Over which physiological abnormalities in ME/CFS is there a scientific consensus about?

I am not sure that there are any data on a decent population based cohort. Reports from people like Peter Rowe are hard to make anything of because they involve tertiary centre referral cohorts that are probably heavily influenced by presuppositions.

 

What constitutes a consensus? 80% or higher?

Cerebral hypoperfusion as demonstrated by SPECT scans (vs MRI and PET), perhaps? Not sure about this as SPECT scans are more or less frowned upon in US for last few years...

 

@Jonathan Edwards

Thank you for your description of consistent findings re physiological abnormalities.

Tragically, a lot of the research on ME is all over the place. Overly inclusive case definitions, and lack of biomedical funding have contributed of course.

I had assumed there have to be a great many successful replications for consensus. Interesting that it's not the case.

 

@duncan

Exactly my question. What constitutes a consensus?

 

The consensus issue comes out in everyday issues for people with mystery, or controversial illnesses such as ME. Waiting for consensus on research that is at best funded at a snail's pace is very difficult to say the least.

 

From my perspective a consensus is just when at a scientific meeting if you went round asking people if such and such a finding looked solid most would say yes.

It has nothing to do with any specific number of studies. It has much more to do with convincing detail in a very few studies. If someone has shown a study with a very repeatable kinetic profile to a physiological effect - like a glucose tolerance test curve in diabetes for instance - and they present it in a way that looks well thought through you probably get a consensus there and then. If, like demonstrating a consistent T cell response in active TB infection, getting any corroborative detail is difficult, it may take a decade or more for consensus to be achieved.

And of course consensus can be wrong - as for the reconditioning theory of ME which may have been widely agreed. But if we are talking about demonstrating a specific physiological change that tends to be less an issue.

 

Thank you very much for your detailed explanation @Snow Leopard. Are there primers on the basics of the biology needed to understand CPET testing?

 

ME needs to be sub-grouped and researched separately. For example the subgroup who suffer an adverse reaction to exercise.

 

One result I've been wondering about recently is the supposed shift in cytokine profile found by Hornig in 2015.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4465185/

It's important because it was used by the NIH (I don't have a source for this, I am going off memory) to justify only studying patients with me/cfs for less than 3 years. There may be some value to it but basically the pathology is going on 20, 30 years later as well.

It seemed absurd to me at the time, and probably contributed to them constantly being unable to recruit patients (again according to them, I also have doubts about how hard it is to recruit patients when they could possibly have any reasonable misdiagnosis ruled out in one go, a dream for many early on).

We also never really validated that CDR metabolic shift from Naviaux, did we?

 

This also reminds me of the people who were asking whether participants were already suffering from PEM during the first test. So in that case it is a question of how much is needed to further exacerbate. Some participants (depending on underlying fitness and health) may need to do a higher intensity of exercise on the first day before a noticeable drop is measured on the second day.

Do you mean the actual process, or understand what is going on physiologically? I have not found much on the latter, I've had to piece it together from many papers. However, for the former, there was a primer by the Workwell foundation that explains the process of conducting a CPET.

 

Given our current knowledge is it reasonable to expect anywhere near 100% on any physiological measure.

We have a range of operational definitions of ME/CFS which are evolving in a bit of a ‘pulling ourselves up with our own boot straps’ way, that we reasonably hope refer to a real biomedical entity, but the exact relationship between the reference, the label ME/CFS, and the referent, the presumed underlying biomedical condition, remains unclear.

Ramsey’s ME criteria were specific and probably would not include everyone fitting the most recent ME/CFS definitions, then there was the nightmare of the all including Oxford Criteria so all those with idiopathic chronic fatigue and indeed other conditions such as depression were snuck in, but also we tend to forget how recent it is that PEM has become regarded as a key diagnostic symptom in the process of narrowing down again those who actually have the presumed condition.

As PEM becomes better defined, as assessing orthostatic intolerance becomes more routine and as other issues become better understood, the criteria for diagnosing ME/CFS will evolve further. With the physiological studies we are unlikely to see 100% results, so we desperately need large enough studies to pick up any sub groupings, and accept that individuals on the edges are likely to be in the uncomfortable position of dropping out and/or dropping back into the condition.

 

I'd rather see the research funding going towards figuring out what we all have in common, rather than studying downstream symptoms that only some PWME have. If resources were unlimited, sure, maybe it would lead to a treatment for a symptom faster than trying to find one that treats all ME symptoms at once, but sadly, resources aren't unlimited.

 

I read that people doing this test are supposed to be well rested for two weeks before doing the test. Otherwise the second day's results won't look any different than day one. Supposedly only people with ME/CFS will have a difference in results between the two days.

 

What is going on physiologically, i.e. what is the biological/physiological rooting of the measurements being taken during a CPET.

 

We have to perform more studies to find out, but I detailed several general explanations in my previous post.

 

Though not a literal replication, Hornig followed up the blood cytokine study with a similar study examining the cerebrospinal fluid of patients. This group of patients had been ill an average of about 8 years, so it likely was not a large group for the study of short term patients. However, the long term patients showed lower cytokine levels vs. controls in spinal fluid just as patients from the previous study had shown lower cytokine levels in their blood samples after a few years.

Also, I don't think the lower cytokine levels would necessarily be a sign that the patient would feel better. The low levels are also abnormal and, in a talk she gave in 2015, Dr. Hornig mentioned how the cytokine network was more dysregulated in long term patients with their lower (perhaps "exhausted") cytokine levels.

https://www.youtube.com/watch?v=bAbK8B6Mu1Y

 

Thanks, just a quick thought on the csf study is it uses controls that got csf drawn on "routine testing" so I don't know how great a reference sample they are because that's obviously not routine. Horning's study was included in a meta analyses of MS cytokines and doesn't seem to match up particularly well. CXLC8, for example was high on average MS csf study vs controls, but very low in Hornig's study.

https://www.frontiersin.org/articles/10.3389/fnins.2019.01026/full#F3

I'm going to watch the video later and think more about it when I have more time/energy.

 

My thoughts on the Horning spinal fluid study is it wouldn’t be replication regardless, but isn't high quality enough to be supportive because

• 1) The unusual control group, and the variable MS group

• 2) Some highly unusual results

• 3) The logic Hornig uses to justify the study as suggesting replication doesn’t make sense – most cohorts would show “immune exhaustion” due to average patient illness being longer than 3 years in most studies

• 4) It’s spinal fluid versus serum

Regarding 2), IL6 being almost 15-20x lower would be a monumental finding. It’s not even mentioned in the text of the study but Hornig rightly brings it up right away in the video. It’s suspect because nothing so dramatic has been consistently shown in past or future studies.

I’m worried part of what may be going on here is that the ND controls are getting their spinal fluid tested because they are feeling ill. So, they have higher cytokines than healthy controls and possibly significant illness. Hence every cytokine in the ND controls being greater than in MS as well (CXCL10 the lone exception).

I only found 2 direct attempts to replicate the original Horning “immune exhaustion” finding. Both failed to do so. One was a decent looking study from Montoya, 2016:

And a less reliable one from Knoop in 2017, at least partly because of his background imo, but with the same result. Worth noting in addition because Horning brough up Anakinra.

Another study, Landi 2016, found some lowering of cytokines but studied only long duration illness and used either Fukuda or CCC. I only looked at this study briefly tbh as I got a bit overwhelmed by cytokines.

The Griffith University group conducted an overview of cytokines in 2019 that included 4 studies on spinal fluid and none had consistent results and nothing like Hornig's widespread findings.