Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID 2023,Tate et al

Sly Saint

Sly Saint

Senior Member (Voting Rights)
Abstract:
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person.

A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options.

Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination.

Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.

https://www.mdpi.com/1422-0067/24/6/5124
 
While I appreciate the effort that has clearly been put into this research, I'm afraid Warren Tate has completely blown any credibility he may have had as a commentator on treatments with this awful section (my bolding):

12. Patient Lifestyle Self-Management of ME/CFS and Long COVID
Most ME/CFS patients learn by experience how to manage their condition as best they can, given the lack of therapeutic options and incomplete knowledge of the illness of their clinicians. This can involve diet, supplements, relaxing modalities such as yoga and meditation and other strategies that provide them incremental improvements. In our experience and through contact with patients, we have seen the ME/CFS community show impressive resilience and a desire to improve their own lives using novel coping strategies, despite the currently bleak outlook in having this illness. For many years, graded exercise and cognitive behavioural therapy were recommended as the preferred treatment options despite post exertional malaise being a core symptom, with reinforcement from the PACE trial in the United Kingdom [128,129]. The results of the PACE trial have been discredited by biostatisticians, and finally in 2021 the Nice guidelines [130] removed these treatment modalities as the preferred ones, and this was simultaneously re-enforced by specialist ME/CFS clinicians in North America as well.
Intense cognitive behavioural therapies such as the Lightning process [131] have continued with promises of a high cure rate but without independent validating evidence. The claims seem incompatible with a phenotype/subtype model for ME/CFS discussed here. Whereas some patients obtain benefit, others are often left with incredible guilt for failing to cure themselves, and so these therapies can be counterproductive. Evidence-based trials are lacking. However, behavioural therapies have an important place, if transparent, and are an affordable option that might provide possible benefit to patients incrementally, and not as an instant cure. One such treatment option was brought to our attention recently by a New Zealand patient who, from a low place, obtained incremental benefit over several months from a programme, ‘dynamic neural retraining system’, based around recognising the brain’s neuroplasticity and potential to change its circuitry. There exists the potential to reverse patterns of interoceptive pathways that maintain a ‘sickness response’ where the brain circuity is wired to perceive ‘ongoing danger’ as a result of hormonal or cytokine signalling [64]. The ‘Dynamic Neural Retraining system’ was developed by Annie Hopper, and described in her book, ‘Wired for Healing’ [132]. She managed to reverse her severe neurological symptoms. Now this programme is offered publicly so others with chronic conditions may possibly benefit. The ME/CFS blog site Health Rising recently highlighted one case of a woman who benefited from this programme. Though initially wheelchair-bound with her ME/CFS, she returned to running again in a year after embracing the programme [133].
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In a paper in a scientific journal this section is unforgivable in my view.
There is no evidence supporting any of yoga, supplements, LP or the Annie Hopper stuff.

Warren Tate et al. if you are reading this, I think that section of the paper should be withdrawn. It's clearly outside your field of expertise and you make fools of yourself and do patients harm by including it. I'm sure you wouldn't recommend a drug on the basis of a few individual anecodotes, so why this confident assertion, on the basis of no evidence that these psychological and behavioural practices are helpful.
 
Trish said:
While I appreciate the effort that has clearly been put into this research, I'm afraid Warren Tate has completely blown any credibility he may have had as a commentator on treatments with this awful section (my bolding):



In a paper in a scientific journal this section is unforgivable in my view.
There is no evidence supporting any of yoga, supplements, LP or the Annie Hopper stuff.

Warren Tate et al. if you are reading this, I think that section of the paper should be withdrawn. It's clearly outside your field of expertise and you make fools of yourself and do patients harm by including it. I'm sure you wouldn't recommend a drug on the basis of a few individual anecodotes, so why this confident assertion, on the basis of no evidence that these psychological and behavioural practices are helpful.
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Excellent point @Trish

Normally, care is taken when prescribing drugs for patients. However, some mainstream practitioners seem to ignore common sense, scientific care and logic when handing out advice on unproven so called mental health treatments. There are two sets of standards here.
 
Trish said:
Annie Hopper stuff
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I wonder if he has actually read her book?

from the comments on amazon this seems to be the consensus
"I bought this expecting to find guidance on solving my health issues but there is no guidance/advice in it what so ever. It's just a collection of testimonials about how wonderful the classes are and how you should sign up to them."

eta:
another (sounds familiar ie LP)
"The author is very protective of her 'program' and reveals absolutely nothing about what her clients do - not even an example. If you want to know how the program works exactly or what kinds of activities are practiced to rewire your brain, you will find nothing here. I wasted my money."
 
Thread on Annie Hopper stuff:
Annie Hoppers Dynamic Neural Retraining System

Thread on Lightning Process (among many on the forum):
Lightning Process - discussion thread

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events.
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That's a really bad start to a paper.

I find it really hard to understand how a scientist, actually a celebrated scientist, can fall for all this sort of nonsense, and not apply scientific thinking when evaluating treatments in order to provide guidance to clinicians and patients. I'm at a loss to know what to do about this.
 
I had a thought about GET this morning: they may be misapplying cause and effect. When I'm having a "feeling a bit better" period, I take advantage of that by doing more physical activities (hiking, biking, etc). Could whatever evidence is supporting GET be from recording extra activity while the patients are having unexpected "better" days? I suppose it depends on how rigorous their study is, which I doubt is very rigorous. It's probably easy to rig the study to allow cherrypicking of data.
 
A number of us have had conversations with him in the past; a number of us have donated to his research program. I could try again I guess, but I don't feel very hopeful that he will change his mind about things.

I guess he's of the view that patients have told him that something helps, so he's just passing that on. As in, maybe it will help someone. What he doesn't realise in propagating these ideas, is what it does for the credibility of people with the ME/CFS label.

There's this section for example, which reports the results of a small survey of people with ME/CFS and Long Covid. When reporting rates of mental illness and the frequency and recovery times from childhood illnesses, there are no corresponding rates from controls, ideally not just healthy controls but people with other diseases who might have cause to look back very carefully over their medical history and find unusual events and patterns. Perhaps there is something that is true and useful here, but it really is impossible to know.

For example, around 20% adults in Aotearoa NZ had been diagnosed with a mood and/or anxiety disorder in 2018. In that context, the reported rates from this small survey of pre-existing mental health conditions of 36.3% in ME/CFS and 17.5% in Long Covid don't really seem remarkable. This is especially so when we think of how easy it is for someone who is struggling in the early pre-diagnosis years of ME/CFS with both the symptoms and the consequences of the illness on relationships and their ability to work to be given a mood and/or anxiety disorder diagnosis. But there is no discussion of this, no context is given, and so the rates of reported mental illness are allowed to contribute to the overall sense of what a person who develops ME/CFS or Long Covid is like.
To investigate susceptibility factors in ME/CFS and Long COVID, we conducted a quantitative survey with 160 ME/CFS patients and 57 of the first wave of Long COVID patients in New Zealand to determine whether their prior personal history was a predictor of developing the syndrome, and whether family history was indicative of genetic factors being significant [14]. The phenotypic overlap found between Long COVID and ME/CFS participants in this study in terms of symptomology, severity of symptoms and capacity for activity provided further support for the suggestion that Long COVID and ME/CFS are closely related conditions as hypothesised by published literature [15,16,17,18,19], albeit perhaps with certain features specific to the SARS-CoV-2 virus.

The initiating triggers of ME/CFS in patients and the severity of the SARS-CoV-2 infection in the case of the Long COVID patients is shown in Table 1A. Only 16.6% of participants reported having no underlying health conditions, whereas many patients reported preexisting underlying health conditions (Table 1B). For conditions not specified in the questionnaire, reported as ‘other’ (45.6%), the most common were asthma, endometriosis, Ehlers–Danlos Syndrome and fibromyalgia. Of the specified conditions, gastrointestinal issues were the most reported condition (42.4%). Mental health conditions were more commonly reported in ME/CFS (36.3%) than in Long COVID (17.5%). Moreover, many reported having experienced relatively long times to recover from childhood illnesses (70% of ME/CFS patients, and 45% of Long COVID patients took between two weeks and two months). ME/CFS patients reported childhood illnesses were frequent (28.5%), while those with Long COVID somewhat less (17.5%). Hence, there was an overall pattern of a history of frequent illness during childhood that required significant time to recover, followed by underlying health conditions prior to contracting ME/CFS or Long COVID from the initiating stress. The environmental effect might be from a vaccination [20], a previous viral infection [21] or stress from a life crisis [22]. Either singly (genetic or environmental) or in combination, such effects might provide an impetus in a susceptible person for the health response to the stressor not being transient as in most people, but for it to become chronic and ongoing. If that extends to more than six months, then the criterion for a diagnosis of ME/CFS is met.
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The same applies to the data on recovery times from childhood illness and a history of frequent illness in childhood. 28.5% of ME/CFS patients reported frequent childhood illnesses, 17.5% of people with Long Covid. How do these percentages compare to healthy controls? How do they compare with people with other diseases where they may have a reason to look for past patterns of illness? In the absence of a context, these percentages do not seem to warrant the conclusion that "Hence, there was an overall pattern of a history of frequent illness during childhood...".

Perhaps there is a clue here, I myself have wondered if, for example, chronic ear infections might be a contributing factor. But we aren't going to produce useful data on which to base hypotheses with small samples, retrospective recollections and no control comparisons. We need our scientists to do better than the idle speculation that we as patients understandably engage in; we need scientists studying ME/CFS to do a lot better than this.
 
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I agree with Hutan's concerns. The thing that puzzles me about this paper is that its authors are biochemists. Yet they are trying to research epidemiological predisposing factors, and doing it very badly, and making unevidenced statements about psychological treatments.

They are straying way outside their areas of expertise and making a mess of it in ways that will harm patients.

Why do they do it?

In the past Warren Tate has done some interesting biochemical research on ME. Why not stick to developing that?
 
Trish said:
In a paper in a scientific journal this section is unforgivable in my view.
There is no evidence supporting any of yoga, supplements, LP or the Annie Hopper stuff.
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I took it on the chin and watched Annie Hopper's interview here. Nothing about this bears any relationship to my experience. If I were to try to follow her pillars of dynamic neural retraining I honestly don't know what I'd even do, because as far as I can tell without buying the book/course, I am already in the optimal end zone of what she's trying to achieve.

I believe I contributed data to this paper (I'm probably the 1/57 'no symptoms from Covid infection' datapoint) from a questionnaire I completed in April last year. It is very disappointing to see Warren veering off into this territory when there is so much biological data. There's no evidence and no need for this framing.

I think the problem starts with the opening line "Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a neurological disease". It might be, but no-one can say that with any certainty. It looks like it's biasing thinking toward the brain being at fault and that it can be trained out of the pathological state — I don't buy either aspect.
 
Thoroughly baffled by this paper.

The DNRS bit just shouldn't be in there, full stop. The only reason patient anecdotes should be mentioned in a scientific paper is as part of a qualitative study or where they've inspired a larger study or survey. Not the case here. The comments are unnecessary, unsupported and illogical. The only reason I can guess at is that a combination of empathy for patients plus wanting to appear undogmatic ran off with the authors and they failed to take the crucial step of tempering empathy and open-mindedness with rationality. But, hellooooo peer reviewers, anyone home....?

Also baffled by the purpose of yet another review, one that doesn't seem to add anything new to all the other reviews already out there. We seem to be having more reviews than original papers these days. Do the authors hope, by dint of repetition, to interest overseas researchers in their hypothesis so that somebody else with more access to funding than available in NZ (basically zero) might be persuaded to properly test the hypothesis (the review does read a little like a hypothesis paper dressed up as review)? Or do they hope to convince commercial interests to fund this:
study said:
In New Zealand, a plant extract has been discovered that could reverse neuroinflammation in a zebra fish and a mouse model of obesity and glucoregulation, and also showed positive benefits in a first human trial. This stimulated us to plan first-stage testing with ME/CFS and Long COVID patients to determine whether the extract can improve the neurological symptoms and show any molecular changes in the signatures of the syndromes [127].
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The link to ref #127 didn't work for me but it seems to be a dahlia extract being researched for diabetes.
 
As I wrote in my previous post, I don't understand what the idea behind this review is. It's a lengthy paper and seems to want to fit every finding ever made into a single bigger picture. Given how many findings in ME are based on studies which are too small, not replicated and/or poorly done that doesn't strike me as the best way forward at this stage. Many of those findings won't hold up once they're investigated with more rigour but we don't know which ones until that is done. Right now it would be more sensible to identify which of those preliminary studies are currently being used as key foundation stones for the various ME hypotheses and are therefore in most urgent need of getting replicated so we don't spend years going down blind alleys.

So that could be a suitable topic for a targeted review.

Another good topic for a targeted review is discussed in the the present paper but could have been explored in more depth, and that is the issue of subgroups (see section "What Is the Significance of ‘Subtypes/Phenotypes’ in ME/CFS?" of the paper).

This team has done some very interesting work identifying differences at the molecular level in pwME who outwardly present very similarly. The cohorts were minuscule (because NZ funding...) so the findings may just represent random noise. But to me they are high priority for replication in expanded studies because if they do hold up that would have disconcerting implications. Then, in all other studies and even in well-characterised cohorts, any findings in a patient group could be cancelling each other out if one subgroup presents with elevated molecule x and another subgroup presents with decreased molecule x, with the resulting average looking statistically insignificant. Or, if one subgroup is substantially larger than the others, a signal may show leading to subsequent research focusing only on the larger subgroup. This may not be a problem if all subgroups suffer from the same primary problem with the heterogeneity all caused by downstream factors. Treatment aimed at the primary problem could still help all. But if there are several primary problems, or if treatments aim at downstream symptoms, the smaller subgroups would remain as stuffed as ever.

Several studies have looked at some of the more obvious subgroup candidates - sex, age, type of onset, illness duration or severity, that sort of thing - and found they may play a role. Every study should do this as standard. Requires suitably large cohorts of course. But we don't know what we're dealing with in terms of subgroups. It could be something nobody has even thought of yet. So how to zero in on that? I can think of only two approaches.

One would be to look again at existing studies where the findings in the ME group have a much wider spread than the control group to see if anything can be found there. Only possible where enough data was collected in a suitable format and is available for reanalysis.

The other approach would be for all future studies to add fishing expeditions to their analyses, reported separately from their planned - and hopefully preregistered - outcomes. Requires large enough cohorts and careful and extensive data collection, funding...
 
study said:
Current experience is that some patients can show benefit from a treatment, others no change and yet a third group have their symptoms become worse.
...
phenomenon of benefit/no change/harm is also found not uncommonly with promising medications or supplements that can help some patients while showing no benefit for others, and even cause an exacerbation of symptoms
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Categorising subtypes/phenotypes on the basis of those individuals who respond to specific treatments may allow treatment plans within a precision medicine framework to be created for each ME/CFS patient.
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Subgroups is one rational explanation for this effect of some improve, some worsen and some stay the same in response to an identical treatment.

Another possible explanation is that none of the treatments make any difference. At any given point some of us will be experiencing improvement, worsening or stability - without any intervention whatsoever. It would really help to have a much better idea of the natural course of the disease.

And then there's the plain misdiagnosis issue. The authors think it isn't a big issue anymore
study said:
Previously variable patterns of symptoms were explained by some patients being misdiagnosed with ME/CFS, however this would now seem to explain only a small component of any differences in disease course and severity. Clinical case definitions for ME/CFS have since become well known and more refined
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I think this is too optimistic.
 
Ravn said:
Subgroups is one rational explanation for this effect of some improve,
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These may be subgroups for symptom presentation. For example, if the core dysfunction for all PWME is astrocytes having some part of them that can get locked in a feedback loop, resulting in an abnormal modulation of neurons, the symptoms will depend on which astrocytes are affected, and which neurons are nearby, which can lead to a large number of direct symptoms with wide variance between individuals. Those direct effects can then cause further downstream symptoms, again depending on the individual.

I think there shouldn't be too much focus on treatments that affect one or two symptoms in one subgroup. That's just treating individual symptoms. Certainly appreciated by people in that subgroup, but R&D funding is limited, so I'd rather see it going to figuring out the root cause.
 
Even if the underlying pathology was exactly the same in all patients, there would still be at least some differentiation in symptom presentation just on the basis of normal non-pathological variation in how individuals generally experience, interpret, and describe the world.
 
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Yes, I can imagine significant (limited) funding going to trying to understand and treat subgroups that are only due to psychological differences. If the funding went to figuring out the core dysfunction, we could possibly treat all the symptoms at once, for all subgroups.
 
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