Myalgic Encephalomyelitis or What? The International Consensus Criteria (Frank Twisk, 2019)

[adambeyoncelowe]

Abstract published today:
Abstract
Myalgic encephalomyelitis (ME) is a neuromuscular disease with two distinctive types of symptoms (muscle fatigability or prolonged muscle weakness after minor exertion and symptoms related to neurological disturbance, especially of sensory, cognitive, and autonomic functions) and variable involvement of other bodily systems.

Chronic fatigue syndrome (CFS), introduced in 1988 and re-specified in 1994, is defined as (unexplained) chronic fatigue accompanied by at least four out of eight listed (ill-defined) symptoms.

Although ME and CFS are two distinct clinical entities (with partial overlap), CFS overshadowed ME for decades.

In 2011, a panel of experts recommended abandoning the label CFS and its definition and proposed a new definition of ME: the International Consensus Criteria for ME (ME-ICC). In addition to post-exertional neuroimmune exhaustion (PENE), a mandatory feature, a patient must experience at least three symptoms related to neurological impairments; at least three symptoms related to immune, gastro-intestinal, and genitourinary impairments; and at least one symptom related to energy production or transportation impairments to meet the diagnosis of ME-ICC.

A comparison between the original definition of ME and the ME-ICC shows that there are some crucial differences between ME and ME-ICC. Muscle fatigability, or long-lasting post-exertional muscle weakness, is the hallmark feature of ME, while this symptom is facultative for the diagnosis under the ME-ICC. PENE, an abstract notion that is very different from post-exertional muscle weakness, is the hallmark feature of the ME-ICC but is not required for the diagnosis of ME.

The diagnosis of ME requires only two type of symptoms (post-exertional muscle weakness and neurological dysfunction), but a patient has to experience at least eight symptoms to meet the diagnosis according to the ME-ICC. Autonomic, sensory, and cognitive dysfunction, mandatory for the diagnosis of ME, are not compulsory to meet the ME-ICC subcriteria for ‘neurological impairments’.

In conclusion, the diagnostic criteria for ME and of the ME-ICC define two different patient groups. Thus, the definitions of ME and ME-ICC are not interchangeable.

https://www.mdpi.com/2075-4418/9/1/1

 

[adambeyoncelowe]

I find this interesting, because I've literally been having this conversation with others the last few weeks. When you compare the different ME criteria (as opposed to the CFS criteria), they all used to focus on muscle fatiguability, and then switched to PEM (brought in from the CFS criteria).

Jason has sort of acknowledged this, I think, by trying to capture muscle fatiguability (MF) in his questionnaires. According to him, MF is more highly endorsed as a description of PEM than the actual descriptions given in ME-ICC, so are the two things the same or not?

It seems to me the repeat hand-grip strength test results are showing MF, while the two-day CPET test is showing PEM.

It's possible both are actually showing MF or that MF is an early warning sign of PEM (perhaps the point at which muscles have depleted their energy stores/ATP, with the delayed effects being the medium-term consequences of running out of ATP on the rest of the body).

What do people think about this? And, returning to the criteria issue again, do the broad and numerous symptoms of ME-ICC better fit the illness or do the two main symptom domains Twisk talks about (muscular, neurological)?

 

[Andy]

And, returning to the criteria issue again, do the broad and numerous symptoms of ME-ICC better fit the illness or do the two main symptom domains Twisk talks about (muscular, neurological)?

It seems to me that the only way to sort out the definition issue is to collect data on a lot of patients, asking the same questions of them all, and then properly analyse it. I would argue that currently we just don't know which definition is the most accurate.

 

[ME/CFS Skeptic]

According to him, MF is more highly endorsed as a description of PEM than the actual descriptions given in ME-ICC

Really? Do you have a link for that? I thought he simply analyszed PEM descriptions and argued that PENE failed to include muscle fatigue which is a part of most other PEM descriptions such as his DePaul Post-Exertional Malaise Questionnaire.

Personally I see PENE and (post-exertional) muscle weakness as elements of the same phenomenon. Jasons new PEM questionnaire is very extensive and includes most of these elements. So I suppose testing the questionnaire in a large sample would help to see which factors differentiate ME patients from other diseases.

 

[Trish]

I think the only way we'll sort it all out is when we have biomedical tests that distinguish the subgroups definitively. If that ever happens.

 

[Unable]

I think the only way we'll sort it all out is when we have biomedical tests that distinguish the subgroups definitively. If that ever happens.

And that will only happen once researchers with a vested interest in a fatigue approach are weeded out of the research pool!

So difficult to always have to scrutinise for the faulty assumptions, data misinterpretations, and over-hyped conclusions, in their stream of publications.

 

[ME/CFS Skeptic]

I think the only way we'll sort it all out is when we have biomedical tests that distinguish the subgroups definitively.

I disagree. This is mostly about clinical information. There seems to be a large group within the ME/CFS entitiy that reports post-exertional relapses that are quite distinct from most other diseases we know of.

So I think researchers just need to pay more attention to what patients are saying. Correct me if I'm wrong but I think the Chu et al. (2018) paper was the first extensive study to look into how ME/CFS-patients described their post exertional relapses.

The bias that this is not a real disease but just some fatigue related complaints has blocked serious research in this area for decades. I don't think we need biomedical tests to get this work done. It seems more like the opposite: we should make better use of the clinical information that's allready there to increase chances of finding a biomedical test.

 

[Trish]

I disagree. This is mostly about clinical information.

Fair enough. You make very good points, and I agree that in the meantime we need patient cohorts in research to be properly diagnosed using a robust definition that separates out people who, for example, have chronic fatigue but no PEM or other symptoms. Discarding the Oxford criteria is supposed to do that.

But I look at all the criteria and decide I fit them all...

 

[adambeyoncelowe]

Really? Do you have a link for that? I thought he simply analyszed PEM descriptions and argued that PENE failed to include muscle fatigue which is a part of most other PEM descriptions such as his DePaul Post-Exertional Malaise Questionnaire.

Personally I see PENE and (post-exertional) muscle weakness as elements of the same phenomenon. Jasons new PEM questionnaire is very extensive and includes most of these elements. So I suppose testing the questionnaire in a large sample would help to see which factors differentiate ME patients from other diseases.

Yes (if I'm reading it right):

However, the PEM question that was most acceptable from [for?] patients was from Ramsay, but other highly endorsed questions were from the ME-ICC and DSQ.

From here: https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise

Ramsay's description is based on MF.

There was this in the study you linked to:

Almost all of the patients, 96.3%, have at least one of the ME-ICC PEM symptoms at the 2-2 level in the General factor; however, the Muscle factor is not assessed with this criteria. Thus, any PEM experience that includes muscle-specific fatigue may not be assessed with the symptoms described in the International Consensus Primer for Medical Practitioners for this case definition (Carruthers et al., 2012).

The DPQ looks like the best questionnaire that we have, but it notably adds to the ME-ICC criteria, rather than relying solely on it.

 

[ME/CFS Skeptic]

Yes (if I'm reading it right):
From here: https://www.researchgate.net/publication/323916016_Patient_perceptions_of_post_exertional_malaise

Ramsay's description is based on MF.

They deconstructed each definition into different statements. The one that was taken from the Ramsay definition and that got the highest score was not muscle fatigability but "Prolonged worsening of symptoms after physical activity’. You can see it in table 3. 'Excessive muscle fatigue with minor activity', 'Muscle fatigability after minor exertion' and 'Muscle weakness after minor exertion' only scored around 70% (which is still quite high for a description that is more concrete and distinct).

The text reads:

The most-liked descriptions include: ‘Prolonged worsening of symptoms after physical activity’ (87.9%, Ramsay); ‘Symptoms worsen with exertion’ (87.8%, ME-ICC); ‘Post-exertional exhaustion that is immediate or delayed’ (85.2%, ME-ICC)

 

[adambeyoncelowe]

They deconstructed each definition into different statements. The one that was taken from the Ramsay definition and that got the highest score was not muscle fatigability but "Prolonged worsening of symptoms after physical activity’. You can see it in table 3. 'Excessive muscle fatigue with minor activity', 'Muscle fatigability after minor exertion' and 'Muscle weakness after minor exertion' only scored around 70% (which is still quite high for a description that is more concrete and distinct).

The text reads:

Good catch! However, this is a part of how Ramsay describes MF:

Muscle fatigability, whereby, even after a minor degree of physical effort, three, four or five days, or longer, elapse before full muscle power is restored and constitutes the sheet anchor of diagnosis. Without it I would be unwilling to diagnose a patient as suffering from ME, but it is most important to stress the fact that cases of ME or mild or even moderate severity may have normal muscle power in a remission. In such cases, tests for muscle power should be repeated after exercise.

 

[ME/CFS Skeptic]

I agree that in the meantime we need patient cohorts in research to be properly diagnosed using a robust definition that separates out people who, for example, have chronic fatigue but no PEM or other symptoms. Discarding the Oxford criteria is supposed to do that.

I think the term PEM has shifted from (1) simply being post-exertional malaise as introduced by the Fukuda criteria – something that is reported in many other diseases – to (2) a collection of all the detrimental effects exertion has on the health of ME/CFS patients. Some of these are quite remarkable and seem to have the potential to characterize and differentiate the disease.

The shift in the meaning of PEM causes confusion but it could also have some perks. Changing the definition of PEM could be an easy way to update the diagnostic criteria we have. Suppose for example that Jason tests his new and extensive PEM questionnaire in a large sample and sees that some elements (delayed onset, muscle weakness, prolonged recovery, the immune-type symptoms or whatever) clearly stand out in differentiating (a subset of) ME/CFS patients from other fatiguing illnesses. That would make it possible to update the CCC or IOM criteria quite easily, namely by requiring PEM to include these elements.

I think international organizations are sort of coming to an agreement that ME/CFS definitions without PEM are no longer acceptable. But I would very much like to see them go one step further and agree that asking patients if they experience malaise, exhaustion or symptom exacerbation after exertion is not enough to measure PEM. Sorry for going a little of topic with this but I think it is quite central to the problem of diagnostic criteria.

This is however based on the view that PEM, PENE and post-exertional muscle weakness are related to each other. Are there some who disagree with this and willing to explain their view?

 

[Patient4Life]

IMO, ME-ICC defines the most severely ill. CCC will capture original ME or people less impacted that would be diagnosed under Fukuda CFS criteria.

I think SEID, CCC, and ICC are all valid but are just capturing different severity or types of the same illness.

 

[adambeyoncelowe]

I think the term PEM has shifted from (1) simply being post-exertional malaise as introduced by the Fukuda criteria – something that is reported in many other diseases – to (2) a collection of all the detrimental effects exertion has on the health of ME/CFS patients. Some of these are quite remarkable and seem to have the potential to characterize and differentiate the disease.

The shift in the meaning of PEM causes confusion but it could also have some perks. Changing the definition of PEM could be an easy way to update the diagnostic criteria we have. Suppose for example that Jason tests his new and extensive PEM questionnaire in a large sample and sees that some elements (delayed onset, muscle weakness, prolonged recovery, the immune-type symptoms or whatever) clearly stand out in differentiating (a subset of) ME/CFS patients from other fatiguing illnesses. That would make it possible to update the CCC or IOM criteria quite easily, namely by requiring PEM to include these elements.

I think international organizations are sort of coming to an agreement that ME/CFS definitions without PEM are no longer acceptable. But I would very much like to see them go one step further and agree that asking patients if they experience malaise, exhaustion or symptom exacerbation after exertion is not enough to measure PEM. Sorry for going a little of topic with this but I think it is quite central to the problem of diagnostic criteria.

This is however based on the view that PEM, PENE and post-exertional muscle weakness are related to each other. Are there some who disagree with this and willing to explain their view?

I agree and I like your thinking on this.

One question that is nagging me, in particular, though, is the pick 'n' mix nature of the ICC. If PENE is too broad, does it do the opposite of what we expect?

Take for instance swollen glands and/or sore throat. I always hear this as an example of PEM from pwME, yet my partner's uncle had very well defined thyroid problems and had the exact same symptom. (There are probably better examples.)

So does widening our understanding of PEM/PENE actually make it more easy to diagnose in people who don't have ME? I'm not sure what the answer is. Obviously, ME-ICC selects more severely affected patients, and fewer patients, but it doesn't necessarily follow that they're more accurately diagnosed patients. It may just be more severely affected patients with complex conditions.

I like the DPQ. I think that's definitely more useful than the CFQ or similar. Although, its weakness is that it's very long compared to those others (I know there is a briefer version), so can we convince clinicians to use it? It's easier if you're filling it in prior to attending a clinic, but less easy in a GP's appointment.

 

[Seven]

They are definitely 2 different things. I think the problem is where patients worst off, have it all toguether confusing things. I had progressive onset ME. Have bad OI bouts seperate from ME so I can tell them all part easier.
You do not need muscle fstigability to have PEM. I think this symptom is more OI related.If I use vassocontriction meds, that goes away, but I still can have PEm( agrevation of flue like symptoms) and brain titunus agrevation, worst insomnia and bad sleep.....
I can on the other hand have muscle fatigability like today and no PEM whatsoever ( I have no other symptom) except Latic acid
Like pain. And I know is becuase I
Forgot my vassocontriction meds

 

[Hoopoe]

I think international organizations are sort of coming to an agreement that ME/CFS definitions without PEM are no longer acceptable. But I would very much like to see them go one step further and agree that asking patients if they experience malaise, exhaustion or symptom exacerbation after exertion is not enough to measure PEM. Sorry for going a little of topic with this but I think it is quite central to the problem of diagnostic criteria.

This is however based on the view that PEM, PENE and post-exertional muscle weakness are related to each other. Are there some who disagree with this and willing to explain their view?

My muscles don't seem to be specifically affected in a post-exertional way. They tire quickly but that would be expected in a sedentary person.

I think there changes that affect the whole body on the day after significant exertion, with effects on body temperature, cognitive function, digestion, appetite, physical performance, autonomic function (OI), mood, and sleep. I run out of breath sooner and have more difficulties doing the same things as the day before. That could be viewed as muscle problem but it's an excessively narrow description.

So I think I'm dealing with a systemic problem that affects many different body parts, and not specifically muscles. Something like reduced oxygen delivery or reduced energy production makes perfect sense.

 

[Hoopoe]

But I would very much like to see them go one step further and agree that asking patients if they experience malaise, exhaustion or symptom exacerbation after exertion is not enough to measure PEM.

I don't think we have a complete and accurate picture of what PEM is, and whether it can be accurately detected by self-report. I'm leaning towards the position that it's not difficult to recognize when the right questions are asked, and it's less about exact symptoms and more about the pattern of symptoms over time and their relation to exertion levels, as well as the impact of this on the person.

 

[Hoopoe]

Finally, there seems to be little objective evidence of specific muscle problems, while there is now substantial objective evidence for PEM.

Is there even a single study that has objectively measured this postexertional muscle weakness?

 

[adambeyoncelowe]

Finally, there seems to be little objective evidence of specific muscle problems, while there is now substantial objective evidence for PEM.

Is there even a single study that has objectively measured this postexertional muscle weakness?

The hand-grip strength test study would seem to capture it.

Maybe that's what the shopping bag study is about?

I would argue, though, that this kind of weakness is possibly due to mitochondrial issues or signalling problems rather than being an obvious thing in the muscles. In which case, it might be PEM after all.

Something similar happens in MS.

 

[Hoopoe]

The hand-grip strength test study would seem to capture it.

From the study

Participants were then instructed to squeeze the hand grip as hard as they could, which took ~ 3 s, in three successive trials with 30 s in between each. The entire procedure took ~ 3 min to complete, including instructions.

That wouldn't tell us anything about postexertional muscle weakness, unless we define postexertional as within tens of seconds of exertion. Is that what Ramsay meant?