The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem (2016), Edwards, JC et al

Edwards JC, McGrath S, Baldwin A, Livingstone M, Kewley A. The biological challenge of myalgic encephalomyelitis/chronic fatigue syndrome: a solvable problem. Fatigue. 2016;4(2):63-69. doi:10.1080/21641846.2016.1160598

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867862/

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is comparable to multiple sclerosis, diabetes or rheumatoid arthritis in prevalence (∼0.2% to 1%), long-term disability, and quality of life,[1–5] yet the scale of biomedical research and funding has been pitifully limited, as the recent National Institutes of Health (NIH) and Institute of Medicine reports highlight.[6,7]

Recently in the USA, NIH Director Francis Collins has stated that the NIH will be ramping up its efforts and levels of funding for ME/CFS,[8] which we hope will greatly increase the interest in, and resources for researching this illness.

Despite scant funding to date, researchers in the field have generated promising leads that throw light on this previously baffling illness. We suggest the key elements of a concerted research programme and call on the wider biomedical research community to actively target this condition.

 

This paper from 2016 summarized the the clues from promising research and made suggestions for future research:

"There are many possible models, but three major categories of causal model appear of most interest:

1. The brain is responding normally and symptoms are due to persistent signal input from peripheral tissues, such as cytokines or metabolites, based on persistent immune dysregulation (as in autoimmunity, for example, or, conceivably, low-grade infection).

2. There is a persistent abnormality of ‘housekeeping’ processes in the brain, such as an increase in activation of microglia following an initial insult, which leads to distorted processing of peripheral signals including autonomic pathway activation.​

3. There is a persistent abnormality in neural signalling in sensory pathways. This may be quantitative (comparable to dopamine depletion in Parkinson’s disease) or qualitative (comparable to post-concussion amnesia or post-traumatic stress disorder) due to CNS structural or regulatory changes following an initial insult.​

I find this review and the proposed potential models still the most informative summary and the most convincing suggestion on how to move forward.

I wonder if an update taking into account the current evidence base would make sense, especially with regard to 'negative' evidence (e.g. the Rituximab study results)

I hope the large genome-wide association study that has been launched in the UK (DecodeME ) will give some enlightening further clues, but if I understood correctly, it's possible that the findings won't be as clear and it could be be difficult to interpret them.

So, as other biomedical research is still needed, and also to restrict further research waste (and the potential waste of trial participants' time, energy and health) from studies based on bad assessment of the evidence for alleged or potential pathophysiology, I think an update of this paper is still worthwhile?


(Discussion on the proposed models see this thread: https://www.s4me.info/threads/is-me-a-metabolic-problem-or-a-signalling-problem.10981/ )

 

If that's 1% of the general population then I just can't justify using those inflated figures. It's shooting ourselves in the foot. Broad criteria lead to meaningless or harmful research and affects credibility for genuine sufferers.

 

The prevalence figure if I remember rightly was intended to refer to multiple sclerosis, diabetes and RA, hence no citation, but I agree it is ambiguous. I agree that 0.2% prevalence is probably the most realistic figure but I disagree that broad criteria necessarily lead to bad research. It depends on what is being studied. I dislike reference to 'genuine sufferers'. Everyone's suffering is genuine.

 

The biggest problem is where ME is seen as a disease of fatigue since fatigue is common to most disease. Using patients with only 6 months of fatigue in common is never going to get any answers for anything except the cause of fatigue and that is presuming that all fatigue springs form the same mechanism. The fatigue in ME is a side show in the same way it is for MS which is not to say that a cure for fatigue would not help people with MS and with ME and diabetes and all the rest of them.

The broader the definition the more larger the trial will have to be to make statistical sense of the answers. Personally, I feel that work done with very strict criteria will give answers that can be tested against the rest of us. We have used broad criteria since the 1980s and it has not helped.

Looking at everyone with a cough will not help find anything useful about TB or lung cancer or bronchitis or asthma.

 

I'd argue that this is just what we need. At the moment we have no way of reliably separating the people with TB from those with asthma or lung cancer, and as you say, we need to do this in order to make progress. Perceptive physicians could tease out some of the differences between the groups, IF they were given the time and resources to do so. It's hard when there's no pathology to observe or measure, but progress could be made.

 

Is there any political will to train perceptive physicians tho?

Given they seem to have spent decades trying to remove freedom of thought and options from medical systems.

As most don't seem to be able to percept their way out a ripped wet paper bag unless they have instructions in flow chart form.

 

If you have patients who don't deteriorate with exercise being included in ME research it's going to give the false impression that exercise can't harm ME patients.

If AIDS was re-defined as 6 months of fatigue and re-branded as CFS don't you think there would be angry patients wanting to separate those with genuine AIDS from those who merely feel a bit tired, genuine suffering or not?

What term would you prefer, "Real ME"?

 

As far as I am concerned there is no such thing as ME research, just research that tells us what is going on.
The assumption that there is 'a disease called ME' is a mistake, as it is for all medical problems. The task is to understand what is going on for everyone who is ill. If we want to focus on the problem of PEM or exercise intolerance then sure we need to study people with that problem. But if we are interested in some other aspect we want to cast the net differently. Having spent my life researching pathophysiology I have some experience in this!

 

Shouldn't researchers continue looking for causative agent(s)? Or are you suggesting focusing solely on a single symptom at a time, or a single cluster? Am I misunderstanding here?

I appreciate diagnostics have failed us, that progress to date has been restrained by the limitations of current diagnostic technology or algorithms. But I hate the thought that all we will do is crunch the numbers on downstream events, perpetually relegated to being unable to see the forest for the trees.

 

It's certainly a big problem, especially if, as some suspect, fatigue is a red herring. Studies are based on definitions. Get the definitions wrong, and the studies could be crap.

Of course, in a way this is ass-backwards. Disease definitions should be ultimately drawn from study results, but medicine is so down a rabbit hole of its own digging, I worry if it will ever see the light of day sometimes.

 

I'm no expert but---
I think that's why GWAS (Chris Ponting's study) and indeed the recently published, much smaller, Norwegian study* are important i.e. they're looking for cause, rather than downstream events (consequence). I recall this comment* since it indicates that the way in (to understand) Lupus was the identification of a gene.

I'm in the lumpers category** i.e. I'd rather we kept the scope broad until we have subgroups which can be researched independently.

*https://www.s4me.info/threads/genet...022-hajdarevic-et-al.25070/page-2#post-411468

**https://www.s4me.info/threads/ends-...s-in-our-2nd-questionnaire.24199/#post-402320

 

Genes. Yep. That's important and might prove to be the mechanism. I was thinking more in lines of infectious or specific immune dysfunction. But really infectious. Who's looking these days, and for what, with what? Aren't most focusing soley on symptoms? I hope I am wrong.

 

Absolutely. That is what I mean by trying to find out what is going on - cause and effect.

 

Our community wants a small loop, the smaller the better. Casting a large loop is not what the patient community wants to hear.

Open Medicine Foundation and Ron Davis was studying the most severe patients. This is what the patient community wants, a very small loop. The patients who would meet the strictest definition of ME, no cause was found. The results are so disappointing they are trickling out years later.

Leonard Jason went in the other direction. He cast a wide loop. Healthy in coming freshmen was included in his loop. He found an abnormality. Jason is now trying to predict who will develop ME after an EBV infection. By casting a wide loop Jason found something, and best of all Jason is now working to replicate his findings. By Jason focusing on healthy people and watching what happens when the healthy become sick he has moved the ball forward.

https://s4me.info/threads/predictor...ectious-mononucleosis-2022-jason-et-al.24902/

Stanford is a much larger campus than DePaul, OMF and Davis could be casting the wide loop for all of Stanford's in coming freshmen. OMF has deeper pockets than Jason, they could build on his success if they wanted to. OMF focuses on the aftereffects. They hope they will find the cause in the aftereffects. That's the low hanging fruit method. That method has been used for the 30 years I've been sick.

Jason's focus is on the event then watching for aftereffects, hoping to find the cause. It's a new method for our disease. So far, it is beginning to yield results. At the very least Jason isn't doing the same thing over and over again expecting a different result.

 

I might suggest that focusing on IM from acute Mono to subsequent ME/CFS diagnosis is not widening the loop, it is narrowing it. And I applaud it, as opposed to his parade of fatigue studies.

 

If you hunt around this forum then you'll find some discussion re EBV in MS [large US Army study] - how that could be replicated for ME/CFS.