BMJ editorial: GET and CBT advised for ME

[alex3619]

This makes bold assertions made repeatedly that are counterfactual, and assumptions that have never been justified.

No evidence of immune issues? Counterfactual. One of the implications here is that CFS is a unitary disorder, a syndrome with one cause.

No evidence of aerobic or metabolic failure? This is now a signature finding - poor aerobic metabolism, though the exact cause/s are still being figured out.

There is no credible evidence that PACE produces substantive physical improvement unless its for a very rare individual ... which is hard to determine as the full data is not disclosed.

This reads like a propaganda piece, not a scientific piece.

This is particularly relevant and does not show in the opening statement of this thread:

Provenance and peer review: Commissioned; not externally peer reviewed.

 

[A.B.]

I suppose this should be interpreted as desperate attempt to save a line of a research that is looking more and more obsolete, especially with the IOM report and various other developments.

 

[Jonathan Edwards]

This is not science but religion. Loyd and vd Meer are extremists in proclaiming CBT and GET. This stems from the fact that these professors have sought their lives for an explanation for this disease. Their vanity reveals their stupidity on the day there is a real breakthrough. At that point everybody can read there sloppy science and they will revealed as clowns.

I had not twigged but I remember now that van der Meer was the clown who panned the Norwegian work and thereby revealed his complete ignorance of how rituximab works in autoimmunity - in fact the reason why I am posting here. Charles Shepherd asked me to comment and I responded on the PlosOne comment board - and so got asked to come to IiME by Oystein Fluge.

 

[Sasha]

I had not twigged but I remember now that van der Meer was the clown who panned the Norwegian work and thereby revealed his complete ignorance of how rituximab works in autoimmunity - in fact the reason why I am posting here. Charles Shepherd asked me to comment and I responded on the PlosOne comment board - and so got asked to come to IiME by Oystein Fluge.

So we owe him a big vote of thanks, actually!

 

[anciendaze]

Here we may have a tiny break in the stonewall by researchers who were presumably not denied access to data. If the results showed "recovery" of only 1/4, and these people see the definition of recovery as "unduly liberal" then some other statements by PACE researchers were highly misleading, at the most generous interpretation.

We also need to ask why other evidence of improved physical performance, increased employment and reduced demand for benefits did not materialize. The CBT group showed absolutely no improvement in the only objective measure of physical performance, and the change in the GET group was not clinically significant, (unless perhaps researchers were able to show that these patients were previously less than 39 meters short of being able to reach their mailboxes to pick up disability checks.) A second "step test" of physical performance showed no statistically significant improvement in physical performance at all -- even in the GET group.

The original intake of 3158 possible "CFS" patients was whittled down to fewer than 900, only 640 of which completed the study. These were divided among four different arms of the study, meaning no more than 160 could have participated in any particular therapy. When it came to objective measures, 1/3 simply declined to take the six-minute walk test both before and after a year of therapy. This did not affect their status as subjects of the study! (Do objective measures have any place in this disease? This failure would reduce Cohen's d parameter to the point there was no significance to the initial, highly-touted results. This supports the later failure to validate.) We are now down to about 100 patients who could have had measured recovery. If only 1/4 of these did recover -- by some rather dodgy interpretation that non-believers are not allowed to check -- we discover that recommendations for treatment of all 3158 shunted into this category by NHS physicians were actually based on no more than 25 patients who might have actually shown improvements in performance which later tests failed to validate. This is under 1% of the original intake. (Ever hear of "cherry picking"?)

Now do you understand why there have been recent efforts to use anecdotal reports of recovery?

Some of these same authors have previously stated that rates of misdiagnoses of CFS by NHS doctors run around 30%. Nowhere in their publications have we seen awareness of possible misdiagnosis by PACE authors. Could the entire set of "responders" be the result of misdiagnosis? I don't know any psychiatric disorder for which rates of misdiagnosis are below 1%. Even if I make the generous assumption that those who would have responded, had they been given the same therapy constituted similar percentages of all groups, this would amount to less than 3% of that initial intake. This is completely consistent with the hypothesis that positive results were entirely the result of misdiagnosis, plus known rates of misdiagnosis in other conditions.

One other possibility has not been mentioned: that PACE demonstrated that the proposed therapies were inappropriate for 97% of those patients diagnosed as CFS patients by ordinary NHS doctors.

 

[alex3619]

One other possibility has not been mentioned: that PACE demonstrated that the proposed therapies were inappropriate for 97% of those patients diagnosed as CFS patients by ordinary NHS doctors.

I think this has been implied in a lot of commentary on PACE. What is unclear is what percentages are really justifiable. Without full release of results then there is always going to be a great deal of uncertainty on the fine details. However the broad picture is starkly obvious. PACE was a failure.

 

[Forbin]

These guys need to get subscriptions to:

The Journal of Pain: Official Journal of the American Pain Society,
Physical Therapy: The Journal of the American Academy of Physical Therapy,
The Journal of Translational Medicine,
and Science Advances

Moderate Exercise Increases Expression For Sensory, Adrenergic And Immune Genes In Chronic Fatigue Syndrome Patients, But Not In Normal Subjects
http://www.jpain.org/article/S1526-5900(09)00574-4/fulltext

Discriminative Validity Of Metabolic And Workload Measurements For Identifying People With Chronic Fatigue Syndrome.
http://ptjournal.apta.org/content/93/11/1484.long

Inability Of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Patients To Reproduce VO2peak Indicates Functional Impairment
http://www.translational-medicine.com/content/12/1/104

Distinct Plasma Immune Signatures In ME/CFS Are Present Early In The Course Of Illness
http://advances.sciencemag.org/content/1/1/e1400121

 

[anciendaze]

I think this has been implied in a lot of commentary on PACE. What is unclear is what percentages are really justifiable. Without full release of results then there is always going to be a great deal of uncertainty on the fine details. However the broad picture is starkly obvious. PACE was a failure.

Let's look at the objective data nobody questions: PACE authors obtained 5 million pounds to run study, and spent all of this. They have used publications derived from this to advance their own agenda. How can you call that a failure?

On the subject of measures of significance, where it is easy to become confused, I wish to illustrate the effect of having patients decline to participate in a test with a simplified model.

Suppose at the time of the first test some patients are having good days and some bad ones. There will be no effect from therapy because they have not experienced it. Now, a year later, consider the effect after therapy. We assume some feel better, and some worse. If all those who feel better take the test, and all those who feel worse decline, you will get an apparent boost in results without any improvement in group mean. Therapy has merely increased stratification. Because the 1/3 who decline outnumber the 1/4 who appear to benefit there is plenty of room in the numbers for this to take place.

If you then run a different test -- which all patients must complete -- the apparent improvement will disappear. This is exactly what the drips of information we are allowed to see seem to show.

 

[Hutan]

The other author of that paper is Professor Andrew Lloyd. He led the Dubbo study (around 2006) - the idea was great; get a number of doctor's surgeries to track all the cases of people presenting with Q fever, Ross River fever and glandular fever and find out who stays sick. And they found that lots of people do stay sick for a long time – it was important, compelling evidence for post-infective fatigue/CFS.


So I was disappointed and puzzled to see him associated with this uninformed paper. As some of you have pointed out, the BMJ paper is actually somewhat nuanced. It isn't saying that everyone with ME/CFS is a mood-disordered hypochondriac. But most readers will take that message away.


I wanted to understand what was going on with Professor Lloyd so I found a recent presentation of Professor Andrew Lloyd’s – 23 April 2014 on YouTube.

It’s long but quite entertaining in places – he had a tough crowd of people with ME/CFS.


Regarding the mood disorders – he is quite clear that the illness comes first. He rejected opportunities to blame past traumas (eg childhood abuse) as a cause of the illness. He says that mood disorders (anxiety, depression) are either caused by the illness directly and/or a result of living with a chronic poorly understood illness, in particular an illness that hits you every time you push a little with physical or cognitive effort. And he’s probably right in that.


That said, he does suggest that people who don’t do well in his fatigue clinic (which does CBT/GET/correction of sleep and mood problems) often have a mood problem (presumably they are too cantankerous or unmotivated ).


My sense is that Prof Lloyd started out enthusiastic, without judgement of people with post-infective fatigue and keen to find the answer to the problem. Then, years of doing experiments and finding nothing has ground him down. He has watched lots of possible theories on cause and treatment be proven wrong and he has grown very sceptical. He probably burned his professional reputation a bit by being associated with CFS and has been criticised by those grumpy frustrated people with CFS too.


He seems to have decided that, for post-infective fatigue, all the problems are a result of the brain getting stuck in the ‘acute sickness response’ (sickness behaviour) mode. And I think he has lost interest and isn’t keeping up with recent advances. In the video, he isn't aware of recent research advances.


So, what compelled him to be a co-author of this paper, I still have no idea.


Regarding his fatigue clinic, Prof Lloyd reported that around 30% of the patients attending improved as a result of the ‘intervention’. He said that he thought that about 70% of the participants have CFS. The clinic relies on the diagnosis made by GPs (primary care physicians) and they don’t do any checking of that. He wasn’t worried that patients with say depression alone were turning up at the clinic as he felt that the clinic could help them too.


He noted that many CFS patients get better without treatment early in the course of the illness – his Dubbo study showed that. He said that the average number of years of illness of the patients attending the clinic is 5.5 years, so he felt that they were getting the patients with more resistant illness (although that average allows for a significant proportion of people who have had the illness for less than 5.5 years).


It was very interesting to hear from the fatigue clinic clinician about what is actually done in the clinic. The GET sounded much more like gentle pacing. The clinician actually mentioned that they often have to get people to initially do less activity rather than more. The two patients touted as success stories appeared to have had quite mild CFS cases when they started the intervention and are still sick now. What they reported was gaining an understanding of their own illness and how to live better within the energy constraints imposed by the illness.


The fatigue clinic clinician was very sweet and empathetic. It would be a very irritable patient indeed who would report, in the 12-week questionnaire, that all her effort for the patient had achieved nothing at all. There doesn’t seem to be any long-term follow-up. There hasn't been any rigorous analysis of the outcomes of his fatigue clinic.


Looking at Prof Lloyd's website at the University of New South Wales now, there is no mention at all of Chronic Fatigue Syndrome apart from in the list of past publications. ‘Post-infective fatigue states’ appears way down the bottom of the list of research interests. Prof Lloyd is currently running a Hepatitis C trial in a prison.

 

[Valentijn]

Their vanity reveals their stupidity on the day there is a real breakthrough. At that point everybody can read there sloppy science and they will revealed as clowns.

I think that day came some time ago. It's downright embarrassing that they are still ignoring repeatedly replicated evidence of undeniable pathology and are instead clinging to their belief in an indepedently disproven model.

The 2-day CPET VO2max measurements reliably produce strikingly abnormal results not seen in physically healthy or deconditioned/sedentary controls. And the paper by Wiborg & Co resulted in the CBT/GET researchers themselves proving that the subjective improvement in physical functioning determined by questionnaires are directly contradicted by objective actometer data in three separate studies.

At this point I can only assume that they are either deliberately lying about the available evidence, or that they are so delusional or negligent in assessing the research that they honestly believe what they are saying. In either case, I can't see how they could be considered to be fit to research, publish, practice medicine/psychology, or teach. They bring disrepute to their professions and their institutions.

 

[Cheshire]

That's what Pr Lloyd says about the 2-day CPET VO2max study. (See video that @Hutan posted)

40:25

This is described in a study where people are being encouraged in a laboratory sort of setting to do some kind of exercise like cycling or trade mill and to keep going until they really [??] and to measure how much oxygen they are consuming. That’s a measure of how metabolism in the muscles is going.

There’s a problem with studies like that, especially when they are repeated the next day and that is that it’s very hard to control some… Hum… Two issues. One is what we call volition. That is how hard you try. And the other is that there are some reflex pathways. If you have pain in your muscles, or pain in your body, it doesn’t matter how hard you try, it will impair your exercise performance. And so those two things are just impossible to control in aerobic exercises.

Twenty years ago, during my PhD, we resolved not to do exercise studies like that, because they are uninformative. And so we chose instead to do a more controlled narrow form of exercise. We just do asymmetric exercise, just like using one muscle group. We can drive the muscle voluntarily, you can drive it with electric stimuli over the [brachial?] plexus. Or you can actually drive it from a magnet on the brain. And we showed that on day one and day two, absolutely OK… Absolutely no deficit whatsoever in the muscles in the couch potatoes versus the patients

From what I understood, the measurments are made when someone reaches his anaerobic threshold, and volition can't interfere. But I'm not at all an expert! Far from that...

I'd be glad to hear your comments because that seems to be the common argument used by those who dismiss the 2-day CPET VO2max studies, and I'd be happy to understand if there is any solid ground in this rejection of these studies.

I'm not sure of two words, I put them in [ ].

 

[Hutan]

And there has been a very recent study done where some muscle cells in a test tube were stimulated on two consecutive days - and the muscle cells from the CFS patients were found to be fatigued in a way that the cells from healthy people were not. So, the researchers concluded that there is something going on in the muscle cells themselves without the involvement of the brain. That study, if correct, really puts the volition and deconditioning arguments to bed.

I haven't explained that very well, but no doubt others can.

I don't know why Prof Lloyd's study with the electrical stimulation didn't find a difference but that lack of a difference seems to have been important in the development of his view of the illness, and no doubt others' views too.

 

[Sidereal]

Twenty years ago, during my PhD, we resolved not to do exercise studies like that, because they are uninformative. And so we chose instead to do a more controlled narrow form of exercise. We just do asymmetric exercise, just like using one muscle group. We can drive the muscle voluntarily, you can drive it with electric stimuli over the [brachial?] plexus. Or you can actually drive it from a magnet on the brain. And we showed that on day one and day two, absolutely OK… Absolutely no deficit whatsoever in the muscles in the couch potatoes versus the patients

I think he is referring to this study of his:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1032921/

ME/CFS is not a neuromuscular disease, you're not going to get anywhere using that approach. I think the problem with this methodology (which was popular in the late 1980s / early 1990s to "prove" that there no metabolic problem in the PVFS muscle) is that exercising one small muscle group is probably not enough to trigger systemic metabolic, autonomic and immunological PEM problems in the mild ambulatory patients that he sees. I suspect he would have obtained very different results in bedridden patients.

 

[Hutan]

Here is the muscles cells in vitro study:

Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome

By A.E. Brown et al.
www.ProHealth.com
April 17, 2015

By A.E. Brown et al.

Abstract

Background: Post exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.

Methods: Skeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.

Results: In the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.

Conclusion: EPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.​

 

[Valentijn]

From what I understood, the measurments are made when someone reaches his anaerobic threshold, and volition can't interfere. But I'm not at all an expert! Far from that...

There are objective indicators of maximal effort built into the CPET. One of those is the Respiratory Quotient (or Respiratory Exchange Rate), which is the ratio of CO2 exhaled to O2 inhaled. This cannot be controlled or faked by the patient. If the RQ gets to 1.1 or higher, the patient has exerted maximal effort, and accusations of slacking off are completely absurd at that point.

He's sounding like a politician trying to score points for his agenda, and is grossly failing to understand or honestly explain the science.

 

[Gijs]

Loyd and van der Meer have both a terrible syndrome. It is called Blaming The Victim Syndrome (BTVS) and The God Complex (TGC). They are sloppy scientists and biased. They ignore many objective studies. Do they really think CBT/GET can make ME patiënts better? Yes, they do but only if the patiënts want to. You can call this gaslighting.

 

[PhoenixDown]

PACE authors obtained 5 million pounds to run study, and spent all of this.

The 5 million was for the FINE trial too. What makes me angry is that thanks to research like this, my GP says GET is the best evidence based treatment for ME.

 

[Gijs]

The 5 million was for the FINE trial too. What makes me angry is that thanks to research like this, my GP says GET is the best evidence based treatment for ME.

If you give me 5 million i take some scientist and prove once and for all CBT and GET doesn't work and is statistical fraud. It isn't evidence based without objective measurements. It Is pseudoscience and fraud.

 

[Mark]

I had not twigged but I remember now that van der Meer was the clown who panned the Norwegian work and thereby revealed his complete ignorance of how rituximab works in autoimmunity - in fact the reason why I am posting here. Charles Shepherd asked me to comment and I responded on the PlosOne comment board - and so got asked to come to IiME by Oystein Fluge.

Thanks for confirming my suspicions on that Jonathan, I said just the other day that was how I thought it had gone down. I thought when I saw your reply to van der Meer, and I'm even more convinced today, that this was a major turning point in ME/CFS history. We owe van der Meer a huge debt of gratitude!

 

[chipmunk1]

Loyd and van der Meer have both a terrible syndrome. It is called Blaming The Victim Syndrome (BTVS) and The God Complex (TGC). They are sloppy scientists and biased..

They aren't real scientists. Unfortunately I can't post what they are because that would be too offensive.