Analysis of five hallmark studies from the Netherlands, 2018, Twisk and Corsius

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FrankTwisk

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An in-depth analysis of five hallmark studies of
the Dutch Expertise Center for Chronic Fatigue (NKCV) confirms that
cognitive behavorial therapy combined with a graded activity protocol (CBT+)
has no objective positive effect on the (health) status of
patients diganosed with chronic fatigue syndrome (CFS).

The outcomes of the analysis
confirm the image of the controversial PACE-trial:
the (far-reaching) conclusions with regard to the proposed positive effects of CBT+
are by no means substantiated by the data published by the researchers.

A recent study of principal PACE trial investigators confirms
that ‘graded activity’ has a negative effect on a subgroup of CFS patients.

In spite of claims to the contrary
the effect of CBT+ on patients diagnosed with Myalgic Encephalomyelitis (ME),
a neuromuscular disease, has never been analysed.

ARTICLE:

An analysis of Dutch hallmark studies confirms the outcome of the PACE trial:
cognitive behaviour therapy with a graded activity protocol
is not effective for chronic fatigue syndrome and Myalgic Encephalomyelitis.
Gen Med Open. 2017. 1(3): 1-12.
doi: 10.15761/GMO.1000117.
Twisk FNM, Corsius LAMM.

Abstract

Myalgic Encephalomyelitis (ME) and Chronic Fatigue Syndrome (CFS)
are considered to be enigmatic diseases.

Several studies propose that
the combination of cognitive behaviour therapy with a graded activity protocol (CBT+),
justified by a so-called (bio)psychosocial (explanatory) model,
is an effective treatment option for CFS (ME).


Objective

A critical review of five Dutch hallmark studies
that allegedly support this claim.


Methods

An analysis of the five CBT+ studies with special attention to
the patients studied,
the criteria (subjective and objective measures and cut-off scores)
used to select participants and
to define improvement and recovery,
the consistency of the definitions of caseness
(being diagnosed as a CFS patient at entry)
versus the definitions of improvement and recovery after CBT+, and
the objective effects.


Results

The studies investigated suffer from various methodological flaws.

Apart from these methodological shortcomings,
the claim that CBT+ is an effective treatment option for CFS
is not substantiated by the data reported.

Some studies investigated CFS patients,
other studies investigated CF patients, labelled as CFS patients, or
combinations of CFS and CF patients.

No study investigated the effect of CBT+
in a group of patients meeting the (original) diagnostic criteria for ME.

The effects of CBT+ on subjective measures,
for example fatigue and disability,
if present, are insufficient to achieve normal values.

Impressive recovery and improvement rates
are based on very loose criteria for subjective measures.

Cut-off scores for subjective measures
used to define improvement and recovery in studies
show overlap with cut-off scores for CFS caseness
in one or more of the other studies.

More importantly, looking at the objective measures,
the proof of clinical improvement after CBT+ is lacking.


Conclusion

Solid evidence of effectiveness of CBT+ for CFS, let alone ME,
is lacking in the five hallmark studies.

The lack of objective improvement indicates CBT+ is ineffective.

This conclusion confirms
the outcome of the large-scale PACE-trial in the UK.


Keywords:

Myalgic Encephalomyelitis, chronic fatigue syndrome, cognitive behaviour therapy, graded exercise therapy, measures, effectiveness



http://www.oatext.com/pdf/GMO-1-117.pdf

http://www.hetalternatief.org/Summary NKCV GMO 2018.pdf
 
Good to see the Knoop et al., 2007 full recovery paper being criticised.
Knoop et al., 2007

Knoop et al., 2007 [35] reported impressive recovery rates for CFS by CBT+: “After treatment, 69% of the patients no longer met the CDC criteria for CFS.”. But as the authors also acknowledge:” The percentage of recovered patients depended on the criteria used for recovery.“. According to Knoop et al., 2007 [35] 23% of the CFS patients fully recovered using “the most comprehensive definition of recovery”. First of all, looking at the co-morbidities reported, one could question the correct application of the diagnostic criteria for CFS [4] to select patients in this study [35]. The diagnosis CFS [4] is only applicable when the patient doesn’t experience medical and psychological comorbidities which can adequately explain “fatigue”. The criteria for ‘recovery from CFS (CDC)’ are very easily met, e.g. an improvement from 35 to 34 for CIS F (range 8-46) combined with an improvement from 700 to 699 for SIP 8 (range 0-5.799) are sufficient to be qualified as being ‘recovered from CFS’ (CIS F <35 and SIP8 <700) in this study. However, these scores are by far insufficient to achieve the ‘normal levels’ as defined by the same study (CIS F ≤27 and SIP8 ≤203). This is illustrated by the observation that the positive effect of CBT+ on the mean SIP 8 score is by far insufficient to reach ‘normal levels’ defined in this study (≤203). Not surprisingly, the criteria employed to define recovery largely determine the ‘recovery rates’. Using ‘more strict’ criteria for recovery (CIS F ≤27, SIP8 ≤203, SF-36 SF-36 PF ≥80, SF-36 Social Functioning subscore ≥75, SF-36 General Health subscore ≥65, and no factors scoring negative on the Fatigue Quality List), the recovery rate drops to 23%. However, even “the most comprehensive definition of recovery” isn’t based on stringent criteria. Curiously, the SIP 8 score, used as a criterion to select patients (caseness) in this study [35] and other trials [7], isn’t included in these two definitions of recovery. The study doesn’t report how many CFS patients reached ‘normal levels’ (≤203), but considering the size of the effect of CBT+ on SIP 8 in this study and other trials, few patients, if any, would reach ‘normal levels’. An important point of criticism on the ‘normal values’ used in this study and other studies by the research group relates to the method by which these ‘normal values’ are determined. The ‘threshold scores’ are defined as the mean +/- 1 SD of the healthy population. However, as the authors acknowledge the SIP 8 and SF-36 PF are not normally distributed but skewed [35]. The same applies to CIS F [16] and other SF 36 subscales [52,53]. Aaronson et al., 1998 [54], cited in Knoop et al., 2007 [35], showed a large ceiling effect of SF-36 PF: 31.9% of the Dutch population scored at the highest scale level. As Knoop et al. [35] state “Therefore one could argue that recovery according to the SIP8 has to be defined as scoring the same or lower than the 85th percentile of the healthy reference group.” Using percentiles as threshold scores instead of the mean +/- 1 SD for all subjective measures has a non-negligible negative effect on ‘recovery rates’: “[T] he recovery rate using the definition of having no disabilities in all domains [..] would decrease from 26 to 20%.”. Likely due to the use of the mean +/-1 SD algorithm for calculating ‘normal values’ and/or the use of non-presentative reference populations, the ‘normal value’ for SF-36 PF for the ‘young’ CFS patient group (mean age: 37.0 years) comes close to the mean SF-36 PF scores for healthy population of seniors aged 55 to 64 years [55], while the ‘normal values’ for SF-36 Social Functioning score resembles the mean score of older people aged 75 to 84 years [55] and the ‘threshold score’ for the SF-36 General health score is comparable with the mean of a population of 65 to 74 years [55]. If percentiles of representative populations were employed to define ‘normal values’ and the SIP 8 score was included in the “the most comprehensive definition of recovery” the ‘recovery rate’ based on the subjective measures used would drop dramatically.

The impressive recovery rates reported by the Knoop et al., 2007 study [35] aren’t justified by the data, since the study lacked a control group and non-intervention showed to have positive effects on the subjective measures in substantial patient subgroups in other studies [7-31]. Furthermore, the effect of CBT+ on the other symptoms defining CFS [4] aren’t reported. The study lacked objective measures to substantiate ‘recovery’. Finally, the study reported much lower recovery rates for patients with comorbidities, while many CFS patients experience comorbidities [56].
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I believe there is a small error here. It should see a score of 60 or more not 61. They are talking about PACE Trial.
For example, a score of 61 for the SF-36 PF criterion is sufficient to be qualified as ‘recovered’ after CBT+ [61], while this score indicates “severely impairment” in other studies [31,62].
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Issues relating to participants include high rates of self-selection, since “CFS patients are skeptical of psychological interventions” [35], ‘moderate’ and ‘severe cases’ not being able to participate, the use of strongly varying subjective criteria to be eligible to participate, substantial numbers of eligible patients refusing to participate [7], and substantial drop-out rates.
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I don't think this is a strong point with these data. The dropout figures are given in table 1 and similar between the intervention and control groups.
 
Conclusion
[..]
Moreover, there are indications that CBT+ can have detrimental effects.
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I think this is the only outcome measure that could be referred to for this point within these 5 trials:
Bazelmans et al., 2005

[..]

Curiously non-intervention had a positive effect on functional impairment (mean SIP 8 score at baseline 1,710, at 6 months: 1,417), but CBT+ had a small negative effect on the mean SIP 8 score (before: 1,707, after: 1,736). As the authors phrased it: “For functional impairment, the effect was opposite to what was expected”. Looking at the improvement of SIP 8 in the non-intervention group one could argue that CBT+ is impeding the naturally-occurring recovery process.
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There could have been individuals who deteriorated in the trials but I don't believe such data was published. There is some evidence from surveys that some people report being made worse by CBT.
 
Knoop et al., 2007

[..]

Finally, the study reported much lower recovery rates for patients with comorbidities, while many CFS patients experience comorbidities [56].
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The Effect of Medical Co-Morbidity

Twenty-two of the 96 patients (23%) had a medical comorbid condition beside CFS. Fifteen patients had one medical co-morbidity: treated hyperthyroidism, gonadal dysgenesis with normal karyotype, menorrhagia, controlled diabetes mellitus, quiescent ulcerative colitis, nephrotic syndrome, controlled asthma, allergy (2), recurrent sinusitis, epilepsy, migraine, periodic leg movement disorder, multiple traumas, intramedullary haemangioma on medication. Seven patients had two co-morbidities: treated hyperthyroidism and epilepsy, controlled diabetes mellitus and Forestier’s disease, controlled asthma and chronic low back pain (2), allergy and treated sleep apnoea, single transient ischaemic attack and cervical arthrosis, chronic headache and treated high blood pressure.
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Some comorbidities like fibromyalgia are not listed. I imagine some of the patients did have such comorbidities in which case the comorbidity rate is higher than 23%.

Also this use dthe CDC criteria so some of the initial sample probably had comorbidities but were excluded from the research study but in clinical practice might still get the diagnosis of CFS.

So I'm not convinced about this point.
 
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