Is ME a metabolic problem or a signalling problem?

Simbindi, yes, my daughter also uses the word "poisoned." She says: I feel as if I'm poisoned, toxic toxic all over

 

I also get severe problems with my eyes in PEM, which has been the case since I first got ME 28 years ago. It feels like my tears are acidic (or very alkaline?) and I want to tear out my eyes from their sockets just to stop the pain, but I have never been able to find out any metabolic problem online that is linked to this symptom.

 

I am utterly 'fatigued' about the constant reference to Fatigue. The three of you are really getting it right, your language is short and to the point and accurate. Bravo.

 

Mostly, I just recycle ideas that other forum members worded better on diverse threads. If I don't bookmark or otherwise save what I find interesting, I forget where I read it.

 

Forum members have really helped both clarify my understanding of, and also have given me the language to be able to much better describe and articulate, my symptoms.

 

Sorry if repeating something already said haven’t read entire thread. But don’t we have suggestive evidence that at its root ME is neither of the two?

That what is stated in OP are more downstream consequences and it’s immune mediated given that corticosteroids (not low dose) temporarily and effectively prevent PEM and the other symptoms for anyone who takes them? We just cannot take steroids as a solution for more than a few days for the well known reasons why they can’t be used as a treatment.

 

@strategist @Simbindi @Perrier this is my experience exactly as well. All of it, poisoned toxic feeling all over body and brain, sleep disorder and disturbances becoming exponentially worse with overexertion, eyes aching in sockets and hurting when I turn them similar to having a nasty hangover. In the early years PEM and crashes had a number of exacerbated flu-like and immune activation symptoms in addition to the above symptoms, that slowly changed and now much less or zero of flu-like immune activation but the above symptoms became stronger.

 

For me during the triggering viral infection and months afterwards I had much more hypersomnia. The severe insomnia, sleep disturbances and disordered sleep started to manifiest in the second half of the first year. I always say just the sleep-related symptoms of ME for me are by themselves so disabling and having a tremendous effect on my life.

 

What is the alternative?

I'd also argue that it could be both a metabolic problem and a signalling problem.

 

Sorry I should’ve written that! LOL I had written something similar in another thread and got mixed up that I also wrote it here.

The hypothesis I was referring to is a non B-cell mediated autoimmunity/immune dysfunction that’s been talked about on various threads, such as aberrant T-cell activation causing release of cytokines, chemokines, or other signals causing chronic inflammation in particular compartments and a cascade of other issues because it doesn’t turn off.

The case I made for that in the other post was the suggestive evidence that non low-dose corticosteroids squash PEM and symptom exacerbation pretty strongly if taken early enough before PEM and this has been anecdotally reported by quite a number of people who’ve trialed steroids. I think there would be countless more reports but most don’t trial non low-dose steroids because it’s a dead end, you cannot take them for more than a short period of time because of the nasty side effects so most say why bother trying to get an Rx from the doctor for it.

I’m not saying what @Trish wrote in OP is wrong at all, the metabolic and brain signaling problems could definitely be happening too, it’s that it might be a more downstream consequence of this immune hypothesis.

 

Eyes are a big issue for my daughter but in different ways

Feel dry but eye drops fall out

Feel too big for sockets

Muscles so tight it feels like bring cross eyed and rolling into head at same time

Sleep makes no difference and can make things feel worse on waking ( REM perhaps factors into this )

Referred pain at back of neck

Induces nausea

Mentioning this to GP makes her sound nuts

 

like @Simbindi i also have big problems with my eyes.

I have big issues with dry eyes but also could be related to sjogrens/lupus crossover. (I have sjogrens on my medical records too so at some point someone must have suggested it! Might be related to having the sjogrens anti body).

the eye drops I use for dry eyes are for specifically for moderate / severe dry eyes recommended by the optician; normal ones don’t work or they hurt. Theloz Duo eye drops. They have different ingredients in them to normal, and they really help me. Combined with an eye mist as the skin just under / over my eyes gets very dry. They do fall out when you blink, but it doesn’t matter as a lot of the ingredient still does get in, and put it in when lying down.

I get the other same eye symptoms as well. I’ve been told it could be related to migraines. But I think it’s also a part of ME and PEM for me.

 

Chris Armstrong (2015), and Fluge and Mella* (2016), have both pointed to increased metabolism of amino acids [specifically amino acids that bypass PDH/pyruvate "blockage" in the citric acid cycle]. Chris Armstrong is now being funded by OMF to look at protein (nitrogen) metabolism.
Fluge and Mella* suggested a signalling factor was causing this change in metabolism. I have wondered whether switching to using tryptophan, with increased (toxic) intracellular concentrations, would produce some sort of threat response --- ME/CFS. As Robert Phair has pointed out, ME/CFS, is a stable condition (bi-stability) on the face of it aberrant signalling could maintain this pathological state [ME/CFS].
There's a bit of genetic evidence potentially implicating protein metabolism here**

It looks like GWAS*** is a potential way to make progress here --- funding for Chris Ponting's GWAS study has been approved.
Maybe lobby for funding via ME Action, Solve ---

*"According to this model, ME/CFS is caused by immune interference with an unidentified target, potentially a signaling factor, which ultimately causes metabolic dysfunction and induction of secondary rescue mechanisms."[https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161229/]

**"SLC25A15 encodes the Ornithine Transporter type 1 protein that transports ornithine (as well as lysine and arginine) across the inner membrane of mitochondria to the mitochondrial matrix. Ornithine is an amino acid that plays a role in the urea cycle. A person with the rs7337312 CFS risk allele is expected to produce lower amounts of SLC25A15 mRNA resulting in reduced transport of ornithine into the mitochondrion and higher amounts of ornithine in blood. Yamano et al. (44) and Naviaux et al. (14), but not Armstrong et al. (45), report some evidence in support of this prediction."[]

***"Genome-Wide Association Study A genome-wide association study (GWAS) is ideal for discovering genetic causes of disease and new biology particularly when disease aetiology is unknown, as is the case for ME/CFS."

https://watermark.silverchair.com/d...iCtIBnKX2vZuB46ERXeBkBit-7Zn63Co7uXs04QEUwyTM

 

There is a subset for whom corticosteroids are a disaster

 

Daily low-dose hydrocortisone that many have trialed to replace suspected low levels due to adrenal exhaustion etc? Or taking only periodically one off standard doses of stronger steroids before overexertion and PEM? For the former yes that is true the treatment doesn’t work for many but the latter I haven’t read stories that this doesn’t work?

 

Yep this is an example of this alternative hypothesis, so at its root not a brain signaling or metabolic problem but actually an immune system problem causing signaling to affect metabolism or brain dysfunction.

It could be wrong, just presenting an alternative to the OP. It could actually be a purely cellular metabolic problem or a purely neurological problem causing PEM and other symptoms.

 

See what @Jonathan Edwards recently wrote in another thread, this is an alternative hypothesis to which I was referring

https://www.s4me.info/threads/open-medicine-foundation-omf-news.11075/page-8#post-317211

 

The low dose daily option was suggested for nominally low morning cortisol levels by endo. He didn't respond to dosage queries when it all went tits up and left gp to deal with queries.
Pretty disastrous all in all.

 

Ok, though hope I’ve been coming across that I wasn’t referring to the daily low-dose steroid regimen as this you are right doesn’t help for many.

But this is different than periodically taking a single immunosuppressive (so much higher) dose of stronger steroids before significant exertion, which anecdotally has shown to squash PEM and other symptoms. It’s initially suggestive that ME might be immune mediated.

You can’t do that every day or even that often, but periodically. It’s kind of useless as a treatment but suggestive for research and pathophysiology.

 

Just was reminded of this thread by several other recent posts.

People repeatedly report that their symptoms are relieved a bit by antihistamine medications.

I wonder if the role of histamine / histamine receptors and antagonists could be relevant in ME?

Especially as histamine also seems to be involved in motion sickness, appetite regulation etc. (according to wikipedia).

Does that mean you can feel sick due to too much histamine production without any classic allergic symptoms or mast cell disease involved?

But how are neurotransmitters and receptors being researched?

How can an abnormal high level of histamine in blood or tissue be measured? And how would you know whether there is an over-production of histamine or a malfunctioning of receptors?

Or, as there are different types of receptors for histamine, what if just one type of receptors doesn't work well? Or, is it also possible that the same type of receptors do their job in certain parts of the body but not in other parts/ tissue?

So, would any pathological activity of histamine production and/or reception show up in an abnormal measure of histamine in the blood at all?

wikipedia: https://en.wikipedia.org/wiki/Histamine

eta 1: see also @Snow Leopard's posts above on the biochemistry of signalling etc. (which I should have read earlier -- sorry, still only able to skim the forum.)

eta 2: Would an issue with histamine fit in somehow in the 2 day CPET findings?