Post-Exertional Malaise - a discussion including defining and measuring PEM

Regarding malaise. I understand malaise is a term some PWME don't like.

For me, I would be extremely worried over a loved one who has taken to bed with malaise. It is serious in my understanding of the term

 

I think malaise describes how I feel on a daily basis very well. However, I can understand the reservations about it. It has a certain fin de siècle dramatic/hysterical ring to it, perhaps because it's a French word.

 

Same, except the SSRI part. I was told it was TATT - Tired All The Time - and told never to come to this office EVER again. I never mentioned the word fatigue or tiredness, by the way. My presenting complaint was tachycardia.

 

Ischaemic stroke causes significant disruption to the blood-brain barrier and resulting neuroinflammation. There are major effects on the immediate penumbra and brain further from the primary site of devascularisation.

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Neuroinflammation, Stroke, Blood-Brain Barrier Dysfunction, and Imaging Modalities (2022)
Eduardo Candelario-Jalil; Rick M. Dijkhuizen; Tim Magnus

Maintaining blood-brain barrier (BBB) integrity is crucial for the homeostasis of the central nervous system. Structurally comprising the BBB, brain endothelial cells interact with pericytes, astrocytes, neurons, microglia, and perivascular macrophages in the neurovascular unit. Brain ischemia unleashes a profound neuroinflammatory response to remove the damaged tissue and prepare the brain for repair. However, the intense neuroinflammation occurring during the acute phase of stroke is associated with BBB breakdown, neuronal injury, and worse neurological outcomes.

Here, we critically discuss the role of neuroinflammation in ischemic stroke pathology, focusing on the BBB and the interactions between central nervous system and peripheral immune responses. We highlight inflammation-driven injury mechanisms in stroke, including oxidative stress, increased MMP (matrix metalloproteinase) production, microglial activation, and infiltration of peripheral immune cells into the ischemic tissue. We provide an updated overview of imaging techniques for in vivo detection of BBB permeability, leukocyte infiltration, microglial activation, and upregulation of cell adhesion molecules following ischemic brain injury. We discuss the possibility of clinical implementation of imaging modalities to assess stroke-associated neuroinflammation with the potential to provide image-guided diagnosis and treatment. We summarize the results from several clinical studies evaluating the efficacy of anti-inflammatory interventions in stroke. Although convincing preclinical evidence suggests that neuroinflammation is a promising target for ischemic stroke, thus far, translating these results into the clinical setting has proved difficult.

Due to the dual role of inflammation in the progression of ischemic damage, more research is needed to mechanistically understand when the neuroinflammatory response begins the transition from injury to repair. This could have important implications for ischemic stroke treatment by informing time- and context-specific therapeutic interventions.

Link | PDF (Stroke)


Neuroinflammatory mechanisms of blood-brain barrier damage in ischemic stroke (2019)
Changjun Yang; Kimberly E. Hawkins; Sylvain Doré; Eduardo Candelario-Jalil

As part of the neurovascular unit, the blood-brain barrier (BBB) is a unique, dynamic regulatory boundary that limits and regulates the exchange of molecules, ions, and cells between the blood and the central nervous system. Disruption of the BBB plays an important role in the development of neurological dysfunction in ischemic stroke. Blood-borne substances and cells have restricted access to the brain due to the presence of tight junctions between the endothelial cells of the BBB. Following stroke, there is loss of BBB tight junction integrity, leading to increased paracellular permeability, which results in vasogenic edema, hemorrhagic transformation, and increased mortality. Thus, understanding principal mediators and molecular mechanisms involved in BBB disruption is critical for the development of novel therapeutics to treat ischemic stroke. This review discusses the current knowledge of how neuroinflammation contributes to BBB damage in ischemic stroke. Specifically, we provide an updated overview of the role of cytokines, chemokines, oxidative and nitrosative stress, adhesion molecules, matrix metalloproteinases, and vascular endothelial growth factor as well as the role of different cell types in the regulation of BBB permeability in ischemic stroke.

Link | PDF (American Journal of Physiology-Cell Physiology)

 

I don't think anyone understands mental fatigue. Sleep is known to be needed to reverse it. There is a genetic condition in which sleep becomes progressively more impossible to achieve - maybe around the age of 40-50. And it is always fatal. It cannot be a lack of energy supply because that is refreshed every second.

I would not be at all surprised if the mechanism was interfered with in ME. And I think it very plausible that physical fatigue in ME is caused by the same thing as mental fatigue. It is in flu - both are caused by gamma interferon.

Neurons tend to be able to fire regularly all the time and much of the time have to be told not to. But firing is only any use if it is a response to co-ordinated input integration. It might be that controlling timing gets difficult if the brain has recently logged some things it wants to lay down in memory for instance. Or the relevant circuits are set as if so when it isn't.

Again, what comes to mind is the computer with too much memory filled with Apps and files. The brain needs to make space to think properly.

I think it is unlikely that shortage of ATP is relevant. ATP is a bit like the mains. It tends to work OK except in the rare case of a power cut. Much more often clever trip switches cause trouble. A neuron may well have 100 of those to go wrong and they are proteins that could get caught up in immune mechanisms whether innate or adaptive.

 

To me, it feels like whatever process causes mental fatigue in normal people causes PEM in ME, just at a much lower threshold. Why is it tiring for someone to play in a chess tournament all day? Why is it tiring for an introvert to have video meetings all day? Whatever is going on there seems like it could well be the same thing that triggers PEM in ME. I think some people would just call that stress and maybe it is, in a sense.

 

Cognitively I think that might be true for me, but not physically. It seems more as if physical activity prompts the production of something really unhelpful that takes time to manufacture. High levels of it cause PEM symptoms, which will eventually subside if it gets chance to wash out before the cycle starts again.

That's another imaginary bit of biochemistry, but hey.

 

We have had decades of patients using their own words to describe their symptoms, using such words as tired or fatigued.

Definitions from various online dictionaries,

Tired - " in need of rest or sleep", "weary; fatigued", "depleted of strength or energy", "feeling that you want to rest or sleep", "as in exhausted. depleted in strength, energy, or freshness"

Fatigue - "extreme tiredness resulting from mental or physical exertion or illness", "extreme tiredness", "weariness or exhaustion from labor, exertion, or stress", "an overall feeling of tiredness or lack of energy"

but sure, talking directly of energy is going to confuse the matter, as it is so clear at the moment.

 

But doesn't the evidence suggest an impairment in energy metabolism? For instance, just a few of the studies...

1. Komaroff and Lipkin. Insights from myalgic encephalomyelitis/chronic fatigue syndrome may help unravel
the pathogenesis of postacute COVID-19 syndrome https://doi.org/10.1016/j.molmed.2021.06.002
This review concluded reduced generation of ATP from (see article for references):

- Glucose via the tricarboxylic acid (TCA) cycle [96], reduced levels of fatty acids and of acyl-carnitine [97], and reduced levels of amino acids via the urea cycle [96,98].
- Impaired oxidative phosphorylation [99,100].
- Glycolysis: either a compensatory increase [101] or a decrease [98].​

2. Fluge Ø, Mella O, Bruland O, et al. Metabolic profiling indicates impaired pyruvate dehydrogenase function in myalgic encephalopathy/chronic fatigue syndrome. JCI Insight. 2016; 1(21):e89376.

The amino acid pattern suggested functional impairment of pyruvate dehydrogenase (PDH), supported by increased mRNA expression of the inhibitory PDH kinases 1, 2, and 4; sirtuin 4; and PPARδ in peripheral blood mononuclear cells from both sexes. 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.
​

3. Tomas C, Brown A, Strassheim V, Elson J, Newton J, Manning P (2017) Cellular bioenergetics is impaired in patients with chronic fatigue syndrome. PLoS ONE 12(10): e0186802. https://doi.org/10.1371/journal.pone.0186802

The lower maximal respiration in CFS PBMCs suggests that when the cells experience physiological stress they are less able to elevate their respiration rate to compensate for the increase in stress and are unable to fulfil cellular energy demands. The metabolic differences discovered highlight the inability of CFS patient PBMCs to fulfill cellular energetic demands both under basal conditions and when mitochondria are stressed during periods of high metabolic demand.​

Then there's those CPET studies showing an earlier shift to anaerobic metabolism

 

Would like to hear others experience on this but for me physical exertion is orders of magnitude worse than mental exertion in terms of bringing on PEM. I've generally assumed this is the case for others too but perhaps not.

Mental exertion PEM for me when milder has usually been more insidious and arisen in times of high mental stress over a longer period of a few weeks. Mental exertion PEM for me can be more acute when I'm severe, but correspondingly physical activity during these times would still be far far worse.

 

I don't think so, @Medfeb.

With any disease that is hard to explain there will always be a raft of studies suggesting that it is due to what seems superficially obvious. What is 'superficially obvious' in ME is that it is due to lack of energy production. But if you ask questions about how that would work and actually explain symptoms it all falls apart.

Secondly, each of these studies seems to implicate something different. That is a pretty good indicator that none of them mean much. When I was a doctoral student I became known for my interest in animal models but by the end of that period I realised that if you have 100 animal models each based on some different process then at least 99 of them will be off target - only one can be right. And if 99 can be wrong very likely 100 are wrong. The same applies to claims for metabolic defects in ME if they are all different.

We have no consistent finding that would justify putting in a textbook and saying it is likely to be real.

And remember that the CPET studies by and large show normal capacity at first testing. How can that be if there is a deficit in ME, which, as Andy says, most people sense is there all the time, just worse with PEM.

A metabolic defect would not explain sensitivity to noise and light. It would not explain pain. It would not explain orthostatic intolerance. It would not explain PEM. It would not explain the wild shifts in capacity that people often experience, from being quite well today to being confined to bed. It would not really explain anything. And when I have flu or am confined to a sofa for weeks post Covid I seem to have many of the problems of ME but I have no reason to think there is any metabolic defect. If there was, why would ibuprofen help a bit? The general view is that feeling ill is due to signalling molecules inhibiting capacity, not a lack of ATP.

 

It's a good indicator that none of them point to a metabolic defect as the driver of the disease, but is that the same as saying they don't mean much at all? They are quite different experimental set ups and I don't think they necessarily contradict each other. One is a study where they put patient serum onto cultured myoblasts and observe increased aerobic respiration, and another is showing reduced aerobic respiration in PBMCs taken from patients when assayed in vitro. One of Maureen Hanson's papers also argued reduced aerobic respiration in T cells taken from patients.

You could argue those data are consistent with this couldn't you? If exposure to some serum signalling molecule caused oxphos activity to increase, but when you take cells out of the patient they are in some way damaged due to this chronic exposure? Is it possible high oxphos activity is associated with some kind of protective or anti-viral cell state? If you threw inteferon gamma onto these cells for instance do you see a phenotype like this?

I accept they might not mean much from the perspective of them being small studies without replication i.e false positives, but not necessarily from what the data appear to show.

 

I have had and may still have raised gene expression for Ifn gamma and TNF alpha. My thinking has been that these may corrupt control mechanisms (make it harder for the pilot) and also make the system more difficult to control and possibly be testimony to e.g. underlying ongoing infection and/or autoinflammatory and/or autoimmune phenomena.

 

Not necessarily relevant but just to chip in acute sarcoidosis has been found to show elevated ox phos while chronic sarcoid shows reduced ox phos. Whether this appplies in all cases I don't know.

 

Are you aware of Cara Thomas work which showed poor o2 uptake in peripheral MBC? She found normal mitochondria in her group but some probs in oxygen uptake. Her work is referred to on the ME Assoc website.

 

Maybe all kind of things going on to different degrees in different people and all united in "Betrayal by the Brain" as Jay Goldstein said. The light sensitivity, pain and OT are shared by some Lyme patients and sarcoid patients suggesting common mechanisms at some level perhaps. Perhaps the brain is not the only "traitor"?

Is it possible that build up phenomena are involved as in epilepsy or migraine (at least in cases where there is a clear and swift decline from higher functioning to marked PEM??

 

They might be indirect clues to something but being realistic I suspect they mean nothing much. They were all reported as potential explanations for symptoms that they don't really explain. We want to know the driving mechanism, not the fallout.

From my experience with cells in the lab I think it pretty unlikely that studies of cultured muscle or peripheral blood cells are going to tell us anything reliable. They could potentially if studies were done on a large scale with rigorous controls but in the reality of lab life this is never achievable.

I am being a bit cynical in principle, yes, but that is based on decades of experience of how things really pan out in the lab and how easy it is for lab workers to hope they have found something.

 

I respect your experience and small studies, cohort issues etc will dog the debate. But on the subject of low O2 uptake I read around and found that major depression is marked by low o2 uptake and so is lupus. With lupus an association was found with glutamine and glutamine administration helped rectify it. One could read around forever and I do not know the final conclusion/ongoing research but all this picking away in labs may cast light which may prove useful. There is some Australian work on glutamine in ME where problems with complex 5 of the cycle are mooted.