‘Sick and tired’ of rigid attitudes and flawed science.
Artist: Wolgang Stiller
‘The worst days, many hundreds of them, saw me so ill that I was unable to move my arms and legs, open my eyes or speak. For those hundreds of days, I could do nothing but lie motionless in bed, our house dark and shrouded in silence in order to spare me the agony of light and noise. I felt so terribly ill that even having somebody clean my teeth for me was more than I could bear. Some days my family struggled to tell whether I was conscious or not; it did not seem possible I would survive.
The best days, in more recent years, I have been able to enjoy short outings in my wheelchair, to sit in the garden and feel the sun and fresh air or chat to a friend. Such simple things are so very precious because they are so rare. I cannot count the days when I have been torn apart with grief at seeing life pass me by.’
Naomi is 30. Every day during the last 17 years has been lived under the shadow of ME. Her story is recorded in a powerful iilustrated book called Lost Voices (from a hidden illness), compiled by Natalie Boulton for the charity ‘Invest in ME’.
In the spring of 1955, a strange infectious illness occurred at The Royal Free Hospital in London. It started with a handful of people but then in July of that year, almost 300 members of staff were taken ill (of which 255 had to be hospitalised). As a result, the hospital was forced to close until the early part of October. It was Dr Melvin Ramsay of the hospital’s Infectious Diseases department who coined the term Myalgic Encephalomyelitis, referring to the effects on the muscles, brain and nerves. ‘These included a unique form of muscle fatigue whereby, even after a minor degree of physical effort, three, four or five days or even longer can elapse before full muscle power is restored. Tenderness of the muscle also occurs quite frequently. The extremities are often cold. There is increased sensitivity to climatic change and episodes of copious sweating. Memory and concentration are impaired. There are difficulties in completing a line of thought, mixing up words , sleep disturbance and emotional lability.’ Dr Ramsay also noted that all his patients reported a characteristic variability and fluctuation of symptoms throughout the day an there was a strong possibility that the illness could become chronic and disabling.
Not all cases of ME had the complete range of clinical features or a history of previous infection. So in 1988, the name was changed to Chronic Fatigue Syndrome, though many patients adhere to ME or the hybrid CFS/ME.
There is a marked similarity between CFS/ME and IBS and extensive overlap between the two conditions. About 30% of people with IBS suffer from chronic fatigue and altered bowel habit and abdominal discomfort is common in CFS/ME. Both IBS and CF/ME may be instigated by an infectious illness. Both conditions are controversial and defy a consistent medical explanation, but they show similar changes in immune reactivity and hormonal activity. And, of course, both IBS and CFS/ME can cause severe disability that can last for years, but may recover for no obvious medical reason. One might therefore be forgiven for thinking these are different expressions of the same illness. It has even been suggested that the dyad of IBS/Constipation and IBS/Diarrhoea is analogous and may overlap with the dyad of CFS/ME and Fibromyalgia.
Psychological trauma and stress have been implicated in both conditions. The fact that both commonly start in teenage years might suggest the dramatic life changes and dangers that occur that time might instigate both conditions. But teenage is also a time of travel and greater exposure to novel infections. IBS may be instigated bottom up by infection or broad spectrum antibiotics or top down by trauma (and often both together), resulting in a resetting of immune, endocrine, physiological systems. It is likely that something similar might apply to CFS/ME. Nevertheless the dominant medical treatment for the latter has been cognitive behavioural therapy and graded exercise therapy, in which patients were assigned to a regimen of increasing exercise. The evidence has never been that strong and patients have long objected that these measures are either useless or made them worse.
In the last few years, a team of researchers, led by Professor of Psychiatry, Michael Sharpe from Edinburgh University, have conducted their four way randomised controlled clinical trial, called PACE. The trial, which cost £5 million pounds, compared Cognitive Behavioural Therapy (CBT), Graded Exercise Therapy (GET), Specialist Medical Care (SMC) and Adaptive Pacing Therapy (APT). The results showed that CBT and GET were each successful in 22% of patients, three times as many as in the other limbs. Patients demanded to see the details of the study protocol and the data . When these were eventually revealed under the Freedom of Information Act, a small group of patients and academic statisticians analyzed it and published their findings on Virology Blog. And with that, the PACE trial’s 22 percent recovery rates “went up in smoke,” wrote Julie Rehmeyer, a journalist who is also an ME/CFS patient. In this new independent but hardly unbiased analysis the “recovery” rates fell to single digits, and the results were not statistically significant. There have been demands to the journal and the authors for retraction.
David Tuller, lecturer in public health and journalism at the University of California at Berkeley, published a blistering attack on current treatments for CFS/ME and the PACE trial last week: Worse than the Disease. He not only pointed out that patients knew which treatments they were getting, but also that the researchers biased their results by publishing glowing testimonials in their newsletter while the study was in progress. He also noted discrepancies between the entry criteria and criteria for recovery. He claimed that patients were identified using only fatigue rather than the full diagnostic criteria, raising the possibility that many may have been suffering from depression which is known to respond to CBT. He revealed that the investigators revised their criteria for improvement and recovery after the study began. Finally he detected a conflict of interest, claiming that some of the investigators also worked for disability insurers. Tuller’s comprehensive critique, published just a few days ago has attracted many glowing endorsements, but a deafening silence from the investigators and the medical establishment. We need to hear their rebuttal.
So, it seems from the evidence that Tuller has amassed in his damning indictment, that another study on CFS/ME had generated invalid data. In response to mounting criticism, the Agency for Healthcare Research and Quality, which had previously recommended graded exercise therapy and cognitive behavior therapy, reversed their stance. In a new analysis excluding PACE and other Oxford-criteria studies, the agency found no evidence that graded exercise therapy was effective and minimal evidence for cognitive behavior therapy.
This is very unfortunate, because not only does it leave the treatment of CFS/ME in limbo but it calls into question clinical trials of treatment of other ‘unexplained illnesses’ including IBS, where there are also no measurable endpoints. Clinical trials are only as valid as the measurements of their outcomes; symptom assessments, quality of life, well-being are always going to be subject to observer bias. CFS/ME, like IBS, is, as Dr Melvin Ramsay concluded, a highly individual illness that does not lend itself to RCT studies that assume that patients with the same diagnosis will behave in a similar way.
In the meantime, Naomi remains in bed waiting for something to happen.
The Sensitive Gut 
I was initially intrigued by the title of this post but came away with disappointment as my first response,
I think it extremely ironic that you talk of bias in relation to the pace trial, by sufferers, medical professionals and academics (many sufferers are also in the medical profession/academics) who expressed their concerns regarding the validity of the study design, inclusion criteria, recovery criteria and the methods of data analysis and interpretation.
I would say that your post, whilst quite a useful summary, reads as perhaps also biased. You mention the new analysis as being biased, however you don’t mention that the reanalysis was using the original study protocols that the Pace researchers changed part way through their study. The changes that the Pace researchers made, resulted in the higher percentage of successful recovery rates which they suggested supported using CBT and GET as successful treatments for CFS/ME.
There is an argument for the Pace researchers being biased towards a particular outcome based on their own theories about CFS/ME and this introduced bias into the Pace study. If scientific studies are to be of any use, we need studies to be carried out objectively, bias to be reduced as much as possible and meeting standards of ethical and good quality science. There is a strong argument for open data and data sharing and this is happening now within the scientific community relating to these issues.
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Thank you, Sarah. I agree with your comments. Perhaps I didn’t express myself clearly enough.
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Claire recently wrote about this post on Facebook
There is currently another trial called MEGA, that on first read sounds promising, it uses promising language in it…but on further reading it is run by many of those of were involved with the PACE trial. There is a petition against this trial, which has been signed by several drs well known in the field, who agree that the MEGA trial is a waste of time and will only do more damage. The petition is called OMEGA (opposing MEGA) and can be found here if you wish to sign. https://www.change.org/p/opposing-mega-a-vote-of-no-confidence-in-mega-research-for-me-cfs?recruiter=159543284&utm_source=share_petition&utm_medium=copylink
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I thought since the OMEGA petition has been posted, that the petition for supporting the proposed MEGA study should also be up here too for people to read and there is info on the proposed study plus blogs and Q&As from the researchers who make up the MEGA team.
https://www.change.org/p/support-this-huge-biomedical-m-e-cfs-study-and-its-application-to-major-uk-research-funders
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Thank you, Sarah.
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Not sure I agree with your conclusion. The PACE trial was flawed for a number of reasons, but that doesn’t mean that studies that don’t have those flaws (e.g. when more complete criteria are used, data isn’t published part-way through a trial and the success criteria aren’t changed after a trial has been approved) are under threat.
There will always be difficulty blinding trials that involve some sort of personal therapy or routine interaction with test subjects, but you can still ensure patients are selected by firmly agreed criteria, are randomised by individuals not involved in the evaluation of the data, that you agree in advance what success looks like and for how long after you will monitor, and that the people who collate the results and do the initial analysis are blinded to the types of treatment received.
For IBS, we have the Rome IV criteria. While we can agree that these may not be perfect (and indeed the definition of IBS by NICE doesn’t exactly match the Rome criteria) at least we have a standard. Alternatively, we can be clear about what we are measuring the outcomes of (pain, diarrhoea, constipation, Bristol Stool Scale). How long do these changes last for, and is that with the continued use of therapy or after it has been withdrawn?
I agree that highly individual illnesses like IBS may not lend themselves well to randomised controlled trials, but well-run trials are preferable to trials as flawed as PACE seems to be.
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Thank you for your comments. You make some good points.
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Yesterday I listened to Professor Esther Crawley from the Department of Child Health in Bristol talk about a new 3 year trial that has just been funded to treat 500 children with CFS/ME in Bristol. It is based on a successful study conducted in Holland, in which CBT was delivered over the internet and resulted in 63% recovery. The Bristol team propose to compare CBT delivered by Skype with three sessions of activity management delivered over the internet by occupational therapists, including encouragement of good sleep patterns. Dr Crawley’s trial works on the premise at if you change the biology, the illness will improve. She works with young people to get their work, activity and sleep, eating patterns in synch to gain control of their biology. Although she accepted that there was good data suggesting that CFS/ME was a biological condition, in the absence of a biological cure, CBT and activity management could be very effective. Perhaps it is easier to bring about a change in children before the illness has become established. Of course, there is great resistance to CBT which many patients and their carers see as trying to convince people they have a wrong belief, though it could be more about showing people that a change in behaviour – ‘doing what my body needs’ – can alter how they feel and think about the disease.
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