program, it means 37% (=10/27) of the participants
decreased how much they worked (which would have included stopping). A Dutch study of CBT
reported better results, with the number of hours worked increasing from a mean (median) of 9.4
(0) hours to 11.4 (0) hours (186). No data was available on the number of people whose hours
worked had decreased; however, the mean (median) number of contract hours (cf. hours actually
worked) decreased from 16.2 (10) hours to 14.9 (7) hours.
So, even if it were the case that there were no biological harms associated with GET and CBT,
individuals with ME/CFS or their physicians could believe that the potential for these secondary
or indirect harms might mean that the treatment is not suitable for a specific individual at a
particular time.
As is often the case when harms are being recorded, specific checklists may need to be
developed that assess some iatrogenic effects – in this case non-biological harms. Spontaneous
reporting of harms may not pick up some unintended consequences. Additionally, a greater use
could be made of patient-oriented outcome measures. Some might claim that the SF-36
questionnaire (187) would be suitable. However, criticisms have been made that it covers few
fields of functional limitation and that several questions cover the same field (two items on
“stairs” and three items on “walking”) (188). These five questions make up 50% of the physical
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((77!
!
functioning subscale which is sometimes used on its own in ME/CFS trials. Given the nature of
GE/GA/CBT programs, this may not be a suitable tool to measure functional impairment when
assessing such interventions.
ME/CFS studies have found apparent improvements using this subscale without any actual
increase in total physical activity (184,189) or a difference with the control group on this
instrument was recorded despite no difference in actigraphy (147,190-192). A similar
phenomenon has been observed with fatigue scales where an improvement in (self-reported)
fatigue scores did not correspond with increased activity (147,184,189,192). Indeed, a recent
systematic review of patient-reported outcome measures (PROMs) confirmed that the quality
and acceptability of those that have been used in ME/CFS studies as “limited ... [as] [c]lear
discrepancies exist between what is measured in research and how patients define their
experience of CFS/ME. Future PROM development/evaluation must seek to involve patients
more collaboratively to measure outcomes of importance using relevant and credible methods of
assessment.”(193)
5.7 Follow subjects for a longer period post-intervention
Only one study of CBT was recorded by the Cochrane Collaboration as having a follow-up of
over 1 year – it involved just 53 patients (35). Similarly, among GET trials reviewed by the same
group, the longest period of follow-up was 1 year post-intervention, leaving the authors to
comment that there is a need for more long-term follow-up data from GET studies (36).
As was pointed out in subsection 5.4., a ceiling of activity appears to exist for at least some
ME/CFS patients (178). During a trial, an individual may be able to increase the quantity or
intensity of exercise up to a certain level without experiencing significant adverse effects,
particularly if they are substituting this activity for other activities in their lives (184). However,
one cannot necessarily extrapolate from such data that patients can use the same program to
safely work their way up to a normal, or pre-ME/CFS, level of functioning, because of the
ceiling of activity nor that, post-study, they will be able to maintain gains. This point was
illustrated in a case study of a graded activity intervention (192):
"[T]his patient largely overcame his initially reported fear of triggering symptom
exacerbations. Yet his concern about exceeding the maximum prescribed weight lifting
levels appeared to be realistic because scheduled attempts to exceed these levels
consistently triggered symptom flare-ups. In addition, the work-related 4-week relapse
revealed an apparent upper limit on his ability to work. This suggests that eradication of a
fear-based activity avoidance will facilitate functional improvements up to a point, beyond
which a more biologically based mechanism of symptom generation may be involved."
With harms from some pharmaceutical treatments, some adverse reactions may only occur
following a certain number of “doses” of the treatment or take a relatively long period to
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((78!
!
manifest. Similarly, given some of the mechanisms through which exercise might cause harm in
ME/CFS (59,194,195), adverse reactions may not become apparent with short-term treatment or
follow-up. Since the full recovery rate from ME/CFS, in general, is 5% over a decade (196),
many patients have been ill for longer than 5 years (79,85), and ME/CFS is known to be a
remitting-relapsing condition (197), it would behove researchers investigating this condition to
design studies with longer term follow-up (38).
5.8 Check for clustering/therapist effects
Therapist effects could be assessed to see whether certain types of results, whether positive or
negative, cluster with specific centres or therapists (198). If, for example, a particular
intervention were associated with a low rate of significant harms with all therapists except one
individual, that might suggest an intervention had less potential for harm than if the effect were
more uniform. Alternatively, if a significant rate of harms were recorded with most of the
therapists except a small number or those in a particular centre, interesting information might be
able to be gleaned from investigating how the treatments were executed differently. However,
the importance of the issue for GET and GA-based CBT for ME/CFS is uncertain. One recent
paper reviewed the results of 374 CFS patients who received CBT with 12 therapists (3 clinical
psychologists and 9 nurses with specialist CBT training) (199). The variance explained by
therapists, when demographic covariates were accounted for, was 0% for fatigue and under 2%
for disability. A review of therapist effects in general found that manualized therapies tend to
produce smaller therapist effects (200).
5.9 Interpret results of studies taking into account previous studies
!
Discussion sections should place trial results within the context of prior and current ongoing
research. CONSORT suggests that “[i]nterpretation [be] consistent with results, balancing
benefits and harms, and [that] other relevant evidence”, including that which does not support the
study the paper is based on, should be considered (100). Furthermore, researchers are
encouraged to “contrast the results on harm…with observational data from spontaneous
reporting, automated databases, case-control studies, and case reports” (56). The qualitative and
quantitative harms data presented in Section 3 of this paper have existed for several years yet has
rarely been mentioned in prior CBT or GET trials. RCTs play an important role in medical
research, but their results should not be overemphasized to the exclusion of basic research and
other clinical studies that may offer pertinent evidence to advance the field.
6. PACE Trial A model of excellence in harms reporting?
Within a week of receiving initial comments about this paper from reviewers, the Lancet
published the PACE Trial, a multi-centered randomised trial in the United Kingdom comparing
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((79!
!
specialist medical care (SMC), GET+SMC (hereafter GET), CBT+SMC (hereafter CBT), and
SMC combined with a form of adaptive pacing therapy (APT) (hereafter APT) as treatment for
ME/CFS (90). The form of CBT evaluated in PACE aimed to “change the behavioural and
cognitive factors assumed to be responsible for perpetuation of the participant’s symptoms and
disability” based on the “fear avoidance theory of CFS”; this included “making collaboratively
planned gradual increases in both physical and mental activity” (90). The trial set out to not only
assess efficacy but also look at harms with outcome measures in the protocol paper designated as
“efficacy measures” or “adverse outcomes”.
The PACE Trial brought the reporting of harms in trials of non-pharmacologic interventions in
the field of ME/CFS to a new standard: compared to prior GET/ CBT studies, the PACE
researchers made available their interventions and protocols online and in published resources,
put forth some effort to establish a system of tracking adverse effects, and provided greater detail
about serious adverse events and reactions (SAEs and SARs). This transparency of PACE
researchers is to be praised and allows researchers to understand, evaluate, and replicate the trial
prudently. However, there remain some concerns about how harms data were collected,
interpreted, and reported and many of the considerations delineated in Section 5 could still be
applied to PACE and future trials; some of these are discussed below.
From online and published protocols, harms surveillance appears to have been active in the sense
that a harms detection system was set up but potential anticipated adverse events were not
specifically solicited by research staff and left open-ended (201,202).!!Therapists had the most
contact with participants but it is unclear what their role was in terms of reporting harm. The
manuals indicate that research nurses (RNs) were responsible for monitoring adverse events
(AEs) at 12, 24, and 52 weeks as well as when a participant dropped out of the trial. While some
examples were given to nursing staff regarding what was a SAE, RNs were still required to use
their clinical experience to decide what constituted a SAE and how severe of an impact a “non-
serious” adverse event could have. If an RN assessed the AE as an SAE, was unsure whether it
was a SAE or was concerned about the event generally, he/she was advised to seek the opinion
of other professionals.
Information conveyed to participants may influence whether certain symptoms were reported
and participants’ interpretation of them. Both GET and CBT models are based on a model of
inactivity/ deconditioning as the major driver in perpetuation of CFS symptoms (34). Thus,
patients were informed that a range of symptoms were due to inactivity. While some, such as
changes in muscle function or reduced tolerance to activity, are well-recognized consequences of
physical inactivity (although whether deconditioning could explain all muscle abnormalities in
ME/CFS is debatable [21,63,169,179,203-216]), other symptoms, such as visual/ hearing
changes, regulation of body temperature, and impairment of mental functioning, are more
questionable. Patients were also told to “consider increased symptoms as a natural response to
increased activity”, that “most people with CFS/ME felt either ‘much better’ or ‘very much
better’ with GET”, and that “the benefits of continuing with cognitive behaviour therapy makes
overcoming the difficulties worthwhile” (34).
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((80!
!
Simultaneously, therapists were told that adverse effects of GET were “due to inappropriately
planned or progressed exercise programmes” without mention of what these effects were and
were instructed to encourage patients to focus on their symptoms less (33). This sort of priming
could easily lead to instances of symptoms not being reported. Previous research has
demonstrated that questionnaires, and especially interviews, addressing sensitive topics,
including physical activity, are susceptible to social desirability response bias (154-157,217).
Participants consciously or unconsciously (self-deception) present inaccurate information about
themselves to conform to what they believe the researcher expects. Participants may also worry
that their performance or demeanor during the trial might negatively influence their physician’s
treatment of them (the consent form included release of information to patients’ regular
healthcare providers) and receipt of disability benefits. Thus, given the way information was
conveyed to both patients and therapists, it is possible that there may be underreporting of
adverse effects.
SAEs and SARs were sub-divided into the following categories in the final report (218):
“a) Death; b) Life-threatening event; c) Hospitalisation (hospitalisation for elective
treatment of a pre-existing condition is not included), d) Increased severe and persistent
disability, defined as a significant deterioration in the participant’s ability to carry out
their important activities of daily living of at least four weeks continuous duration; e) Any
other important medical condition which may require medical or surgical intervention to
prevent one of the other categories listed; f) Any episode of deliberate self-harm.”
Details of all the SAEs were combined notation such as superscripts could have been used so
readers could identify which arm of the trial the participants had been in, as recommended by the
CONSORT guidelines. For SARs, these were divided up by intervention along with the
assessment of whether it was felt each individual SAR was associated with the intervention.
Given the large number of participants (n=640), the number of SARs was relatively small: APT
[2], CBT [4], GET [2] and SMC alone [2]. Apart from one SAR in the SMC arm (“Worse CFS
symptoms and function” (category d) which was rated as “probably related”), all the other SARs
were rated as “possibly related” [to the intervention]. The SARs listed for CBT were “Episode of
self harm” (category f), “Low mood and episode of self harm” (e & f), “Worsened mood and
CFS symptoms” (d) and “Threatened self harm” (e); for GET, the SARs were “Deterioration in
mobility and self-care” (d) and “Worse CFS symptoms and function” (d).
What adverse events are deemed to be serious or to be causally related to the interventions may
be debatable. For SAE/ SAR category (d), some researchers, clinicians, and patients might
argue that if a management program resulted in impairing a participant’s ability to function for a
lesser amount of time than 4 weeks continuously, that it should be still considered a serious
event. For example, many workplaces would not tolerate an employee who was out on sick leave
for a week or two at a time on a few occasions yet this would not be deemed a serious event due
to the lack of sensitivity of these criteria.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((81!
!
In contrast to the low number of SAEs and SARs, a large number of what were classed as “non-
serious adverse events” (APT: 949, CBT: 848, GET: 992 and SMC: 977) were recorded amongst
the 640 participants; virtually everyone had at least one adverse event (APT: 96%, CBT: 89%,
GET: 93% and SMC: 93%) but we are not given any information about what these events were,
whether certain events were a one-time occurrence or recurrences for a given participant, or
when the event occurred, important factors suggested by CONSORT (56). This meant that of the
3774 adverse events (AEs) recorded in the trial, we were given both the intervention and details
of the event for 0.26% (=10/3774) of them. Given that this was a trial of non-pharmacologic
therapies (cf. surgical and pharmacological interventions) on a group of individuals with an
average age of less than 40 throughout the trial, who could not have a range of medical and
psychiatric disorders and who were deemed capable of participating in an outpatient exercise
program, more information on adverse events would have been desirable, particularly if the
investigators want to claim, as they did in the Lancet paper, that the interventions were “safe”
(27,41,90,218,219).
The protocol stated that an “operationalised Likert scale of the nine CDC symptoms of CFS”
would be used as a secondary outcome measure (201,219). This potentially could have given
useful information on whether there were deteriorations in particular symptoms. Unfortunately,
in the final paper, we were only given information on the “chronic fatigue syndrome symptom
count” and the presence or absence (i.e. not the Likert scores) of two symptoms: “Poor
concentration or memory” and “Postexertional malaise.” Sleep scores were reported separately,
using the Jenkins sleep scale; however, no information on pain symptoms was presented despite
the importance of such symptoms in the condition (7,85,128,220-222) and existing findings of
increased pain following activity and exercise testing (60,63-65,173). It might also have been
useful to allow participants to rate the severity of adverse events outside those of the nine CDC
symptoms. It is also unclear how safety monitoring staff determined which events were causally
related to the interventions. If safety monitoring staff believe that GET or CBT is safe to begin
with, they might not be as vigilant about monitoring adverse events or attributing them to the
interventions.
The researchers did not explain why they changed or did not report on pre-specified adverse
outcomes from the 2006 PACE Final Protocol. Originally, adverse outcomes were defined as a
“score of 5-7 on the self-rated Clinical Global Impression” (PCGI) or a drop of 20 points on the
SF-36 physical function score (187) from the prior measurement (201). By the time the Lancet
paper was published, “serious deterioration in health” is defined as (90):
“a short form-36 physical function score decrease of 20 or more between baseline and any
two consecutive assessment interviews;[ref] scores of much or very much worse on the
participant-rated clinical global impression change in overall health scale at two
consecutive assessment interviews;[ref] withdrawal from treatment after 8 weeks because
of a participant feeling worse; or a serious adverse reaction.” [bolding by author]
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((82!
!
The Lancet paper does not include data on those participants with a PCGI score of 5 (“a little
worse”) and instead this rating is combined with “no change” and “a little better” to form the
category “minimum change”. We are also not given information about participants whose SF-36
PF score (187) dropped by 20 points from the previous measurement. Instead, a serious
deterioration now necessitates a change from the baseline score at two consecutive assessment
interviews. Given that there are 12 weeks between the first and second assessment and 26 weeks
between the second and third assessment and that the baseline scores for the four arms of the
trial all averaged below 40, a participant’s score would on average need to sustain a drop of
more than 50% of their function over a period of at least 12 weeks to qualify as a serious
deterioration in health. Another effect of this change is that any declines after 24 weeks would
not be counted as there is only one more assessment, at 52 weeks, after 24 weeks.
At the same time, the change required for a participant to be considered improved was modified
between the time that the final PACE protocol was published and publication of the trial and
sustainment of improvement was only needed between baseline and one other assessment (i.e.
52 weeks) to qualify as clinically significant.
“A clinically useful difference between the means of the primary outcomes was defined as
0.5 of the SD of these measures at baseline,[ref.] equating to 2 points for Chalder fatigue
questionnaire and 8 points for short form-36.
The justification for using the threshold of 0.5SD threshold comes from a 2002 paper by Guyatt
et al. but Guyatt also points out that the same threshold could be used for deteriorations (223);
unfortunately data on such deteriorations (e.g. participants who declined 8 points on the SF-36)
are not given. Likewise, if it was felt one could not be confident a deterioration had occurred
based on a measurement at one point in time, it suggests one should also probably not be
confident a participant has “improved” (the phrase in the paper) using one time point. In the
paper, Guyatt refers to another group of researchers who had used a similar definition in a trial
comparing temozolomide and procarbazine for recurrent glioblastoma multiforme (223); they
required that improvement in quality of life had to continue for two assessment points to be
considered clinically significant (224). As was discussed in section 5.6, PROMs need to be
further developed in the ME/CFS field (193): this would give better information on what should
be considered “important” changes. In the meantime, it would seem reasonable if there was
consistency in the reporting of improvements and deteriorations, with symmetrical clinically
useful differences scores and time periods unless there are clear rationales given to do otherwise.
Another major issue with PACE is the lack of detail about implementation of the interventions
and participant compliance. Participant compliance was considered to be adequate if a
participant attended 10 (out of a maximum of 15) therapist sessions but the contents of those
sessions are not described in the Lancet paper. Audio- and videotapes of participant-research
staff contact and rating of participant compliance by therapists were executed but these are
indirect measures. PACE CBT and GET manuals directed at therapists and participants give very
detailed instructions how to establish baselines and goals, how/ when to increase activity/
exercise, and how to manage setbacks; in addition, participants are to maintain an activity record.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((83!
!
For example, CBT participants are to set specific activity goals that incorporate the type of
activity, how long the activity will last, and how frequently they plan to perform the activity e.g.
“To walk for 15 minutes daily” or “To do gardening x 3 per week for half an hour.”
When they reach certain milestones, like achieving their targets 75% or more of the time, they
are advised to increase their activity. Likewise, GET participants are to start with gentle stretches
and light exercise that they can maintain for 5 days out of a week. Once they reach that level,
they are then to increase the duration of that activity up to 30 minutes a day at which point,
therapists can begin to increase the level of intensity as measured by heart rate. Ideally, objective
measure of correct implementation of the assigned intervention or good compliance via
actigraphy, heart rate monitors, etc. or direct observation of activity/ exercise by research staff
would be preferred but in absence of this, detailed reporting from participants’ activity logs
would have been helpful to assess compliance and confirm that participants did indeed receive
the intervention as intended. There is no mention in the paper of whether participants achieved
their target goals, exercised an increased amount via increased duration/ frequency/ or intensity,
or maintained/ increased activity despite symptoms.
A possible alternative to the use of motion sensors during treatment would have been their use as
an outcome measure: given the nature of the CBT and GET interventions being assessed, over
the course of 12 months, with good compliance one would expect reasonably large increases in
activity levels, particularly if an individual was coming from a low baseline. Unfortunately,
although the investigators initially planned to employ them on completion and indeed took a
week of measurements at baseline, they were dropped as an outcome measure in the final
protocol (225). The only objective outcome measure reported in the Lancet paper, the 6 minute
walking distance (6MWD), could conceivably be used for a similar purpose (90). Data was
available for only 72% of participants; for other outcomes, data was presented for 89%-94% of
participants. Reasons for this difference are not given. The CBT group only increased from an
average 6MWD of 333m to 354m, the same change as the SMC group; the GET cohort went
from 312m to 379m, or an (adjusted) increase of 35.3 metres compared to SMC. Both sets of
figures make one wonder what percentage of participants had a high rate of compliance,
especially when the final 6MWDs were still much lower than 644m, the predicted value for an
age- [39 years] and gender-matched [77% female] cohort of average height [176.5cm (male),
163.1cm (female)] (226,227). Decreases on such objective measures could also give useful
information on adverse events.
There is much to recommend in the PACE Trial with regard to its reporting of harms; however,
there are also important omissions which could be improved upon in future trials. White el al. do
mention that they “plan to report ... moderators and mediators, whether subgroups respond
differently, and long-term follow-up in future publications” (90). I look forward to reading these
papers and hope that they will consider reporting or sharing the data from their important trial
with other researchers to respond to the points raised by this paper.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((84!
!
7. Other issues
Due to the length of this paper, some other issues of relevance have not been broached: (i)
differences in regulatory requirements for pharmacologic and non-pharmacologic interventions
with no equivalent to post-marketing surveillance for interventions of the latter type; (ii) lack of
litigation concerning harms of GET or CBT leading to less focus on, or concerns about, harm;
(iii) conflicts of interest (COIs) and how they might affect harms reporting; and (iv) the
possibility that cognitive biases, beliefs, attitudes and behaviours of investigators and healthcare
professionals might influence the reporting of adverse events. Also, there has not been space to
cover some of the possible effects, such as coercion of patients to participate in GET or CBT,
that poor reporting might produce.
8. Conclusion
It is hoped that this paper will lead to a greater focus on the reporting of harms in ME/CFS, not
just those that might be associated with GET or CBT, but from any posited treatment.
Interventions should not be presumed to be harmless when there exists evidence of potential
harm and there have not been well-planned systematic methods to track and assess harms both
within and outside trials. Potential strategies to improve reporting of harms are summarized in
Table 3. ME/CFS research should at least conform to standards being recommended for the
majority of medical research while taking into account the unique features of the disease, such as
its relapsing-remitting nature. Moreover, in the ME/CFS field, comparisons are often not made
just within the classes of pharmacologic interventions and non-pharmacologic interventions but
also between pharmacologic and non-pharmacologic treatments (38). False conclusions could be
reached that a non-pharmacologic intervention is “safer” than a pharmacologic agent if harms-
related data was collected more rigorously for the latter (87).
Individuals with ME/CFS can face many challenges and have not always been treated as well as
they should have been by healthcare professionals (76,122,228-232). Many feel that their
symptoms have been downplayed and their negative experiences of some treatments ignored.
This can lead to a mistrust of the medical profession. Furthermore, healthcare professionals who
strive to help their patients cannot do so without assessing risks versus benefits for each
intervention they prescribe. To do this suitably, they need good data on harms. Greater vigilance
for harms could restore patient trust and assist clinicians in adhering to the maxim, "Primum non
nocere" (first, do no harm).
Acknowledgements:
I would like to thank Lily Chu, MD, MSHS for her invaluable assistance. I would also like to
thank the reviewers and the many people who gave comments on earlier drafts of the paper. This
paper is dedicated to the memory of Amberlin Wu, who helped proofread the first draft.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((85!
!
Conflicts of Interest:
I am the Information Officer and Assistant Chairperson of the Irish ME/CFS Association. All my
work for the organisation is voluntary (i.e. unpaid).
References:
(1) The Chronic Fatigue and Immune Dysfunction Syndrome Association of America and The
Centers For Disease Control and Prevention Press Conference at The National Press Club to
Launch a Chronic Fatigue Syndrome Awareness Campaign. November 3, 2006. CDC Web site.
http://www.cdc.gov/media/transcripts/t061103.htm . Accessed: September 16, 2011
(2) Department of Health. A report of the CFS/ME Working Group. Report to the Chief Medical
Officer of an Independent Working Group. London, The Stationery Office. 2002
(3) Reyes M, Gary HE Jr, Dobbins JG, et al. Surveillance for chronic fatigue syndrome--four
U.S. cities, September 1989 through August 1993. MMWR CDC Surveill Summ. 1997 Feb
21;46(2):1-13.
(4) Njoku MG, Jason LA, Torres-Harding SR. The prevalence of chronic fatigue syndrome in
Nigeria. J Health Psychol. 2007;12:461-74.
(5) Jason LA, Porter N, Brown M, et al. CFS: A Review of Epidemiology and Natural History
Studies. Bull IACFS ME. 2009;17:88-106.
(6) Reyes M, Nisenbaum R, Hoaglin DC, et al. Prevalence and incidence of chronic fatigue
syndrome in Wichita, Kansas. Arch Intern Med 2003;163:1530-6.
(7) Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic fatigue
syndrome. Arch Intern Med 1999;159:2129 -37.
(8) Goudsmit EM., Stouten B, Howes S. Illness intrusiveness in myalgic encephalomyelitis. An
exploratory study. Journal of Health Psychology. 2009, 14, 2, 215-221.
(9) Hardt J, Buchwald D, Wilks D, Sharpe M, Nix WA, Egle UT. Health-related quality of life in
patients with chronic fatigue syndrome: an international study. J Psychosom Res. 2001
Aug;51(2):431-4.
(10) Jason LA, Benton MC, Valentine L, Johnson A, Torres-Harding S. The economic impact of
ME/CFS: individual and societal costs. Dyn Med. 2008;7:6.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((86!
!
(11) Reynolds KJ, Vernon SD, Bouchery E, Reeves WC. The economic impact of chronic
fatigue
syndrome. Cost Eff Resour Alloc. 2004;2:4.
(12) Bibby J, Kershaw A. How much is ME costing the country? Report prepared by the Survey
and Statistical Research Centre, Sheffield Hallam University. 2006
(13) Collin SM, Crawley E, May MT, Sterne JAC, Hollingworth W, National Outcomes
Database U. The impact of CFS/ME on employment and productivity in the UK: a cross-
sectional study based on the CFS/ME National Outcomes Database. BMC Health Services
Research 2011, 11:217
(14) Jason LA, Richman JA, Friedberg F, et al. Politics, science, and the emergence of a new
disease: The case of Chronic Fatigue Syndrome. American Psychologist. 1997;52:973-983.
(15) Devanur LD, Kerr JR. Chronic fatigue syndrome. J Clin Virol. 2006;37:139-50.
(16) Wessely S, Hotopf M, Sharpe M. Chronic Fatigue and Its Syndromes. Oxford: Oxford
University Press. 1998.
(17) Jason LA, Sorenson M, Porter N, Belkairous, N. An etiological model for Myalgic
Encephalomyelitis/chronic fatigue syndrome. Neuroscience & Medicine. 2011;2:14-27.
(18) Lombardi VC, Ruscetti FW, Das Gupta J, et al. Detection of an infectious retrovirus,
XMRV, in blood cells of patients with chronic fatigue syndrome. Science. 2009;326:585-9
(19) Friedberg F, Jason LA. Chronic fatigue syndrome and fibromyalgia: Clinical assessment
and treatment. Journal of Clinical Psychology, 2001;57:433-455.
(20) Chia JK, Chia A. Diverse etiologies for chronic fatigue syndrome. Clin Infect Dis.
2003;36:671-2
(21) Fulle S, Pietrangelo T, Mancinelli R, Saggini R, Fanò G. Specific correlations between
muscle oxidative stress and chronic fatigue syndrome: a working hypothesis. J Muscle Res Cell
Motil. 2007;28:355-62.
(22) Jason LA, Corradi K, Torres-Harding S, et al. Chronic fatigue syndrome: The need for
subtypes. Neuropsychology Review. 2005;15:29-58.
(23) 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
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((87!
!
(24) 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.
(25) 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.
(26) Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case
definition. Ann Intern Med. 1988 Mar;108(3):387-9.
(27) Sharpe MC, Archard LC, Banatvala JE, et al. A report--chronic fatigue syndrome:
guidelines for research. J R Soc Med. 1991 Feb;84(2):118-21.
(28) Reeves WC, Wagner D, Nisenbaum R, et al. Chronic fatigue syndrome--a clinically
empirical approach to its definition and study. BMC Med. 2005 Dec 15;3:19.
(29) 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. Retrieved from
http://www.scipub.org/fulltext/ajbb/ajbb62120-135.pdf
(30) Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic Encephalomyelitis:
International Consensus Criteria. J Intern Med. 2011 Jul 20. doi: 10.1111/j.1365-
2796.2011.02428.x. [Epub ahead of print]
(31) Goudsmit EM, Shepherd C, Dancey CP, Howes S. ME: Chronic fatigue syndrome or a
distinct clinical entity? Health Psychology Update, 2009, 18, 1, 26-33.
(32) Bazelmans E, Prins JB, Bleijenberg G. Cognitive behavior therapy for relatively active and
for passive CFS patients. Cogn Behav Pract. 2006;13:157-166.
(33) Bavinton J, Darbishire L, White PD - on behalf of the PACE trial management group.
Graded Exercise Therapy for CFS/ME (Therapist manual): http://www.pacetrial.org/docs/get-
therapist-manual.pdf Accessed: September 16, 2011
(34) Burgess M, Chalder T. PACE manual for therapists. Cognitive behaviour therapy for
CFS/ME. http://www.pacetrial.org/docs/cbt-therapist-manual.pdf . Accessed September 16, 2011
(35) Price JR, Mitchell E, Tidy E, Hunot V. Cognitive behaviour therapy for chronic fatigue
syndrome in adults. Cochrane Database Syst Rev. 2008;(3):CD001027.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((88!
!
(36) Edmonds M, McGuire H, Price J. Exercise therapy for chronic fatigue syndrome. Cochrane
Database Syst Rev. 2004;(3):CD003200.
(37) Mulrow CD, Ramirez G, Cornell JE, Allsup K: Defining and Managing Chronic Fatigue
Syndrome. Agency for Healthcare Research and Quality. 2001. Evidence Report/Technology
Assessment No. 42. AHRQ publication No. 02-E001. Rockville (MD).
(38) 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.
(39) Report of the Joint Working Group of the Royal Colleges of Physicians, Psychiatrists and
General Practitioners. Chronic fatigue syndrome. Cr54. London: RCP, October 1996.
(40) Royal Australasian College of Physicians Working Group. Chronic fatigue syndrome.
Clinical practice guidelines — 2002. Med J Aust 2002; 176 (9 Suppl): S17-S55.
(41) National Collaborating Centre for Primary Care: NICE clinical guideline 53. Chronic
fatigue syndrome/myalgic encephalomyelitis (or encephalopathy): diagnosis and management of
CFS/ME in adults and children London: National Institute for Health and Clinical Excellence;
2007.
(42) Deale A, Chalder T, Marks I, Wessely S. Cognitive behavior therapy for chronic fatigue
syndrome: a randomized controlled trial. Am J Psychiatry. 1997;154:408-14.
(43) Deale A, Husain K, Chalder T, Wessely S. Long-term outcome of cognitive behavior
therapy versus relaxation therapy for chronic fatigue syndrome: a 5-year follow-up study. Am J
Psychiatry. 2001;158:2038-42.
(44) Powell P, Bentall RP, Nye FJ, Edwards RH. Randomised controlled trial of patient
education to encourage graded exercise in chronic fatigue syndrome. BMJ. 2001;322:387-90.
(45) Powell P, Bentall RP, Nye FJ, Edwards RH. Patient education to encourage graded exercise
in chronic fatigue syndrome. 2-year follow-up of randomised controlled trial. Br J Psychiatry.
2004;184:142-6.
(46) Ridsdale L, Godfrey E, Chalder T, et al, Fatigue Trialists' Group. Chronic fatigue in general
practice: is counselling as good as cognitive behaviour therapy? A UK randomised trial. Br J
Gen Pract. 2001;51:19-24.
(47) Jason LA, Melrose H, Lerman A, et al. Managing chronic fatigue syndrome: A case study.
AAOHN Journal 1999;47:17–21.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((89!
!
(48) Goudsmit EM, Howes S. Pacing: A strategy to improve energy management in chronic
fatigue syndrome. Health Psychology Update 2008;17(1):46-52.
(49) Jason LA, Torres-Harding S, Friedberg F, et al. Non-pharmacologic interventions for CFS:
A randomized trial. Journal of Clinical Psychology in Medical Settings, 2007;14:275-296.
doi:10.1007/s10880-007-9090-7
(50) Field TM, Sunshine W, Hernandez-Reif M, Quintino O, Schanberg S, Kuhn C, Burman I:
Massage therapy effects on depression and somatic symptoms in chronic fatigue syndrome. J
Chronic Fatigue Syndr 1997; 3:43–51
(51) Taylor RR, Jason LA, Shiraishi Y, Schoeny ME, Keller J. Conservation of resources theory,
perceived stress, and chronic fatigue syndrome: Outcomes of a consumer-driven rehabilitation
program. Rehabilitation Psychology. 2006;51:157–165.
(52) Marshall R, Paul L, McFadyen AK, Wood L. Evaluating the effectiveness of Myofascial
Release to reduce pain in people with Chronic Fatigue Syndrome (CFS): A Pilot Study (U.K.
study). Second International Fascia Research Congress, 2009. Amsterdam, the Netherlands.
http://www.fasciacongress.org/2009/abstract_pdf/posters/J_081%20marshall%20evaluating%20t
he%20effectiveness%20of%20myofascial%20release.pdf Accessed: September 16, 2011
(53) Lopez C, Antoni M, Penedo F, et al. A pilot study of cognitive behavioral stress
management effects on stress, quality of life, and symptoms in persons with chronic fatigue
syndrome. J Psychosom Res. 2011;70:328-34.
(54) Núñez M, Fernández-Solà J, Nuñez E, Fernández-Huerta JM, Godás-Sieso T, Gomez-Gil E.
Health-related quality of life in patients with chronic fatigue syndrome: group cognitive
behavioural therapy and graded exercise versus usual treatment. A randomised controlled trial
with 1 year of follow-up. Clin Rheumatol. 2011;30:381-9.
(55) ME Association. Comprehensive ME Association response to NICE Guideline on ME/CFS
(draft four - November 8th). Co-Cure. 2006. http://listserv.nodak.edu/cgi-
bin/wa.exe?A2=ind0611B&L=CO-CURE&P=R218 . Accessed September 16, 2011.
(56) Ioannidis JP, Evans SJ, Gøtzsche PC, et al, for the CONSORT Group. Better reporting of
harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med.
2004;141:781-8. Available at: http://www.annals.org/content/141/10/781.full. Accessed
September 16, 2011
(57) Breau RH, Gaboury I, Scales CD Jr, Fesperman SF, Watterson JD, Dahm P. Reporting of
harm in randomized controlled trials published in the urological literature. J Urol.
2010;183:1693-7.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((90!
!
(58) Cooper DM, Radom-Aizik S, Schwindt CD, Zaldivar F. Dangerous exercise: lessons
learned from dysregulated inflammatory responses to physical activity. J Appl Physiol.
2007;103:700–709.
(59) Twisk FNM, Maes M. A review on Cognitive Behavorial Therapy (CBT) and Graded
Exercise Therapy (GET) in Myalgic Encephalomyelitis (ME)/Chronic Fatigue Syndrome (CFS):
CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many
patients with ME/CFS. Neuro Endocrinol Lett. 2009;30:284-299.
(60) White AT, Light AR, Hughen RW, et al. Severity of symptom flare after moderate exercise
is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010;474:615-24.
(61) VanNess JM, Snell CR, Strayer DL, Stevens SR. Subclassifying chronic fatigue syndrome
through exercise testing. Med Sci Sports Exerc 2003;35:908–913.
(62) VanNess JM, Snell CR, Stevens S. Diminished Cardiopulmonary Capacity During Post-
Exertional Malaise. J Chronic Fatigue Syndr. 2008;14(2):77-85.
(63) Light AR, White AT, Hughen RW, Light KC. Moderate exercise increases expression for
sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal
subjects. J Pain. 2009;10:1099-112.
(64) Nijs J, Almond F, De Becker P, Truijen S, Paul L. Can exercise limits prevent post-
exertional malaise in chronic fatigue syndrome? An uncontrolled clinical trial. Clin Rehabil.
2008;22:426-35.
(65) VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in
women with chronic fatigue syndrome. J Womens Health (Larchmt). 2010;19:239-44.
(66) Stordeur S, Thiry N, Eyssen M. Syndrome de Fatigue Chronique : diagnostic, traitement et
organisation des soins. Health Services Research (HSR). Bruxelles: Centre fédéral d'expertise
des soins de santé (KCE); 2008. KCE reports 88B (D/2008/10.273/59)
http://www.kce.fgov.be/Download.aspx?ID=1223 Accessed September 16, 2011 (English with
French summary)
(67) Rapport d’évaluation (2002–2004) portant sur l’exécution des conventions
de rééducation entre le Comité de l’assurance soins de santé (INAMI) et les Centres de référence
pour le Syndrome de fatigue chronique (SFC). 2006.
http://www.inami.fgov.be/care/fr/revalidatie/general-information/studies/study-sfc-
cvs/pdf/rapport.pdf!. Accessed September 16, 2011 (French language edition)
(68) Evaluatierapport (2002–2004) met betrekking tot de uitvoering van de
revalidatieovereenkomsten tussen het Comité van de verzekering voor geneeskundige verzorging
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((91!
!
(ingesteld bij het Rijksinstituut voor Ziekte- en invaliditeitsverzekering) en de Referentiecentra
voor het Chronisch vermoeidheidssyndroom (CVS). 2006. Available online:
http://www.inami.fgov.be/care/nl/revalidatie/general-information/studies/study-sfc-
cvs/pdf/rapport.pdf Accessed September 16, 2011 (Dutch language version)
(69) Stouten B. Identification of ambiguities in the 1994 chronic fatigue syndrome research case
definition and recommendations for resolution. BMC Health Serv Res. 2005;5:37.
(70) Morriss RK, Wearden AJ, Mullis R. Exploring the validity of the Chalder Fatigue scale in
chronic fatigue syndrome. J Psychosom Res. 1998;45:411-7.
(71) Goudsmit EM, Stouten B, Howes S. Fatigue in Myalgic Encephalomyelitis. Bulletin of the
IACFS/ME 2008, 16(3). Available at: http://www.iacfsme.org/BULLETINFALL2008/ Fall08
GoudsmitFatigueinMyalgicEnceph/tabid/292/Default.aspx . Accessed September 16, 2011
(72) Jason LA, Jessen T, Porter N, Boulton A, Njoku MG, Friedberg F. Examining types of
fatigue among individuals with ME/CFS. Disability Stud. Q. 2009, 29. Available at:
http://www.dsq-sds.org/article/view/938/1113 . Accessed September 16, 2011
(73) Basch E. The missing voice of patients in drug-safety reporting. N Engl J Med. 2010 Mar
11;362(10):865-9.
(74) Ethgen M, Boutron I, Baron G, Giraudeau B, Sibilia J, Ravaud P. Reporting of harm in
randomized, controlled trials of nonpharmacologic treatment for rheumatic disease. Ann Intern
Med. 2005;143:20-5.
(75) 25% ME Group. Severely Affected ME (Myalgic Encephalomyelitis) Analysis Report On
Questionnaire Issued January 2004. Troon, Scotland. March 2004.
(76) Crowhurst G. 25% Group Submission to the Gibson Inquiry. Troon, Scotland. The 25%
Severe ME Group. 2005. www.stonebird.co.uk/gibson.doc . Accessed September 16, 2011
(77) Pheby D, Saffron L. Risk Factors for Severe ME/CFS. Biology and Medicine. 2009;1:50–
74.
(78) ME Action. ME Action Survey (1990). Cited by: Shepherd C. Living with M.E.: The
Chronic, Post-viral Fatigue Syndrome. London, England: Cedar Books;1992:224.
(79) 1999 Chronicle Reader Survey. Charlotte, NC: CFIDS Association of America. CFIDS
Chronicle. 1999;12(4):9.
(80) Action for M.E. Severely Neglected: M.E. in the UK—Membership Survey. London:
Action for M.E.; 2001. Available at: http://www.docstoc.com/docs/21870572/Sev-Neglected-
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((92!
!
brochure-aw Accessed September 16, 2011] Additional information:
http://www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/
DH_4064840 . Accessed September 16, 2011.
(81) Koolhaas MP, de Boorder H, van Hoof E (2008). Cognitive behaviour therapy for chronic
fatigue syndrome from the patient’s perspective [Cognitieve gedragstherapie bij het chronische
vermoeidheidssyndroom (ME/CVS) vanuit het perspectief van de patiënt] [Dutch]. Medisch
Contact. ISBN: 978-90-812658-1-2.
http://home.planet.nl/~koolh222/cgtbijmecvsvanuitperspectiefpatient2008.pdf . Accessed
September 16, 2011.
(82) Action for ME and Association of Young People with ME. ME 2008: What progress? 2008
May. Available at: http://www.ayme.org.uk/files/MEAW2008-report.pdf . Accessed: September
16, 2011. Additional information: http://afme.wordpress.com/ Accessed September 17, 2011.
(83) Veer, A.J.E. de, & Francke, A.L. (2008). Zorg voor ME/CVS-patiënten. Ervaringen van de
achterban van patiëntenorganisaties met de Gezondheidszorg. Utrecht: NIVEL.
http://www.nivel.nl/pdf/Rapport-draagvlakmeting-CVS-ME-2008.pdf Accessed September 16,
2011.
(84) Bjørkum T, Wang CE, Waterloo K. [Patients' experience with treatment of chronic fatigue
syndrome.] Tidsskr Nor Laegeforen. 2009 Jun 11;129(12):1214-6
(85) Managing my M.E. - What people with ME/CFS and their carers want from the UK’s health
and social services. Gawcott, England: ME Association; May 2010. Available at:
http://www.meassociation.org.uk/wp-content/uploads/2010/09/2010-survey-report-lo-res10.pdf.
Accessed September 16, 2011.
(86) Rawlins M. De Testimonio: on the evidence for decisions about the use of therapeutic
interventions. Clin Med. 2008;8:579-88.
(87) Chou R, Aronson N, Atkins D, et al. Assessing harms when comparing medical
interventions. In: Agency for Healthcare Research and Quality. Methods Reference Guide for
Comparative Effectiveness Reviews [posted November 2008]. Rockville, MD. Available at:
http://www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-
reports/?productid=327&pageaction=displayproduct#2602 Accessed September 16, 2011.
(88) Fulcher KY, White PD. Randomised controlled trial of graded exercise in patients with the
chronic fatigue syndrome. BMJ. 1997 Jun 7;314(7095):1647-52.
(89) Moss-Morris R, Sharon C, Tobin R, Baldi JC. A randomized controlled graded exercise trial
for chronic fatigue syndrome: outcomes and mechanisms of change. J Health Psychol.
2005;10:245-59.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((93!
!
(90) White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management
group. 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;377:823-36.
(91) Wallman KE, Morton AR, Goodman C, Grove R, Guilfoyle AM. Randomised controlled
trial of graded exercise in chronic fatigue syndrome. Med J Aust. 2004;180:444-8.
(92) Sharpe M, Hawton K, Simkin S, et al. Cognitive behaviour therapy for the chronic fatigue
syndrome: a randomized controlled trial. BMJ. 1996;312:22-6.
(93) Jason LA, Ferrari JR, Taylor RR, Slavich SP, Stenzel CL. A national assessment of the
service, support, and housing preferences by persons with chronic fatigue syndrome. Toward a
comprehensive rehabilitation program. Eval Health Prof. 1996;19:194-207.
(94) Comiskey C, Larkan F. A national cross-sectional survey of diagnosed sufferers of myalgic
encephalomyelitis/chronic fatigue syndrome: pathways to diagnosis, changes in quality of life
and service priorities. Ir J Med Sci. 2010;179:501-5.
(95) Price JR, Couper J. Cognitive behaviour therapy for adults with chronic fatigue syndrome.
Cochrane Database Syst Rev 2000;(2):CD001027 [review].
(96) Marks, DF. Editorial: How Should Psychology Interventions Be Reported? J Health
Psychol. 2009;14:475-489.
(97) Prins JB, Bleijenberg G, Bazelmans E, et al. Cognitive behaviour therapy for chronic fatigue
syndrome: a multicentre randomised controlled trial. Lancet 2001;357:841-7.
(98) Van Houdenhove B, Luyten P. Treatment of chronic fatigue syndrome: how to find a 'new
equilibrium'? Patient Educ Couns. 2009;77:153-4.
(99) Pardaens K, Haagdorens L, Van Wambeke P, Van den Broeck A, Van Houdenhove B. How
relevant are exercise capacity measures for evaluating treatment effects in chronic fatigue
syndrome? Results from a prospective, multidisciplinary outcome study. Clin Rehabil.
2006;20:56-66.
(100) Schulz KF, Altman DG, Moher D; CONSORT Group. CONSORT 2010 Statement:
updated guidelines for reporting parallel group randomised trials. BMC Med. 2010;8:18.
Available at: http://www.biomedcentral.com/1741-7015/8/18/ . Accessed September 16, 2011.
(101) The CONSORT Statement. CONSORT Group. http://www.consort-statement.org/consort-
statement/ . Accessed September 16, 2011.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((94!
!
(102) CONSORT Endorsers - Journals. CONSORT Group. http://www.consort-
statement.org/about-consort/consort-endorsement/consort-endorsers---journals/ . Accessed
September 16, 2011.
(103) MacPherson H, Altman DG, Hammerschlag R, et al. on behalf of the STRICTA Revision
Group. Revised STandards for Reporting Interventions in Clinical Trials of Acupuncture
(STRICTA): extending the CONSORT statement. PLoS Med. 2010 Jun 8;7(6):e1000261.
(104) MacPherson H, White A, Cummings M, Jobst K, Rose K, Niemtzow R. Standards for
reporting interventions in controlled trials of acupuncture: The STRICTA recommendations.
STandards for Reporting Interventions in Controlled Trials of Acupuncture. Acupunct Med.
2002 Mar;20(1):22-5.
(105) Boutron I, Moher D, Altman DG, Schulz K, Ravaud P, for the CONSORT group.
Extending the CONSORT Statement to randomized trials of nonpharmacologic treatment:
explanation and elaboration. Ann Intern Med. 2008:295-309. http://www.consort-
statement.org/index.aspx?o=1415. Accessed September 16, 2011
(106) Moher D, Jones A, Lepage L; CONSORT Group (Consolitdated Standards for
Reporting of Trials). Use of the CONSORT statement and quality of reports of randomized
trials: a comparative before-and-after evaluation. JAMA. 2001 Apr 18;285(15):1992-5.
(107) Thabane L, Chu R, Cuddy K, Douketis J. What is the quality of reporting in weight loss
intervention studies? A systematic review of randomized controlled trials. Int J Obes (Lond).
2007;31:1554-9.
(108) Prady SL, Richmond SJ, Morton VM, Macpherson H. A systematic evaluation of the
impact of STRICTA and CONSORT recommendations on quality of reporting for acupuncture
trials. PLoS One. 2008 Feb 13;3(2):e1577.
(109) Hammerschlag R, Milley R, Colbert A, et al. Randomized Controlled Trials of
Acupuncture (1997-2007): An Assessment of Reporting Quality with a CONSORT- and
STRICTA-Based Instrument. Evid Based Complement Alternat Med. 2011;2011. pii: 183910.
(110) Ioannidis JP, Lau J. Completeness of safety reporting in randomized trials: an evaluation of
7 medical areas. JAMA. 2001;285:437-43.
(111) Derry S, Kong Loke Y, Aronson JK. Incomplete evidence: the inadequacy of databases in
tracing published adverse drug reactions in clinical trials. BMC Med Res Methodol. 2001;1:7.
(112) Loke YK, Derry S. Reporting of adverse drug reactions in randomised controlled trials—a
systematic survey. BMC Clin Pharmacol. 2001;1:3.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((95!
!
(113) Edwards JE, McQuay HJ, Moore RA, Collins SL. Reporting of adverse effects in clinical
trials should be improved: lessons from acute postoperative pain. J Pain Symptom Manage.
1999;18:427-37.
(114) Cuervo LG, Clarke M. Balancing benefits and harms in health care. BMJ. 2003;327:65-6.
(115) Papanikolaou PN, Churchill R, Wahlbeck K, Ioannidis JP. Safety reporting in randomized
trials of mental health interventions. Am J Psychiatry. 2004;161:1692-7.
(116) Arnett SV, Alleva LM, Korossy-Horwood R, Clark IA. Chronic fatigue syndrome - A
neuroimmunological model. Med Hypotheses. 2011 Jul;77(1):77-83.
(117) Jason LA, Torres-Harding SR, Jurgens A, Helgerson J. Comparing the Fukuda et al.
criteria and the Canadian case definition for chronic fatigue syndrome. J Chronic Fatigue Syndr.
2004;12(1):37-52.
(118) Jason LA, Torres-Harding SR, Taylor RR, Carrico AW. A comparison of the 1988 and
1994 diagnostic criteria for chronic fatigue syndrome. J Clin Psych Med Setting 2001;8:337-343.
(119) Jason LA, Helgerson J, Torres-Harding SR, Carrico AW, Taylor RR: Variability in
diagnostic criteria for chronic fatigue syndrome may result in substantial differences in patterns
of symptoms and disability. Eval Health Prof. 2003;26:3-22.
(120) Reeves WC, Jones JF, Maloney E, et al. Prevalence of chronic fatigue syndrome in
metropolitan, urban, and rural Georgia. Popul Health Metr 2007;5:5.
(121) Hawk C, Jason LA, Torres-Harding S. Differential diagnosis of chronic fatigue syndrome
and major depressive disorder. International Journal of Behavioral Medicine. 2006;13:244-251
(122) Jason LA, Richman JA. How science can stigmatize: The case of CFS. J Chronic Fatigue
Syndr. 2008;14(4):85-103.
(123) Jason LA, Najar N, Porter N, Reh C. Evaluating the Centers for Disease Control’s
empirical chronic fatigue syndrome case definition. Journal of Disability Policy Studies.
2009;20:93-100.
(124) Kindlon T. Criteria used to define chronic fatigue syndrome questioned. Psychosom Med.
2010;72:506-7
(125) Vercoulen JH, Swanink CM, Galama JM, et al. The persistence of fatigue in chronic
fatigue syndrome and multiple sclerosis: development of a model. J Psychosom Res. 1998
Dec;45(6):507-17.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((96!
!
(126) Song S, Jason LA. A population-based study of chronic fatigue syndrome (CFS)
experienced in differing patient groups: An effort to replicate Vercoulen et al's model of CFS. J
Ment Health 2005, 4:277-289
(127) Darbishire L, Seed P, Ridsdale L. Predictors of outcome following treatment for chronic
fatigue. Br J Psychiatry. 2005 Apr;186:350-1.
(128) De Becker P, McGregor N, De Meirleir K. A definition-based analysis of symptoms in a
large cohort of patients with chronic fatigue syndrome. J Intern Med 2001;250:234-240.
(129) Jason LA, Richman JA, Rademaker AW, et al. A community-based study of chronic
fatigue syndrome. Arch Intern Med. 1999 Oct 11;159(18):2129-37.
(130) Ho-Yen DO. Patients' beliefs about their illness were probably not a major factor. BMJ
1996;312:1097
(131) Lerner AM, Beqaj SH, Deeter RG, Fitzgerald JT. Valacyclovir treatment in Epstein-Barr
virus subset chronic fatigue syndrome: thirty-six months follow-up. In Vivo. 2007;21:707-13.
(132) Lerner AM, Beqaj SH, Gill K, Edington J, Fitzgerald JT, Deeter RJ. An update on the
management of glandular fever (infectious mononucleosis) and its sequelae caused by Epstein–
Barr virus (HHV-4): new and emerging treatment strategies. Virus Adaptation and Treatment.
2010;2: 135-145.
(133) Dellwo A. Dr. A. Martin Lerner: Protecting the Heart. 2009. Available at:
http://chronicfatigue.about.com/b/2009/10/30/chronic-fatigue-syndrome-exercise-the-heart.htm
Accessed October 9, 2010.
(134) Roberts ADL, Charler M-L, Papadopoulos A, Wessely S, Chalder T, Cleare AJ (2009).
Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue
syndrome? Psychol Med. 2010;40:515-22.
(135) Jason LA, Torres-Harding S, Maher K, et al. Baseline cortisol levels predict treatment
outcomes in chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome. 2007;14(4):39-59.
(136) Jason LA, Torres-Harding S, Brown M, et al. Predictors of change following participation
in non-pharmacologic interventions for CFS. Tropical Medicine and Health. 2008;36: 23–32.
(137) Cella M, Chalder T, White PD. Does the Heterogeneity of Chronic Fatigue Syndrome
Moderate the Response to Cognitive Behaviour Therapy An Exploratory Study. Psychother
Psychosom. 2011 Aug 6;80(6):353-358. [Epub ahead of print]
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((97!
!
(138) Wallman KE, Morton AR, Goodman C, Grove R. Exercise prescription for individuals
with chronic fatigue syndrome. Med J Aust. 2005;183:142-3.
(139) Chou R, Helfand M. Challenges in systematic reviews that assess treatment harms. Ann
Intern Med. 2005;142:1090-9.
(140) Stephens MDB, Talbot JCC, Routledge PA, eds. The Detection of New Adverse
Reactions. 4th ed. London: Macmillan Reference; 1998.
(141) Wallin J, Sjovall J. Detection of adverse drug reactions in a clinical trial using two types of
questioning. Clin Ther. 1981;3:450-2.
(142) Burney KD, Krishnan K, Ruffin MT, Zhang D, Brenner DE. Adherence to single daily
dose of aspirin in a chemoprevention trial. An evaluation of self-report and microelectronic
monitoring. Arch Fam Med. 1996;5:297-300.
(143) Wu JR, Moser DK, Chung ML, Lennie TA. Objectively measured, but not self-reported,
medication adherence independently predicts event-free survival in patients with heart failure. J
Card Fail. 2008;14:203-10.
(144) Applebaum AJ, Reilly LC, Gonzalez JS, Richardson MA, Leveroni CL, Safren SA. The
impact of neuropsychological functioning on adherence to HAART in HIV-infected substance
abuse patients. AIDS Patient Care STDS. 2009;236:455-62.
(145) Jasti S, Siega-Riz AM, Cogswell ME, Hartzema AG. Correction for errors in measuring
adherence to prenatal multivitamin/mineral supplement use among low-income women. J Nutr.
2006;136:479-83.
(146) White P. How exercise can help chronic fatigue syndrome. Pulse: 1998. June 20:86-87.
(147) 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.
(148) Van Houdenhove B, Onghena P, Neerinckx E, Hellin J. Does high 'action-proneness' make
people more vulnerable to chronic fatigue syndrome? A controlled psychometric study. J
Psychosom Res. 1995 Jul;39(5):633-40.
(149) Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommen H. Premorbid
"overactive" lifestyle in chronic fatigue syndrome and fibromyalgia. An etiological factor or
proof of good citizenship? J Psychosom Res. 2001 Oct;51(4):571-6.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((98!
!
(150) Van Houdenhove B, Bruyninckx K, Luyten P. In search of a new balance. Can high
"action-proneness" in patients with chronic fatigue syndrome be changed by a multidisciplinary
group treatment? J Psychosom Res. 2006;60:623-5.
(151) Scheeres K, Knoop H, Meer J, Bleijenberg G. Clinical assessment of the physical activity
pattern of chronic fatigue syndrome patients: a validation of three methods. Health Qual Life
Outcomes. 2009;7:29.
(152) Vercoulen JH, Bazelmans E, Swanink CM, et al. Physical activity in chronic fatigue
syndrome: assessment and its role in fatigue. J Psychiatr Res. 1997;31:661-73.
(153) Meeus M, Van Eupen I, Willems J, Kos D, Nijs J. Is the International Physical Activity
Questionnaire-Short Form (IPAQ-SF) valid for assessing physical activity in chronic fatigue
syndrome? Disabil Rehabil. 2010. Online May 6. doi:10.3109/09638288.2010.483307.
(154) Taber DR, Stevens J, Murray DM, Elder JP, Webber LS, Jobe JB, Lytle LA. The effect of
a physical activity intervention on bias in self-reported activity. Ann Epidemiol. 2009;19:316-22.
(155) Adams SA, Matthews CE, Ebbeling CB, et al. The effect of social desirability and social
approval on self-reports of physical activity. Am J Epidemiol 2005;161:389–98.
(156) Sims J, Smith F, Duffy A, et al. The vagaries of self-reports of physical activity: a problem
revisited and addressed in a study of exercise promotion in the over 65s in general practice. Fam
Pract 1999;16:152–7.
(157) Stevens J, Taber DR, Murray DM, et al. Advances and controversies in the design of
obesity prevention trials. Obesity (Silver Spring) 2007;15:2163–70.
(158) Aaron LA, Buchwald D. Fibromyalgia and other unexplained clinical conditions. Curr
Rheumatol Rep. 2001;3:116-22. Review.
(159) Friedberg F. Chronic fatigue syndrome, fibromyalgia, and related illnesses: a clinical
model of assessment and intervention. J Clin Psychol. 2010;66:641-65.
(160) Meyer BB, Lemley KJ. Utilizing exercise to affect the symptomology of fibromyalgia: a
pilot study. Med Sci Sports Exerc. 2000;32:1691-7.
(161) Vermeulen RC, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue
syndrome performed worse than controls in a controlled repeated exercise study despite a normal
oxidative phosphorylation capacity. J Transl Med. 2010;8:93.
(162) Suárez A, Guillamó E, Roig T, et al. Nitric oxide metabolite production during exercise in
chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt). 2010;19:1073-7.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((99!
!
(163) VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in
women with chronic fatigue syndrome. J Womens Health (Larchmt). 2010;19:239-44.
(164) Jammes Y, Steinberg JG, Delliaux S, Brégeon F. Chronic fatigue syndrome combines
increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. J Intern
Med. 2009;266:196-206.
(165) Thambirajah AA, Sleigh K, Stiver HG, Chow AW. Differential heat shock protein
responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched
healthy controls. Clin Invest Med. 2008;31:E319-27.
(166) Neary JP, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Prefrontal cortex
oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct
Imaging. 2008;28:364-72.
(167) Yoshiuchi K, Cook DB, Ohashi K, et al. A real-time assessment of the effect of exercise in
chronic fatigue syndrome. Physiol Behav. 2007;92:963-8.
(168) Bazelmans E, Bleijenberg G, Voeten MJ, van der Meer JW, Folgering H. Impact of a
maximal exercise test on symptoms and activity in chronic fatigue syndrome. J Psychosom Res.
2005;59:201-8.
(169) Jammes Y, Steinberg JG, Mambrini O, Brégeon F, Delliaux S. Chronic fatigue syndrome:
assessment of increased oxidative stress and altered muscle excitability in response to
incremental exercise. J Intern Med. 2005;257:299-310.
(170) Ohashi K, Yamamoto Y, Natelson BH. Activity rhythm degrades after strenuous exercise
in chronic fatigue syndrome. Physiol Behav. 2002 Sep;77(1):39-44.
(171) LaManca JJ, Sisto SA, DeLuca J, et al. Influence of exhaustive treadmill exercise on
cognitive functioning in chronic fatigue syndrome. Am J Med. 1998;105:59S-65S.
(172) Blackwood SK, MacHale SM, Power MJ, Goodwin GM, Lawrie SM. Effects of exercise
on cognitive and motor function in chronic fatigue syndrome and depression. J Neurol Neurosurg
Psychiatry. 1998;65:541-6.
(173) Van Oosterwijck J, Nijs J, Meeus M, et al. Pain inhibition and postexertional malaise in
myalgic encephalomyelitis/chronic fatigue syndrome: an experimental study. J Intern Med.
2010;268:265-78.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((100!
!
(174) Davenport TE, Stevens SR, VanNess MJ, Snell CR, Little T. Conceptual model for
physical therapist management of chronic fatigue syndrome/myalgic encephalomyelitis. Phys
Ther. 2010;90:602-14.
(175) Knoop H, Bleijenberg G, Gielissen MF, van der Meer JW, White PD. Is a full recovery
possible after cognitive behavioural therapy for chronic fatigue syndrome? Psychother
Psychosom. 2007;76:171-6.
(176) Physiotherapy. Chronic Fatigue Syndrome/ME Service at St. Bartholomew's Hospital.
http://www.bartscfsme.org/physiotherapy.htm. Accessed December 24, 2007.
(177) St Bartholomew's Hospital Chronic Fatigue Services submission. National Institute for
Health and Clinical Excellence CFS/ME consultation draft 29 September – 24 November 2006
Comments on chapter 6 on the draft NICE guidelines on CFS/ME. 2007:308.
http://www.nice.org.uk/nicemedia/live/11630/36186/36186.pdf . Accessed September 16, 2011
(178) Black CD, McCully KK. Time course of exercise induced alterations in daily activity in
chronic fatigue syndrome. Dyn Med. 2005;4:10.
(179) VanNess, MJ, Snell CR, Stevens SR, Stiles TL. Metabolic and Neurocognitive Responses
To An Exercise Challenge In Chronic Fatigue Syndrome (CFS). Med Sci Sports Exerc. 2007;39
(5 Suppl):S445.
(180) Kerr JR, Cunniffe VS, Kelleher P, Bernstein RM, Bruce IN. Successful intravenous
immunoglobulin therapy in 3 cases of parvovirus B19-associated chronic fatigue syndrome. Clin
Infect Dis. 2003;36(9):e100-6.
(181) Protecting Human Research Subjects: Institutional Review Board Guidebook (1993),
Washington, D.C.: Office for the Protection from Research Risks, NIH, PHS, DHHS.
http://www.hhs.gov/ohrp/archive/irb/irb_guidebook.htm . Accessed September 16, 2011
(182) Rid A, Emanuel EJ, Wendler D. Evaluating the risks of clinical research. JAMA.
2010;304:1472-9.
(183) Paul L, Wood L, Behan WM, Maclaren WM. Demonstration of delayed recovery from
fatiguing exercise in chronic fatigue syndrome. Eur J Neurol. 1999;6:63-9.
(184) 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.
(185) Szapocznik J, Prado G. Negative effects on family functioning from psychosocial
treatments: a recommendation for expanded safety monitoring. J Fam Psychol. 2007;21:468-78.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((101!
!
(186) Scheeres K, Wensing M, Bleijenberg G, Severens JL. Implementing cognitive behavior
therapy for chronic fatigue syndrome in mental health care: a costs and outcomes analysis. BMC
Health Serv Res. 2008 Aug 13;8:175.
(187) Ware JE, Sherbourne CD (1992) The MOS 36-Item Short-Form Health Survey (SF 36): I.
Conceptual Framework and Item Selection. Medical Care. 1992;30:473-483.
(188) Robine J-M, Jagger C, Egidi V. Selection of a coherent set of health indicators. Final draft.
A first step towards a user's guide to health expectancies for the European Union. Montpellier,
France: Euro-REVES; 2000. Available at:
http://ec.europa.eu/health/ph_information/indicators/docs/userguide_en.pdf . Accessed
September 16, 2011.
(189) Brown M, Khorana N, Jason LA. The role of changes in activity as a function of perceived
available and expended energy in nonpharmacological treatment outcomes for ME/CFS. J Clin
Psychol. 2011;67:253-60
(190) Stulemeijer M, de Jong LW, Fiselier TJ, Hoogveld SW, Bleijenberg G. Cognitive
behaviour therapy for adolescents with chronic fatigue syndrome: randomised controlled trial.
BMJ 2005; 330: 14.
(191) Knoop H, van der Meer JW, Bleijenberg G. Guided self-instructions for people with
chronic fatigue syndrome: randomised controlled trial. British Journal of Psychiatry.
2008;193:340–341.
(192) Friedberg, F. Does graded activity increase activity? A case study of chronic fatigue
syndrome. Journal of Behavior Therapy & Experimental Psychiatry, 2002;33:203-215.
(193) Haywood KL, Staniszewska S, Chapman S. Quality and acceptability of patient-reported
outcome measures used in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME): a
systematic review. Qual Life Res. 2011 May 18. [Epub ahead of print]
(194) Jason LA, Porter N, Herrington J, Sorenson M, Kubow S. Kindling and oxidative stress as
contributors to Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Journal of Behavioral
and Neuroscience Research. 2009;7:1-17.
(195) Pierce S, Pierce PW. The Physiology of Exercise Intolerance in Patients with Myalgic
Encephalomyelitis (ME) and the Utility of Graded Exercise Therapy. Journal of IiME.
2008;2(2):55-60.
(196) Cairns R, Hotopf M. A systematic review describing the prognosis of chronic fatigue
syndrome. Occup Med (Lond). 2005; 55(1):20-31.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((102!
!
(197) What's the clinical course of CFS? CDC. 2010
http://www.cdc.gov/cfs/general/symptoms/index.html . Accessed September 16, 2011.
(198) Lee KJ, Thompson SG. Clustering by health professional in individually randomised trials.
BMJ. 2005;330:142-4.
(199) Cella M, Stahl D, Reme SE, Chalder T. Therapist effects in routine psychotherapy
practice: an account from chronic fatigue syndrome. Psychother Res. 2011 Mar;21(2):168-78.
(200) Crits-Christoph P, Mintz J. Implications of therapist effects for the design and analysis of
comparative studies of psychotherapies. J Consult Clin Psychol. 1991;59:20-6
(201) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R; on behalf of the PACE trial
group. Protocol for the PACE trial: a randomised controlled trial of adaptive pacing, cognitive
behaviour therapy, and graded exercise, as supplements to standardised specialist medical care
versus standardised specialist medical care alone for patients with the chronic fatigue
syndrome/myalgic encephalomyelitis or encephalopathy. BioMed Cent Neurol 2007; 7: 6.
(202) Pacing, graded Activity, and Cognitive behaviour therapy; a randomised Evaluation. Final
Protocol Version 5.0. 2006 http://www.meactionuk.org.uk/FULL-Protocol-SEARCHABLE-
version.pdf Accessed September 15, 2011
(203) Jones DE, Hollingsworth KG, Taylor R, Blamire AM, Newton JL. Abnormalities in pH
handling by peripheral muscle and potential regulation by the autonomic nervous system in
chronic fatigue syndrome. J Intern Med. 2010;267:394-401.
(204) Pietrangelo T, Mancinelli R, Toniolo L, et al. Transcription profile analysis of vastus
lateralis muscle from patients with chronic fatigue syndrome. Int J Immunopathol Pharmacol.
2009;22:795-807.
(205) Pietrangelo T, Toniolo L, Paoli A, et al. Functional characterization of muscle fibres from
patients with chronic fatigue syndrome: case-control study. Int J Immunopathol Pharmacol.
2009;22:427-36.
(206) McCully KK, Malucelli E, Iotti S. Increase of free Mg2+ in the skeletal muscle of chronic
fatigue syndrome patients. Dyn Med. 2006;5:1.
(207) Lane RJ, Soteriou BA, Zhang H, Archard LC. Enterovirus related metabolic myopathy: a
postviral fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003;74:1382-6.
(208) Vecchiet J, Cipollone F, Falasca K, et al. Relationship between musculoskeletal symptoms
and blood markers of oxidative stress in patients with chronic fatigue syndrome. Neurosci Lett.
2003;335:151-4.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((103!
!
(209) Fulle S, Mecocci P, Fanó G, et al. Specific oxidative alterations in vastus lateralis muscle
of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med. 2000;29:1252-
9.
(210) McCully KK, Natelson BH. Impaired oxygen delivery to muscle in chronic fatigue
syndrome. Clin Sci (Lond). 1999;97:603-8
(211) Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R. Heterogeneity in chronic fatigue
syndrome: evidence from magnetic resonance spectroscopy of muscle. Neuromuscul Disord.
1998;8:204-9.
(212) Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC. Muscle fibre
characteristics and lactate responses to exercise in chronic fatigue syndrome. J Neurol Neurosurg
Psychiatry. 1998;64:362-7.
(213) Vecchiet L, Montanari G, Pizzigallo E, et al. Sensory characterization of somatic parietal
tissues in humans with chronic fatigue syndrome. Neurosci Lett. 1996;208:117-20.
(214) Wong R, Lopaschuk G, Zhu G, et al. Skeletal muscle metabolism in the chronic fatigue
syndrome. In vivo assessment by 31P nuclear magnetic resonance spectroscopy. Chest. 1992
Dec;102(6):1716-22.
(215) Archard LC, Bowles NE, Behan PO, Bell EJ, Doyle D. Postviral fatigue syndrome:
persistence of enterovirus RNA in muscle and elevated creatine kinase. J R Soc Med.
1988;81:326-9.
(216) Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue
syndrome. Acta Neuropathol. 1991;83:61-5.
(217) van de Mortel TF. Faking it: social desirability bias in self-report research. Aus J Adv Nurs
2008, 25(4):40-48.
(218) White PD, Goldsmith KA, Johnson AL, et al, on behalf of the PACE trial management
group. Appendix to 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;377:823-36.
(219) Reeves WC, Lloyd A, Vernon SD, et al. The international chronic fatigue syndrome study
group identification of ambiguities in the 1994 chronic fatigue syndrome research case definition
and recommendations for resolution. BMC Health Serv Res 2003, 3: 2.
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((104!
!
(220) Marshall R, Paul L, Wood L. The search for pain relief in people with chronic fatigue
syndrome: a descriptive study. Physiother Theory Pract. 2011;27:373-83.
(221) Marshall R, Paul L, McFadyen AK, Rafferty D, Wood L Pain characteristics of people
with chronic fatigue syndrome. Journal of Musculoskeletal Pain. 2010;18:127–137
(222) Nacul LC, Lacerda EM, Pheby D, et al. Prevalence of myalgic encephalomyelitis/chronic
fatigue syndrome (ME/CFS) in three regions of England: a repeated cross-sectional study in
primary care. BMC Med. 2011;9:91
(223) Guyatt GH, Osaba D, Wu AW, et al. Methods to explain the clinical significance of health
status measures. Mayo Clinic Proceedings 2002;77:371–83.
(224) Osoba D, Brada M, Yung WK, Prados M. Health-related quality of life in patients treated
with temozolomide versus procarbazine for recurrent glioblastoma multiforme. J Clin Oncol.
2000;18:1481-1491.
(225) White PD, Sharpe MC, Chalder T, DeCesare JC, Walwyn R, for the PACE trial
management group. Response to comments on “Protocol for the PACE trial”. BMC Neurol.
2007, 7:6 http://www.biomedcentral.com/1471-2377/7/6/comments/#306608 Accessed:
September 16, 2011
(226) Craig R, Mindell J, Hirani V (eds) Health Survey for England 2008, London: The
Information Centre. 2009 http://www.ic.nhs.uk/pubs/hse08physicalactivity Accessed: August 30,
2011
(227) Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults.
Am. J. Respir. Crit. Care Med., 1998; 158: 1384–1387
(228) Tymes Trust. The forgotten children: a dossier of shame. Essex, England. 2003.
http://tymestrust.org/pdfs/theforgottenchildren.pdf . Accessed September 29, 2010
(229) Anderson JS, Ferrans CE. The quality of life of persons with chronic fatigue syndrome. J
Nerv Ment Dis. 1997;185:359-367
(230) Maes M, Twisk FN. Chronic fatigue syndrome: la bête noire of the Belgian health care
system. Neuro Endocrinol Lett. 2009;30:300-11.
(231) Friedberg F, Jason LA. Understanding chronic fatigue syndrome: An empirical guide to
assessment and treatment. Washington, DC: American Psychological Association; 1998.
(232) Green J, Romei J, Natelson BH. Stigma and chronic fatigue syndrome. J Chronic Fatigue
Syndr. 1999;5(2):63–75
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((105!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((106!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((107!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((108!
!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((109!
!
!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((110!
!
!
!
!
!
!
Bulletin(of(the(IACFS/ME((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((((111!
!
!
Bulletin of the IACFS/ME. 2011;19(2): 59-111. © 2011 IACFS/ME
... Such patients were probably included in the CF populations. An important issue, however, is that it seemed that the main problem in ME patients is their reduced ability to adapt and recover from exercise or exertion intolerance, in general, rather than deconditioning or reduced exertion capacity itself [106]. GET intensity may have been too high for the ME/CFS patients with PEM, causing deteriorations and non-compliance. ...
... Few studies reported on the occurrence of adverse events or non-adherence due to intolerance to the intervention. However, in intervention research involving ME/CFS patients with PEM, reporting of adverse effects seems of particular significance [106]; interventions are not necessarily harmless when adverse effects and compliance not have been systematically reported. ...
Article
Full-text available
Background Due to the inconsistent use of diagnostic criteria in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), it is unsure whether physiotherapeutic management regarded effective in ME/CFS is appropriate for patients diagnosed with criteria that consider post-exertional malaise (PEM) as a hallmark feature. Purpose To appraise current evidence of the effects of physiotherapy on symptoms and functioning in ME/CFS patients in view of the significance of PEM in the applied diagnostic criteria for inclusion. Methods A systematic review of randomized controlled trials published over the last two decades was conducted. Studies evaluating physiotherapeutic interventions for adult ME/CFS patients were included. The diagnostic criteria sets were classified into three groups according to the extent to which the importance of PEM was emphasized: chronic fatigue (CF; PEM not mentioned as a criterion), CFS (PEM included as an optional or minor criterion) or ME (PEM is a required symptom). The main results of included studies were synthesized in relation to the classification of the applied diagnostic criteria. In addition, special attention was given to the tolerability of the interventions. Results Eighteen RCTs were included in the systematic review: three RCTs with CF patients, 14 RCTs with CFS patients and one RCT covering ME patients with PEM. Intervention effects, if any, seemed to disappear with more narrow case definitions, increasing objectivity of the outcome measures and longer follow-up. Conclusion Currently, there is no scientific evidence when it comes to effective physiotherapy for ME patients. Applying treatment that seems effective for CF or CFS patients may have adverse consequences for ME patients and should be avoided.
... We acknowledge that exercise is not always effective for people with chronic conditions in certain situations; clients with CFS reported a worsening of fatigue after receiving graded exercise training (GET), and GET was one of the risk factors for severe illness (p = 0.02). 89 One recommendation is that if symptoms get worse after increasing the intensity or duration of exercise, clients should stay at their current level of exercise until the symptoms stabilise. 89 This corresponds to the exercise programmes included in our review, which were inspired by self-management principles. ...
... 89 One recommendation is that if symptoms get worse after increasing the intensity or duration of exercise, clients should stay at their current level of exercise until the symptoms stabilise. 89 This corresponds to the exercise programmes included in our review, which were inspired by self-management principles. Continuous monitoring of fatigue levels and exercise progress and adjusting exercise intensity and duration accordingly may prevent people from exacerbating their symptoms. ...
Article
Full-text available
Objective The aim of this study was to investigate the effectiveness of occupational therapist-/physiotherapist-guided fatigue self-management for individuals with chronic conditions. Methods Eight databases, including MEDLINE and EMBASE, were searched until September 2019 to identify relevant studies. Randomised controlled trials and quasi-experimental studies of self-management interventions specifically developed or delivered by occupational therapists/physiotherapists to improve fatigue symptoms of individuals with chronic conditions were included. A narrative synthesis and meta-analysis were conducted to determine the effectiveness of fatigue self-management. Results Thirty-eight studies were included, and fatigue self-management approaches led by occupational therapists/physiotherapists were divided into six categories based on the intervention focus: exercise, energy conservation, multimodal programmes, activity pacing, cognitive-behavioural therapy, and comprehensive fatigue management. While all exercise programmes reported significant improvement in fatigue, other categories showed both significant improvement and no improvement in fatigue. Meta-analysis yielded a standardised mean difference of the overall 13 studies: 0.42 (95% confidence interval:−0.62 to − 0.21); standardised mean difference of the seven exercise studies was −0.55 (95% confidence interval: −0.78 to −0.31). Discussion Physical exercises inspired by the self-management principles may have positive impacts on fatigue symptoms, quality of life, and other functional abilities.
... The PACE trial by White et al. [33] reported that CBT and GET are safe, but they assessed safety in the following manner: "Safety was assessed primarily by recording all serious adverse events, including serious adverse reactions to trial treatments," and "adverse events were considered serious when they involved death, hospital admission, increased severe and persistent disability, self-harm, were life-threatening, or required an intervention to prevent one of these". Patient surveys on the other hand, have shown over the last 20 years that both therapies often exacerbate ME/CFS symptoms, cause relapses, and lead to (severe) health deterioration [48][49][50]. In other words, patients do not complain about the things that were used by the PACE trial to assess the safety of CBT and GET. ...
Article
Full-text available
For the last few decades, medical guidelines have recommended treating patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) with graded exercise therapy (GET) and cognitive behavioural therapy (CBT). Moreover, doctors have questioned the recovery behaviour of these patients and stimulated them to follow these treatments so that they would be able to go back to work. In this article, we reviewed trials of GET and CBT for ME/CFS that reported on work status before and after treatment to answer the question of whether doctors should continue to question the recovery behaviour of patients with ME/CFS. Our review shows that more patients are unable to work after treatment than before treatment with CBT and GET. It also highlights the fact that both treatments are unsafe for patients with ME/CFS. Therefore, questioning the recovery behaviour of patients with ME/CFS is pointless. This confirms the conclusion from the British National Institute for Health and Care Excellence (NICE), which has recently published its updated ME/CFS guideline and concluded that CBT and GET are not effective and do not lead to recovery. Studies on CBT and GET for long COVID have not yet been published. However, this review offers no support for their use in improving the recovery of patients with an ME/CFS-like illness after infection with COVID-19, nor does it lend any support to the practice of questioning the recovery behaviour of these patients.
... Similarly, a 2011 review of eight surveys found that 51% of survey respondents had reported that GET had made their health worse [51]. An analysis of primary and secondary surveys found that 54-74% of patients responded negatively to GET [52]. ...
Article
Full-text available
Background and Objectives: There is some evidence that knowledge and understanding of ME among doctors is limited. Consequently, an audit study was carried out on a group of hospital doctors attending a training event to establish how much they knew about ME and their attitudes towards it. Materials and Methods: Participants at the training event were asked to complete a questionnaire, enquiring about prior knowledge and experience of ME and their approaches to diagnosis and treatment. A total of 44 completed questionnaires were returned. Responses were tabulated, proportions selecting available options determined, 95% confidence limits calculated, and the significance of associations determined by Fisher’s exact test. Results: Few respondents had any formal teaching on ME, though most had some experience of it. Few knew how to diagnose it and most lacked confidence in managing it. None of the respondents who had had teaching or prior experience of ME considered it a purely physical illness. Overall, 91% of participants believed ME was at least in part psychological. Most participants responded correctly to a series of propositions about the general epidemiology and chronicity of ME. There was little knowledge of definitions of ME, diagnosis, or of clinical manifestations. Understanding about appropriate management was very deficient. Similarly, there was little appreciation of the impact of the disease on daily living or quality of life. Where some doctors expressed confidence diagnosing or managing ME, this was misplaced as they were incorrect on the nature of ME, its diagnostic criteria and its treatment. Conclusion: This audit demonstrates that most doctors lack training and clinical expertise in ME. Nevertheless, participants recognised a need for further training and indicated a wish to participate in this. It is strongly recommended that factually correct and up-to-date medical education on ME be made a priority at undergraduate and postgraduate levels. It is also recommended that this audit be repeated following a period of medical education
... 19 35 Some persons with illness may also develop considerable medical knowledge after intensively researching their condition, and the contributions of patients to medicine can be valuable in shaping critical conversations and debate. [36][37][38][39] Equally, clinicians may accrue deeper appreciation and insights about healthcare delivery by experiencing life as a patient. [40][41][42] In summation, as Blease et al argue, 'Injustice arises with respect to epistemic privilege when one group fails to recognise the unique expertise of another group, or when an individual fails to fully appreciate the epistemic contributions of another individual'. ...
Article
Full-text available
In many countries, including patients are legally entitled to request copies of their clinical notes. However, this process remains time-consuming and burdensome, and it remains unclear how much of the medical record must be made available. Online access to notes offers a way to overcome these challenges and in around 10 countries worldwide, via secure web-based portals, many patients are now able to read at least some of the narrative reports written by clinicians (‘open notes’). However, even in countries that have implemented the practice many clinicians have resisted the idea remaining doubtful of the value of opening notes, and anticipating patients will be confused or anxious by what they read. Against this scepticism, a growing body of qualitative and quantitative research reveals that patients derive multiple benefits from reading their notes. We address the contrasting perceptions of this practice innovation, and claim that the divergent views of patients and clinicians can be explained as a case of epistemic injustice. Using a range of evidence, we argue that patients are vulnerable to (oftentimes, non-intentional) epistemic injustice. Nonetheless, we conclude that the marginalisation of patients’ access to their health information exemplifies a form of epistemic exclusion, one with practical and ethical consequences including for patient safety.
... Category I treatment options with the highest response rates (50%+), high levels of evidence and highest full remissions rates: Behavioral treatment or cognitive behavioral therapy (CBT) has been widely used for CFS until recently. However, surveys from patient organizations have found considerable rates of harm from CBT in CFS patients [50,51]. Moreover, the two largest UK patient charities, ME Association and Action for ME, have called for the use of CBT to challenge "illness beliefs" to be withdrawn and for health care providers to warn patients of the potential for harm [52]. ...
Article
Full-text available
Background: Chronic fatigue syndrome (CFS) is a poorly understood disease and information on effective treatments is sparse. A vast variety of vague treatment regimens including self-treatment with over-the-counter painkillers and muscle relaxants with little definitive evidence in improving the course of disease has further augmented the complexity of management of CFS. The aim of this review article is to compare and contrast the efficacy of different treatment protocols currently in practice based on a four-category regimen system. Methods: We performed a systematic search of 612 studies on PubMed and other sources and found 51 frequently prescribed medications for CFS. These treatments were classified into four categories I-IV (category I being the most effective therapies and category IV being the least). Results: Out of 51 frequently prescribed medications for CFS, 3 (Omega 3 Fatty Acids, Nexavir, Amphotericin B) have demonstrated high response rates (50%+), high symptom remission (50%+) and high full remission rates (40%+). Conclusion: Our understanding of CFS/ME is rapidly evolving. Numerous research discoveries have been made in the key aspects of CFS/ME, disease prevalence, etiology, biomarkers symptom manifestation, and treatment modalities. The four-category drug regimen outlined in our systematic review can be used as a starting point for future CFS/ME treatment and research.
... [11] In multiple surveys, CFS patients report that they found GET unhelpful or even harmful. [12,13] This discrepancy between the results of randomized trials and the concerns expressed by patient organizations requires explanation. ...
Article
Full-text available
Background: Several randomized trials have reported that graded exercise therapy (GET) is an effective treatment for chronic fatigue syndrome (CFS). These trials were not blinded and relied on patient-reported outcome measures (PROMs). We investigate whether bias introduced by this study design influenced the results. Methods: We extracted standardized mean differences from the most recent meta-analysis on exercise therapy for CFS to analyse their size, consistency over time, and congruence with objective measurements. A narrative review methodology was used to examine mediation analyses, plausible mechanisms of improvement, and risk of response bias. Results: Patient-reported improvements in exercise trials for CFS tend to be small, transient, and poorly supported by objective measurements. The risk of expectancy effects and response bias was high as patients were actively encouraged to adopt a positive attitude towards exercise therapy. Mediation analyses suggest that self-reported improvements in fatigue and physical function are not mediated by objective measures of fitness. Conclusions: Treatment effects seen in exercise trials for CFS could be the result of bias associated with the use of PROMs in non-blinded trials. This might explain the discrepancy between positive results reported in randomized trials and views on exercise therapy expressed by patient organizations. We hope that this case study furthers critical assessment of patient-reported improvements in areas of medicine where blinding of therapists and trial participants faces practical limitations.
... While most ME/CFS patient advocacy groups claim CBT and GET (BPS model treatments) are harmful and ineffective [72], psychiatrists have characterised this opposition as an example anti-psychiatry activism: ...
Article
Full-text available
Background Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling condition that greatly impacts the lives of sufferers. Many sufferers report problems getting a confirmatory diagnosis and difficulties getting doctors to believe them and offer support. Objective: This paper explores this issue by examining a biopsychosocial (BPS) model of ME/CFS promoted within psychiatry and its potential influence on how doctors might view and manage the illness. Method: A narrative literature review is undertaken to identify salient theory and discourse for consideration. Findings: Psychiatrists proffer a hypothetical model of ME/CFS aetiology and continuance, that instructs doctors to view the illness as a syndrome perpetuated by psycho-social factors that sustain unexplained symptoms such as fatigue, pain and post-exertional malaise, rather than symptoms being related to biological disease processes. The psychiatric model theorises that patients’ symptoms are maintained by their maladaptive beliefs and behaviours, requiring psychotherapy. Conclusion: The psychiatric BPS model of ME/CFS may negatively bias how physicians approach the illness, with doctors directed to view patients’ complaints as manifestations of psychological distress, rather than physical symptoms that require medical investigation or intervention. This finding may help explain why many ME/CFS patients feel disbelieved and unsupported after seeking medical care. Psychiatric theory fails to acknowledge or incorporate a substantial body of evidence showing biological deficits associated with ME/CFS. Medical trainees and physicians need more training and clinical exposure to ME/CFS patients, armed with better awareness of misleading and unproven claims associated with the BPS model.
... Re-analyses of GET trials like PACE using the original rather than post-trial, modified protocols have shown that the percentage of patients recovering with GET (4%) is not substantially different from those receiving usual care (3%) [49]. Referring healthcare providers may not realize that 50% of thousands of patients, surveyed across countries and years, report that GET worsened their health [50,51]. Thus, entities like the US Centers for Disease Control and Prevention and Northern California Kaiser Permanente are withdrawing GET as a treatment for ME/CFS [52,53]. ...
Article
Full-text available
Background: Today, 24% of college and university students are affected by a chronic health condition or disability. Existing support programs, including disability services, within colleges and universities are often unaccustomed to addressing the fluctuating and unpredictable changes in health and functioning faced by students with severe chronic illnesses. This situation is especially difficult for students with lesser-known, invisible diseases like myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), a complex disease affecting up to 2.5 million Americans which often begins in late adolescence or young adulthood. Objective: Educate occupational therapists (OTs) about ME/CFS and steps they can take to assist studentsMETHODS:This work is based on a review of the scientific literature and our collective professional/ personal experiences. Results: ME/CFS' effects on multiple organ systems combined with the unusual symptom of post-exertional malaise frequently and substantially decrease function. Currently, no effective disease-modifying treatments have been established. Nevertheless, OTs can help student maximize their participation in university life by identifying potential obstacles, formulating practical solutions and negotiating with their institutions to implement reasonable, environmental accommodations. Conclusions: Through understanding this disease, being aware of possible support options, and recommending them as appropriate, OTs are in unique position to greatly improve these students' lives.
Article
Full-text available
The present study found adult rates of chronic fatigue syndrome (CFS) in Nigeria that were somewhat higher than rates from community-based CFS epidemiologic studies in the USA. The rates of chronic fatigue for both adults and children were also higher than in existing community-based studies. It is possible that the presence of several fatiguing illnesses such as malaria and typhoid, the lack of adequate healthcare resources and poverty in Nigeria, place individuals at greater risk for fatigue and its syndromes. There is a need for more epidemiologic studies on the prevalence and sociodemographic characteristics of CFS in developing countries.
Article
Full-text available
Reduced functional capacity and post-exertional malaise following physical activity are hallmark symptoms of Chronic Fatigue Syndrome (CFS). That these symptoms are often delayed may explain the equivocal results for clinical cardiopulmonary exercise testing with CFS patients. The reproducibility of VO2 max in healthy subjects is well documented. This may not be the case with CFS due to delayed recovery symptoms. Purpose: To compare results from repeated exercise tests as indicators of post-exertional malaise in CFS. Methods: Peak oxygen consumption (VO2 peak), percentage of predicted peak heart rate (HR%), and VO2 at anaerobic threshold (AT), were compared between six CFS patients and six control subjects for two maximal exercise tests separated by 24 hours. Results: Multivariate analysis showed no significant differences between control and CFS, respectively, for test 1: VO2 peak (28.4 ± 7.2 ml/ kg/min; 26.2 ± 4.9 ml/kg/min), AT (17.5 ± 4.8 ml/kg/min; 15.0 ± 4.9 ml/ kg/min) or HR% (87.0 ± 25.4%; 94.8 ± 8.8%). However, for test 2 the CFS patients achieved significantly lower values for both VO2 peak (28.9 ± 8.0 ml/kg/min; 20.5 ± 1.8 ml/kg/min, p = 0.031) and AT (18.0 ± 5.2 ml/kg/min; 11.0 ± 3.4 ml/kg/min, p = 0.021). HR% was not significantly different (97.6 ± 27.2%; 87.8 ± 9.3%, p = 0.07). A follow-up classification analysis differentiated between CFS patients and controls with an overall accuracy of 92%. Conclusion: In the absence of a second exercise test, the lack of any significant differences for the first test would appear to suggest no functional impairment in CFS patients. However, the results from the second test indicate the presence of a CFS related post-exertional malaise. It might be concluded then that a single exercise test is insufficient to demonstrate functional impairment in CFS patients. A second test may be necessary to document the atypical recovery response and protracted malaise unique to CFS.
Article
Full-text available
PURPOSE: The etiology and pathophysiology of CFS remain unknown, but it is widely accepted that pain and fatigue are the two most common symptoms. However, only a few studies have investigated the treatment of chronic pain in CFS despite 94% of people diagnosed with CFS reporting muscle pain and 84% reporting joint pain (1). Treatment for pain in CFS relies heavily upon pharmacological intervention and many people have experienced serious side affects from taking medication. Therefore, the aim of this study was to evaluate the effectiveness of Myofascial Release to reduce musculoskeletal pain in people with CFS. METHODS: This study was of a repeated measure design. All participants met the Centre of Disease Control research criteria for CFS (2) and the Canadian Guidelines (3). Participants were randomised to either the treatment group (Myofascial Release, MFR) or the control group (Usual Care). MFR treatment was tailored to the needs of the patient and was provided once a week, for eight weeks. Assessments were conducted at baseline, week eight and at follow up (week 12). Outcome measures included the McGill Pain Questionnaire, Visual Analogue Scale, the Margolis Body Chart, the Pain Anxiety Symptoms Scale -20 and measures of physical activity. RESULTS: Eleven participants were recruited (treatment group n= 8, control group n=3). Participants who received MFR reported a significant reduction of pain severity and intensity compared to those people who received Usual Care (P
Article
Full-text available
Because the pathogenesis of Chronic Fatigue Syndrome (CFS) has yet to be determined, case definitions have relied on clinical observation in classifying signs and symptoms for diagnosis. The selec-tion of diagnostic signs and symptoms has major implications for which individuals are diagnosed with CFS and how seriously the illness is viewed by health care providers, disability insurers and rehabilitation planners, and patients and their families and friends. Diagnostic criteria also have implications for whether research based on varying definitions can be synthesized. The current investigation examined differences be-tween CFS as defined by Fukuda et al. (1994) and a set of criteria that has been proposed for a clinical Canadian Case definition. There were twenty-three participants who met the Canadian criteria, 12 in the CFS (Fukuda et al. (7) criteria) group and the 33 from the chronic fatigue (CF)-psychiatric group. Dependent measures included: work status, psychiatric comorbidity, symptoms, and functional impairment (measured by the Medical Outcomes Study). People meeting the Fukuda et al. and Canadian criteria were compared with people who had a chronically fatiguing illness explained by a psychiatric condition. Statistical tests used included binomial logistic regression and analysis of variance. The Canadian criteria group, in contrast to the Fukuda et al. criteria group, had more variables that statistically significantly differentiated them from the psychiatric comparison group. Overall, there were 17 symptom differences between the Canadian and CF-psychiatric group, but only 7 symptom differences between the CFS and CF-psychiatric group. The findings suggest that both the Canadian and Fukuda et al. case definitions select individuals who are statistically significantly different from psychiatric controls with chronic fatigue, with the Canadian criteria selecting cases with less psychiatric co-morbidity, more physical functional impairment, and more fatigue/weakness, neuropsychiatric, and neurological symptoms.
Article
Full-text available
The purpose of this study was to evaluate predictors of change in physical function in individuals diagnosed with chronic fatigue syndrome (CFS) following participation in nurse delivered, non-pharmacologic interventions. Participants diagnosed with CFS were randomly assigned to one of four, 6-month interventions including cognitive behavior therapy, cognitive therapy, anaerobic exercise, or a relaxation control group. Baseline measures including immune function, actigraphy, time logs, sleep status, and past psychiatric diagnosis significantly differentiated those participants who demonstrated positive change over time from those who did not. Understanding how patient subgroups differentially respond to non-pharmacologic interventions might provide insights into the pathophysiology of this illness.
Article
Full-text available
The Centers for Disease Control and Prevention (CDC) recently developed an empirical case definition that specifies criteria and instruments to diagnose chronic fatigue syndrome (CFS) in order to bring more methodological rigor to the current CFS case definition. The present study investigated this new definition with 27 participants with a diagnosis of CFS and 37 participants with a diagnosis of a Major Depressive Disorder. Participants completed questionnaires measuring disability, fatigue, and symptoms. Findings indicated that 38% of those with a diagnosis of a Major Depressive Disorder were misclassified as having CFS using the new CDC definition. Given the CDC’s stature and respect in the scientific world, this new definition might be widely used by investigators and clinicians. This might result in the erroneous inclusion of people with primary psychiatric conditions in CFS samples, with detrimental consequences for the interpretation of epidemiologic, etiologic, and treatment efficacy findings for people with CFS.
Article
Full-text available
A 36-item short-form (SF-36) was constructed to survey health status in the Medical Outcomes Study. The SF-36 was designed for use in clinical practice and research, health policy evaluations, and general population surveys. The SF-36 includes one multi-item scale that assesses eight health concepts: 1) limitations in physical activities because of health problems; 2) limitations in social activities because of physical or emotional problems; 3) limitations in usual role activities because of physical health problems; 4) bodily pain; 5) general mental health (psychological distress and well-being); 6) limitations in usual role activities because of emotional problems; 7) vitality (energy and fatigue); and 8) general health perceptions. The survey was constructed for self-administration by persons 14 years of age and older, and for administration by a trained interviewer in person or by telephone. The history of the development of the SF-36, the origin of specific items, and the logic underlying their selection are summarized. The content and features of the SF-36 are compared with the 20-item Medical Outcomes Study short-form.
Article
Background: The objectives of this study were to measure fatigue in patients with well-defined Myalgic Encephalomyelitis (ME) and to assess if there are any problems associated with the Chalder Fatigue Scale, which has been widely used to assess fatigue in patients with chronic fatigue syndrome (CFS). Methods: Twenty-six patients were recruited from a local support group. All had been diagnosed by physicians and met research criteria for ME. They completed the 11-item Chalder Fatigue Scale and were also asked to rate the severity of their illness. The fatigue scores were calculated using both the Likert method (0,1,2,3) and the bimodal method (0,0,1,1,). Results: The mean Likert score was 26.65 (SD 5.36) and the mean bimodal score was 9.81 (SD 2.04). Fifty per cent of the patients recorded the maximum score using the bimodal method and 77% recorded the two highest scores. Moreover, there was a marked overlap between those who rated themselves as moderately or severely ill. These findings are indications of a low ceiling. Conclusions: The findings from this study using the Chalder Fatigue Scale show that the low ceiling associated with the bimodal method means that this scoring system is not suitable for use in clinical trials. Researchers may wish to consider alternative instruments to obtain a more accurate measure of fatigue in patients with moderate to severe ME and similar conditions.
Article
Patiënten met het chronisch vermoeidheidssyndroom (ME/CVS) willen graag een richtlijn, waarin huisartsen, specialisten, psychologen en andere zorgverleners afspreken hoe ze omgaan met de aandoening. Veel van deze patiënten zeggen nu niet de medische zorg en ondersteuning te krijgen die ze nodig hebben, zo blijkt uit onderzoek onder de achterban van patiëntenorganisaties. Moeilijke diagnose De diagnose ME/CVS is moeilijk te stellen. Veel patiënten ervaren dat ze afhankelijk zijn van de persoonlijke opvattingen over ME/CVS van de zorgverlener die ze behandelt. Heeft deze wel voldoende kennis over de ziekte? Hoe wordt de diagnose gesteld? Welke behandelingen kunnen helpen? Patiënten voelen zich vaak niet serieus genomen en krijgen niet de medische zorg en ondersteuning die ze willen. De achterban van de ME/CVS-patiëntenorganisaties wil daarom graag een multidisciplinaire richtlijn voor ME/CVS. Huisartsen, specialisten en andere zorgverleners kunnen op basis van de beschikbare kennis in de richtlijn afspreken hoe ze omgaan met de aandoening. En bedrijfs- en verzekeringsartsen kunnen door zo’n richtlijn beter rekening houden met de beperkingen van ME/CVS-patiënten. Daarnaast verwachten patiënten dat de richtlijn helpt bij het toewijzen van de uitkeringen en voorzieningen die ze nodig hebben. Shoppen Het Kwaliteitsinstituut voor de gezondheidszorg CBO liet het NIVEL (Nederlands instituut voor onderzoek naar de gezondheidszorg) de ervaringen en meningen van patiënten met ME/CVS in kaart brengen. Het onderzoek werd gesubsidieerd vanuit het ZonMw-programma Chronisch Vermoeidheidssyndroom. De uitkomsten ervan worden gebruikt bij de ontwikkeling van een multidisciplinaire richtlijn ME/CVS door het CBO en het Trimbos-instituut. NIVEL-onderzoeker Anke de Veer: “Mensen met ME/CVS hebben ernstige klachten, maar artsen weten vaak niet waar ze de oorzaak moeten zoeken en zijn daardoor niet in staat de juiste hulp te bieden. Patiënten die hierdoor gaan ‘shoppen’ komen vaak met lege handen thuis. De richtlijn zou bijvoorbeeld moeten aangeven op grond van welke bevindingen de diagnose gesteld moet worden en welk onderzoek daarvoor nodig is. Patiënten kunnen dan beter worden voorgelicht over het diagnostisch proces en zullen minder snel het gevoel krijgen dat ze niet serieus worden genomen.” Onderzoek Het onderzoek is uitgevoerd in samenwerking met de ME/CVS-Stichting Nederland, de Steungroep ME en Arbeidsongeschiktheid en ME/CVS Vereniging, die de resultaten van het onderzoek inbrengen in het ontwikkeltraject van de richtlijn. Aan het onderzoek werkten 412 patiënten mee uit de achterban van de patiëntenorganisaties. De meesten (85,1%) beoordelen hun gezondheid als matig of slecht en kunnen niet meer dan vier uur per dag actief zijn.