Assessing cellular energy dysfunction in CFS/ME using a commercially available laboratory test, 2019, Morten, Newton et al

[Esther12]

The first thing I ought to do is declare my interest which is that I depend on Dr Myhill's diagnosis to provide medical evidence for benefits assessment i.e. PIP and ESA. I don't know of another doctor in the UK who will provide a diagnosis as evidence and back it up with written statements as she has done for me, for which I am grateful. Other doctors I saw before finding Dr Myhill, who had diagnosed aspects of my condition had turned me down flat when it came to providing evidence for benefits assessment. This is my financially and politically influenced medical reality and an example of how the medical establishment closes ranks against ME patients in the face of uncertainty, with the exception of a few brave souls like Dr Myhill who has paid a price for nonconformity. So in my view she is a hero even if the mito test is an uncertain quantity. What is science about if not investigating the uncertain?

I had these mitochondrial tests (ATP translocation) from Dr Myhill and Drs McClaren Howard which provided evidence at one point along with cell free DNA tests for benefits assessment. To be honest at the time they provided really good value for money as they meant I could win the "card game" with the DWP who have twice now tried to unfairly and improperly disallow my claim and drop me in the meat grinder of coerced activity, which would be very counterproductive for me indeed as I have the real deal with PEM which can get very nasty for me.

These are important points. When pseudo-science is being used against patients to class them as undeserving of financial support, having pseudo-science to fight back with can be genuinely valuable. It's absurd that we're in this situation, and I think that any associaition with Myhill and broader advocacy efforts will be unhelpful, but I can see how many patients will still get good value from her so long as they go in with their eyes open.

edit: Though it also leaves people to the danger of the DWP being able to effectively undermine any claims from Myhill.

 

[NelliePledge]

Not aware that any of the other well known Drs who see ME patients in the U.K. use this test, or indeed any of the GPs who will be going under the radar. Their diagnoses and reports will also be being used for claims for benefits from DWP and/or pension schemes. I don’t think Dr Myhill has a monopoly on supporting ME patients.

 

[boolybooly]

These are important point. When pseudo-science is being used against patients to class them as undeserving of financial support, having pseudo-science to fight back with can be genuinely valuable. It's absurd that we're in this situation, and I think that any associaition with Myhill and broader advocacy efforts will be unhelpful, but I can see how many patients will still get good value from her so long as they go in with their eyes open.

edit: Though it also leaves people to the danger of the DWP being able to effectively undermine any claims from Myhill.

Dont Panic ! Not a problem if diagnosis is made on clinical presentation, which I probably should have said, was the case, especially for my PIP appeal after the test results changed, which was the point of providing alternative evidence.

The test did previously help provide evidence when it showed a problem but I no longer believe it to be diagnostic.

I believed it showed something, just not definitively or reliably ME CFIDS.


The issue of sample treatment is important in case it produces false positives or negatives but so is the issue of Canadian Consensus Criteria (CCC) the Diagnostic Guidelines Forum summary of criteria is helpful.
https://www.s4me.info/threads/main-diagnostic-criteria-and-guidelines.189/

Canadian Consensus Criteria

1. Fatigue:
2. Post-Exertional Malaise and/or Fatigue:
3. Sleep Dysfunction:
4. Pain:
5. Neurological/Cognitive Manifestations
6. At least one symptom from two of the following categories (see article for complete list):

• a. Autonomic Manifestations
• b. Neuroendocrine Manifestations
• c. Immune Manifestations

7. The illness persists for at least six months.

My anecdotal perspective aside, I dont trust the CCC because not everyone with autonomic or endocrine dysfunction also has immune dysfunction so there could be three or more different etiologies included in the CCC.

So the use of CCC to disprove a correlation for the mito test is not necessarily conclusive, since the stats for one subtype could be washed out by a factor of two thirds-ish by patients included on the basis of the other two (actually three if you include the triple) main symptom combinations.

 

[Amw66]

My aunt is severe, stuck in bed, no support. GP clueless and not interested - she has already been told that there is nothing they can do despite having symptoms of comorbidities. Basically abandoned, like many others.
The ATP profiles test was useful in showing a level of debilitation. From memory I think there was indication of membrane damage which could have been related to pesticides ( worked as a florist) , but I am not sure on this - it was 3 years ago.

Initially she looked to Optimum, but given that she has always been a healthy eater, input was limited. Testing for viruses didn't throw up anything relevant, she found the supportive psychology useful as she has had a fair amount of s***t in life. Talking to her I think she does regret not continuing with Optimum for longer - I think she felt that progress was not being made - at initial stages she was not bedbound, and expectations were perhaps unrealistic.

Support from Myhill has improved thyroid function, access to other tests ( such as stool analysis ) shows potential issues with fat metabolism ( so similar to recent research). Yes, NHS does stool testing, but not for ME- it does SIBO testing, but not for ME, you could have headaches investigated - but not with ME. A flexible GP is good, but there are limits to what GPs are willing to refer/ explore which is dependent on their world view of the condition.
The biggest difference she has experienced has been via magnesium injections - these have made a huge impact on heart palpitations- chances of a GP doing this ?
You can knock Myhill's presentation skills, and some woo-woo, but she can and does make a difference for some, she also remains curious - that in itself is a good thing. She can't make a difference for everyone, and outwith the NHS everything is expensive.

Our GP is willing to refer, but curious is one thing that she is not. The most curious has been the optician.

 

[richie]

Well, I'm unimpressed by that response. If the test is not diagnostic, why the hell is it being done? And she seems to be trying to suggest that the authors ran a different test than the one she uses, which I highly doubt. And finally what seems to be a refusal to defend the protocol further seems to me a concession that it is indefensible.

Diagnostic tests for a syndrome is a bit of a word game anyway. What gets diagnosed? Is the syndrome being explained by the test and therefore no longer a syndrome but an understood disease/illness or is an exclusion diagnosis being implied for a subgroup? BPS cynics are always ready to point out such inconsistency, call us naive and then sell their "objective" tale to journos who are three times as naive again.

I remain hopeful that the Myhill/McL test has some validity but Mito probs are regularly found in Parkinson's, MS, depression etc etc and even if reliably ascertained by a given test, this would not necessarily show a direct path to symptoms or elucidate causes.

We need mito groups, cytokine/(pro)inflammation groups, autonomic groups, hybernation groups, infection groups, 2 day cpet groups all working together.

 

[richie]

Multiple names and definitions have contributed to the mess we are in. Why add another when your object is to help patients?

Charles Shepherd says above, "I do not believe that there is any robust research evidence, at present, to confirm the use of the term encephalomyelitis - inferring significant and active inflammation involving the brain and spinal cord...."

There is the evidence from autopsies of eg Sophia Mirza.

i believe CS is politically wise inn this matter. The trouble is that SM had dorsal root ganglionitis which is not encephalomyelitis. We already have neurologists ranged against us saying we do not have a neurological disease. IMO it is important not to provoke dismissal. Encephalopathy is defensible in terms of symptoms and can encompass encephalomyelitis. The reverse is also true but encephalopathy does not put the emphasis on a specific, unproven and disputable process. It is a foot in the door with skeptics -"Look sth is wrong here, we don't know what, let's search together" inviting a possible "OK" rather than "This is myalgic encephalomyelitis" - "How do you know? I see no evidence, bye, bye"

All the nomenclature stuff is of course vexing.

 

[JemPD]

Is the syndrome being explained by the test and therefore no longer a syndrome but an understood disease/illness

The word 'syndrome' doesn't necessarily mean unexplained/not understood, it just means a collection of signs/symptoms that appear together. Eg Down Syndrome, Anderson Syndrome, Toxic Shock Syndrome - all with well understood aetiology/pathogenesis.

ETA - I do agree with your point though, and indeed with your next post about encephalopathy.
As I understand it dorsal root ganglion are not part of the spinal cord so the autopsies don't prove encephalomyelitis.

 

[richie]

The word 'syndrome' doesn't necessarily mean unexplained/not understood, it just means a collection of signs/symptoms that appear together. Eg Down Syndrome, Anderson Syndrome, Toxic Shock Syndrome - all with well understood aetiology/pathogenesis.

ETA - I do agree with your point though, and indeed with your next post about encephalopathy.
As I understand it dorsal root ganglion are not part of the spinal cord so the autopsies don't prove encephalomyelitis.

Fair point. I have fallen into the ME patients' trap of associating "syndrome" with "unexplained". You are right.

I do think my point about diagnostic tests raising the question of an exclusion diagnosis still stands. All Downs people can (as far as I know) have one or other test to prove they have the chromosomal abnormality. That is one or other a diagnostic tests for Downs 100%. If 60% or 80%of ME diagnosed have abnormal test Z results, the question is then whether test Z is diagnostic for ME and what to do with the remainder or whether the 60/80% should be relabelled as having a newly understood syndrome or various other interpretations. It remains important while there are people about who think a positive result on "their" test means they have ME and others do not, which takes us back to the vexed question of nomenclatures and what ME stands for and back again to the central importance of symptoms for diagnosis of a syndrome still widely known under one label i.e ME. It's a fine mess.

 

[Evergreen]

About the diagnostic test/tool question:

Both Dr Myhill's initial response (see @Sarah94 ‘s message #25 above) and this response by Dr McLaren-Howard stress that

[Dr Myhill:] This test was never “marketed” as a diagnostic test for CFS/ME! It is simply a measure of mitochondrial function

[Dr McL-H:] This test has never been presented as a diagnostic test for CFS/ME by me or by Dr Myhill. It was designed to explore ATP-related energy pathways in patients with chronic fatigue.

[Dr McL-H:] In their conclusions, the authors advise that the MES test should not be used as a diagnostic tool for CFS/ME. It never has been!

@Snowflake already pointed out that Dr Myhill seems to suggest otherwise in her book (#31 this thread).

Here are quotes from the Myhill team’s three publications on the ATP profile/mitochondrial function tests:

In the 2009 paper http://www.ijcem.com/files/IJCEM812001.pdf:

The “ATP profile” test is a powerful diagnostic tool and can differentiate patients who have fatigue and other symptoms as a result of energy wastage by stress and psychological factors from those who have insufficient energy due to cellular respiration dysfunction.

In the 2012 paper http://www.ijcem.com/files/IJCEM1204005.pdf:

The ATP Profile is a valuable diagnostic tool for the clinical management of ME/CFS.

The ATP Profile as a diagnostic tool for ME/CFS

In terms of a diagnostic test, none of these patients are in the normal region for MESinh and Nfn and none are in the normal region for just Nfn…We should still be cautious because of the small sample sizes and because no mildly ill patients were tested. Within these limitations the ATP profile is an inclusive and sensitive test for ME/ CFS. However, we cannot claim that it is specific to ME/CFS because there are other neurological illnesses [6, 7] and metabolic syndromes [8] associated with mitochondrial dysfunction [9].

Diagnosis of ME/CFS The ATP profile is a test which provides numerical values of 6 biomedical quantities regarding energy provision by the mitochondria in neutrophils, the main effectors of the innate immune system. The ATP Profile is an objective test of ME/CFS and clearly shows that this illness has a physical basis.

Implications for the treatment of ME/CFS Here we have emphasized the use of biomedical tests to aid in the diagnosis and to vastly improve our knowledge of the pathophysiology involved in this illness. In addition, these biomedical tests can act as a valuable guide for medical and therapeutic interventions.

In the 2012/2013 paper http://www.ijcem.com/files/IJCEM1207003.pdf:

In this paper we will show that the ATP Profile is a valuable diagnostic and clinical management tool for ME/CFS.

Finally, mitochondrial function tests do not constitute a diagnostic tool for chronic fatigue simply because the symptom of fatigue can result for many possible reasons. However in seriously afflicted ME/CFS patients, we find that poor mitochondrial function is invariably present as is a high level of cell-free DNA usually accompanied by poor anti-oxidant status.

Clinically we have found the mitochondrial function tests to be the single most useful diagnostic and therapeutic aid in the management of ME/CFS. They should be made available to all who need them.

Given those quotes it seems quite reasonable that Tomas et al said that the test is "marketed as a diagnostic test for CFS/ME". I can’t see how those quotes are consistent with the claim that Myhill & McLaren-Howard never saw the test as a diagnostic tool. What am I missing?

Do Myhill & McLaren-Howard just mean that you wouldn't diagnose ME or CFS based on this test alone? That what you're diagnosing with the test is not ME or CFS but mitochondrial problems? And that they're using the test to guide which supplements to recommend i.e. management rather than diagnosis?

 

[Evergreen]

I’m really pleased that Tomas and her team did this important piece of work. My impression, from hearing other people’s test results and how they got on with recommended supplementation and repeat test results, was that the test was probably not reliable. But I would have been very interested if Tomas’s team had been able to replicate the Myhill team’s findings.

I found it interesting to read Dr John McLaren-Howard’s comments. Maybe he will be intrigued enough to play around with delays and other variables and see whether this changes test results. If there is something to the test, they should be able to design a study to show it.

I didn’t find Dr Myhill’s response helpful. To me, it read as marketing for her publications, book, test, website and supplements, until the very last section. The idea of having one patient’s blood tested in both labs on the same day is interesting, but as far as I know is not a requirement of, or even a desirable part of, or prerequisite to, a replication study.

It seems to me that if a test is valid and reliable, you should be able to replicate it in another lab with different patients by following the test protocol. If you think there are differences between how the original and replication studies analysed the samples that account for the differences in findings, then design a study to show how those differences affect findings.

 

[Mithriel]

i believe CS is politically wise inn this matter. The trouble is that SM had dorsal root ganglionitis which is not encephalomyelitis. We already have neurologists ranged against us saying we do not have a neurological disease. IMO it is important not to provoke dismissal. Encephalopathy is defensible in terms of symptoms and can encompass encephalomyelitis. The reverse is also true but encephalopathy does not put the emphasis on a specific, unproven and disputable process. It is a foot in the door with skeptics -"Look sth is wrong here, we don't know what, let's search together" inviting a possible "OK" rather than "This is myalgic encephalomyelitis" - "How do you know? I see no evidence, bye, bye"

All the nomenclature stuff is of course vexing.

This was Shepherd's rationalisation for the change of name, but it has been years and did not make the slightest bit of difference. It has only added to the confusion of names and loses the association with the WHO listing as neurological. A waste of time, not a single neurologist has said "Oh, right, I believe you now. They dismiss us by lying about us and refusing to see us, distorting our illness for their own benefit. I used to think facts would change their mind but that was just naivety on my part.

Also there has always been evidence of inflammation in the brain and damage found in brain scans and on proper examination and history taking.

 

[wigglethemouse]

Usually when there is such a big disagreement you need to get both parties in the same room and figure out why. I'm surprised the ME Association has not facilitated this. Shame on them if they haven't.

Can't John Mclaren Howard and someone from this research paper get together at the Acumen labs and do some very simple tests with both present every step of the way, and troubleshoot. Say 2 patients, 2 controls, fresh blood and 24 hour blood, blinded samples and see what happens to the results. Loser buys dinner and the beers.

This would help identify where in the process is the issue. Is it really time delay as the paper states, or is it a process issue? Or somewhere in the middle.

 

[richie]

This was Shepherd's rationalisation for the change of name, but it has been years and did not make the slightest bit of difference. It has only added to the confusion of names and loses the association with the WHO listing as neurological. A waste of time, not a single neurologist has said "Oh, right, I believe you now. They dismiss us by lying about us and refusing to see us, distorting our illness for their own benefit. I used to think facts would change their mind but that was just naivety on my part.

Also there has always been evidence of inflammation in the brain and damage found in brain scans and on proper examination and history taking.

I do see your point and there is the problem with WHO, which you rightly point out.

As I see it ME encephalopathy = one less thing to be attacked on. I cannot with certainty say I have encephalomyelitis and I would prefer to avoid the argument with aggressive sceptic types.

I suppose CS gets round this by fudge and I do have sympathy for that. Not sure there is an ideal approach as yet.

There was a discussion on here as to whether the brain activity in e.g. Younger's work was actual inflammation and there is the issue of pro-inflammatory cytokine presence vs actual inflammation, which @jonathanedwards pointed out. Personally given Japanese and French researchers have also noted some kind of inflammatory activity in the brain and given inflammatory processes are also involved in neuroimmune physical and mental illness, I reckon there will be brain inflammation of some sort or at least proinflammatory cytokine activity among at least some sufferers, but it may not be encephalomyelitis and we need to push the research/recognition and see how it equates to e.g. the CPET findings.

Appreciate your reservations re. encephalopathy.

 

[richie]

Usually when there is such a big disagreement you need to get both parties in the same room and figure out why. I'm surprised the ME Association has not facilitated this. Shame on them if they haven't.

Can't John Mclaren Howard and someone from this research paper get together at the Acumen labs and do some very simple tests with both present every step of the way, and troubleshoot. Say 2 patients, 2 controls, fresh blood and 24 hour blood, blinded samples and see what happens to the results. Loser buys dinner and the beers.

This would help identify where in the process is the issue. Is it really time delay as the paper states, or is it a process issue? Or somewhere in the middle.

Great post. I get so frustrated when I think people of integrity are not getting together to hammer things out. Relative waste of two teams' talents.

 

[boolybooly]

I think it was good that Tomas et al decided to look at this and I hope they will stay interested and keep asking questions as I am sure they are sincere.

It is a shame they could not do the translocator study and as they mentioned, the study was small but assuming the outcome is indicative it raises questions, regarding how the ATP ratio results are not significant for PWME if the conclusions of metabolomics studies etc are accurate?

Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome
https://insight.jci.org/articles/view/89376

Myoblasts grown in presence of serum from patients with severe ME/CFS showed metabolic adaptations, including increased mitochondrial respiration and excessive lactate secretion. The amino acid changes could not be explained by symptom severity, disease duration, age, BMI, or physical activity level among patients. These findings are in agreement with the clinical disease presentation of ME/CFS, with inadequate ATP generation by oxidative phosphorylation and excessive lactate generation upon exertion.

Does this show us that the mitochondrial ATP making machinery is decoupled from metabolic substrate and is not the source of impediment? Or... I am not sure if I am missing something as I am a bit tired... obviously... but the question I would ask is whether this Histopaque method of isolating and separating the cells as part of the experimental protocol could have removed blood plasma factors which some experiments, like above and the nanoneedle stress test etc, appear to indicate are mediating measurable dysfunction? I genuinely do not know.

 

[Andy]

Usually when there is such a big disagreement you need to get both parties in the same room and figure out why. I'm surprised the ME Association has not facilitated this. Shame on them if they haven't.

Why should it be the ME Associations responsibility? Should Myhill be the one to reach out to try to resolve this, concerned that she might be taking money for a test that isn't accurate?

 

[wigglethemouse]

Why should it be the ME Associations responsibility? Should Myhill be the one to reach out to try to resolve this, concerned that she might be taking money for a test that isn't accurate?

I just thought it was the decent think to do, given the damning statements in this paper about the Accumen test. I don't ever remember reading such strong language in a Scientific paper. The UK produces very little biomedical research as it is, why antagonise further......... now we have "press releases" rather than some quiet phone calls to resolve differences.

Of course, Myhill/McLaren-Howard should reach out too. But they have been "slapped in the face" hard, and in public, and I would expect them to be very upset. I would, if it was my work.

 

[Esther12]

I'm not a fan of the 'quiet phonecall' approach to science... that seems to end up costing patients in the long run. Wessely is great at it.

 

[richie]

I do find it hard to believe that if Mc/My have found regular ME/control differences it's all down to processing time. Just seems bizarre that that would occur.

 

[InitialConditions]

I do find it hard to believe that if Mc/My have found regular ME/control differences it's all down to processing time. Just seems bizarre that that would occur.

exactly. you'd likely have to have a dependency of processing time on patient illness severity.