Dr Alan Moreau's new, low-stress protocol for provoking PEM.[Thoughts?]

[Simon M]

Dr Alan Moreau presented preliminary results of his work on micro-RNAs (miRNA) at the recent Stanford (2:26) and CMRC conferences. Micro-RNAs are small molecules that regulate gene expression by binding to messenger RNA and blocking their translation into proteins. miRNAs might be new to you and me, but it is an ancient system of gene regulation and some of our micro-RNAs are similar to those of fish. Moreau reported significant differences in miRNAs between ME/CFS patients and controls, particularly after a PEM test.

However, what really caught my eye about his work was his new, low intensity protocol for provoking PEM, which potentially has wide application in ME/CFS research. It is a deliberately "low stress" approach using a gentle arm massage from an inflatable cuff, similar to a blood pressure cuff but using about a 10th of the pressure. It is hard to imagine this has much effect, but Moreau said "believe me, it works". And he has some data to back up his claim.

I'm keen to hear what others make of this approach.



Intriguingly, the idea was suggested by the patient he referred to as "Christian". The arm massage is gentle but goes on a bit - 90 minutes. Because it is relatively gentle test it is suitable for more typical patients than the maximal exercise tests used to provoke PEM at the moment. And that means it can be applied to more representative patients than the maximal exercise test. Moreau has recruited over a hundred patients and most of those are housebound, with testing done by a nurse who makes home visits.

So far, Moreau's study has preliminary data on 25 patients, just under a quarter of the total cohort.

The study measured symptoms experienced following the test (I think perhaps a couple of days) and recorded "post exertional malaise" experiences on the day of the test and the two days that followed it.

Importantly, a quarter of patients showed no sign post exertional malaise, or other symptoms. Moreau said he didn't want to make the test more intense because he didn't want to cause harm to the three quarters of patients who did show signs of PEM.

So here's the symptom data. To make things a bit more complicated, the results are broken into four subgroups, which emerged from the preliminary micro-RNA data:




The next results are specifically for post exertional malaise, though the question wording shown relates to fatigue/tiredness.



______

I am planning to get in touch with Dr Moreau about the test, because I think very interesting approach with great potential. And I was planning to summarise any significant points that emerge here and can pass on any questions as well.

 

[Mij]

To add, a video where Dr. Moreau discusses his test

 

[Adrian]

I am planning to get in touch with Dr Moreau about the test, because I think very interesting approach with great potential. And I was planning to summarise any significant points that emerge here and can pass on any questions as well.

I think the third slide is a little confusing because the catagories seem to overlap but I guess people were told to choose the best fitting sentence.

I also wonder if severity rather than some class may be significant in whether PEM is experienced.

Has he reported the blood results? Did they correlate with symptoms - there is always a reporting (and perception) problem anyway.

I like the way he has a nurse go to peoples homes so that they are relatively rested or its a cleaner comparison rather than having to control for the complexity of the journey to the blood center. But even having a nurse come can be additional stress which takes energy and could cause PEM.

I do think he is on the right approach for testing with the multiple blood tests and introducing a simple well controlled level of activity to compare before and after.

From what you say he was dealing with house bound patients so the test may not help with those with a higher level of function.

 

[Sasha]

Thanks for raising this interesting issue, @Simon M!

A few questions occur to me:

Is he measuring PEM or post-exertional fatigue? The categories used on the pie charts suggest the latter, perhaps.

Would it be worth doing the sort of blood tests that the Lights did to see if this test is creating the same sort of PEM?

Do we have figures on how many patients crash in response to an exercise challenge (the usual way of producing PEM?), in order to demonstrate whether this is safer? (Perhaps this isn't relevant, given that he seems to want a test that even severely affected patients can do, and they probably wouldn't be able to do such a test.)

 

[Simon M]

To add, a video where Dr. Moreau discusses his test

Sorry. The Stanford video is best https://www.s4me.info/threads/cfs-r...ymposium-sept-29-2018.3255/page-5#post-109963 @ 2:26

Has he reported the blood results? Did they correlate with symptoms - there is always a reporting (and perception) problem anyway.

He did, and he made a case for several: for example, mental fatigue could be explained by one of the micro RNA findings. But note that these are preliminary results based on only a quarter of all patients being tested, and as each micro RNA can affect up to 200 different genes , it might not be that difficult to create a plausible explanation. I think the jury is out on this.

I also wonder if severity rather than some class may be significant in whether PEM is experienced.

Yes, and is this related to a final point as well?

But even having a nurse come can be additional stress which takes energy and could cause PEM.

that’s a fair point, but it’s probably a lot less stressful than going to the clinic (that’s always been an issue raised about any kind of testing of patients; the samples . are always taken after patients have made a probably-exhausting journey to a clinic. )

From what you say he was dealing with house bound patients so the test may not help with those with a higher level of function.

Good point. There is a case that we need a different test based on the patient’s severity. But also based on how easily they get post exertional malaise, which isn’t simply a function of severity. Ideally, you would have a type of test, or a level of test, that is appropriate for each individual patient so they get stressed the right amount, and not too much.

Thanks for raising this interesting issue, @Simon M!

A few questions occur to me:

1. Is he measuring PEM or post-exertional fatigue? The categories used on the pie charts suggest the latter, perhaps.

2. Would it be worth doing the sort of blood tests that the Lights did to see if this test is creating the same sort of PEM?

3. Do we have figures on how many patients crash in response to an exercise challenge (the usual way of producing PEM?), in order to demonstrate whether this is safer? (Perhaps this isn't relevant, given that he seems to want a test that even severely affected patients can do, and they probably wouldn't be able to do such a test.)

1. That would be my question too. It might be interesting to ask patients who done the test
a) asking if they have post exertional malaise post test (perhaps it with the Institute of Medicine PEM description as a prompt)
B). Does it feel the same as they normally experience with PEM. in every day life?
3.much as they I am intrigued by the Lights‘ results, given that they have never been replicated, it doesn’t seem appropriate to treat it as a gold standard reference.

 

[ME/CFS Skeptic]

It is a deliberately "low stress" approach using a gentle arm massage from an inflatable cuff, similar to a blood pressure cuff but using about a 10th of the pressure.

I find it hard to believe this causes PEM.

Its a bit of a catch 22. Hard to say this but if you're looking for a test where patients do not suffer/deteriorate at all, then you're probably not studying PEM.

That doesn't exclude that Moreau is studying something else that is interesting. I'm just worried about the inflation of the term PEM.

 

[ScottTriGuy]

I find it hard to believe this causes PEM.

At first blush I would agree - but thinking how sensitive my arms are to effort, more so than my legs (and this is the opposite of one ME friend who can use her arms a lot relative to her legs), perhaps over 90 minutes it would cause me PEM - so wonder if that impacts who gets PEM from the blood pressure cuff?

If I was sitting with the cuff, it would more likely cause me PEM than being horizontal.

 

[Andy]

I find it hard to believe this causes PEM.

Its a bit of a catch 22. Hard to say this but if you're looking for a test where patients do not suffer/deteriorate at all, then you're probably not studying PEM.

That doesn't exclude that Moreau is studying something else that is interesting. I'm just worried about the inflation of the term PEM.

I too have reservations in this regard. @Simon M , do we know if Moreau has compared miRNA measurements between PwME who have taken a 2-day CPET and PwME who have taken this arm massage challenge? If he has, does it show similarities? To me, this would go some way towards showing that the two challenges are in some way comparable.

 

[Trish]

Even if it's not PEM he's inducing, doing biomedical test that compare the effect of 'activity' of this sort between healthy people and pwME could provide some useful science about how our bodies respond to activity.

 

[NelliePledge]

I think it’s possible 90 minutes could provoke PEM I find massage difficult to tolerate for more than 30 minutes and only very gentle and I have mild/moderate ME not housebound.

 

[Hoopoe]

I see that he is collecting objective data before and after this PEM provocation method. That seems important because in a fluctuating condition where people know they are supposed to get PEM from this (maybe just a mild one due to the mildness of the method) it's probably easy to get false positives.

 

[dreampop]

I think the concept is related to releasing metabolites like lactic acid in the local tissue. It seems similar to this Straud study, where they have patients do a grip exercise and use a cuff to trap the metabolites in the arms. The authors argued that was evidence of central sensitization (of fatigue/pain receptors like ASIC, P2X, TRPV). However, it's not clear, to me, at least, that either are provoking feeling like shit or provoking PEM. Moreau's responses don't really read like PEM to me. Also not clear that the receptors heightened response is "sensitization" as it is often misunderstood or part of a biologic shift.

That being said, I have responded poorly to massage. Like a 60 minute full body massage usually does not improve symptoms, and if anythign makes me feel like worse. But it's been a long time, so I don't know if it was PEM or not.

 

[Sid]

This would be in line with anecdotal observations discussed on other fora that massage makes many patients worse. I don't know that it's actual PEM he's measuring but it's interesting nonetheless that something this innocuous elicits symptoms and biological alterations.

 

[rvallee]

I like the way he has a nurse go to peoples homes so that they are relatively rested or its a cleaner comparison rather than having to control for the complexity of the journey to the blood center. But even having a nurse come can be additional stress which takes energy and could cause PEM.

I think it's possible he has a different homebound cohort but for my part I went to the hospital, which itself is definitely demanding in energy, but otherwise they understand the limitations of patients. The nurse is there the whole time and asks some questions at the beginning and throughout. Always a good occasion to share some of the info I gathered over the years.

There is an initial blood draw before the cuff is place. At this point it's fair to say that just going there has already raised the metabolism a bit. That's the only real flaw I can see since the "stress" from the cuff itself is about comparable with making the trip itself. Frankly talking for over an hour exhausted me more

We get a call a few days later to ask about PEM but the test is gentle enough that it didn't set me much, even with the trip. It's mostly just asking if there is significant PEM and any symptoms. Not as exhaustive as during the test. I would say this does not really provoke full PEM, just the immediate response to exertion that have been found in other studies. The follow-up seems more about just making sure to get any data that could be useful, even if it's not apparent.

 

[dreampop]

This would be in line with anecdotal observations discussed on other fora that massage makes many patients worse. I don't know that it's actual PEM he's measuring but it's interesting nonetheless that something this innocuous elicits symptoms and biological alterations.

I'm impressed you know the plural of forum!

 

[Dechi]

I am part of this study. I had the cuff test done but I don’t clearly remember my answers to the afterwards questionnaire. I remember I had fatigue from the test, maybe more difficulty sleeping. But nothing even remotely as bad as the 2-day CPET test (I crashed for 3 weeks).

There is part II coming up and if it’s the same, with my baseline having dropped, I will definitely have difficulty tolerating the pressure, and yes, maybe even PEM this time.

 

[Sid]

I'm impressed you know the plural of forum!

I knew those endless hours of studying Latin declensions in junior high would finally pay off in a big way one day.

 

[Tilly]

I am part of this study. I had the cuff test done but I don’t clearly remember my answers to the afterwards questionnaire. I remember I had fatigue from the test, maybe more difficulty sleeping. But nothing even remotely as bad as the 2-day CPET test (I crashed for 3 weeks).

There is part II coming up and if it’s the same, with my baseline having dropped, I will definitely have difficulty tolerating the pressure, and yes, maybe even PEM this time.

Just wanted to say thank you for doing both of these tests, I think that is amazing.

I also wanted to ask if the sleep problems were wired yet tired/exhausted/fatigued or were more of more sleep needed. I think the two differences are part of the problem as in two different parts.

Second thing is do you think that the CEP test is too much to expect to put patients through.

 

[andypants]

This would be in line with anecdotal observations discussed on other fora that massage makes many patients worse. I don't know that it's actual PEM he's measuring but it's interesting nonetheless that something this innocuous elicits symptoms and biological alterations.

I get significantly worse from massages, however I'm not sure if it's from PEM or if its an immune reaction/inflammation (which is the point of a massage, sort of, but likely is too much for PwME vs healthy people). I've avoided them for a while and didn't think to consider the possibilities at the time, now my memory is too unreliable to say. Does the inflammation result in PEM or do you just get worse because there's an inflammatory response?

I went to a chiropractor for the pain between my shoulder blades 2,5 years ago. He told me that as knotted up as I was, I would likely have an immune reaction that would last for 2-3 days where I would feel a little fluey. It lasted for 7-8 weeks and permanently worsened my ME (undiagnosed at the time). Not exactly a massage, it was an adjustment, but the reaction absolutely brought on PEM/worsening along with a heavy inflammatory response.

I just remembered that when I use a massage pillow I have to limit it to one session of 20 minutes, or I'll be wiped out. I have a gut feeling 90 minutes would make me feel pretty awful, however mild the massage is. I'm looking forward to seeing their results, it should be interesting regardless.

 

[Amw66]

I think the concept is related to releasing metabolites like lactic acid in the local tissue. It seems similar to this Straud study, where they have patients do a grip exercise and use a cuff to trap the metabolites in the arms. The authors argued that was evidence of central sensitization (of fatigue/pain receptors like ASIC, P2X, TRPV). However, it's not clear, to me, at least, that either are provoking feeling like shit or provoking PEM. Moreau's responses don't really read like PEM to me. Also not clear that the receptors heightened response is "sensitization" as it is often misunderstood or part of a biologic shift.

That being said, I have responded poorly to massage. Like a 60 minute full body massage usually does not improve symptoms, and if anythign makes me feel like worse. But it's been a long time, so I don't know if it was PEM or not.

My daughter can inly tolerate 10 mins for neck and shoulder massage. Initial 15 mins try was too much and took a day in bed to get some energy back, so this would seem feasible to me