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

Discussion in 'Laboratory and genetic testing, medical imaging' started by borko2100, Jun 8, 2021.

  1. borko2100

    borko2100 Senior Member (Voting Rights)

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    All the time I read papers claiming that they found abnormality X or Y or Z, but very rarely are those abnormalities replicated in multiple well designed and reliable studies. It seems like it's always one or several of the following: poorly designed study giving misleading results, novel study that never gets replicated, novel study that gets replicated, but then gets contradicted later.

    As far as I am aware of, the only physiological abnormality that has been replicated enough to be considered proven is a performance reduction in a 2 day CPET test.

    So, after so much research the only thing that we can conclusively say, with scientific certainty, is that people with ME have reduced cardiovascular performance after demanding activities. And that's it. Not even PEM is a proven entity, since a CPET test can only detect reductions cardiovascular performance, but not reductions in mental performance and physical symptoms. Pretty disappointing if you ask me.

    Is anyone aware of other abnormalities in ME/CFS that there is scientific consensus about? I think there was quite a few studies showing abnormal lactate build up, but my memory is a bit fuzzy on those.
     
  2. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    In 2015 a prestigious organization, the Institute of Medicine, now the National Academy of Medicine, published an important report on ME. They noted results of the 2 day CPET, and orthoststic intolerance as having enough proof to be recognized as forming a core of ME signs/ symptoms. If memory serves they also noted something about Natural Killer cells, either number or function - maybe both - not sure. I think there was also something about unrestful sleep.

    I'm not near my computer right now, but will find links a bit later.

    ETA: and PEM
     
    Last edited: Jun 9, 2021
  3. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    This is the full IOM/NAM report on ME/CFS; there is a free download:

    https://www.nap.edu/catalog/19012/b...hronic-fatigue-syndrome-redefining-an-illness

    The above report has a section on findings re NK Cells. I seem to remember this was not as conclusive as the other signs/symptoms the Committee found and agreed on.


    The CDC has IOM/NAM info on its website as well:
    https://www.cdc.gov/me-cfs/healthcare-providers/diagnosis/iom-2015-diagnostic-criteria.html


    There are other abbreviated parts to this work by the IOM/NAM Committee; Clinicians' Guide
    :https://www.nap.edu/resource/19012/MECFScliniciansguide.pdf


    Page 2 of the Report Brief lists the signs/symptoms the IOM/NAM Committee agreed upon:

    Report Brief
    : https://www.nap.edu/resource/19012/MECFS_ReportBrief.pdf


    MEpedia on this report
    :

    https://me-pedia.org/wiki/Institute_of_Medicine_report

    Hope this helps.
     
  4. MSEsperanza

    MSEsperanza Senior Member (Voting Rights)

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  5. James Morris-Lent

    James Morris-Lent Senior Member (Voting Rights)

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    I'd go with "None", unfortunately
     
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  6. ME/CFS Skeptic

    ME/CFS Skeptic Senior Member (Voting Rights)

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  7. MSEsperanza

    MSEsperanza Senior Member (Voting Rights)

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    I missed that.

    I realize everyone's scarce capacities at the moment. But could be a worthwhile future project to use that collection to revise this paper from 2016?

    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/

    which is referenced in:

    https://www.s4me.info/threads/trial...cussion-of-exercise-and-long-term-harm.12625/

    And there's also @Andy's thread:

    https://www.s4me.info/threads/a-pot...-advocates-need-to-know-and-understand.11610/
     
  8. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    Sadly I don't think anything has changed. The NK story looks dead now. The CPET story may start to hold up with further studies reported but I for one still find it quite hard to see clear evidence of a consistent physiological abnormality.
     
  9. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    What is the threshold required to be met for there to be a consensus on research findings. Obviously, impossible for all to agree. The ME situation very clearly points that out. Also with ME, the "consensus", if one can call it that, has been driven by money and power. Not at all a clean scientific approach.

    Given the controversy with ME, perhaps there isn't even consensus on what the threshold is for agreement on medical issues in general. I don't know.
     
  10. Ariel

    Ariel Senior Member (Voting Rights)

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    Is the CPET angle not going anywhere either? :( I thought it was
     
  11. Mij

    Mij Senior Member (Voting Rights)

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    All my lymphocytes (CD4, CD8 etc) are all below normal, only normal range counts are my NK cells.

    I've read that CD8 deficiencies also occurs in healthy blood relatives of patients with autoimmune diseases, suggesting it is genetically determined.
     
  12. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    I don't see a problem with the threshold. When the research community finds something solid consensus on that falls into place pretty automatically. Nothing in the ME field except perhaps the CPET stuff gets near the level needed.

    @Snow Leopard is the person who understands the CPET issues best. Maybe he could give us an update on the recent findings just briefly here. Exactly what is it that the PWME's physiology does not do on day 2 and are we sure it is not influenced by voluntary factors?
     
  13. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    @Jonathan Edwards

    OK, non-scientist question here: could you tell me what constitutes consistent physiological abnormality? For example, 95%?

    But then how many replications are required?

    I'd have to look it up, but I think Dr. Peter Rowe said 97% of pwME have OI.

    IMHO, due to the measly funding levels for decades, it's not surprising consistent physiological abnormalities haven't been found in ME.
     
  14. mango

    mango Senior Member (Voting Rights)

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    Bryceson and Theorell's NK study was presented at the IiME colloquium in London in 2017. Accoding to an email conversation with Jonas Blomberg and other Swedish ME researchers at the time, one big unanswered question was whether the "something in the blood" affects the NK test results, and if that effect varies depending on the methods used.

    Has any research been done since, in order to find out if there's a difference between experiments done on whole blood and frozen, isolated cells?

    Would it really be fair to discard the whole NK story, without first trying to find the answer to these questions?
     
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  15. Snow Leopard

    Snow Leopard Senior Member (Voting Rights)

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    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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  16. Creekside

    Creekside Senior Member (Voting Rights)

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    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.
     
  17. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    Maybe more studies required, however the IOM report summary on OI says, "Sufficient evidence..." please see "Conclusion" below:


    From the 2015 IOM report: https://www.nap.edu/read/19012/chapter/6#102:

    "ORTHOSTATIC INTOLERANCE AND AUTONOMIC DYSFUNCTION



    Summary

    There is consistent evidence that upright posture is associated with a worsening of ME/CFS symptoms, as well as the onset of other symptoms such as lightheadedness, nausea, and palpitations. While there is variability in the reported prevalence of orthostatic intolerance in ME/CFS, heart rate and blood pressure abnormalities during standing or head-up tilt testing are more common in those with ME/CFS than in those without ME/CFS. Heart rate variability analyses demonstrate a sympathetic predominance of autonomic tone in those with ME/CFS, including during sleep.

    Conclusion: Sufficient evidence indicates a high prevalence of orthostatic intolerance in ME/CFS, as measured by objective heart rate and blood pressure abnormalities during standing or head-up tilt testing or by patient-reported exacerbation of orthostatic symptoms with standing in day-to-day life. These findings indicate that orthostatic intolerance is a common and clinically important finding in ME/CFS."

    https://www.nap.edu/read/19012/chapter/6#107
     
  18. DokaGirl

    DokaGirl Senior Member (Voting Rights)

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    You hit the nail on the head here, @Creekside - "properly done CPET test." (my bolding)
     
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  19. Jonathan Edwards

    Jonathan Edwards Senior Member (Voting Rights)

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    By consistent physiological abnormality I really just mean finding the same thing each time people look. So one study finding low NK numbers and normal function and another showing normal numbers and low function is no good. It is also no good if the findings don't look to be measuring the same effect as in study A finds X is 80 in ME and 40 in normals and study B finds X is 120 in ME and 100 in normals. On the other hand if study A finds 80% of PWME with high X and study B only finds 30% of PWME with high X that could be a selection problem so would not be so much a problem.

    For most of the things reported abnormal in ME there are about as many reports of not finding anything as finding something and the findings tend to be different in significant aspects in each study.

    When somebody reported antibodies to Ro and La in SJogren's syndrome half a dozen labs all over the world had found exactly the same thing within a year or so. Moreover, thousands of labs have been finding the same thing for decades since. Similarly people with asthma show reduced peak expiratory flow rate relative to vital capacity all over the world.

    I am not surprised that nobody has found consistent physiological abnormalities in ME. It is quite difficult to work out what one would be looking for.

    Orthostatic intolerance is a symptom pattern and that is different from a physiological abnormality per se. Almost anyone who feels significantly ill is likely to have orthostatic intolerance for one reason or another. Orthostatic tachycardia would be a physiological abnormality but it remains very unclear to me that this is a consistent finding in ME OI.
     
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  20. BurnA

    BurnA Senior Member (Voting Rights)

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    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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