Research priorities for ...(ME/CFS): the results of a James Lind alliance priority setting exercise, 2022, Tyson et al

ABSTRACT
Objective: To identify research priorities of people with myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) and those who support and care for them.

Method: Using the James Lind Alliance’s protocols, online surveys and workshops were held. The first survey asked participants from the U.K. to submit research questions about ME/CFS which were important to them. In the second, participants prioritised frequently submitted questions from the 1st survey. These were short listed and then workshop discussions were held to reach consensus on the top ten research priorities.

Results: 1565 participated in the 1st survey and 5300 research priorities were submitted. 1752 participated in the 2nd. In both surveys, the predominant demographic was white, middle-aged women with ME/CFS. 15–17% were family/carers of people with ME/CFS and 4–6% were health and social care workers. From the 1st survey, 59 summary questions were identified. These were prioritised and short listed to 18 questions. Of these, the top 10 covered 1. Post-exertional malaise, 2. Use of existing drugs for other conditions, 3. Diagnosis, 4. Autoimmunity, 5. Sub-types, 6. Post-infective cause, 7. Neurological symptomology, 8. Genetics, 9. Severe ME/CFS, 10. Mitochronical dysfunction and 10 (equal) Oxygenation dysfunction.

Conclusion: People with ME/CFS, their families and carers, and health care professionals worked together to identify, for the first time, the research priorities for ME/CFS. These focus on the biomedical causes of ME/CFS and how to diagnose, treat and manage it. Researchers and funding bodies should consider these in their plans for future research.

https://www.tandfonline.com/doi/full/10.1080/21641846.2022.2124775?src=

 

No statement of limitations. I don't think a paper should sound quite so pleased with itself. My overriding gripe - not one appearance of the word "epidemiology".

 

Here's some context: This paper describes how the ME/CFS Priority Setting Partnership decided on their priorities.
I'd say their approach to coming up with priorities was sensible and inclusive. Their priorities are quite good too. Very similar to where I'd prioritize research.

 

I welcome this exercise, although I think it needs to be understood that what seems a good idea for research may in practice not be.

The exercise will impact the government working party on ME research - it is part of the agenda. Hopefully the working party members will be free to use it as an inspiration rather than a straightjacket.

Taking the priority list as it is:
1.Documenting PEM seems to me a very good top priority. We need to have reliable representative data that show us the shape of PEM and nail it as a real phenomenon.
2. Repurposing drugs for other conditions is a nice idea but at the moment I cannot think of any candidates I would invest money in. There is some pressure to give this priority on the basis of anecdotal evidence but for the candidates that get mentioned I think we already have fairly negative evidence. What has been included in the working group agenda is a focus on outcome measures and I think that is something we could make progress on. That is partly for its own sake to get a robust measure with subjective elements and objective backup and partly to set a bar that poor quality therapist -delivered treatment trials have to match up to.
3. Diagnosis is not for me a priority. The priority is documenting PEM. Beyond that the diagnosis is as long as a piece of string.
4. Autoimmunity would be worth looking into more if we had good leads or new techniques. The evidence over the last five years has been mostly negative but something may be being missed.
5. Sub-types: there will be sub-types but I am not sure how you address that other than addressing the biological mechanisms.
6. Post-infective causes: I am not sure what that would entail other than monitoring post Covid progress maybe.
7. Neurological symptomatology: if there was anything specific associated with ME I think it would have been documented by now.
8. Genetics is certainly a good target and is being done.
9. Severe ME deserves special attention, especially in terms of people who cannot eat etc.
Maybe we need a study of weight loss in severe ME.
10. I am not sure why mitochondrial function should be a priority but at least it is a recognisable target. I doubt there isa problem with oxygenation.

 

Specific to or with? If you can take this literally, clearly a range of cognitive deficits is widely acknowledged in pwME. Other brain stuff, too, like balance and autonomic dysfunction (which since it's rooted in the brain I imagine qualifies as neurological).

 

I think diagnosis is really important. Obviously patients deserve recognition and a lot of disability and other aspects will associated with diagnosis but I think an objective test will expose the real numbers of sufferers, stop them being tortured with GET/CBT and lift them from psychological intervention and research and critically give researchers real access to patients, funds and interest. It makes it a real condition that can be tested and seen, we can objectively test how badly someone is ill and if an intervention helped or not. A good diagnostic does a lot for sufferers to accelerate everything else necessary to finding treatments.

 

I was assuming the wording was intended to refer to things other than cognitive impairment. I am not sure that anything much has been established. Neurogenic balance problems have not been clearly documented and I am doubtful about autonomic too. People have symptoms but whether or not they have a neurological origin is less clear.

 

I think there is a widespread misconception about diagnostic tests. If a test is discovered to pick out a certain group of people and there is a good reason to think it is reflecting some specific disease, then you have discovered part of the mechanism. The problem we have at present is that even research directed specifically at trying to find a mechanism isn't getting very far.

In other words, a diagnostic test will inevitably come, and only come, when research into mechanism has progressed. So it comes under the other headings - genetics, autoimmunity, post-infection...

My experience with half a dozen chronic diseases is that for the most part diagnostic tests are irrelevant. Often tests like C-reactive protein are helpful in judging disease activity but these are not diagnostic tests. They may validate illness but they are not diagnostic.

 

On the good news side of things, there are no priorities surrounding psycho-social, rehab and soft targets. Patients have spoken, biological studies are needed and overdue. I hope that the funders of research will listen and direct funding for advancement of biomedical knowledge, and starve those who have looked at psychologizing ME.

 

The shape is all vague and wobbly, because it's likely a set of downstream symptoms that varies with genetics, epigenetics, and various other factors. Those factors affect our individual responses to various other factors too. My priority for PEM would be to find some people with reliable responses to triggers, and do exhaustive testing to try to find out what changes. I'd focus those tests on the brain, since I don't believe that the core part of PEM will be found in blood or non-neural tissue. Even CSF might not reveal the core dysfunction if it's highly localized to a small part of the brain.

I agree. Unless someone stumbles across something that works reliably for a significant portion of PWME, there's nothing to repurpose. I think that item is just wishful thinking. It's no more likely to produce a useful treatment than trying to find a new drug.

Official diagnosis is probably important for someone living somewhere where it makes an economic difference, which isn't everyone, so I think funding for that should come from those countries. Finding a reliable marker might be useful for everyone, since it might be a thread that leads to the core dysfunction.

Autoimmunity, genetics, viral triggers, and mitochondrial/oxygenation are hypotheses, as yet unproven to be part of ME. It might not be the virus that is important, but our immune response to them that is the actual trigger. Thus I would put this at a low priority.

A week or so ago, I came across a report about a bi-directional communication link between the brain and fat cells. If ME is altering neural functions, it could be changing the 'set point' for fat storage. Thus PWME might find their bodies storing more or less fat than it did before.

Is brainfog not a neurological symptom? Also, brain function is difficult to study (delicate, encased in thick bone and a BBB, etc), so no, it's not necessary that dysfunction in the brain would have to be documented by now. Just a week or so ago I read a report about a new microscopy technique that could image cilia on (neurons? synapses? I forget which). Researchers have been ignoring these cilia--which could potentially be involved in ME--because they didn't have the tools to study them. A couple of years ago was another report about a complex lymphatic network in the brain, previously unknown (actually, discovered long ago, but dismissed by fellow researchers). No, neurological research is my top choice for ME research, partly because my symptoms seem neurological in origin, and partly because the brain still has so much that isn't understood. The heart has been studied in great detail, so it's unlikely that the root cause of ME will be found by further studying the heart. The brain is still largely 'unmapped waters'.

 

There's also basic work that as far as I know still hasn't been done on a sizeable cohort yet, which may reveal something worth knowing. Activity levels and patterns, yes; but also changes in blood pressure, temperature, heart rate and variability, breathing rate, urine output and composition, sleep, gait, gaze tracking... Boring stuff in some ways, but important because you can get reasonably reliable hard measurements.

 

In my opinion, in reference to PEM, we also need even more basic stuff than described above, which would be to ask large numbers of pwME to simply describe what PEM is to them. You only need to look at the discussions around PEM here on the forum to see that while there is broad agreement, there are variations in peoples experiences.

 

For reference, here is our discussion thread on the process that lead to this publication, UK: Priority Setting Partnership for ME/CFS

 

Would this be necessary? Many of us thankfully don't experience complete collapse on a regular basis, yet we still suffer symptoms debilitating enough to rule out earning a viable income.

The demands of daily living are often enough to initiate PEM, and if it is possible to measure the changes it brings on (and we don't really know that yet), "ordinary" PEM should be good enough. At this stage we don't necessarily need to be able to define or measure the whole spectrum of it from mild to very severe, we need to know whether there's a set of core signs, and if so, what they are.

 

similarly it is vital that any research done on PEM adheres to a much tighter set of symptoms/definition and not just what the researcher thinks it is (eg fatigue post exercise/activity).

 

No, that's not necessary. Some of us, such as myself, had reliable PEM that gave reliable symptoms but didn't cause lengthy crashes. A 40 km bike ride (hilly terrain) would reliably trigger PEM 24 hrs later, which would last a day or so. Surely I'm not the only one who had such reliable PEM without 'complete collapse'. I would have volunteered for testing. I did volunteer when I had a reliable PEM blocker, but no one contacted me. I still consider that a serious missed opportunity: testing everything possible with PEM and with the PEM blocked.

I expect that some people with reliable PEM and with serious lengthy crashes would probably volunteer too, in the hope that it would lead to a treatment for PEM.

 

I was thinking more about this one. Are there any ME symptoms that absolutely 100% cannot be due to neurological dysfunction? Even muscle dysfunction could probably result from neurological dysfunction, possibly through many steps, but the brain is the master controller for the body. It may be difficult to identify a root neurological cause, due to being many steps upstream of the observed symptom, but that doesn't mean that it isn't the root cause.

I'll repeat the question, since I think it is worthwhile: Are there any ME symptoms that absolutely 100% cannot be due to neurological dysfunction?

 

Quite likely not. I think one major possibility for ME is that the continuing problem is located in the brain.

I quite agree that brain investigation is a good avenue to go down. I am not sure that was what was meant by studying neurological symptoms though.

 

What about swollen lymph nodes?