Is this the mechanism underlying PEM?

How does one describe PEM in the severe years? Layers and layers of PEM is only way I can describe it. I couldn't bear to experience those full-on years again.

 

Yes, to me it feels like an immune response. Always did.

 

I'm very interested in this auto inflammatory lead. Please continue.
(On a purely personal note: I'd especially like to know about any blood tests that might remain at variance from the norm even when not in the middle of a crash. Would be a dream to have something that easy to check.)

 

@Subtropical Island, did you see this thread on autoinflammatory diseases?

https://www.s4me.info/index.php?thr...ses-–-what-can-they-tell-us-about-me-cfs.1069

They're not the same as ME, but there may be similar mechanisms involved in both, at least in a subset of ME patients.

Its really hard to know that for sure, because studies are all over the place, with no single cytokine standing out as abnormal in PwMEs. One recent review identified transforming growth factor beta (TGF-B) as reliably higher in PwMEs than in controls:

https://www.s4me.info/index.php?thr...onic-fatigue-syndrome-2017-wyller-et-al.1406/

I'm not a "typical" ME patient, but for me, the only permanently raised marker is my platelet counts, which are through the roof even when I feel okay.

 

I can think of five possible ways to partly understand PEM (I am being redundant, having written this in another thread, but too important a subject!)
An exertion or stressor triggering:

- an immune activation, inflammation
- an ATP drop triggering body systems to shut down
- increased brain hypoperfusion triggering cerebral shutdowns in particular
- increased lactate build-up, especially in the brain
- increased leakiness of gut and bacteremia

When you feel really really shitty, you're maybe stuck with all five at the same time…and more..

 

I spent a lot of time researching this a few years ago and came to the conclusion that none of the cytokines can be biomarkers for fatigue in patients or athletes. The presence (or lack of) and kinetics do not match at all.

I also spent some time looking at the various cytokine receptors and none of them stand out in particular. Some possible clues were looking at the effects of various inhibitors (mostly anticancer drugs) and the reported side effects.

 

@Snow Leopard, that's interesting, and I admit to knowing very little about it.

But what if there is massive, really massive heterogeneity in patients diagnosed with ME? There could be variable cytokine profiles, but also many cases where cytokines aren't at play at all.

What would that heterogeneity look like? Any effects would either wash out completely or would be massively variable across studies. Which is pretty much where we're at now.

Having recently explored the literature on depression, I came to the conclusion that any research aimed at discovering the mechanisms underlying "depression" is doomed to failure. Because depression is many, many different things.

A problem is not just the heterogeneity within the illness category, but also the way in which the category itself is defined, which presupposes certain things are connected - when in reality they might not be. This is true of depression. Its probably also true of ME.

 

When you are looking at common symptoms, not underlying causes, the heterogeneity does not matter so much.

Lots of researchers have wondered about cytokines as a marker for fatigue in healthy people (or athletes), to no avail.

I am confident in saying none of the cytokines are markers for any of the symptoms in ME or CFS.

 

Okay, fair point. And maybe I'm clutching at straws here. But I still worry that "fatigue" is a vague descriptor too, like pain. It might have many causes, that differ widely across people. And even PEM, that we think is so specific, might not be. The reason I think this is that I experience PEM and fatigue, and it's 99% certain that my IL6 levels are elevated (its linked to CRP), and possibly other cytokines too.

I know I'm a weird case, but I meet even the tightest ME criteria - so if cytokines are involved in my case, then surely at least some others? We also know that, in certain people that meet the criteria for depression, cytokines are also definitely involved. And those certain people are the ones whose symptoms overlap most closely with ME (ones with lots of "somatic" symptoms such as fatigue, poor concentration, sleep disturbance).

I realise, though, my recent personal experience could be biasing me here.

 

It sounds as if your case is a useful 'exception that probes the rule' @Woolie. And there is no doubt that many diseases with raging cytokines are associated with fatigue. But @Snow Leopard is making a very good point that shows the weakness of the 'cytokine induced sickness behaviour' story. In diseases like RA the CRP can be all over the place and it correlates to some degree with fatigue but there are many exceptions. You can have a normal CRP and be flat out or a CRP of 150 and feeling fine. So we have to conclude that, since CRP is very tightly related to IL-6, as you say, that IL-6 is not directly casually related to the symptom. It reflects some other process that causes the symptom.

It is anecdotal but my experience is that quite often patients with serious inflammatory disease have come to my clinic with local complaints like swollen joints but still feeling well enough to carry out normal daily activities. The CRP turns out to be sky high and hey presto within a few days the patient is flat on their back with fever and poor renal function and needing acute care. My impression is that the first phase of response to inflammatory stimuli may be for the cytokine system to get working but for other neural and hormonal mechanisms to do their best to keep the show on the road. So when the very first nausea of flu or norovirus hits us we take a breath of fresh air and say 'with luck it will pass'. Six hours later we may be in bed or indeed it may have passed.

So I am thinking of an analogy of building beaver dams with my brother as kids. The stress on the system, an inflow of water, is fairly constant, although from day to day it may go up and down and after a storm it may be unstoppable. The dam is kept intact by constantly running back and forth to fill any gaps at the top that are beginning to let too much water through. A good beaver keeps the top of the dam just even so that water leaks a tiny bit over the top all round. In this model the ME/CFS situation is where the beavers are suffering from any number of problems that make them erratic in their hole filling. The result is that holes keep forming in the dam with water gushing out.

So if the water coming in to the pond is the cytokine drive and the water gushing out causes the symptoms there is no very obvious relation between cytokine levels (pond levels) and symptoms despite the fact that the water coming in is ultimately the source of the symptoms.

Maybe the problem in many cases of ME/CFS lies in the beaver fort-holding signals. Of course TGF beta would traditionally be seen as one of those, although I think neurotransmitters will also be important.

 

This is my experience too at an individual level, @Jonathan Edwards. My CRP levels can be low and I can feel awful, or high and I can feel not bad. So its not the whole story at all. Although when my CRP was really, really high (30+), then it so happens that I have consistently felt absolutely awful. Its at the intermediate ranges where CRP doesn't track with symptoms very well. The feeling I have experienced at times when its been highish (11-16) is not so much fatigue but more a hot prickly, flushed, fluey sensation. That crushed ribs-feeling crushed-burning-headache fatigue feeling must be something else entirely.

Feels a bit like a third variable situation from my point of view. Something else is driving the symptoms and that something else also occasionally causes my CRP levels to skyrocket.

 

I'll add to this discussion the studies of the Lights and Ronald Straud post-exercise genetic expression.

Alan Light

• After a sustained moderate exercise test, CFS patients showed greater increases than control subjects in gene expression for metabolite detecting receptors ASIC3, P2X4, and P2X5, for SNS receptors alpha-2A, beta-1, beta-2, and COMT and IS genes for IL10 and TLR4 lasting from 0.5 to 48 hours (P < .05). (1997)

• Regression analysis predicting these biologic factors using FMS, CFS, depression...revealed that greater expression in factors 1 and 3 was positively associated with CFS and negatively associated with depression severity... but not associated with FMS. Factor 1 is purinergic and cellular modulators, factor 3 is nociception and stress mediators. (I wish I could read this whole study, 2016)

• CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF [Androgen deprived prostate cancer patients]. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). (2013)

• Patients with CFS had greater postexercise increases in fatigue and pain and greater mRNA increases in purinergic type 2X4 receptor, transient receptor potential vanilloid type 1, CD14, and all adrenergic receptors than controls (mean ± standard error = 1.3 ± 0.14- to 3.4 ± 0.90-fold increase above baseline, p = .04-.005). (2012)

Ronald Straud

• Because one of the hallmarks of CFS is often long-lasting fatigue after minor physical exertion we hypothesized that muscle metabolites activate fatigue pathways and thus contribute to this phenomenon. This hypothesis appeared reasonable because pain and fatigue pathways seem to share similar receptors systems (i.e. ASIC, TRPV1, P2X) and sensitization of pain pathways of CFS patients during exercise has been reported previously [55]. Whereas healthy normal controls (NC) demonstrated increased pain thresholds, CFS patients showed incremental reduction in pain thresholds after modest exercise [55]. Normally, exercise increases pain threshold due to endogenous pain modulation including the release of endogenous opioids and growth factors [19]. We hypothesized that trapping of muscle metabolites in the forearms of CFS patients and NC after vigorous handgrip exercise would increase overall fatigue and thus provide indirect evidence for metabolite-induced activation of fatigue receptors and sensitization of fatigue pathways. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4366335/

In one paper, exercise drive study, the Lights did a regression between Il-6 levels and fatigue. I'm too tired to dig it up at the moment, but it was only significant because of a very fatigue, very high IL-6 outlier. Straud posits a central sensitization theory that acid receptors next to peripheral nevers are more sensitive to post-exercise metabolites than controls.

Thought the posibilit remains than another pathology drives the sensitization, seems more reasonable to me.

 

Sorry this is so late, but I am one of several people (all female?) who suffered ill-effects from D-Ribose. I mention it here among other places: http://forums.phoenixrising.me/index.php?threads/d-ribose.52274/#post-864592

(Sorry - gave wrong link earlier)

 

In case anyone is trying to find other texts by this author, his name is actually Roland Staud.

 

That website is partly right and partly wrong.

Yes, it takes more energy to put phosphates on than take them off (ATP= adenosine triphosphate, or adenosine with three phosphate atoms; ADP = adenosine diphosphate, just two; and AMP adinosine monophosphate, only one).

The bond between two phosphates stores a lot of energy (especially the second one). So it takes a lot of energy to make that structure, but by breaking it you get a lot of energy (that's why ATP is used to store energy and supply energy for reactions in the cell).

However it is possible to build ADP or ATP from AMP.
https://www.worldofmolecules.com/life/amp.htm

AMP and cAMP (cyclic AMP, a different form/shape) is used as a cell signalling molecule. If there's lots of that around, it turns on emergency measures for a low energy or other crisis state.

https://pubchem.ncbi.nlm.nih.gov/compound/cAMP#section=Top

For the people who want details and diagrams:
https://mcb.berkeley.edu/labs/krant...-SPRING2008-LECTURE7-METABOLIC_REGULATION.pdf

They actually do use adenosine medically:
https://www.webmd.com/vitamins/ai/ingredientmono-1067/adenosine

This is interesting mechanism:

http://cvpharmacology.com/antiarrhy/adenosine

 

In hypovolemic shock,

I would expect energy to be on the same triage.

I keep looking at shock as a possible part of what's going on in M.E., but not sure all the pathology quite fits.

Nonacute shock is recognized in, for example, Denuge fever.
https://www.cdc.gov/dengue/training/cme/ccm/page72318.html

 

didn't mean to derail the thread, though.

I do think immune stuff is probably related to PEM, just I didn't take a immunology and find it hard to learn new stuff at this point in time, so difficult for me to discuss in detail.

 

Just wanted to add that I've wondered this too. When I use crash as a verb, e.g. "I'm crashing", it's usually an acute, almost emergency-like situation where I need to lay down in a dark, quiet room immediately. I cannot get warm and need multiple blankets. My heart is racing. My face is pale (or deeply flushed and almost swollen). However, I'm usually not frankly hypotensive (if we can get a blood pressure reading, that is, as my pulse is so weak it's often nearly impossible to hear). In the last few years, I've also started having unusual involuntary movements accompany these episodes like muscle twitching/jerking/seizing, rocking back and forth, nodding compulsively, etc.

Also sorry if my reply to @WillowJ is taking thread off course.

 

The immunemodulator (levamisole) I take effets cAMP and cGMP.
I have been taking it for 20 years now and it still helps.

When I had taken it for a short time I tried a higher dosis. That was great but after a few hours all the symptoms came back much stronger.

If I forget to take it I have a huge hangover the next morning.

I wish somebody could explain it.

 

I also started experiencing this around 17 years ago. I had this constant rocking sensation in my head and couldn't sit still It turned out to be a severe magnesium deficiency.