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The evidence base for physiotherapy in myalgic encephalomyelitis/chronic fatigue syndrome when considering post-exertional malaise: a systematic review and narrative synthesis

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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.
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
https://doi.org/10.1186/s12967-020-02683-4
REVIEW
The evidence base forphysiotherapy
inmyalgic encephalomyelitis/chronic fatigue
syndrome whenconsidering post-exertional
malaise: asystematic review andnarrative
synthesis
Marjon E. A. Wormgoor1,2*† and Sanne C. Rodenburg3†
Abstract
Background: Due to the inconsistent use of diagnostic criteria in myalgic encephalomyelitis/chronic fatigue syn-
drome (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 nar-
row 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.
Keywords: Myalgic encephalomyelitis, Chronic fatigue syndrome, Post-exertional malaise, Physiotherapy,
Intervention, Systematic review
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Background
Myalgic encephalomyelitis (ME)/chronic fatigue syn-
drome (CFS) is a serious long-term, multi-system dis-
ease. It is characterized by severe unexplained fatigue
that is not improved by rest and is accompanied by
symptoms related to cognitive, immune and autonomous
Open Access
Journal of
Translational Medicine
*Correspondence: marwor@siv.no
Marjon E. A. Wormgoor and Sanne C. Rodenburg contributed equally to
this work
1 Division of Mental Health and Addiction, Vestfold Hospital Trust,
Tønsberg, Norway
Full list of author information is available at the end of the article
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Page 2 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
dysfunction [1, 2]. Disease severity varies from mild (50%
reduction of premorbid activity level) to very severe
(completely dependent and bedridden).e recovery rate
seems generally poor and most patients never regain
their pre-disease level of health [3].
Previously, and still by some clinicians and research
groups, ME/CFS was understood and approached by
applying a psychogenic or psychosomatic model [4, 5].
Onset and continuance of the illness were then consid-
ered to be perpetuated by patients’ irrational beliefs,
avoidance behavior, health anxiety, hypochondriasis or
personality traits. Yet, although the exact cause of ME/
CFS is still unknown, there is generally consensus on a
biomedical understanding [1, 6]. A number of studies
demonstrated multiple pathophysiological disturbances
mostly comprised of changes in neurological, immuno-
logical, metabolic, endocrinological and cognitive func-
tioning [1, 2, 68].
A considerable amount of the patients diagnosed with
ME/CFS show prolonged exacerbation of their symptoms
after minimal amounts of physical, sensory, emotional or
cognitive effort [1, 911]. is phenomenon is termed
postexertional malaise (PEM). Its onset is often delayed
and has an unpredictable recovery period that may last
days, weeks or even months. e severity and duration of
symptoms are out of proportion to the exertion [1, 12].
Patients tend to describe PEM as the most debilitating
part of the disease [13]. PEM is not synonymous with
post-exertional fatigue, not explained by decondition-
ing or malingering and is rarely found in other fatiguing
illnesses [1, 10]. Hence, patients’ reduction in activity
should not be understood as ‘fear avoidance behavior’,
but rather as a rational and physical response to the
occurrence of PEM [4, 14]. Various biomedical and prov-
ocation studies have confirmed this abnormal response
to exertion [1, 2, 1521].
In the absence of valid diagnostic tests, ME/CFS is
diagnosed with clinical criteria when alternative diag-
noses are excluded. In line with the different perspective
of explanatory models of pathogenesis and pathophysi-
ology, over 20 different diagnostic criteria sets have
been created for research and clinical purposes. PEM is
included in several of the diagnostic criteria, although
there are different views on its significance in the diag-
nosis of ME/CFS. e broadest criteria set, Oxford [22],
is unspecific and only requires severe, disabling fatigue,
affecting physical and mental functioning for a minimum
of six months and does not consider PEM at all. Other
criteria sets include PEM as an optional symptom (e.g.
CDC-94/Fukuda criteria [23]) and require the presence
of more symptoms. e Fukuda criteria are the most fre-
quently applied diagnostic criteria in current research.
e 2003 Canadian Consensus Criteria (CCC) [24], the
newer International Consensus Criteria for ME (ME-
ICC) [25] and Systemic Exertion Intolerance Disease cri-
teria (SEID) [1] require the presence of PEM, substantial
impaired function and other core symptoms including
pain, unrefreshing sleep, cognitive impairment, ortho-
static intolerance or neuroendocrine dysfunction [26].
Consequently, these narrow criteria sets create a more
homogenous patient group with a higher symptom bur-
den and far higher levels of physical and cognitive dis-
ability than broader criteria [27, 28]. Broad diagnostic
criteria may also embrace people who may have a form
of chronic fatigue that, in many cases, primarily involves
psychological factors [29].
Several different names have been proposed for
this disease. e most commonly used are “Myalgic
Encephalomyelitis”, “Chronic Fatigue Syndrome”, and the
umbrella-term ME/CFS. Whether PEM is a cardinal fea-
ture of ME/CFS, and accordingly whether ME and CFS
are distinct clinical entities, has been debated for almost
two decades [30]. For purposes of clarity, in this review,
the label “ME” will be used when PEM is a cardinal fea-
ture and the other core symptoms are present as well
[31]. “CFS” will be used when PEM or other core symp-
toms are optional features. e label “Chronic Fatigue”
(CF) will be applied when PEM is not accounted for at
all. When discussing ME, CFS and/or CF in general, the
umbrella-term “ME/CFS” will be pragmatically applied in
this review.
Physiotherapists are often involved in the manage-
ment of ME/CFS patients [32]. In the last decade, sev-
eral systematic reviews and meta analyses that included
interventions that seem relevant for physiotherapeutic
management of adult ME/CFS patients have been pub-
lished [29, 3346]. However, generally, the applied diag-
nostic criteria were not explicitly accounted for in these
reviews. Patients diagnosed with different criteria may
have different symptoms as well as reactions to certain
interventions, leading to the diagnostic incongruences
and treatment challenges seen in ME/CFS.
In Europe, few countries have guidelines for the clin-
ical approach to ME/CFS [47]. Typically, it is not clear
which diagnostic criteria the recommendations for ill-
ness management are based on, or who the target pop-
ulation is. Despite this, the recommendations mainly
consist of cognitive behavioral therapy (CBT) and
graded exercise therapy (GET) [47]. It is not well doc-
umented how these recommended clinical interven-
tions affect patients with ME, but they are criticized
by clinicians, patients and researchers as being inap-
propriate for patients with PEM [19, 48]. The evidence
of the effect of commonly applied ME interventions is
currently of increased relevance due to possible conse-
quences of the ongoing COVID-19 pandemic. ME/CFS
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Page 3 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
has been linked to many different viruses. Experiences
from past epidemics and current observations sug-
gest that a considerable number of patients recovering
from COVID-19 may develop ME/CFS-like symptoms
[49].
The aim of this review was to appraise current evi-
dence of effects of physiotherapy on symptoms and
functioning in ME/CFS patients in light of the sig-
nificance of PEM in the applied diagnostic criteria for
inclusion. The objectives were:
To summarize current evidence of the effects of
physiotherapeutic interventions on symptoms and
functioning in ME/CFS patients.
To synthesize the findings in light of the significance
of PEM in the applied diagnostic criteria for inclu-
sion.
To evaluate and discuss the reported physiothera-
peutic interventions in view of (potential) harm and
adverse effects for patients with ME.
Methods
Design
A systematic review methodology was utilized to evalu-
ate benefits and potential harms and adverse events of
applied physiotherapeutic interventions in ME/CFS
patients. e studies were grouped and evaluated accord-
ing to the diagnostic criteria used. e review was lim-
ited to randomized controlled trials (RCTs).
Search strategy
e systematic search for relevant RCTs was conducted
according to the Preferred Reporting Items for System-
atic Reviews and Meta-analysis (PRISMA) guidelines
[50] (see Fig. 1). PubMed, CINAHL and PEDro were
Records idenfied through database
searching (n=388)
PubMed (n =211), PEDro (n=92),
CINAHL
(
n=85
)
Screenin
g
Included Eli
g
ibilit
y
Idenficaon
Duplicates removed (n =149)
Records screened
on tle and abstract
(n =239)
Records excluded (n =212)
Not about ME/CFS (n=17)
No physiotherapy modality (n=133)
Not adults (n=11)
Not an RCT (n=8)
Other outcome measure (n=3)
No clinical effect study, incl
protocols (n=38)
No English, Dutch or Scandinavian
language (n=2)
Full-text arcles
assessed for eligibility
(n =27)
Full-text arcles excluded (n = 9)
Secondary effect analyses (n=2)
Follow-up arcles (n=5)
o1 primary study before 2000
o4 primary study aer 2000
Low methodological quality (n=2)
RCT’s included in review
(n=18)
(+ 6 linked arcles)
Fig. 1 Flowchart of study selection
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
searched with the following search words in the title:
myalgic encephalomyelitis, chronic fatigue syndrome,
CFS, chronic fatigue, post-exertional neuroimmune
exhaustion, PENE, systemic exertion intolerance disease
or SEID. e search was filtered to RCTs published since
the year 2000. is literature search was undertaken and
reviewed by the second author between February and
April 2020 and subsequently repeated by both authors.
Eligibility criteria
Articles were screened with the following inclusion cri-
teria: (1) RCT, (2) population of patients diagnosed with
CFS and/or ME, (3) an evaluation of the efficacy of a
physiotherapeutic intervention (i.e. physical activity/
exercise therapies, manual therapies, body awareness,
electrotherapy techniques or health education), (4) out-
come measures evaluating physical or mental symptoms
and/or functioning, including quality of life.
Articles were excluded when they (1) were not avail-
able in full text, (2) were not written in English, Dutch
or a Scandinavian language, (3) had an exclusive under-
age patient population, (4) had a follow-up article of a
primary study published before 2000 or (5) had a poor
methodological quality (PEDro score 0–3).
Methodological quality analysis
e PEDro scale was used in order to evaluate the meth-
odological quality of the RCTs [51]. is is a scale with
11 items, on which a “1” or a “0” can be scored. ere is
a maximum of 10 points to be achieved; a score above
six is considered as high quality, 4–5 as fair and 3 as
poor quality. e methodological quality analysis of all
included RCTs is reported in Table2.
Data extraction
e data extracted for each included RCT consisted
of name of author, year of publication, country, type of
intervention and control group, participant character-
istics, applied diagnostic criteria, treatment duration,
report on adverse events and treatment withdrawal, out-
come measures and result/conclusion. e data extracted
is summarized in Tables3, 4, 5.
Classication ofdiagnostic criteria
e diagnostic criteria were grouped according to the
extent to which the importance of PEM and other core
symptoms, including pain, sleep disturbances, cognitive
impairment and neuroendocrine dysfunction is empha-
sized [52]; CF: “No PEM” (PEM is not mentioned as a
criterion), CFS: “Optional PEM” (PEM is included as
an optional or minor criterion) or ME: “required PEM”
(PEM is a required or main criterion). e categorization
of the diagnostic criteria sets is presented in Table1.
Data analysis
Data analysis was stratified by the three defined sub-
groups according to the status of PEM in the diagnostic
criteria applied in the RCTs. Outcomes measured within
Table 1 Diagnostic criteria classication withrespect tothesignicance ofPEM andother core symptoms
a Requires exercise-induced fatigue, but does not require presence of all core symptoms;
b No PEM required (may be post-exertional fatigue) and does not require presence of all core symptoms;
c Post-exertional neuroimmune exhaustion (PENE)
Criteria set ME/CFS Post-exertional malaise inclusion
Author/institution No PEM (CF) Optional
PEM
(CFS)
Required
PEM (ME)
CDC (1988), Holmes definition Holmes 1988 [53], Centers for Disease Control and
Prevention, USA X
Oxford (1991) Sharpe 1991 [22] X
CDC (1994), Fukuda definition Fukuda 1994 [23], Centers for Disease Control and
Prevention X
London (1994) The National Task Force on CFS/PVFS/ME 1994 [54] Xa
CCC (2003), Canadian Consensus Criteria for ME/CFS Carruthers 2003 [24] X
Empirical CDC (2005) Reeves 2005 [55], Centers for Disease Control and
Prevention, USA X
NICE guideline (2007) Nice 2007 [56], UK’s National Institute for Health and
Clinical Excellence Xb
Canada-revised (2010) Jason 2010 [57] X
ME-ICC (2011), International Consensus Criteria for ME Carruthers 2011 [25] Xc
IOM (2015) (SEID) Institute of Medicine 2015 [1] X
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 2 Methodological evaluation oftheincluded RCTs (PEDro scale [51])
PEDro score: fair 4–5, high 6–10
Author, year Random
allocation Concealed
allocation Groups
similar
atbaseline
Participant
blinding Therapist
blinding Assessor
blinding Adequate
follow-up < 15%
missing
Intention- to-
treat analysis Between-
group
dierences
Point estimate
andvariability Total (0–10)
Chan et al. 2013 [70]Yes No Yes No No No Yes Yes Yes Yes 5–fair
Chan et al. 2014 [69]Yes No Yes No No No Yes Yes Yes Yes 6–high
Clark et al. 2017 [63]Yes No Yes No No No Yes Yes Yes Yes 6–high
Ho et al. 2012 [71]Yes No Yes No No Yes No Yes Yes Yes 6–high
Kos et al. 2015 [64]Yes Yes Yes No No Yes No No Yes Yes 6–high
Meeus et al. 2010 [65]Yes Yes Yes No No Yes Yes No Yes Yes 7–high
Moss-Morris et al. 2005 [74]Yes Yes Yes No No Yes Yes Yes Yes Yes 8–high
Nùñez et al. 2011 [68]Yes Yes Yes No No Yes Yes No Yes Yes 7–high
Oka et al. 2014 [72]Yes No Yes No No No Yes No Yes Yes 5–fair
Pinxsterhuis et al. 2017 [67]Yes No Yes No No Yes Yes No Yes Yes 6–high
Powell et al. 2001 [60]Yes Yes Yes No No No Yes Yes Yes Ye s 7–high
Sutcliffe et al. 2010 [62]Yes Yes Yes Yes No No Yes No Yes Yes 7–high
Taylor et al. 2004 [75]Yes Yes Yes No No Yes Yes Yes Yes Ye s 8–high
Thomas et al. 2008 [61]Yes Yes No No No Yes No No Yes Yes 5–fair
Vos-Vromans et al. 2016 [66]Yes Yes Yes No No No Yes Yes Yes Yes 7–high
Wallman et al. 2004 [73]Yes No Yes No No No Yes No Yes Yes 5–fair
Wearden et al. 2010 [59]Yes Yes Yes No No No Yes Yes Yes Yes 7–high
White et al. 2011 [58]Yes Yes Yes No No No Yes No Yes Yes 6–high
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 3 Included RCTs withdiagnostic-inclusion criteria withoutPEM asacriterion (CF patients)
Author,
Year
Country
Intervention (I) Comparison
(C) Participants
details (I/C)
Number
allocated (N),
Mean age (year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions
(ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse
events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
“PACE-trial”
White et al.
2011, 2013
[58, 85] (2007
[86])
Bourke et al.
2014 [120]
Sharpe et al.
2015 [121]
Chalder et al.
2015 [122]
McCrone et al.
2012 [79]
UK
GET or APT, each in
addition to SMC SMC
SMC + CBT (not
evaluated
here)
N = 641
(160,160/161)
Age: 38
76–80%
Oxford
(51% London
criteriad, 67%
empirical
CDC)
GET: 14 ss,
23 weeks
APT: 14 ss,
23 weeks
SMC 3 ss,
52 weeks
12 rand (mid-
therapy)
24 (= post)
52 rand
134 (104–230)
rand
1: CFQ, SF-36-PF
2: WSAS, HADS,
JSQ, PGIC, CFS
symptoms, pain,
fibromyalgia,
PEM occur-
rence and poor
concentration or
memory, EQ-5D,
6-min walking
ability, self-
paced step test
of fitness, lost
employment
Yes [83]
24/15/17
No
Post: CFQ: GET signif, APT
ns; SF-36-PF: GET signif,
APT ns
Long-1 year: CFQ: GET
p < 0.01, APT ns; SF-36-PF:
GET p < 0.01, APT ns
WSAS/JSQ/HADS/PGIC:
GET p < 0.05, APT ns;
PGIC/ + : GET 6/41%,
APT: 7/31%. Concentra-
tion and memory: ns;
PEM occurrence, pain,
fibromyalgia: GET p < 0.05,
ATP ns 6-min walking:
GET p < .001/ns, APT ns;
Fitness, lost employment,
EQ-5D: GET, APT ns
Serious adverse events
were infrequent, non-
serious adverse events
were common, physical
deterioration occurred
most often after APT,
p < 0.001
Long-2 year CFQ: GET, APT
ns, SF-36-PF: GET, APT ns
Concl: 1 year: GET can safely
be added to SMC to
moderately improve out-
comes for chronic fatigue
syndrome, but APT is not
an effective addition. GET
was more effective in
reducing the frequency
of both muscle and joint
pain than APT and SMC,
but small effect sizes
2 year: There was little
evidence on long-term
differences between
groups
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 3 (continued)
Author,
Year
Country
Intervention (I) Comparison
(C) Participants
details (I/C)
Number
allocated (N),
Mean age (year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions
(ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse
events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
“FINE-trial”
Wearden et al.
2010 [59]
UK
PR—Pragmatic
rehabilitation
(CBT + GET )
GP-TAU
SL-Supportive
listening,
general treat-
ment
N = 296
(95/101/100)Age: 45
78%
Oxford
(London criteria:
30%/31%/33%)
10 ss
18 weeks 20 basel
70 basel CFQ, SF-36-PF,
HADS, JSQ Yes
18/17
Yes
Short: CFQ, HADS-depr, Jen-
kins, p < 0.05, SF-36-PF ns
Long: all variables ns, No
adverse events
Concl: Pragmatic reha-
bilitation improved sleep,
fatigue and depression in
CFS patients, but has no
long-term effect
Powell et al.,
2001, 2004
[60, 123]
UK
Education to
encourage GET
1. Minimum inter-
vention
2. Min. + tel-
ephone
3. Min. + face to
face treatment
TAU (medical
assessment,
information,
advice book-
let, encourag-
ing activity
and positive
thinking)—
delayed onset
(1 year)
N = 148
(37/39/38/34)
Age: 34/32/33/34
78%
Oxford 1: 3 h, 2 ss
2: + 30 min, 7
tel ss
3: + 1 h, 7 ss,
12 weeks
12 rand
26 rand
52 rand
104 rand
1: SF-36-PF, CFQ
2: HADS, JSQ, PGIC No
5,7,7/2
Yes
Long-1 year: CFQ, SF-36,
HADS, JSQ: p < 0.001, 56%
fulfilled no longer CFS
trial criteria. PGIC/ + :
–/78%
Long-2 year: benefit
sustained, 56% fulfilled no
longer CFS trial criteria
Difference between inter-
vention groups ns
Intervention resulted in
substantial improvement
compared with TAU.
Benefits sustained until
2 year follow-up. Delayed
treatment was associated
with lower efficacy
Ss: sessions: ns non-signicant, APT: Adaptive Pacing Therapy; CBT: Cognitive Behavioural Therapy; GET: Graded exercise therapy; TAU : Treatment As Usual; SMC: Specialist Medical Care, CFQ: Chalder Fatigue scale/
Questionnaire; EQ-5D: Euroqol Questionnaire; HADS: Hospital Anxiety and Depression Scale; JSQ: 4-item Jenkins Sleep Questionnaire; PGIC: Patient Global Impression of Change; PGICdet/impr: PGIC (very) much worse/
better; SF-36–PF: Short Form Health Survey - Physical Functioning; WSAS: Work and Social Adjustment Scale
a Rand: from randomisation moment, basel.: from baseline, post: (at) post-treatement
b Data for at least one key outcome was analyzed by ‘intention to treat’ analysis (ITT)
c Results in favour of intervention. If results favours comparison intervention, ‘[C]’ is added. Post: post-treatment, Short-time follow-up, Long-longtime follow-up
d ‘Second-version’, with unknown modications
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 4 Included RCTs withdiagnostic-inclusion criteria withPEM asanoptional criterion (CFS patients)
Author, Year
Country Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age
(year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions (ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
Kos et al. 2015
[64]
Belgium
Activity pacing
self-manage-
ment (APSM)
Relaxation
therapy N = 33 (16/17)
Age: 41
100%
CDC-94/Fukuda 60–90 min
weekly
3 weeks
Post COPM, CIS,
SF-36, CFS
symptom list
No
1/3
No
Post: CIS p < 0.05,
SF-36-PF and other
scores ns No adverse
events
ASPM is feasible and
effective in increasing
participation in daily
life activities and
decreasing fatigue in
women with CFS
Taylor et al. 2004
[75]
USA
Immediate pro-
gram group:
peer-based,
education,
including
activity pacing
using the
envelope
theory
Delayed pro-
gram group N = 47 (23/24)
Age:47
91%/100%
CDC-94/Fukuda 8 Biweekly group
sessions over
16 weeks + 7 months
peer counseling
52, from base-
line CFSSRF (incl
CFQ), QoL
index
No
?
Yes
Long: Time × condi-
tion interaction: QoL,
CFSSRF-Symptom
severity: p < 0.05,
CFQ. not reported,
other items ns
Concl.: Patient driven
programs like this
can have a positive
effect on symptom
severity and QoL over
time in CFS/ME
Meeus et al.
2010 [65]
Belgium
Pain physiology
education Pacing and self-
management
education
N = 48 (24/24)
Age: 40
92%/75%
CDC-94/Fukuda Once 30 min education Post 1: NPT
2: PCI, PCS, TSK,
pressure pain
threshold
No
None
No
Post: NPT p < 0.001,
PCS-rumination,
-worry, -distrac-
tion p < 0.05, other
PCI-scales, TSK, Pain
thresholds ns
Pain education results
in better understand-
ing of pain and less
catastrophizing at
short term
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Page 9 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 4 (continued)
Author, Year
Country Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age
(year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions (ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
Wallman et al.
2004 [73]
Australia
GET with pacing Flexibility and
relaxation N = 68 (34/34)
Age: 43
77%
CDC-94/Fukuda max 30 min/ss
3–4 ss/week
12 weeks
4 post PGIC, HADS,
CFQ, Activity
levels, Stroop
test, physio-
logical assess-
ments (HR, BP,
VO2,RER, net
blood lactate
production),
RPE OAESI
No
2/5
No
Post: CFQ, HADS-depr,
physiological assess-
ments resting (except
diastolic BP) and
exercise, Stroop test
p < 0.05/ns, HADS-
anx, RPE, PGIC/ + r:
0/60%, activity level:
ns
Concl: GET was associ-
ated with improve-
ments in physical
work capacity, as well
as in specific psycho-
logical and cognitive
variables
Thomas et al.
2008 [61]
UK
Multi-conver-
gent
therapy (MCT),
including
CBT, GET and
pacing
Relaxation
therapy
(+ non-
randomized
control)
N = 31 (17/14)
Age: 48/45
71%
CDC-94/Fukuda 10 1 h ss, 10 weeks Post
26 1: Karnofsky
performance
scale
2: PGIC overall,
function,
fatigue
Yes
5/0
No
Post: Karnofsky (83%
vs 21% normal score,
consultant-rated),
PGIC overall p < 0.001,
PGIC fatigue
p < 0.001, PGIC func-
tion p < 0.05
Short: PGIC p < 0.001,
PGIC fatigue
p < 0.001, PGIC func-
tion p < 0.05
No adverse events
Concl: MCT seemed
more effective than
relax therapy
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Page 10 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 4 (continued)
Author, Year
Country Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age
(year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions (ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
Vos-Vromans
et al
2016 [66] (2012
[76])
The Netherlands
MRT (CBT,
gradual
reactivation,
body aware-
ness therapy,
pacing, social
reintegration)
CBT N = 122 (60/62)
Age: 40
80%
CDC-94/Fukuda
criteria CBT: 45–60 min,
16 ss, 6 months
MRT: 33 h,
10 weeks
26 basel (post)
52 basel 1: CIS-f, SF-36
2: SES, SCL-90,
MAAS, SIP-8,
CAL, LSQ, EET,
PSCG, activity
monitor
Yes, but no
reported
6/12
Yes
Short: CIS: ns, SF-
36-MCS ns, SF-36-PCS
ns, SES p < 0.05,
PSCG < 0.001, all
others ns
Long: CIS p < 0.05, SF-
36-MCS ns, SF-36-PCS
ns, SES p = 0.01,
PSCG < 0.001,
EET < 0.05 all others
ns
Concl: MRT is more
effective than CBT in
reducing long-term
fatigue severity in
CFS
Clark et al
2017 [63], (2016
[124])
UK
Guided graded
exercise self-
help (GES) and
four guidance
sessions with
physiothera-
pist
SMC N = 211 (97/102)
Age: 38
82%/76%
NICE (71% CDC-
94 and 81%
Oxford)
8 weeks 12 rand
52 rand 1: SF-36-PF, CFQ
2: PGIC-health
adverse
outcomes,
PGIC, HADS,
PHQ-13, WSAS,
IPAQ,
Yes
29%/–
Yes
Short: CFQ p < 0.001;
SF-36-PF p < 0.01,
WSAS p < 0.05,
HADS p < 0.01, IPAQ
p < 0.001, PHQ-13,
PGIC/+ : 0/14%, ns
Long: not reported
(yet?)
No serious adverse
reactions, serious
deterioration: ns
Concl: GES is a safe
intervention that
might reduce fatigue
and, to a lesser
extent, physical dis-
ability for CFS
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Page 11 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 4 (continued)
Author, Year
Country Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age
(year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions (ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
Moss-Morris
et al. 2005 [74]
New Zealand
GET SMC N = 49 (25/24)
Age: 41
71%
CDC-94/Fukuda 12 weeks Post
42 basel PGIC, CFQ,
SF-36-PF, VO2
peak (tread-
mill), IPQ-R,
IMQ
No
3/–
Yes
Post: PGIC/ + :
–/56% p < 0.05, CFQ:
p < 0.05, IMQ-symp-
tom focus p < 0.05
SF-36-PF, VO2 peak,
IPQ-R: ns
Short: Phys. CFQ < 0.05,
mental CFQ, SF-36-PF
ns
Concl: GET appears to
be an effective treat-
ment for CFS and it
operates in part by
reducing the degree
to which patients
focus on their symp-
toms
Nùñez et al.
2011 [68]
Spain
MRT (group CBT-
and GET, and
conventional
pharmacologi-
cal treatment)
Exercise coun-
selling
(and conven-
tional phar-
macological
treatment)
N = 120 (60/60)
Age: 43
93% / 14%
CDC-94/Fukuda
criteria CBT: 90 min, 9 ss,
GET: 60 min, 9 ss
10–12 weeks
52 post 1: SF-36
2: HAQ, HADS,
FIS
SF-36 reduced
2/3
No
Long: SF-36-BP: (C)
(p < 0.05), other
results ns
Concl: MRT was
not superior to
usual treatment at
12 months in terms
of HRQL (SF-36). The
combination of GET
and CBT is ineffective
and might be harm-
ful to some patients
Sutcliffe et al.
2010 [62]
UK
Home orthos-
tatic (tilt) train-
ing (HOT)
Sham training N = 38 (19/19)
Age: 48
84% / 79%
CDC-94/Fukuda 40 min. 26 weeks 4 rand (mid
treatment)
Post
1: Compliance/
tolerability
2: FIS, hemo-
dynamic
parameters
Yes, but not
reported
5/5
No
Short: FIS: ns, systolic
blood pressure drop
with active stand
p < 0.05, other hemo-
dynamics ns
Concl: HOT is well toler-
ated and generally
complied with
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Page 12 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 4 (continued)
Author, Year
Country Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age
(year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions (ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
Oka et al. 2014
[72]
Japan
Isometric sitting
yoga (and
pharmaco-
therapy)
Waitlist (phar-
macotherapy
alone)
N = 30 (15/15)
Age: 38
80%
CDC-94/Fukuda 20 min 5.8x/week,
9.2 weeks (mean 5.6ss
with instruction)
Post
8POMS (F and
V), CFQ, SF-8,
occurrence
Yes
None
No
Post: POMS-F p < 0.001,
POMS-V p < 0.01
Short: CFS p < 0.01, SF-8
total ns. Absence
of serious adverse
events or PEM
Concl: Isometric yoga
reduced fatigue and
improved vigor
Chan et al. 2014
[69]
Hong Kong
Qigong (Badu-
anjin) Waitlist N = 150 (75/75)
Age: 39
46%/62%
CDC-94/Fukuda 16 lessons of 1.5 h over
9 weeks Post
12 post PSQI, CFQ,
HADS, PGIC Yes
4–49/–
Yes
Short: PSQL: ns,
CFQ: p < 0.001,
HADS < 0.05/ < 0.001.
PGIC/ + : –/68%.
Except muscle ache,
adverse events were
uncommon
Concl: Qigong was
an efficacious and
acceptable treatment
for sleep disturbance
in CFS
Chan et al. 2013
[70]
Hong Kong
Qigong Waitlist N = 154 (77/77)
Age: 42
72% / 82%)
CDC-94/Fukuda 2 times/week
5 weeks + 12 weeks
home-based practice
Post CFQ, HADS Yes
5/12
Yes
Post: CFQ, HADS
p < 0.001
No adverse events
were reported
Concl: Qigong may
not only reduce the
fatigue symptoms,
but also has antide-
pressive effect
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Page 13 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 4 (continued)
Author, Year
Country Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age
(year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions (ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared to controlc
Concl.—Authors own
conclusion
Ho et al. 2012
[71]
Hong Kong
Qigong Waitlist N = 70 (35/35)
Age = 42
76% / 84%
CDC-94/Fukuda 5 weeks group
qigong + 12 weeks
home-based practice
Post CFQ, SF-12 Yes
8/10
Yes
Post: SF-12-PF: ns CFQ,
SF-36 MF: p < 0.001
No adverse effects
were reported
Concl: Qigong exercise
may improve CFS
and mental function-
ing
Ss: sessions: ns non-signicant, CBT: Cognitive Behavioural Therapy; GET: Graded exercise therapy; MRT: Multidisciplinary Rehabilitation Treatment; SMC: Specialist Medical Care, BP: blood pressure; CAL: Causal Attribution
List; CFQ: Chalder Fatigue scale/Questionnaire; CFSSRF: Chronic Fatigue Syndrome Symptom Rating Form; CIS/CIS-f: Checklist Individual Strength – Fatigue severity subscale; COMP: Canadian Occupational Performance
Measure; EET: Improvement and Satisfaction questionnaire; EQ-5D: Euroqol Questionnaire; FIS: Fatigue Impact Scale; HADS: Hospital Anxiety and Depression Scale; HAQ: Health Assessment Questionnaire; HR: heart
rate; IMQ: Illness Management Questionnaire: IPQ: Illness-Perception Questionnaire; LSQ: Life Satisfaction Questionnaire; MAAS: Mindfulness Attention Awareness Scale; NPT: Neurophysiology of Pain Test; OAESI: Older
Adult Exercise Status Inventory; PAQ: International Physical Activity Questionnaire; PCI: Pain Coping Inventory; PCS: Pain Catastrophizing Scale; PGIC: Patient Global Impression of Change; PGICdet/impr: PGIC (very) much
worse/better; PHQ-13: Patient Health Questionnaire-13; POMS: Prole of Mood States, Fatigue and Vigor; PSCG: Patient-Specic Complaints and Goals questionnaire; RPE: Ratings of perceived exertion; RER: respiratory
exchange ratio; SF-8/12/36: Short Form Health Survey (–PF physical functioning, -MF mental functioning - BP: Bodily Pain, -PCS: physical component summary, -MCS mental component summary); SCL-90: Symptom
Check List-90; SES: Self-Ecacy Scale; SIP-8: Sickness Impact Prole, 8 items; TSK: Tampa Scale of Kinesiophobia; VO2 oxygen uptake; WSAS: Work and Social Adjustment Scale
a Rand: from randomisation moment, basel.: from baseline, post: (at) post-treatement
b Data for at least one key outcome was analyzed by ‘intention to treat’ analysis (ITT)
c Results in favour of intervention. If results favours comparison intervention, ‘[C]’ is added. Post: post-treatment, Short-time follow-up, Long-longtime follow-up
d ‘Second-version’, with unknown modications
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Page 14 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
Table 5 Included RCTs withdiagnostic inclusion criteria withPEM asarequired criterion (ME patients)
Ss: sessions: ns non-signicant, CAU: Care As Usual, FSS: Fatigue Severity Scale; ICQ: Illness-Cognition Questionnaire; SES: Self-Ecacy Scale; SF-36: Short Form Health Survey
a Rand: from randomisation moment, basel.: from baseline, post: (at) post-treatement
b Data for at least one key outcome was analyzed by ‘intention to treat’ analysis (ITT)
c Results in favour of intervention. If results favours comparison intervention, ‘[C]’ is added. Post: post-treatment, Short-time follow-up, Long-longtime follow-up
d ‘Second-version’, with unknown modications
Author,
Year
Country
Intervention (I) Comparison (C) Participants
details (I/C)
Number
allocated (N),
Mean age (year)
Gender (%
female)
Diagnostic
criteria Duration
Session duration
Frequency
No. ofsessions
(ss),
period (# weeks)
Outcome
measure
momentsa
(weeks)
Main outcome
measures
1 Primary
2 Secondary
Adverse events
Treatment
withdrawn
(I/C)
ITTb
Results (benets),
compared
to controlc
Concl.—authors
own conclusion
Pinxsterhuis et al
2017 [67]
Norway
Group-based self-
management
education,
based on a self-
efficacy theory
and the ‘energy
envelope’ theory
(pacing)
CAU N = 146 (73/73)
Age: 44
94% / 82%
CCC and CDC-94/
Fukuda criteria 2.5 h
every 2 weeks,
16 weeks
26
52 1: SF-36
2: FSS, SES, ICQ No
2/6
No
Short: SF-36 ns, FSS
(C) p < 0.05, SES
p < 0.05, ICQ ns
Long: all outcome
ns
Concl.: this self-
management
program for CFS
patients did not
show a sustained
effect
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Page 15 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
one month of the end of treatment were regarded as post-
treatment measurements (post). Follow-up assessed one
to six months after treatment was considered short-term
effects (short) and measurements more than six months
following treatment were viewed as long-term effects
(long). e statistical significance (p < 0.05) of interven-
tion effects was reported with emphasis on fatigue and
physical functioning. Results are described for each
diagnostic category. For each subgroup, weighted mean
values of both the Chalder Fatigue Scale (CFQ) and the
physical functioning subscale of the Short Form 36-item
health survey (SF-36-PF) were calculated from the avail-
able before- and after-treatment scores (preferably at
short-term follow-up or the nearest measure moment).
Substantial changes (much or very much worse/better)
in patient-reported global impression of change (PGIC)
score were reported (PGIC/+) as well. Conclusively, it
was considered whether the findings were relevant for
ME patients.
Results
Description ofincluded studies
Study selection
e search, with applied filters, initially resulted in 239
articles. Eighteen met all eligibility criteria and were
included. ree protocols, two additional effect evalu-
ations and four additional follow-up articles linked to
included RCTs were evaluated as well. e selection pro-
cess for inclusion/exclusion of studies in this review is
presented in a PRISMA flow diagram (Fig.1).
e majority of the studies were conducted in Europe;
six studies in the UK [5863], two in Belgium [64, 65],
and one each in e Netherlands [66], Norway [67] and
Spain [68]. Four studies were performed in Asia: three in
Hong Kong/China [6971], one in Japan [72]. Addition-
ally, one RCT was conducted in each of the countries of
Australia [73], New Zealand [74] and USA [75]. Tables3,
4 and 5 summarize the characteristics and results of the
included RCTs.
Patient characteristics anddiagnostic criteria
e study samples varied between 30 and 641 partici-
pants, with a total of 2320 participants. All participants
were diagnosed with CF, ME or CFS with one of the men-
tioned criteria sets. Mean age varied from 34 to 48years
across the studies and 78% of the participants were
women.
ree studies [5860] used the Oxford criteria in
which PEM is not included, 14 studies [6166, 6875]
used the CDC-94/Fukuda criteria that consider PEM
as an optional symptom [23], and one study [63] used
the NICE criteria that requires PEM or post-exertional
fatigue, but not all other core symptoms. One study used
the Canadian Consensus Criteria, the only study that
applied a diagnostic criteria set requiring PEM and other
core symptoms.
e largest study, the PACE trial [58], applied the
Oxford criteria and reported that 67% of the partici-
pants met the empirical CDC (optional-PEM) and 51%
the London ME criteria (modified version) as well. In the
FINE trial [59] 31% of the participants, who all fulfilled
the Oxford criteria, met the London criteria as well.
Intervention characteristics
e therapeutic applications evaluated in this review and
considered relevant for physiotherapy consisted of one
or more of the following elements: physical activity, body
awareness, health education or orthostatic training.
e main physical activity interventions were GET and
activity pacing (AP). GET is based on the notion that the
fatigue is maintained by deconditioning and avoidance of
activity. Accordingly, it is assumed that one can overcome
the fatigue by increasing the activity level and physical
fitness by means of low-level aerobic exercise with a rigid
gradual increase of intensity and amount. In some stud-
ies, heart rate monitors were used during exercise ses-
sions to help participants meet the prescribed intensity
levels [58, 61, 73, 74]. GET was given alone [58, 74] or as
part of a rehabilitation program [59, 68, 76]. AP is a strat-
egy aimed at reducing the frequency and severity of PEM
by focusing on awareness and knowledge of one’s limits
and early signs of exacerbation. It targets on prioritizing
of activities, being as active as possible within one’s lim-
its, and alternating active and rest periods [77]. In some
programs focusing on AP [67, 75], the principles of the
Energy Envelope eory [78] were applied. According to
this theory, ME/CFS patients should not expend more
energy than they perceive they have (energy-envelope),
as this results in PEM and increased disability. In another
program [58], adapted pacing therapy (APT) was applied
to encourage participants to restrict their activity lev-
els to below 70% of their perceived limits. AP was given
alone as a therapy [58], as part of GET with pacing [73],
as graded exercise self-help (GES) guided by symptoms
[63], as part of a rehabilitation [61], educational [75] or
self-help program [63, 64, 67], or as a comparison inter-
vention [65]. Body awareness incorporates coordinated
body posture and movement, breathing, and meditation
techniques. Two original eastern approaches of exercise
and healing techniques, Qigong [6971] and isometric
yoga [72], were evaluated. In addition, body awareness
therapy was included in a rehabilitation program [66].
Several health education programs with different objec-
tives were included. ey aimed at encouraging GET
[60] or AP [75], focused on pain physiology [65] with
the intention to alter pain cognitions and thereby reduce
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Page 16 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
catastrophizing and kinesiophobia, or provided self-
management education aimed at accepting and improv-
ing ability to cope with ME [67]. In one study, orthostatic
(tilt) training was used to reduce orthostatic intolerance
[62].
e control interventions consisted of care as usual
[5860, 63, 67, 74], waitlist for intervention [6972],
relaxation therapy [61, 64, 73], exercise [65, 68], CBT [58,
76], sham-training [62] or supportive listening [59]. One
of the RCTs included CBT [58] and one supportive lis-
tening [59] as additional experimental arms; these were
considered as control interventions in this review.
e median treatment duration was 12weeks. It was
not always clear by whom the intervention was deliv-
ered, but all interventions were considered relevant for
physiotherapy despite the fact that some were led in
cooperation with or by peers [67, 75], a nurse [59], an
occupational therapist [58, 64, 67], a clinician therapist
[60], an exercise physiologist [58, 73], a yoga instruc-
tor [72], a qigong master [6971] or an interdisciplinary
team [66, 68].
Outcome measures
Outcomes were mainly measured by patient-reported
outcome measures (PROMs). Almost all studies had
included outcome measures on fatigue and physical
functioning, some on mental functioning, sleep, illness
beliefs, pain and global impression of change. A total
of 30 different PROM tools were applied. Most RCTs
applied multiple primary outcome measures.
e 36-item Short Form Health Survey (SF-36) or the
shorter forms, assessing physical and mental health sta-
tus and resulting impact on everyday life (labelled here as
‘health status’), were most frequently used (69%). Some
studies evaluated only single domains, usually Physical
Functioning (PF). Other frequently used outcome meas-
ures included the Chalder Fatigue Questionnaire/Scale
(CFQ) (56%), Hospital Anxiety and Depression Scale
(HADS) (44%) and Checklist Individual Strength (CIS)
(25%). Two studies [58, 72] reported on PEM occurrence.
Seven studies included a PGIC score.
Seven studies reported on objective outcome measures:
employment loss [79], activity monitoring [66, 73], walk-
ing ability [58], fitness [58], cardiopulmonary exercise
testing [73, 74], blood biomarkers, hemodynamic and
autonomic parameters [62]. One study reported auto-
nomic function indices and blood biomarkers solely in
the intervention group [80].
Methodological quality ofthestudies
Two studies [81, 82] were excluded because of poor
quality. All included studies scored high (n = 15) or fair
(n = 4) on the PEDro scale; PEDro scores ranged from
five to eight with six as a median (Table2). Only Sutcliffe
[62] reported successful participant blinding by offering
sham training to the control group. For all other inter-
ventions, it seemed unfeasible to allow participants and
therapist blinding.
Seven studies measured effects of the intervention at
long-term follow-up, after one year or longer.
Synthesis ofresults inview ofthesignicance ofPEM
Tables3, 4 and 5
RCTs withdiagnostic inclusion criteria withoutPEM
asacriterion
All three RCTs (Table3) showed effectiveness of GET or
GET-encouraging interventions on post- or short-term
fatigue and mental health in CF patients. Effects might
sustain until 1-year follow-up. Effect on physical function
was significant following GET and education. APT did
not seem effective. Long-term effects on mental fatigue
and physical function are unclear. In the PACE study,
both GET and APT were not able to reduce employment
loss or increase fitness [58, 79]. Improvements on the
walking test were greater for the GET group than for the
control [58]. However, improvements and group differ-
ences were small and all results were still just over half of
normal values.
e intervention groups’ mean CFQ scores (11-item
version, 2 RCTs) were 28.4 at pre, 22.7 at post, and SF-
36-FP (3 RCTs) were 34.6 at pre, 46.2 at post.
RCTs withdiagnostic inclusion criteria withPEM
asanoptional criterion
In CFS patients (Table4), it was unsure whether GET
improved fatigue and mental health, while effect on
physical functioning was absent or negative. AP, GET
with pacing, qigong and yoga seemed effective in reduc-
ing post-treatment and short-term fatigue. Effects on
health status and physical functioning, in particular, were
unlikely while effects on mental health and physiological
parameters were unsure.
In the intervention group, the mean CFQ scores (14-
item version, 6 RCTs) were 28.7 at pre, 18.4 at post, and
SF-36-FP (7 RCTs) were 41.8 at pre, 46.7 at post.
RCTs withdiagnostic inclusion criteria withPEM asarequired
criterion
One RCT evaluated an intervention for ME patients
(Table5). Pinxsterhuis 2017 [67] compared group-based
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Page 17 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
self-management to care as usual. e program focused
on AP and illness coping and was effective at short-term
follow-up for fatigue and self-efficacy. ere were no sig-
nificant differences between the groups with regard to
physical functioning. e program for ME patients did
not show long-term effects.
In the intervention group, the mean SF-36-FP scores
were 48.1 at pre, 46.5 at post.
Adverse events andcompliance
Ten studies mentioned the occurrence of adverse
events. Two of the GET studies in CF patients reported
on adverse events. e PACE study devoted an entire
paper on this subject [83]. e conclusion was that the
numbers of adverse events did not differ significantly
between trial treatments (GET 8%, APT 9%), but physi-
cal deterioration occurred most often after APT (GET
11%, APT 25%). No adverse events were reported follow-
ing pragmatic rehabilitation [59]. e two GET studies
in CFS patients (Nùñez [68] and Moss-Morris [74]) did
not evaluate adverse events. However, in the discussion
of Nùñez it was mentioned that the intervention might
have been harmful for some participants due to a signifi-
cant pain increase (SF-36-BP). In addition, Moss-Morris
[74] mentioned that the physiological assessment tests
were experienced as harmful to more than 50% of the
participants. Two studies on GET with pacing evaluated
adverse events in CFS patients. No adverse events were
found following multi-convergent therapy [61]. In the
GES-trial [63], serious adverse events were uncommon,
but in the guided graded exercise self-help group, as well
as in the control group, about a quarter of participants
reported deterioration of physical functioning (reduction
of SF-36-PF score of 10 points). e four RCTs on qigong
[6971] or yoga [72] reported that adverse events were
either not seen or uncommon, except for some muscle
ache. In addition, it was explicitly mentioned that none of
the participants reported PEM after practicing yoga [72].
e orthostatic training also seemed to be well tolerated
[62]. In the RCT with ME patients, adverse events were
not evaluated [67].
Compliance with the activity protocols was seldom
directly evaluated. In the PACE trial, however, ‘adequate
treatment’ (participation in 10 of the 14 sessions) was
reported: 85% for GET and 90% for APT (ns). In the GES
trial [63], the physiotherapists reported that 42% of the
participants adhered to GES completely or very well,
30% moderately well, and 29% slightly or not at all. Vos-
Vromans [66] reported that all participants in the MRT
group and 88% in the CBT group reached the 70% level of
compliance to treatment. In one of the Qigong trials [70],
it was reported that 25% had completed < 9 sessions and
32% had completed all 16 sessions.
Discussion
e main aim of this literature review was to appraise
the effect of physiotherapeutic interventions on symp-
toms and functioning of patients with ME/CFS, in view
of the significance of PEM in the applied diagnostic crite-
ria. e intention was thereby to contribute to improving
recommendations for evidence-based physiotherapeutic
care for the ME/CFS patients with PEM.
Many researchers and health professionals fail to
acknowledge ME as a distinct clinical entity. Accordingly,
the labels CFS and ME are often used synonymously in
both research and clinical practice. Also, patients that
obtained a CF label in this review are frequently labeled
as CFS elsewhere and CFS patients may be categorized as
ME patients. erefore, all relevant RCTs with ME/CFS
patients that investigated the effect of an intervention
considered relevant for physiotherapy were analyzed. In
order to establish the potential benefit or possible harm
of the studied interventions, the RCTs were synthesized
narratively in terms of the applied diagnostic criteria
for inclusion, the results, the focus on possible adverse
events, and the conclusions.
Summary ofmain results
is review found indications that GET was moder-
ately effective, possibly until 1-year follow-up, in reduc-
ing fatigue for CF patients diagnosed with the broad
Oxford criteria. In CFS patients, mainly diagnosed with
the Fukuda criteria, several interventions, including
GET, GET-encouraging interventions, GET with adap-
tive pacing, qigong and yoga seemed moderately effective
in reducing fatigue, though only at post-treatment. e
interventions might also have been effective in improv-
ing physical functioning in CF patients, but not in CFS
patients. However, effects, if any, vanished when evalu-
ating objective outcomes; no convincing effects were
obtained in fitness, level of physical activity, employment,
etc. AP appeared not to be effective in CF, though possi-
bly effective for post-treatment fatigue reduction in CFS.
Only one RCT for ME patients experiencing PEM was
identified [67]. Unfortunately, the self-management and
AP education program evaluated in this RCT seemed
ineffective. us, one cannot draw conclusions on the
effect of applied physiotherapeutic interventions to date
for this patient group. e shortage of trials evaluating
effectiveness of interventions in ME patients is not spe-
cifically related to the physiotherapy field, as it has been
seen in pharmacological, psychological and behavioral
interventions as well [33, 44, 84].
Methodological considerations oftheincluded studies
ere are some methodological inadequacies in the
included RCTs concerning method of diagnosis, choice
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
of outcome measures, selective reporting and heteroge-
neity of the samples.
In the majority of the studies it was not clear how the
ME/CFS diagnosis was set; following a prior thorough
clinical examination or solely using self-reported symp-
toms. Some trials that applied wide criteria had incor-
porated more narrow criteria for subgroup analyses. e
PACE [58] and the FINE trials [59] evaluated London cri-
teria (CFS-criteria) in addition to the Oxford criteria and
found that a considerable subgroup fulfilled both criteria.
e PACE trial assessed fulfillment of the empirical CDC
CFS criteria as well. Contrary to expectation, diagnostic
subgroup analysis in the PACE trial showed comparable
treatment effects on fatigue and physical functioning.
However, the correctness of these diagnoses is uncertain
as the evaluation of symptoms of these additional diag-
nostic criteria covered only the last week, and not the
previous six months as defined in the criteria sets [85].
Another critical point is that adverse events in these sub-
groups were not evaluated. For the FINE trial, subgroup
analyses were not reported at all.
Concurring with the inclusion criteria, all included
articles were graded as ‘high’ or ‘fair’ quality accord-
ing to their PEDro score. Maximum achieved score was
8 out of 10, as blinding of subjects and therapists seems
unfeasible in most physiotherapeutic practice. Despite a
comprehensive design and protocol, well-powered and
with a high-quality score, the most extensive and influ-
ential RCT, the PACE trial [58, 86], has been heavily criti-
cized [87]. Besides criticism for using the broad Oxford
criteria, it has been denounced for protocol changes of
effectiveness. Re-analysis demonstrated that most of the
modest improvements did not reach the level of signifi-
cance in the GET group when compared to the control
group [88]. Another critical issue is the absence of long-
term follow-up results and lack of group differences in
the objective outcome measures, which were more or less
ignored in the reporting.
Although several ME/CFS symptoms can be assessed
using well accepted objective testing methods [89, 90],
the conclusions of the evaluated RCTs were primar-
ily based on subjective PROMs. Remarkably, the clini-
cal relevance of the achieved improvements was rarely
discussed. Fatigue and physical functioning were most
frequently evaluated. e occurrence of PEM was
assessed as an outcome measure in only two RCTs [58,
72]. Its operationalization was unclear in both studies
and remarkable in one study, where several participants
reported PEM at baseline and did not fulfil the 1994 Lon-
don criteria [54] that requires post-exertional fatigue.
To evaluate changes in PEM, interventions towards ME
should report on several specific aspects of PEM; not
only the occurrence of PEM, but also perceived severity.
Assessments of changes in presence, frequency, and
intensity of various PEM symptoms, time aspects and
trigger intensities would be valuable. A couple of PROMs
[11, 9193] and objective tests [89] are available to evalu-
ate PEM. Apart from fatigue, other core symptoms were
usually not evaluated either. In contrast, in many RCTs,
depression and anxiety symptoms were evaluated as an
outcome measure. is seems to be a paradox since, in
most diagnostic criteria sets, psychiatric conditions are
listed as an exclusion criterion.
With ME/CFS, even if the participants improved on
average, it is of particular interest to know how many
participants experienced negative changes and to what
degree. Selective reporting of patient-reported impres-
sion of change scores made it difficult to evaluate this.
Seven RCTs included a PGIC score, but only three stud-
ies reported both the portions that experienced substan-
tially negative and positive change [58, 63, 73].
irteen of the 18 RCTs applied the CFQ. However,
comparing results among different interventions and
diagnostic subgroups appears difficult as two differ-
ent versions (11 and 14 items) and two scoring methods
(bimodal and Likert scale) were applied. Nonetheless,
it is clear that changes were modest. Further, the after-
treatment CFQ values (mean approx. 22) were still far
above normal (approx. 14 [94]) and long-term effects
were mostly lacking. Another important issue is that
CFQ appears inappropriate to evaluate changes in fatigue
in ME/CFS patients because of ceiling effects. e high
mean inclusion scores indicate that most of the par-
ticipants had reported a maximum score (“much more
than usual”) on most items at pretest. Consequently, it
is impossible to rate any exacerbations, only potential
improvements. is was pointed out earlier by Morris as
well [95].
Improvements on the physical function subscale of
SF-12/36 were not as frequent as for fatigue; SF-PF
was only significant in two of the three CF trials and in
one out of 6 CFS trials. However, similar to the CFQ,
improved SF-36 scores at follow-up (approx. 47 on aver-
age) were still far below normative data (approx. 90 in the
corresponding age group, 35–54years) and even below
the norm of age group 75–84 years, which averages a
mean SF-36-PF score of 58 [96].
Even though most interventions involved physi-
cal activity aspects, only one third of the RCTs’ applied
objective outcome measures to assess physiological or
functional capacity changes. A few studies obtained sta-
tistically significant improvements on these measures,
but they were often hardly or not clinically relevant. Like
the subjective measures, values were considerably below
normal values for (sedentary) healthy people. is clearly
indicates lasting reduced physical functional capacity in
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
patients with ME/CFS [97]. Aside from Wallman (2004
[73]), who assessed cognitive function with a modified
Stroop color test, objective assessments of other aspects
of neurocognitive functioning or other dimensions like
PEM, lack of energy, muscle function or sleep impair-
ment were lacking.
CF populations and, to a lesser extent, CFS populations
may comprise a mixed group of fatigued patients with or
without PEM. is may complicate appropriate adjust-
ment of intensity of physical activity instructions for all
participants. PACE’s APT instructed the participants to
do 30% less than their available energy might allow [98].
It has been suggested that if the expended energy was
consistently lower than available energy, as instructed
in APT, participants both with and without PEM, might
have become too inactive, resulting in reduced physical
and mental functioning and increased social isolation
instead [77]. is may have been problematic, especially
for the 33% of participants in the PACE study [58] who
had a depressive disorder (and probably not ME). Even
so, absence of convincing objective improvements fol-
lowing GET at group level may suggest that the level of
intensity may not have been appropriate for everyone.
As depressed participants and other chronic fatigued
patient groups often tolerate exercise well, they may
accordingly achieve improved physical capacity [99, 100].
Such patients were probably included in the CF popu-
lations. 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. is may
have reduced average improvements on the group level.
Non-compliance was demonstrated in a GET-like case–
control study in which daily activity was assessed by an
accelerometer [101]. Initially, the ME/CFS patients were
able to reach the prescribed activity goals, however, after
4–10days, they seemed unable to sustain target activity
levels and reported pronounced worsening of symptoms.
Repeated testing or monitoring over time may therefore
give more relevant data than just one single exertion test.
Several GET studies applied heart rate monitoring to
guide training intensity and to reduce participants’ focus
on bodily symptoms. Unfortunately, no RCT included
in this review evaluated these or other objective meas-
ures to report on compliance with the exercise regime.
Potential associations with the measured PROMs were
generally not reported on either. However, a recent study
reported positive correlations between objectively meas-
ured and patient reported physical functioning (SF-PH)
in ME/CFS patients [102]. Continuing low SF-PH scores,
as seen in this review, may therefore confirm the impres-
sion that the participants’ level of physical activity did not
notably increase following the interventions.
From this review, it seems that proven effectiveness
of physical exercising in ME/CFS is associated with the
subjectivity of the applied outcome measures. PROMs
that evaluate subjective experiences of fatigue more
frequently obtained statistically significant differences
than scoring of self-perceived limitations to perform
specific physical activities, as in SF-36. Further analy-
ses of data from PACE and two other CBT studies illus-
trated that effect sizes increased when the subjectivity
of the outcome measure increased [103]. is was also
reported in re-analyses of the Cochrane review on exer-
cise therapy for ME/CFS. is review based its conclu-
sions on PROMs only and suggested that exercise therapy
likely has a positive effect on fatigue [35]. Analyses of
the objective outcomes of the included RCTs, however,
demonstrated that GET does not lead to clinically signifi-
cant objective improvements [104]. Using PROMs only
may therefore be incorrect in ME/CFS research. is is
consistent with findings of clear discrepancies between
what is measured in research and patients’ reported per-
ception in a systematic review of PROMs in ME/CFS
research [105].
Besides the reduced effectiveness with diminished out-
come objectivity, physiotherapeutic treatment effectivity
also seems to disappear when follow-up time or diagnos-
tic specificity increases. Unfortunately, this leaves us with
little evidence when it comes to effective physiotherapeu-
tic management of ME patients.
Current evidence concerningpotential negative responses
totreatment
From the studies in this review, no clear and direct indi-
cation was found regarding participants’ tolerability of
the interventions. Few studies reported on the occur-
rence of adverse events or non-adherence due to intol-
erance 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.
Furthermore, absence of substantial mean improve-
ments on PROMs and objective measurements may indi-
cate that some participants have improved, while other
participants may have worsened on these measures.
PGIC scores confirm that not all participants perceived
substantial improvement following the interventions;
across the RCTs, 22% to 86% rated their change from
very much worse to a little better. Only one included
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
GET study with CFS patients commented on the harm-
fulness of the intervention [68].
Clear indications of potential negative patient-reported
experiences of common ME/CFS interventions are sum-
marized in a review of 11 patient surveys [107]. More
than half (55%) of the ME/CFS patients undertaking GET
(n = 4876) reported negative outcomes and only 27%
reported a decrease of symptom severity. In contrast,
pacing (n = 8981) obtained the lowest negative response
rate (4%) and the highest reported benefit (81%).
e concerns regarding exercise programs are con-
firmed in several case control studies evaluating
responses on sub-maximal activity in ME/CFS patients.
Adverse responses have been found as disproportional
increases of fatigue, sleep disturbances and pain, as well
as disturbances in muscular, neuroimmunological and
cognitive functioning [1, 2, 19, 108, 109]. ese adverse
responses are supported by evidence of exercise-induced
maladaptive findings across multiple systems during or
after maximal or submaximal physical activity. Devia-
tions have been reported, for instance, in brain activa-
tion, immune and autonomic response, pain modulation,
lowered aerobic metabolism and metabolic deficits [1, 2,
1521]. Several of these alterations are correlated with
the perceived intensity of PEM [12, 109, 110]. Although
we mainly focused on physical exertion here, this largely
applies to cognitive, sensory and psychological stressors
as well.
Even though the results of this review did not reveal
substantial negative responses, the marginal and doubt-
ful effects, patient-reported experiences and evidence
coming from biomedical research strongly suggest an
overall reduction in tolerance of physical exertion in ME
patients.
Strength andlimitations ofthis review
A strength of this review is that the included RCTs
reported on a broad specter of outcome measures, inter-
ventions and aim of treatment. A limitation was the
heterogeneity of comparison groups, group sizes and fol-
low-up duration. is heterogeneity limited the possibil-
ity to compare results and calculate effect sizes across the
different treatments and diagnostic groups. erefore, a
narrative synthesis was conducted.
is systematic review was limited by deficiencies of
the trials. Several of these have already been described
in the methodology overview. One of the objectives was
to evaluate and discuss the reported physiotherapeutic
interventions in view of (potential) harm and adverse
effects for patients with ME. A limitation of this current
review was therefore the lack of focus in the RCTs on
participants’ tolerability of the interventions and modest
reporting of possible adverse effects.
To improve evidence quality, searches were restricted
to RCTs published since the year 2000. We may thereby
have missed additional valuable knowledge concern-
ing other relevant interventions that were only reported
in weak methodological RCTs or non-randomized tri-
als. Although the first criteria set that required PEM, the
Canadian Consensus Criteria, was published in 2003, we
found only one RCT that studied ME patients, which is
an insufficient basis for assessing the effects of physi-
otherapy. Remarkably, these newer diagnostic criteria
are still rarely used in intervention studies. is was
observed in a recent systematic review covering 55 RCTs
targeting ME/CFS as well [33].
As far as we know, this is the first available review
that stratified synthesized evidence of ME/CFS RCTs
according to significance of PEM in the inclusion cri-
teria. However, several previous systematic reviews
mentioned some uncertainty as to whether findings in
studies with Oxford or Fukuda criteria are applicable
to ME/CFS patients diagnosed with criteria requir-
ing PEM [33, 35, 37, 44]. In an update to an evidence
report concerning ME/CFS [84], any evidence of bene-
ficial effect for GET disappeared by excluding the trials
using Oxford criteria for inclusion. In contrast, a recent
review restricting their search to European RCTs that
applied diagnostic criteria excluding mental health ill-
nesses (7 Fukuda, 1 CCC) [43] concluded that effects of
rehabilitation and activity pacing were inconsistent and
comparable to previous systematic reviews that had
included Oxford criteria. e newly published system-
atic review of Ahmed (2020 [44]) had a partly similar
intention as this current review, but was restricted to
CBT and GET interventions. All RCTs included Oxford
or Fukuda criteria only. ey could not find evidence
to conclude that CBT and GET are effective treatments
for CFS patients.
We are aware of one earlier systematic review on the
effect of physiotherapy in ME/CFS patients [34]. It
focused on RCTs published 2007–2017 and included
four studies. Two of these studies were excluded in our
review because they either involved a younger popula-
tion or were listed as a separate RCT [111] while actually
reporting secondary analyses of an already included RCT
[66]. In this current review a much broader spectrum of
physiotherapeutic interventions for ME/CFS patients is
included. We have, indeed, included some interventions
that were guided by other health care professionals but
nonetheless considered relevant for physiotherapy. Still,
we do not fully understand why the other 12 RCTs we
found in the same period were not included in the sys-
tematic review of Galeoto 2018 [34]. ey might have
had a dissimilar view of what may be applied as a physi-
otherapeutic intervention.
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
In the literature, CBT interventions have been pre-
dominant in published RCTs targeting ME/CFS [33].
Although it has been suggested that other health care
professionals than clinical psychologists may deliver
CBT-based treatment strategies [112], CBT studies were
not included in this review. CBT usually addresses pos-
sible depressive symptoms, maladaptive thoughts and ill-
ness beliefs that may impair recovery. In ME/CFS, CBT
often applies a graded increase in physical activity strat-
egies as well. In physiotherapy, however, the rationali-
zation to apply GET may rather be to reverse a cycle of
inactivity and deconditioning. ere may be other inter-
ventions of debatable relevance that were excluded in this
review as they were assumed to fall outside the general
skillset of a physiotherapist; acupuncture is one example
we are aware of.
e majority (78%) of the participants were women,
which is in accordance with the general ME/CFS patient
population that has a female-to-male ratio ranging from
2:1 to 5:1 [113]. Inclusion of severely affected patients,
however, did not seem representative. In general, 10
to 25% of the ME/CFS population is severely or very
severely affected and house- or bedbound [114]. In the
included studies, most participants were apparently
mildly or moderately affected. is was expected, as
severely affected patients are often unable to participate
in trials if attendance to a healthcare facility is required. It
is therefore doubtful whether the findings of this review
are applicable for severely affected patients. However,
including them in experimental RCTs seems unethical. In
agreement with Mengshoel (2020 [43]), we underline the
need for case studies and patient experiences to develop
meaningful physiotherapeutic management procedures
for this group of patients as well.
Classification of the diagnostic criteria sets was not
entirely unambiguous. Although the focus was primar-
ily on the presence of PEM, other core symptoms were
emphasized as well. is is in line with a diagnostic algo-
rithm described by the US Institute of Medicine (IOM,
2015 [1]) that required the presence of PEM, unrefresh-
ing sleep, cognitive impairment and orthostatic intol-
erance. e NICE [56] and London criteria [54] both
mention the inclusion of PEM-like symptoms (exercised
induced fatigue and post-exertional fatigue), but do not
require the presence of all core symptoms and were
therefore classified in the CFS cluster.
Implications forclinical practice
Expanding knowledge concerning effects and possible
consequences of physiotherapy in ME patients seems
necessary [1, 115]. In general, the prescription of a physi-
cal activity program is common and considered ben-
eficial in physiotherapeutic practice [116]. Contrary to
most conditions, however, it seems that even briefly
increased physical activity may cause abnormal detri-
mental responses in ME patients [108, 117]. Unfortu-
nately, knowledge of ME/CFS, and PEM in particular,
still seems insufficient among physiotherapists. is is in
line with findings of a recent survey among ME patients
[32]; around half of the respondents had received physio-
therapy, but a worrying 53% of them reported that physi-
otherapy made their ME symptoms worse.
Many researchers and health professionals still fail
to acknowledge that subgroups of ME/CFS require dif-
ferent management approaches, which can have seri-
ous adverse consequences for ME patients [118]. A few
European countries have national guidelines for treat-
ment of ME/CFS [47]. Their recommendations are
solely based on (weak) evidence from RCTs with CF
or CFS patients, but are extrapolated to ME patients
as well. This brings up an unusual aspect of external
validity in the translation to clinical practice; the study
samples in ME/CFS research usually seem to be more
heterogenic than those of the more distinct ME popu-
lation. GET, together with CBT, is still the treatment
most often recommended in the European guidelines
[47]. In USA, however, the CDC removed GET and
CBT as recommended treatments in 2017.
For physiotherapists, it is important to take into
account the diagnostic criteria used in research and
recommendations when translating this evidence into
practice and selecting appropriate therapy for ME
patients. is also applies to the patients with greater
disease severity. Although some of the concepts of the
discussed interventions in this review may be applica-
ble, the interventions themselves are potentially harm-
ful for patients with severe or very severe ME.
As the present review shows, there is currently no
scientific evidence for curative or beneficial treatment
for ME. It is essential to acknowledge this and refrain
from applying potentially harmful treatments. Here,
one needs to rely even more on patient and clinician
experience and evidence from biomedical research.
Physiotherapeutic management should focus on symp-
tom relief and increasing or maintaining health status
and quality of life, by improving the ability to cope with
ME, guiding self-management and avoiding PEM, in
particular. With this in mind, health education, pacing
and body awareness can be valuable approaches.
With the current public health situation, these
approaches may also be very relevant for recovered
COVID-19 patients who experience persistence of
symptoms [49]. Here, it is important for physiothera-
pists to understand that ME may be a potential compli-
cation of a viral infection [119] and that standard care
may be detrimental for these patients.
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Wormgoorand Rodenburg J Transl Med (2021) 19:1
is review focused on physiotherapeutic interven-
tions only. It is not to be expected that physiotherapy
may cure ME, but it may contribute to symptom relief,
coping and maintenance or improvement of function-
ing. In addition to this, and hopefully to find a cure for
ME, we need to lean on biomedical research and future
effective pharmacological therapy.
Implication forfuture research
To generate strategies for effective treatment, further
understanding of the pathophysiological bases of the
disease is essential [6]. is review documents impor-
tant knowledge gaps about the consequence of the
presence of PEM on physiotherapeutic management
of ME patients. It identifies a critical need for con-
sensus to apply updated diagnostic criteria in future
diagnosing, interventional and biomedical research to
further understanding of ME. At present, the CCC or
updated ME-ICC seem to be the most obvious alterna-
tives for this. Generally, it is important to differentiate
between CF, CFS and ME. Without this clear distinc-
tion between patients with or without PEM, it is unfea-
sible to provide health care providers with evidence of
the most adequate treatment. ME is a complex condi-
tion with an extensive clinical heterogeneity. erefore,
even if proper diagnostic criteria are used, it is impor-
tant to apply subgroup, predictor and moderator analy-
ses to attain better targeted therapeutic options.
As diagnosis is still based on patient-reported symp-
toms, inclusion of PROMs in ME/CFS research is obvi-
ous. ese PROMs need to cover several core symptoms
of ME, including PEM, and must be capable of assess-
ing both improvements and deteriorations in symptoms
and functioning. In ME/CFS it is of particular relevance
to report the proportion of participants that may expe-
rience exacerbation of symptoms and not only average
changes for the study population. Further, one also has
to ascertain whether PROM changes are associated with
objectively measured changes and are clinically meaning-
ful. From a clinical point of view, it is relevant to ensure
adequate length of follow-up and to report and evaluate
harms, other adverse effects, adherence and reasons for
withdrawal.
Conclusion
Currently, there is no scientific evidence when it comes
to effective physiotherapy treatment for ME patients
diagnosed with narrow diagnostic criteria sets that
include PEM. Findings indicating effectiveness of physi-
otherapeutic interventions for ME/CFS are mainly based
on RCTs involving patients diagnosed with diagnos-
tic criteria that do not require PEM. Possible evidence
vanished when diagnostic specificity, outcome objectivity
or follow-up time increased.
As any exertion may cause long-lasting exacerba-
tion of symptoms in ME patients, some interven-
tions may have adverse consequences. Hence, in the
translation of ME/CFS research evidence to clinical
practice, it is crucial to differentiate between patients
diagnosed by criteria with or without PEM as a
required feature.
To improve evidence, well-defined ME populations,
reporting of adverse effects, sufficient follow-up and
incorporation of relevant and objective measures are
essential in interventional research.
Abbreviations
AP: Activity pacing; APT: Adapted pacing therapy; CBT: Cognitive behavioral
therapy; CCC : Canadian consensus criteria; CDC: Centers for Disease Control
and Prevention, USA; CF: Chronic fatigue; CFQ: Chalder fatigue scale; CFS:
Chronic fatigue syndrome; GET: Graded exercise therapy; IOM: Institute of
Medicine; MCT: Multi-convergent therapy; ME: Myalgic encephalomyelitis; ME-
ICC: International consensus criteria; MRT: Multidisciplinary rehabilitation treat-
ment; ns: Non-significant; PEM : Post-exertional malaise; PGIC: Patient global
impression of change; PGIC/+ : Substantial changes on PGIC: (very) much
worse/better; PROM: Patient-reported outcome measures; RCT : Randomized
controlled trial; SEID: Systemic exertion intolerance disease; SF-12/36: Short
form 12/36-item health survey; SF-36-PF/BP/PH: SF-36-physical functioning/
bodily pain/ physical health subscale.
Acknowledgements
SCR is grateful for the helpful feedback received by supervisor Jolanda van
Lieshout at the Hanze University of Applied Sciences in Groningen, the
Netherlands, in the process of writing her graduation assignment for the
International Physiotherapy Bachelor. The authors are also grateful to Prof.em.
Ola Didrik Saugstad at the University of Oslo, Norway, and Prof. Jens Egeland at
the University of Oslo and Vestfold Hospital Trust for their useful comments on
the manuscript. Academic editing of English was provided by Lauren Sluyter
Olsen.
Author’s contributions
Both authors, MEAW and SCR, contributed to all parts of the manuscript, read
and approved the manuscript.
Funding
None.
Availability of data and materials
The articles reviewed in this study are available in the public domain.
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Author details
1 Division of Mental Health and Addiction, Vestfold Hospital Trust, Tønsberg,
Norway. 2 Division Physical Medicine and Rehabilitation, Vestfold Hospital
Trust, Stavern, Norway. 3 Department of Physiotherapy, Hanze University
of Applied Sciences Groningen, Groningen, The Netherlands.
Received: 6 October 2020 Accepted: 15 December 2020
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 23 of 26
Wormgoorand Rodenburg J Transl Med (2021) 19:1
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... Other management by medications for ME/CFS includes treating with azithromycin, remdesivir, favipiravir, infliximab, tocilizumab, siltuximab, hydrocortisone, rituximab, rintatolimod, and intravenous immunoglobulin [17,18]. The overall physiotherapy management for ME/ CFS aims to improve the painful status, cardiorespiratory functions, adaptive coping for fatigue, energy consumption and restoration, and improving physical and psychological well-being [19]. Physiotherapy management of ME/CFS cases includes exercise, pacing, and different indicative approaches such as cognitive behavioral therapy [19,20]. ...
... The overall physiotherapy management for ME/ CFS aims to improve the painful status, cardiorespiratory functions, adaptive coping for fatigue, energy consumption and restoration, and improving physical and psychological well-being [19]. Physiotherapy management of ME/CFS cases includes exercise, pacing, and different indicative approaches such as cognitive behavioral therapy [19,20]. A wide range of exercise therapies can be prescribed for ME/CFS, including customized exercise, aerobic exercise, and adapted physical activity and therapeutic exercise programs [11,19,20]. ...
... Physiotherapy management of ME/CFS cases includes exercise, pacing, and different indicative approaches such as cognitive behavioral therapy [19,20]. A wide range of exercise therapies can be prescribed for ME/CFS, including customized exercise, aerobic exercise, and adapted physical activity and therapeutic exercise programs [11,19,20]. Evidence suggests adaptive physical activity and therapeutic exercise programs are more effective than passive control or cognitive behavioral therapy for non-COVID patients having ME/CFS [13]. ...
Article
Full-text available
Background Physiotherapy interventions effectively improved fatigue and physical functioning in non-COVID patients with myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS). There is a research gap on the effectiveness of physiotherapy interventions versus drug management on ME/CFS in post-COVID-19 conditions (PCC). Methods We planned a three-arm prospective randomized control trial on 135 PCC cases with ME/CFS who are diagnosed between 20 November 2023 and 20 May 2024 from a population-based cohort. The study aims to determine the effectiveness of physiotherapy interventions as adapted physical activity and therapeutic exercise (APTE) provided in institution-based care versus telemedicine compared with drug management (DM). Participants will be assigned to three groups with the concealed location process and block randomization with an enrollment ratio of 1:1:1. The post-treatment evaluation will be employed after 2 months of interventions, and follow-up will be taken after 6 months post-intervention. The Chalder fatigue scale will measure the primary outcome of fatigue. SF-36 and the disability-adjusted life years (DALYs) will measure the secondary outcome of physical functioning and episodic disability. Discussion This study will address the research gap to determine the appropriate approach of physiotherapy or drug management for ME/CFS in PCC cases. The future direction of the study will contribute to developing evidence-based practice in post-COVID-19 condition rehabilitation. Trial registration The trial is registered prospectively from a primary Clinical Trial Registry side of WHO CTRI/2024/01/061987. Registered on 29 January 2024.
... Both the APTE-I and APTE-T participants will receive treatment according to the e-Delphi consensus from a Bangladeshi research group [27], Malaysian Ministry of Health guidelines for managing Post COVID-19 conditions [28], Cochrane review [10], previous RCTs [22] and a systematic review from a research group in Norway [29]. The adapted physical activity and therapeutic exercise (APTE) will be composed of breathing exercises and breathing control exercises [29], exercises to improve flexibility and motor control [10], exercises to improve aerobic capacity [10,28,29], and interventions to maintain a healthy lifestyle [27,28]. ...
... Both the APTE-I and APTE-T participants will receive treatment according to the e-Delphi consensus from a Bangladeshi research group [27], Malaysian Ministry of Health guidelines for managing Post COVID-19 conditions [28], Cochrane review [10], previous RCTs [22] and a systematic review from a research group in Norway [29]. The adapted physical activity and therapeutic exercise (APTE) will be composed of breathing exercises and breathing control exercises [29], exercises to improve flexibility and motor control [10], exercises to improve aerobic capacity [10,28,29], and interventions to maintain a healthy lifestyle [27,28]. All the interventions will be provided according to the guidelines recommended by Safe Long COVID rehabilitation [26]. ...
... Both the APTE-I and APTE-T participants will receive treatment according to the e-Delphi consensus from a Bangladeshi research group [27], Malaysian Ministry of Health guidelines for managing Post COVID-19 conditions [28], Cochrane review [10], previous RCTs [22] and a systematic review from a research group in Norway [29]. The adapted physical activity and therapeutic exercise (APTE) will be composed of breathing exercises and breathing control exercises [29], exercises to improve flexibility and motor control [10], exercises to improve aerobic capacity [10,28,29], and interventions to maintain a healthy lifestyle [27,28]. All the interventions will be provided according to the guidelines recommended by Safe Long COVID rehabilitation [26]. ...
Article
Full-text available
Background: Adaptive pacing improved fatigue and physical functioning in non-COVID patients with chronic fatigue syndrome. Safe long COVID-19 rehabilitation recommends patient-centred, customised, and safer approaches. There is a research gap on the effectiveness of telerehabilitation versus institution-based Adapted Physical Activity and Therapeutic Exercise Program (APTE) on long COVID-19 patients with chronic fatigue syndrome (CFS). Methods: We planned a three-arm prospective randomised control trial on 124 long COVID-19 cases with chronic fatigue syndrome to determine the effectiveness of APTE in institution-based care versus the telerehabilitation approach compared to active control. Participants will be recruited from a population based on the inception cohort and assigned to three groups with the concealed location process with an enrollment ratio of 1:1:1. Between May and July 2023, Participants will be assessed by blinded assessors and during the baseline evolution posttest. After two months and follow-up after six months post-intervention, the Chalder Fatigue Scale will measure primary outcome fatigue. SF-36 and the DALYs will measure the secondary outcome of physical functioning and episodic disability. Discussion: Previous studies suggest that adapted physical activity effectively manages fatigue symptoms in CFS cases in 12 sessions. In Long COVID-19, chronic fatigue syndrome is a prominent symptom that causes episodic disability and impacts a person's physical functioning, activities, and participation. To manage patients with long COVID-19, Telerehabilitation is a widely accepted process. This study will fill the research gap to determine the appropriate approach to APTE compared to active control. The future direction of the study will guide the determination of interventions in long COVID-19 rehabilitation. Trial registration: The trial is registered prospectively from a primary Clinical Trial Registry side of WHO CTRI/2023/03/050808 [Registered on: 17/03/2023] Keywords: Long COVID, Chronic Fatigue Syndrome, Adapted physical activity and Therapeutic exercise program, Telerehabilitation
... This strategy has previously been used in patients with similar symptoms to PCC-POTS, for example in populations with myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Pacing and slow progression have successfully been applied to reduce negative effects, post-exertional malaise (PEM), and worsening of symptoms within these populations [53][54][55] . For the participants in this study, a slower progression and/or lower intensity might have reduced the described negative effects further, warranting a longer period of intervention in future randomized controlled trials 56 . ...
... The potential for recruitment and completion of exercise training may be considered as very good, which is promising for proceeding to a full-scale randomized controlled trial (RCT) 20,21,54,69,70 . The feasibility study did not evaluate the willingness to randomization-thus there is a lack of knowledge regarding the likelihood of succeeding with enrollment to an RCT. ...
Article
Full-text available
Postural orthostatic tachycardia syndrome (POTS) occurs in approximately 30% of people with highly symptomatic post-COVID-19 condition (PCC). It involves several symptoms that limit physical and psychological functions and cause reduced quality of life. Evidence for different treatments of POTS and PCC is limited, and this study aimed to evaluate the feasibility of individually tailored physical exercise. The secondary aim of the study was to evaluate the preliminary effectiveness of this intervention. Twenty-six participants (81% female, median age 41 years) were enrolled and performed individually tailored endurance and strength training, with progression, for twelve weeks. During the intervention period, the participants had weekly support from a physiotherapist. Feasibility was evaluated with good compliance, with 76% adherence to exercise prescription and 96% completing the study protocol. The treatment was safe, and the evaluation methods (questionnaires, physical assessments, and accelerometer monitoring) were judged to be feasible. After the intervention, improvements in symptom burden as well as in psychological and physical functions were observed. In conclusion, future randomized controlled trials can be performed with only minor adjustments and could include questionnaires, physical assessment and accelerometer monitoring, which were demonstrated as feasible by this study.
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The long noncoding RNAs (lncRNAs) comprise a wide range of RNA species whose length exceeds 200 nucleotides, which regulate the expression of genes and cellular functions in a wide range of organisms. Several diseases, including malignancy, have been associated with lncRNA dysregulation. Due to their functions in cancer development and progression, lncRNAs have emerged as promising biomarkers and therapeutic targets in cancer diagnosis and treatment. Several studies have investigated the anti-cancer properties of lncRNAs; however, only a few lncRNAs have been found to exhibit tumor suppressor pro- perties. Furthermore, their length and poor stability make them difficult to synthesize. Thus, to overcome the instability of lncRNAs, poor specificity, and their off-target effects, researchers have constructed nanocarriers that encapsulate lncRNAs. Recently, translational medicine research has focused on deliver- ing lncRNAs into tumor cells, including cancer cells, through nano-drug delivery systems in vivo. The developed nanocarriers can protect, target, and release lncRNAs under controlled conditions without appreciable adverse effects. To deliver lncRNAs to cancer cells, various nanocarriers, such as exosomes, microbubbles, polymer nanoparticles, 1,2-dioleyl-3-trimethylammoniumpropane chloride nanocarriers, and virus-like particles, have been successfully developed. Despite this, every nanocarrier has its own advantages and disadvantages when it comes to delivering nucleic acids effectively and safely. This article examines the current status of nanocarriers for lncRNA delivery in cancer therapy, focusing on their potential to enhance cancer treatment.
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Hepatocellular carcinoma (HCC) is the third leading cause of cancer‐related death worldwide. Functionally uncharacterized genes are an attractive repository to explore candidate oncogenes. It is demonstrated that C21orf58 displays an oncogenic role in promoting cell growth, tumorigenesis and sorafenib resistance of HCC cells by abnormal activation of STAT3 signaling. Mechanistically, a novel manner to regulate STAT3 signaling that adaptor C21orf58 forms a ternary complex is reveal with N‐terminal domain of STAT3 and SH2 domain of JAK2, by which C21orf58 overactivates wild‐type STAT3 by facilitating its phosphorylation mediated by JAK2, and hyper‐activates of constitutively mutated STAT3 due to preferred binding with C21orf58 and JAK2. Moreover, it is validated that inhibition of C21orf58 with drug alminoprofen, selected by virtual screening, could effectively repress the viability and tumorigenesis of HCC cells. Therefore, it is identified that C21orf58 functions as an oncogenic adaptor, reveal a novel regulatory mechanism of JAK2/STAT3 signaling, explain the cause of abnormal activity of activated mutants of STAT3, and explore the attractive therapeutic potential by targeting C21orf58 in HCC.
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Background: Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by persistent and disabling fatigue, exercise intolerance, cognitive difficulty, and musculoskeletal/joint pain. Post–exertional malaise is a worsening of these symptoms after a physical or mental exertion and is considered a central feature of the illness. Scant observations in the available literature provide qualitative assessments of post–exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. To enhance our understanding, a series of outpatient focus groups were convened. Methods: Nine focus groups totaling 43 patients who reported being diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome were held between November 2016 and August 2019. Focus groups queried post–exertional malaise in daily life and participants' retrospective memory of post–exertional malaise that followed an exercise provocation with a cardiopulmonary exercise test. Data analysis followed the grounded theory method to systematically code and categorize the data to find meaningful patterns. A qualitative software package was used to move text into categories during data coding. Results: A wide range of symptoms were attributed to exertion both in daily lives and following cardiopulmonary exercise testing. While three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints), participants' descriptions were notable for their unique individual variations. Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test. Patients described post–exertional malaise as interfering with their ability to lead a “normal” life. Conclusion: The experience of post–exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome varies greatly between individuals and leads to a diminished quality of life. myalgic encephalomyelitis/chronic fatigue syndrome patients describe post–exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Given the extensive variability in patients, further research identifying subtypes of post–exertional malaise could lead to better targeted therapeutic options.
Article
Full-text available
Background: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. Method: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. Results: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. Conclusion: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.
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Introduction: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe and disabling chronic disease. Grading patient's symptom and disease severity for comparison and therapeutic decision-making is necessary. Clinical grading that depends on patient self-report is subject to inter-individual variability. Having more objective measures to grade and confirm clinical grading would be desirable. Therefore, the aim of this study was to validate the clinical severity grading that has been proposed by the authors of the ME International Consensus Criteria (ICC) using more standardized measures like questionnaires, and objective measures such as physical activity tracking and cardiopulmonary exercise testing. Methods and results: The clinical database of a subspecialty ME/CFS clinic was searched for patients who had completed the SF 36 questionnaire, worn a SensewearTM armband for five days, and undergone a cardiopulmonary exercise test. Only patients who completed all three investigations within 3 months from each other-to improve the likelihood of stable disease-were included in the analysis. Two-hundred-eighty-nine patients were analyzed: 121 were graded as mild, 98 as moderate and 70 as having severe disease. The mean (SD) physical activity subscale of the SF-36 was 70 (11) for mild, 43 (8) for moderate and 15 (10) for severe ME/CFS patients. The mean (SD) number of steps per day was 8235 (1004) for mild, 5195 (1231) for moderate and 2031 (824) for severe disease. The mean (SD) percent predicted oxygen consumption at the ventilatory threshold was 47 (11)% for mild, 38 (7)% for moderate and 30 (7)% for severe disease. The percent peak oxygen consumption was 90 (14)% for mild, 64 (8)% for moderate and 48 (9)% for severe disease. All comparisons were p < 0.0001. Conclusion: This study confirms the validity of the ICC severity grading. Grading assigned by clinicians on the basis of patient self-report created groups that differed significantly on measures of activity using the SF-36 physical function subscale and objective measures of steps per day and exercise capacity. There was variability in function within severity grading groups, so grading based on self-report can be strengthened by the use of these supplementary measures.
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Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with unknown causes. From the perspectives on the etiology and pathophysiology, ME/CFS has been labeled differently, which influenced changes in case definitions and terminologies. This review sought to feature aspects of the history, developments, and differential symptoms in the case definitions. Methods: A search was conducted through PubMed published to February 2020 using the following search keywords: case definition AND chronic fatigue syndrome [MeSH Terms]. All reference lists of the included studies were checked. Of the included studies, the number of citations and the visibility in the literatures of the definitions were considered for comparisons of the criteria. Results: Since the first 'ME' case definition was developed in 1986, 25 case definitions/diagnostic criteria were created based on three conceptual factors (etiology, pathophysiology, and exclusionary disorders). These factors can be categorized into four categories (ME, ME/CFS, CFS, and SEID) and broadly characterized according to primary disorder (ME-viral, CFS-unknown, ME/CFS-inflammatory, SEID-multisystemic), compulsory symptoms (ME and ME/CFS-neuroinflammatory, CFS and SEID-fatigue and/or malaise), and required conditions (ME-infective agent, ME/CFS, CFS, SEID-symptoms associated with fatigue, e.g., duration of illness). ME and ME/CFS widely cover all symptom categories, while CFS mainly covers neurologic and neurocognitive symptoms. Fatigue, cognitive impairment, PEM, sleep disorder, and orthostatic intolerance were the overlapping symptoms of the 4 categories, which were included as SEID criteria. Conclusions: This study comprehensively described the journey of the development of case definitions and compared the symptom criteria. This review provides broader insights and explanations to understand the complexity of ME/CFS for clinicians and researchers.
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Background: Post-exertional malaise (PEM) is an exacerbation of symptoms that leads to a reduction in functionality. Recognition of PEM is important for the diagnosis and treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Objective: Symptoms following cardiopulmonary exercise testing were compared between ME/CFS patients and healthy controls. Methods: Open-ended questionnaires were provided to subjects following two maximal exercise tests, 24 hours apart. Subjects evaluated how they felt at five time points. Responses were classified into 19 symptom categories. Results: ME/CFS subjects (n = 49) reported an average of 14±7 symptoms compared to 4±3 by controls (n = 10). During the seven days afterwards, ME/CFS subjects reported 4±3 symptoms. None were reported by controls. Fatigue, cognitive dysfunction, and sleep problems were reported with the greatest frequency. ME/CFS patients reported more symptom categories at higher frequencies than controls. The largest differences were observed in cognitive dysfunction, decrease in function, and positive feelings. Conclusions: A standardized exertional stimulus produced prolonged, diverse symptoms in ME/CFS subjects. This provides clues to the underlying pathophysiology of ME/CFS, leading to improved diagnosis and treatment.
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Background: Cochrane recently amended its exercise review for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) in response to an official complaint. Objective: To determine if the amended review has addressed the concerns raised about the previous review and if exercise is an effective treatment that restores the ability to work in ME/CFS. Method: The authors reviewed the amended Cochrane exercise review and the eight trials in it by paying particular interest to the objective outcomes. We also summarised the recently published review of work rehabilitation and medical retirement for ME/CFS. Results: The Cochrane review concluded that graded exercise therapy (GET) improves fatigue at the end of treatment compared to no-treatment. However, the review did not consider the unreliability of subjective outcomes in non-blinded trials, the objective outcomes which showed that GET is not effective, or the serious flaws of the studies included in the review. These flaws included badly matched control groups, relying on an unreliable fatigue instrument as primary outcome, outcome switching, p-hacking, ignoring evidence of harms, etc. The review did also not take into account that GET does not restore the ability to work. Conclusion: GET not only fails to objectively improve function significantly or to restore the ability to work, but it's also detrimental to the health of≥50% of patients, according to a multitude of patient surveys. Consequently, it should not be recommended.
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Purpose The EU COST Action 15111 collaboration on myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) aims to assess current research and identify knowledge gaps in Europe. Presently, our purpose is to map the effects of non-pharmacological therapies (NPTs) for ME/CFS, and what patients find important in the treatment process. Methods A scoping mixed methods literature review of European studies identified 16 papers fulfiling our inclusion criteria. The quantitative and qualitative studies were synthesized separately in tables. Additionally, extracts from the qualitative studies were subjected to translational analysis. Results Effect studies addressed cognitive behavioural therapy (CBT, n = 4), multimodal rehabilitation (n = 2) and activity-pacing (n = 2). CBT reduced fatigue scores more than usual care or waiting list controls. The effects of rehabilitation and activity-pacing were inconsistent. The contents, assessment methods and effects of rehabilitation and activity pacing studies varied. For patients, health professionals’ recognition of ME/CFS and support were crucial, but they expressed ambiguous experiences of what the NPTs entail. Conclusions Methodological differences make comparisons across NPTs impossible, and from a patient perspective the relevance of the specific contents of NPTs are unclear. Future well-designed studies should focus on developing NPTs tailored to patients’ concerns and evaluation tools reflecting what is essential for patients.
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Chronic fatigue syndrome/myalgic encephalomyelitis (CFS) is a complex, multisystem disease that is characterized by long-term fatigue, exhaustion, disabilities, pain, neurocognitive impairments, gastrointestinal symptoms, and post-exertional malaise, as well as lowered occupational, educational, and social functions. The clinical and biomarker diagnosis of this disorder is hampered by the lack of validated diagnostic criteria and laboratory tests with adequate figures of merit, although there are now many disease biomarkers indicating the pathophysiology of CFS. Here, we review multiple factors, such as immunological and environmental factors, which are associated with CFS and evaluate current concepts on the involvement of immune and environmental factors in the pathophysiology of CFS. The most frequently reported immune dysregulations in CFS are modifications in immunoglobulin contents, changes in B and T cell phenotypes and cytokine profiles, and decreased cytotoxicity of natural killer cells. Some of these immune aberrations display a moderate diagnostic performance to externally validate the clinical diagnosis of CFS, including the expression of activation markers and protein kinase R (PKR) activity. Associated with the immune aberrations are activated nitro-oxidative pathways, which may explain the key symptoms of CFS. This review shows that viral and bacterial infections, as well as nutritional deficiencies, may further aggravate the immune-oxidative pathophysiology of CFS. Targeted treatments with antioxidants and lipid replacement treatments may have some clinical efficacy in CFS. We conclude that complex interactions between immune and nitro-oxidative pathways, infectious agents, environmental factors, and nutritional deficiencies play a role in the pathophysiology of CFS.
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Background: Although medical requirements are urgent, no effective intervention has been proven for chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). To facilitate the development of new therapeutics, we systematically reviewed the randomized controlled trials (RCTs) for CFS/ME to date. Methods: RCTs targeting CFS/ME were surveyed using two electronic databases, PubMed and the Cochrane library, through April 2019. We included only RCTs that targeted fatigue-related symptoms, and we analyzed the data in terms of the characteristics of the participants, case definitions, primary measurements, and interventions with overall outcomes. Results: Among 513 potentially relevant articles, 55 RCTs met our inclusion criteria; these included 25 RCTs of 22 different pharmacological interventions, 28 RCTs of 18 non-pharmacological interventions and 2 RCTs of combined interventions. These studies accounted for a total of 6316 participants (1568 males and 4748 females, 5859 adults and 457 adolescents). CDC 1994 (Fukuda) criteria were mostly used for case definitions (42 RCTs, 76.4%), and the primary measurement tools included the Checklist Individual Strength (CIS, 36.4%) and the 36-item Short Form health survey (SF-36, 30.9%). Eight interventions showed statistical significance: 3 pharmacological (Staphypan Berna, Poly(I):poly(C12U) and CoQ10 + NADH) and 5 non-pharmacological therapies (cognitive-behavior-therapy-related treatments, graded-exercise-related therapies, rehabilitation, acupuncture and abdominal tuina). However, there was no definitely effective intervention with coherence and reproducibility. Conclusions: This systematic review integrates the comprehensive features of previous RCTs for CFS/ME and reflects on their limitations and perspectives in the process of developing new interventions.
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