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

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

 

Prof Tate also vouched for the Lightning Process in a webinar last November (I believe it was the ANZMES’ AGM). It is sad that he has fallen for this pseudoscience.

 

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.

 

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."

 

Has anyone reached out to him? This is so disappointing.

 

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.

 

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.

 

I think it was Hopper's DNRS he was talking about, not the LP. Not that this makes it much better

 

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:

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...

 

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

I think this is too optimistic.

 

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.

 

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.