neophyte32
Senior Member (Voting Rights)
or perhaps it only concerns the most severe cases... the gap is so wide between mild and severe, there may indeed be a loss of neurons in a specific area.
Preprint Biological Insights from Genome-Wide Association Studies and Whole Genome Sequencing of [ME/CFS], 2026, Maccallini et al
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V.R.T.
Senior Member (Voting Rights)
But again, you've got people who improve from severe or very severe to moderate or mild, like the prominent German advocate Martin (pausedME is his username in various places i think) you've got people like me who improve back to the top end of severe from borderline very severe and highly sensitive to all stimuli. You have many case studies and reports of severe people who are much better after x or y drug. So even if those drugs don't work, those people really improved. If severe symptoms were caused by irreversible neuron loss that wouldn't happen.
I suppose until we know the mechinism enough for effective treatments to be developed there is always a possibility of the whole permanent untreatable thing, but I'm not sure I buy it.
V.R.T.
Senior Member (Voting Rights)
Actually i didnt do much exercise at all during my prodromal phase. I tried to jog my way back into health 3 and a half years into mild MECFS after being gaslit by doctors.
This is about right though. No PEM to speak of (at least not that I could be certain of) but something wasn't right.
neophyte32
Senior Member (Voting Rights)
I've talked to Martin privately on Twitter a lot, and I know about his treatment. Huge doses of pregabalin every other day, and very high daily doses of lorazepram. He added lamotrigine a few months ago. He's a very rare example of someone with very severe symptoms who has recovered (he fluctuates between mild and moderate now). The treatment is very, very heavy and dangerous in the long term, he knows it.
You're right, there's no proof of neuronal damage. Paolo doesn't know either, but he doesn't rule out the possibility.
LDA helped me go from 300 steps (I'm back to that unfortunately) to 1700 steps for 5 months without too much trouble, with no sensitivity to light, etc. The effect was too short-lived... I'm trying again after a two-month break, but well... it doesn't seem to be working again.
Yes, there's definitely something possible. We are still a long way from knowing, but perhaps with people like Paolo and Edwards we will eventually make progress.
Andy
Senior Member (Voting rights)
So he hasn't recovered, as most people would understand it. A better word to use in my opinion is that he has improved.
neophyte32
Senior Member (Voting Rights)
Yes, you're right, I misspoke. He has made enormous progress, and VRT is right to point that out. He was bedridden, immobilized, and fed through a tube for years. But his treatment is extremely intensive.
I suspect most pwME would argue it can be degenerative, and at some point (probably early on?) absolutely is - but also in a very peculiar manner, can halt its downward spiral, or continue after the wrong provocation to plummet.
I know for a fact my first eight years were a constant downward arc.
The last 20 years have vacillated.
It's also not a single tune. There are melodies over melodies, only none is pleasant, and they lack harmony. Each symptom acts like it's its own entity, like it has discreet volition in deciding when to lessen its volume or blare it.
I know for a fact my first eight years were a constant downward arc.
The last 20 years have vacillated.
It's also not a single tune. There are melodies over melodies, only none is pleasant, and they lack harmony. Each symptom acts like it's its own entity, like it has discreet volition in deciding when to lessen its volume or blare it.
This pretty well describes it for me. I would also add that one aspect of the attempt to "jog" one's way out of things in my case was that, for a very long while, the jogging or walking itself really didn't seem to be a problem - in the moment, it was an effective distraction from everything else that was going on. That is to say, when I couldn't think at all I could just walk, which, for a while, had something like a meditative effect.
Obvious PEM was a late arrival.
neophyte32
Senior Member (Voting Rights)
I also ran until I was practically bedridden. I was doing brisk walking towards the end. It lasted three years.
The prodromal phase was strange, characterized by small fiber neuropathy, intense fatigue after cognitive exertion, and oddly, less physical fatigue at the beginning.
Then came the second trigger, the same one (alcohol and tramadol), and a strange phase of increased physical fatigue with panic attacks (amygdal hyperexcitability) after exertion, and sometimes a sensation of my head exploding while jogging. But I kept going.
In short, yes, as Paolo said, I had a warning sign in 2016, a long time before, with very strange fatigue for a week... again after alcohol. Then I started getting sick more often with intestinal problems (irritable bowel syndrome, gastroenteritis) and recurring genital warts. My cholesterol has increased... it was long time before prodomic phase.
This corroborates a lot of what Paolo said.
Like most, I didn't know my first symptoms were symptoms. Hindsight granted me that insight.
My very first was a balance issue that affected my drive to work. And driving at night. I say "balance" because I cannot think of a better word. Equilibrium?
Then came the issues with writing and reading and comprehension, sleep, weakness....all very gradual, but inexorably worsening.
Even PEM was a lightbulb-on moment which I had to read about before I recognized it.
My very first was a balance issue that affected my drive to work. And driving at night. I say "balance" because I cannot think of a better word. Equilibrium?
Then came the issues with writing and reading and comprehension, sleep, weakness....all very gradual, but inexorably worsening.
Even PEM was a lightbulb-on moment which I had to read about before I recognized it.
@paolo, is this chart based on your genetic findings?
If so, what genetic findings are there in pwME/CFS that related to diabetes?
I had signs that something was wrong before I came down with what one would actually consider ME/CFS, and hypoglycemia was the symptom that brought on severe inability to stay awake.
Is diabetes a neurological disease? Or does it cause neurological issues.
Edit in: One of the main functions of the liver is to maintain healthy blood sugar levels. Insulin, a hormone made by the pancreas, acts as a messenger to alert cells to take up glucose from the blood. But in a liver damaged by fat deposits, scarring or cirrhosis, those cells become less responsive to insulin's signals.
Sleep issues (insomnia) had started long before that. Sore throat that didn't respond to antibiotics was one of the pre symptoms. I actually was intolerant of most medicines I had tried, and then started having multiple chemical sensitivity and difficulty finding food that didn't bother me.
I hope someone figures out how to get out of this condition, I don't want to get Alzheimer's.
PS: Alzheimer's is considered Diabetes T3 by some.
If so, what genetic findings are there in pwME/CFS that related to diabetes?
I had signs that something was wrong before I came down with what one would actually consider ME/CFS, and hypoglycemia was the symptom that brought on severe inability to stay awake.
Is diabetes a neurological disease? Or does it cause neurological issues.
Edit in: One of the main functions of the liver is to maintain healthy blood sugar levels. Insulin, a hormone made by the pancreas, acts as a messenger to alert cells to take up glucose from the blood. But in a liver damaged by fat deposits, scarring or cirrhosis, those cells become less responsive to insulin's signals.
Sleep issues (insomnia) had started long before that. Sore throat that didn't respond to antibiotics was one of the pre symptoms. I actually was intolerant of most medicines I had tried, and then started having multiple chemical sensitivity and difficulty finding food that didn't bother me.
I hope someone figures out how to get out of this condition, I don't want to get Alzheimer's.
PS: Alzheimer's is considered Diabetes T3 by some.
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Utsikt
Senior Member (Voting Rights)
This is why I can’t get on board with the degenerative hypothesis. I just can’t get it to make sense with the observations, unless you have two different diseases where one is degenerative and the other isn’t, and only the ones without it are the ones that have had improvements.
But you could say that for any hypothesis, so it doesn’t help us get any closer to the answer.
But it really doesn’t add up with having massive improvements in some. I have been close to multiple people neurodegenerative diseases my whole life. I don’t recognise any of that at all in ME/CFS. They understand brainfog, but so did I when healthy at ~6000 meters above sea level - so brainfog doesn’t need damage.
What you’re describing is not degeneration, but deterioration.
It would always look like that downwards trend if it was progressive deterioration, but due to the massive upwards fluctuations in some I sincerely doubt ME/CFS is actually progressive, as in biologically bound to go downwards eventually.
Yes, this dendrogram is based on genetic data. More precisely, I used the genes found by PrecisionLife using the DecodeME cohort plus the genes found by Mark Snyder from WGS of 200 or so ME/CFS patients. I then collected genes form the latest GWAS and rare variants studies for other 27 common diseases.
Then, I calculate a pair-wise distance between diseases using three different methods: Jaccard Index, correlation of Z scores in over-representation analysis (ORA) (against Gene Ontology, KEGG, Reactome, and Human Proteome Atlas), and network separation. These three metrics are almost orthogonal one another: Jaccard Index is based on overlapping genes, network separation is based on the connectivity between the gene networks of two diseases, while correlation of zeta scores from ORA on the above-mentioned databases is grounded on pathways, cellular components and tissue expression.
I also built null distributions for correlations of zeta scores and network separations, to derive p values for pair-wise distances. The Jaccard Index has its own p-vale that derives from the hypergeometric test.
Once I had the three distances, I combined them with a method called Similarity Network Fusion. The dendrogram in the figure comes from this combined metric.
The link with diabetes is unclear to me. Same applies to obesity. One may argue that if you are sedentary because of ME/CFS, you are susceptible to obesity and diabetes. My conclusion, when I finally generated the dendrogram was that it told me mainly what ME/CFS is not, rather than what it is. As I wrote, I have to go through the pipeline again and I may try different avenues.
Would this make sense?
"One of the main functions of the liver is to maintain healthy blood sugar levels. Insulin, a hormone made by the pancreas, acts as a messenger to alert cells to take up glucose from the blood. But in a liver damaged by fat deposits, scarring or cirrhosis, those cells become less responsive to insulin's signals."
"What is important here is that NAFLD can cause quite debilitating fatigue – so it's a diagnosis that should always be considered when someone has ME/CFS symptoms, especially when they also have abnormal liver function tests."
Edit in:
Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease
Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model - PMC
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and ...
pmc.ncbi.nlm.nih.gov
Maybe.
For those that report sustained improvement, is that improvement back to before symptom onset?
If not, and for those of us who do not truly improve, I'd stick with degeneration without necessarily the implied downward continuum.
Truth be told, the terms are not mutually exclusive and both may apply.
ETA: Degeneration seems to imply permanence. I am permanently less, so, after three decades. that works for me. Barring divine intervention?
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ChronicallyOverIt
Senior Member (Voting Rights)
This is incredibly interesting as well as extremely impressive, this may need a thread of its own.
My brain battery is running on low, let me ask @mariovitali what he found in this study that had to do with the liver and ME/CFS. (He mentioned it in his Twitter account.)Would this make sense?
"One of the main functions of the liver is to maintain healthy blood sugar levels. Insulin, a hormone made by the pancreas, acts as a messenger to alert cells to take up glucose from the blood. But in a liver damaged by fat deposits, scarring or cirrhosis, those cells become less responsive to insulin's signals."
"What is important here is that NAFLD can cause quite debilitating fatigue – so it's a diagnosis that should always be considered when someone has ME/CFS symptoms, especially when they also have abnormal liver function tests."
Edit in:
Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease
Non-alcoholic fatty liver disease induces signs of Alzheimer’s disease (AD) in wild-type mice and accelerates pathological signs of AD in an AD model - PMC
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease afflicting about one third of the world’s population and 30 % of the US population. It is induced by consumption of high-lipid diets and is characterized by liver inflammation and ...
Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity
Replicated blood-based biomarkers for myalgic encephalomyelitis not explicable by inactivity - EMBO Molecular Medicine
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a common female-biased disease. ME/CFS diagnosis is hindered by the absence of biomarkers that are unaffected by patients’ low physical activity level. Our analysis used semi-parametric efficient estimators, an initial Super Learner...
link.springer.com
And mind boggling.
Utsikt
Senior Member (Voting Rights)
Yes, one example is one of the patients in the Dara pilot. They are completely healthy, working full time in healthcare and exercising. They were severe at their worst, but not fully bedbound when starting the pilot.
It’s simply not accurate so I wouldn’t use it myself.
That’s beyond the point when there is no evidence of degeneration of any kind, and plenty of evidence against it. The same goes for ME/CFS being progressive.
Verity
Senior Member (Voting Rights)
It is simply not possible to tell from observing your symptoms that you have a degenerative disease.
Not all illnesses that worsen without treatment are degenerative. I’m sure many of them feel like they are when totally untreated like ME is.
For example, some autoimmune encephalitises are reversible and certainly could be mistaken for degenerative diseases without treatment.