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

BurnA said:
Why is it unclear - lack of good data or the data is available but does not support the idea that its consistent.

If good data is available but the findings are not consistent, what does that say?
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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.
 
@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.
 
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.
 
Snow Leopard said:
I'd also argue that evidence of central fatigue is also strong for CFS, though the underlying cause of that central fatigue is debated (and sadly, often debated by people who understand very little of the physiology)



The consistent finding is reduced workload (usually measured in watts) at the first ventilatory threshold (VT1, sometimes known as the gas exchange threshold (GET)) between day 1 and day 2.

It is not influenced by voluntary factors as the workrate is fixed - the participant must put out the same amount of power at the same rate of increase, else the test is aborted.

All of this begs the question, what is the gas exchange threshold/why does it occur?

I'd first like to start by saying what it is not.

The VT1/GET is not a point at which the participant will suddenly feel out of breath. There is a second ventilatory threshold, known as the respiratory compensation point which occurs at around 90% of VO2Max where participants (including healthy athletes) start to hyperventilate to compensate for reduced blood PH. At this point, some participants may report feeling out of breath, but not all do. (also, COPD patients may report feeling out of breath at much lower levels of exertion)

The VT1/GET is not a point at which the muscles suddenly run out of oxidative/mitochondrial capacity, indeed it happens well below VO2Max.

The VT1/GET is not synonymous with an 'anerobic threshold', nor is it the same as a 'lactate threshold' which the point at which lactate accumulates significantly in the blood (and thus is additionally related to things like the kinetics of lactate transport).

The VT1/GET is an artefact of the ramped exercise protocol itself. Under uncontrolled exercise conditions, or controlled conditions where there is not a constant increase in workrate (examples include CPETs while fin-swimming), there may not be a clear transition point and the VT (or an anerobic threshold) is not a consequence of reaching a particular heart rate.

The VT1/GET is a non linearity of the graph when VO2 (Volume of O2 consumed) is plotted against VCO2 (Volume of CO2 exhaled). The VT1 can also be indicated using the ventilatory equivalent method, plotting VE/VO2 and VE/VCO2 on the same graph and noting the point where VE/VO2 increases significantly, while VE/VCO2 remains flat (where VE is minute ventilation).

The reason for this non-linearity has often been debated in an chicken or egg type manner. Is it primarily due to a non-linear increase in motor drive, or a shift in nonlinear shift in metabolic balance versus force output? I suggest both are necessary, since they inevitably lead to the other, causing the clear nonlinearity in the graph.

There is a transition in metabolic balance (from aerobic to non-aerobic metabolism) as higher threshold motor units are recruited, which have a lower balance of oxygen consumption versus force output due to physiological reasons (lower muscle fibre capillarisation, increased O2 diffusion distance etc.)

An aside, the ventilatory drive itself is ramped up in parallel with the increase motor drive (upstream of the motor cortex). Also note that autonomic responses (heart rate and blood pressure) lag behind and react to the change in ventilation. Additionally, note that there isn't a clear pattern of O2 Pulse (VO2/Heart rate) differences at VT1, suggesting that the observed differential between the two days likely isn't due to altered autonomic drive of the heart.

So why is there a reduction in workrate at VT1 between the two days in most ME/CFS patients (in 10+ studies), but not controls?

There are several possible answers:

-due to peripheral motor units being fatigued earlier (such as less optimal firing rates, less force output for a given motor drive) due to metabolic factors
-significantly altered muscle capillary blood flow leading to altered O2 kinetics
-due to stimulation of Group III/IV muscle afferents, which alters the balance between ventilatory drive and motor cortex excitability.
-the brain decided to completely re-wire it's afferent signals and bypass all of the normal feedback mechanisms that prevent this from happening for shits and giggles. (Note, the signalling of the fatigue related muscle afferents is much more complex than most other forms of pain and cannot be explained by typical pain central sensitisation models or experiments (in experiments, the phenomena is almost always transient, rather than chronic) as there are more systems involved - the proprioceptive system, the motor drive system (various supplementary areas), and the fatigue-related pain system - all of which have to fail, given the feedback between these systems that prevents things from going out of wack)
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Thank you very much for your detailed explanation @Snow Leopard. Are there primers on the basics of the biology needed to understand CPET testing?
 
Creekside said:
Even that is probably only 'a large subset of PWME' rather than something all PWME have. I didn't notice any reduction in my physical capabilities after significant exertion. I'm guessing that I wouldn't show a reduction on a properly done CPET test.
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It's an interesting question as to whether 100% of people with ME/CFS show the drop in performance at VT. We don't know if a person with ME/CFS could show that drop in a paired CPET, but another week, perhaps when well rested, not show that drop. Or if some people need to do more than 8 minutes cycling to trigger the drop - it seems likely, as there's no particular reason why 8 minutes of cycling should be over the threshold for everyone.

I don't know that the performance drop is something that is necessarily easy to spot. When I did the second CPET, I felt fine, and did not think that the cycling was harder. And yet, my results showed a substantial drop (I think around 20%) in work rate at VT. It makes me think that the physiological problem causing PEM may be happening under the radar for a while, and it's only when things get very bad that we start getting pain, and obvious muscle weakness and clumsiness, and exhaustion and the desperate need to lie down that is PEM.
 
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?
 
Hutan said:
It's an interesting question as to whether 100% of people with ME/CFS show the drop in performance at VT. We don't know if a person with ME/CFS could show that drop in a paired CPET, but another week, perhaps when well rested, not show that drop. Or if some people need to do more than 8 minutes cycling to trigger the drop - it seems likely, as there's no particular reason why 8 minutes of cycling should be over the threshold for everyone.
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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.

cassava7 said:
Thank you very much for your detailed explanation @Snow Leopard. Are there primers on the basics of the biology needed to understand CPET testing?
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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.
 
Hutan said:
It's an interesting question as to whether 100% of people with ME/CFS show … … …
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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.
 
DigitalDrifter said:
ME needs to be sub-grouped and researched separately. For example the subgroup who suffer an adverse reaction to exercise.
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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.
 
Hutan said:
It's an interesting question as to whether 100% of people with ME/CFS show the drop in performance at VT. We don't know if a person with ME/CFS could show that drop in a paired CPET, but another week, perhaps when well rested, not show that drop.
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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.
 
TigerLilea said:
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.
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Yes, the pre-test level of fatigue is an important thing to think about. Unfortunately, I don't think many researchers have thought about it enough. The reality of trials with respect to controlling confounding variables is, I think, often quite different to what we might hope for.

Before my test, I received no instruction in pre-test preparation. The researchers knew I would be coming to the city by plane for the test. I got my household ready for my absence (e.g. prepared meals), packed, got on a plane (with all of the walking and queuing that that involves), got to my accommodation and then stood for 15 minutes beside the road waiting to be picked up to go do the first CPET.
 
Snow Leopard said:
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.
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What is going on physiologically, i.e. what is the biological/physiological rooting of the measurements being taken during a CPET.
 
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dreampop said:
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.
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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.

 
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Forbin said:
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.

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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:

We also compared mean cytokine levels in cases with ≤3-y fatigue duration (n = 30) and those with >3-y fatigue duration (n = 156), as per Hornig et al. (17). We did not find any cytokine to be significantly different between these two groups (SI Appendix, Table S3).
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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.

In this exploratory analysis, both IL-12b and CSF-1 appeared to be elevated in CFS/ME patients (p value 0.004 and 0.049 respectively). Other cytokines did not differ between patients and controls. Dividing the patient group into those with short illness duration, and those with longer illness duration did not change these results (data not shown).
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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.
 
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