Post-exertional malaise in daily life and experimental exercise models in patients with [ME/CFS], 2023, Vøllestad and Mengshoel

[SNT Gatchaman]

Post-exertional malaise in daily life and experimental exercise models in patients with myalgic encephalomyelitis/chronic fatigue syndrome
Vøllestad, Nina K.; Mengshoel, Anne Marit

Post-exertional malaise (PEM) is commonly recognized as a hallmark of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and is often used as one of several criteria for diagnosing ME/CFS. In this perspective paper we want to reflect on how PEM is understood, assessed, and evaluated in scientific literature, and to identify topics to be addressed in future research.

Studies show that patients use a wide variety of words and concepts to label their experience of PEM in everyday life, and they report physical or mental exertions as triggers of PEM. They also report that PEM may have an immediate or delayed onset and may last from a few days to several months. When standardized exercise tests are used to trigger PEM experimentally, the exacerbation of symptoms has a more immediate onset but still shows a wide variability in duration. There are indications of altered muscular metabolism and autonomic nervous responses if exercise is repeated on successive days in patients with ME/CFS. The decreased muscular capacity appears to be maintained over several days following such controlled exercise bouts. These responses may correspond to patients' experiences of increased exertion.

Based on this background we argue that there is a need to look more closely into the processes occurring in the restitution period following exercise, as PEM reaches the peak in this phase.

Link | PDF (Frontiers in Physiology)

 

[SNT Gatchaman]

There are two striking post-exercise differences between patients with ME/CFS and healthy controls: The patients have a higher prevalence of symptoms and higher intensity of symptoms in the days following exercise. It is interesting, and somewhat surprising, that we have limited data on biological factors and processes in the restitution phase.

Submitted in July 2023. Does include eg Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome ME/CFS (2023, Medicina) but not Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients (2023, International Journal of Molecular Sciences)

Apart from the studies employing repeated CPETs, the exercise models have predominantly focused on self-reported symptoms in the post-exercise period. Based on the patients’ descriptions of days and weeks to recover from exercise, research of physiological responses should probably be extended to capture the restitution phase. The focus could then shift from what triggers PEM to why does PEM triggered by exercise show a slower restitution in ME/CFS patients than in healthy controls.

 

[Hoopoe]

research of physiological responses should probably be extended to capture the restitution phase.

I agree, this should be common sense because that's where the abnormalities are most apparent. It's a problem of recovery from exertion, not a problem of doing any activity in particular. The sleep disruption is part of the defective recovery. At least for me.

Edit: also my initial orthostatic hypotension is aggravated during the recovery phase.

 

[Mij]

Studying and measuring the differences(if any) between immediate and delayed PEM onset.

I recover within the same day from immediate PEM without cognitive issues, but delayed PEM which includes all sorts of distressing symptoms normally takes 3 days or more depending on how much I went over my energy limit. There might be similarities and possible distinctive differences between the two because I have an established baseline.

 

[Hutan]

The focus could then shift from what triggers PEM to why does PEM triggered by exercise show a slower restitution in ME/CFS patients than in healthy controls.

Perhaps it is just a difference in how PEM is defined, but I think this sentence indicates that there is still not a clear understanding of what PEM is.

For me, PEM is not something I experienced after exercise when healthy, not even briefly. The experience that I term PEM is when the only thing I can do is lie in bed, feeling as though I have been crushed. Everything hurts, movement takes conscious thought and willpower.

When standardized exercise tests are used to trigger PEM experimentally, the exacerbation of symptoms has a more immediate onset but still shows a wide variability in duration.

My experience is that there can be immediate onset of other symptoms after exercise, or not. But PEM is delayed.

Apart from the studies employing repeated CPETs, the exercise models have predominantly focused on self-reported symptoms in the post-exercise period. Based on the patients’ descriptions of days and weeks to recover from exercise, research of physiological responses should probably be extended to capture the restitution phase.

I don't think it is impossible to define PEM better based on self-reported symptoms. But, so far, it seems to have been very difficult. And so looking at things that are easily measured - heart rates, metabolites, protein expression... in the days following exercise seems like a productive way to proceed. One key thing is controlling exertion, so that you are sure the person has achieved a rested baseline before exerting.

 

[Andy]

Personally I hope very much that research moves on from "immediate PEM" and puts far more focus on the delayed response. It is simply the same response that someone healthy but sedentary might have if they exerted themselves to the same extent that patients do, relative to their available energy.

The delayed part is crucial to look at. The process in the body that allows people to build fitness is obviously impaired/faulty in pwME, and I would imagine would explain our reduced energy levels.

 

[Hoopoe]

By the way, I'm currently in a long period of substantial improvement to point where I can do prolonged and moderately intense exercise and recover within a day or a few. When I exercise like that, the PEM hits as soon as the body begins to wind down from the "activated" state induced by exercise. And the PEM can coexist with the good feeling produced by the exercise. I feel both at the same time.

My muscles feel much healthier nowdays. The PEM that remains feels more like a nervous system problem or some metabolic problem.

 

[bobbler]

Perhaps it is just a difference in how PEM is defined, but I think this sentence indicates that there is still not a clear understanding of what PEM is.

For me, PEM is not something I experienced after exercise when healthy, not even briefly. The experience that I term PEM is when the only thing I can do is lie in bed, feeling as though I have been crushed. Everything hurts, movement takes conscious thought and willpower.

My experience is that there can be immediate onset of other symptoms after exercise, or not. But PEM is delayed.


I don't think it is impossible to define PEM better based on self-reported symptoms. But, so far, it seems to have been very difficult. And so looking at things that are easily measured - heart rates, metabolites, protein expression... in the days following exercise seems like a productive way to proceed. One key thing is controlling exertion, so that you are sure the person has achieved a rested baseline before exerting.

it all seems to sound like it’s thinking scientifically/methodologically then, probably because of not listening to experienced patients I think it misses two pertinent issues:

1. Arbitrary ‘amounts’ of exercise doesn’t equal the same amount of over-exertion in each individual (whilst I know it’s catch 22 of research would have to find out what indicators are of 'this', shall we call it threshold thing, to have this I think it’s a first step)

2. as we are talking about exertion of all kinds and not exercise - again perhaps shows lack of experienced patient involvement in steering research - researchers need to know they must control or log exertion undertaken in the days before (as that PEM from two days ago will be hitting them but adding to accumulation),

and be logging other types of exertion at time to cross-log with symptoms. Eg light or noise then immediately causing cognitive.

 

[Ravn]

Not all bad but not quite there either

On the one hand the authors correctly observe that there are significant problems with the language used to identify PEM

Although, the DSQ is found to have a good internal consistency (Brown and Jason, 2014; Jason et al., 2015a), one may question the items’ face validity since there are deviations between the expressions used by patients in qualitative studies and in questionnaires

As pointed out by Jason and co-workers slight differences in wording may have an impact on the results and conclusions

On the other hand they don't then apply this knowledge when assessing the validity of claims of PEM in other diseases. They simply take PEM reports in other diseases at face value, ignoring the fact that those reports could just as easily be the outcome of ambiguously worded questions. They even cite Hodges whose repeat CPET work actually showed pwME and pwMS recover differently. So while pwMS may well experience some superficially PEM-like symptoms that doesn't necessarily mean they experience ME-PEM.

Interestingly, PEM is not unique and specific for ME/CFS but is quite frequent also in other chronic diseases (Nacul et al., 2021). Studies show relatively high prevalence of PEM-like symptoms in for instance persons with multiple sclerosis or long COVID (Morris and Maes, 2013; Learmonth et al., 2014; Hodges et al., 2018; Jason and Dorri, 2022). The descriptors used by other patient groups than ME/CFS are also similar, but the concept of PEM is not coined to the disease and not part of the diagnostic criteria for the other diseases

But I do agree that the delayed PEM peak - as opposed to onset - has been rather ignored to date. It would be worthwhile looking more closely into the entire trajectory of PEM, including the peak, taking samples at multiple time points not just the one or two typically done

To enhance our understanding of underlying mechanisms of PEM or ME/CFS as a disease, we believe it is particularly important to look more closely into the processes occurring in the restitution period following exercise tests, as PEM reaches the peak in this phase

 

[Midnattsol]

But I do agree that the delayed PEM peak - as opposed to onset - has been rather ignored to date. It would be worthwhile looking more closely into the entire trajectory of PEM, including the peak, taking samples at multiple time points not just the one or two typically done

I also think we need to look at the entire trajectory, we don't know yet if it's something that is being triggered directly after exertion that then at some point passes a threshold and turns into PEM, or if what happens directly after exercise triggers something else down the road and that is again what is causes delayed PEM.

 

[Peter T]

Have not looked at the paper yet, but for me it is vital that any measure of PEM distinguishes it from more ‘rapid fatiguability’.

In many conditions patients get fatigued by activity more rapidly and more readily than they would have been pre-morbidly. This is also true in ME and I assume in any other condition displaying PEM if such exist, however increased fatiguability is essentially an exaggeration of a normal response, whereas PEM is a qualitatively different response.

Any measure of PEM needs to focus on what distinguishes it from normal fatigue:

• potential for delayed response
• cross modality effects, such as cognitive exertion resulting in muscle symptoms
• increase in disease specific symptoms, such as flue like symptoms in ME or swollen glands
• emergence of new symptoms when in PEM not necessarily related to the triggering exertion
• accumulation of total activity over a period of time, for example traveling the day before might increase the effect of subsequent exertion
• accumulation of non specific activity or stimuli, for example bright light or noise, or the amount of time spent upright increases the effect of an exertion episode
  
• paradoxical recovery in that the effects of PEM as well as having a delayed onset can go on increasing despite rest over hours or days
• etc

I believe that fatigue/symptoms starting during the exertion and showing immediate diminution on stopping the activity and/or rest are more likely to reflect increased fatiguability rather than PEM. For example taking my teenage goddaughter perfume shopping I had to leave the shop and sit down as the scents triggered headache and fatigue, but I recovered rapidly over fifteen minutes, this I would classify as increased fatiguability, but the whole shopping trip including travelling and going out for a meal resulting in a dramatic worsening of all my ME symptoms some twenty four hours later would be PEM.

It is confusing as whatever triggered a more rapid fatigue response and any associated hypersensitivity issues can contribute to any subsequent PEM, and when in PEM any fatiguability effects become more rapid and any hypersensitivities are increased. So though PEM and increased fatiguability interact, I would argue they are qualitatively distinct.

 

[Mij]

They even cite Hodges whose repeat CPET work actually showed pwME and pwMS recover differently. So while pwMS may well experience some superficially PEM-like symptoms that doesn't necessarily mean they experience ME-PEM.

Does exertion also affect pwMS ability to effectively process or interpret information, word finding, process and absorb information, impaired blurry vision, do they slur et?

My brain just shuts down, I can't stand upright, I slur and feel nauseas after talking too much.

 

[Mij]

Give pwME a cognitive challenge for half and hour and see how far they can walk a straight line after without staggering and speak coherently.

 

[Kitty]

I also think we need to look at the entire trajectory, we don't know yet if it's something that is being triggered directly after exertion that then at some point passes a threshold and turns into PEM, or if what happens directly after exercise triggers something else down the road and that is again what is causes delayed PEM.

Absolutely.

Moderately ill people often can't predict accurately whether the PEM triggered by a familiar activity will fall into the minimal, pain-in-the-neck, or cancel-everything category. I don't even think this level of variability is understood by many researchers.

 

[Peter T]

Absolutely.

Moderately ill people often can't predict accurately whether the PEM triggered by a familiar activity will fall into the minimal, pain-in-the-neck, or cancel-everything category. I don't even think this level of variability is understood by many researchers.

Understanding variability in ME is so important. This may just be because symptoms and PEM involve complex interactions of cumulative physical, cognitive and emotional exertion over an unknown time span, hypersensitivities, orthostatic intolerance, food intolerances or because variability is further reflecting something else.

Only when I got my food intolerances identified and under control, became aware of orthostatic issues, recognise the contribution of sensory hypersensitivities and recognised that physical, cognitive and emotional activity cumulatively impact on PEM did I get anywhere near being able to predict what activity levels will trigger PEM, but even then there is more variability that I can not predict.

 

[JemPD]

Have not looked at the paper yet, but for me it is vital that any measure of PEM distinguishes it from more ‘rapid fatiguability’.

In many conditions patients get fatigued by activity more rapidly and more readily than they would have been pre-morbidly. This is also true in ME and I assume in any other condition displaying PEM if such exist, however increased fatiguability is essentially an exaggeration of a normal response, whereas PEM is a qualitatively different response.

Any measure of PEM needs to focus on what distinguishes it from normal fatigue:

• potential for delayed response
• cross modality effects, such as cognitive exertion resulting in muscle symptoms
• increase in disease specific symptoms, such as flue like symptoms in ME or swollen glands
• emergence of new symptoms when in PEM not necessarily related to the triggering exertion
• accumulation of total activity over a period of time, for example traveling the day before might increase the effect of subsequent exertion
• accumulation of non specific activity or stimuli, for example bright light or noise, or the amount of time spent upright increases the effect of an exertion episode
  
• paradoxical recovery in that the effects of PEM as well as having a delayed onset can go on increasing despite rest over hours or days
• etc

I believe that fatigue/symptoms starting during the exertion and showing immediate diminution on stopping the activity and/or rest are more likely to reflect increased fatiguability rather than PEM. For example taking my teenage goddaughter perfume shopping I had to leave the shop and sit down as the scents triggered headache and fatigue, but I recovered rapidly over fifteen minutes, this I would classify as increased fatiguability, but the whole shopping trip including travelling and going out for a meal resulting in a dramatic worsening of all my ME symptoms some twenty four hours later would be PEM.

It is confusing as whatever triggered a more rapid fatigue response and any associated hypersensitivity issues can contribute to any subsequent PEM, and when in PEM any fatiguability effects become more rapid and any hypersensitivities are increased. So though PEM and increased fatiguability interact, I would argue they are qualitatively distinct.

This pretty much perfectly reflects my opinion and experience thank you

Particular emphasis on this

Have not looked at the paper yet, but for me it is vital that any measure of PEM distinguishes it from more ‘rapid fatiguability’.

 

[Hutan]

I also think we need to look at the entire trajectory, we don't know yet if it's something that is being triggered directly after exertion that then at some point passes a threshold and turns into PEM, or if what happens directly after exercise triggers something else down the road and that is again what is causes delayed PEM.

Understanding variability in ME is so important. This may just be because symptoms and PEM involve complex interactions of cumulative physical, cognitive and emotional exertion over an unknown time span, hypersensitivities, orthostatic intolerance, food intolerances or because variability is further reflecting something else.

I've said it before, but I would really like to see a proteomic study with multiple CPETs (more than 2, maybe 5, one per day ) done in people with relatively mild ME/CFS (with very careful control of activity levels before and between the tests, and frequent testing of blood and reaction time. It would be risky, but I think there would be some people willing to do it. We need to understand how cumulative exertion affects function and gene expression.

 

[Trish]

I think more than 2 successive CPET's on successive days would be far too risky. Reading patients stories of how they collapsed suddenly from one day to the next into years long severe ME after a relatively short time of doing GET, which is less intensive than CPET, I think it would be unethical to do more than 2.

 

[Hutan]

I know we've had that discussion before. But many people with ME/CFS push themselves to do activities that are as exhausting and risky as a CPET in order to achieve something they think is worthwhile. Fluge and Mella found participants for the cyclophosphamide trial. I think a multiple CPET study could be ethical if the risks were explained very clearly, and if participants knew that they could stop doing the daily CPET at any point.

Such a study could provide useful evidence to explain why GET is a bad idea - thereby helping to prevent much greater harm.

 

[Trish]

I think we already have evidence of why GET is a bad idea from the 2 day CPET tests and the average time it took participants to recover to pre CPET level which on this trial was 12 days.

For example:
Recovery from Exercise in Persons with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) 2023, Moore, Hanson et al
"Using a Symptom Severity Scale (SSS) that includes nine common symptoms of ME/CFS... There was a highly significant difference in judged recovery time (ME/CFS = 12.7 ± 1.2 d; CTL = 2.1 ± 0.2 d, mean ± s.e.m., Chi2 = 90.1, p < 0.0001)."
"Pharmacokinetic models showed an extremely prolonged decay of the PEM response (Chi2 > 22, p < 0.0001) to the 2-day CPET."