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Is there a list anywhere on here?
What are all the theories of what causes ME CFS?
- Thread starter ChookityPop
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Well this might be the best :https://mecfsroadmap.altervista.org/
Isnt it from the living Legend @Hip
Isnt it from the living Legend @Hip
'Moribund' might be a better description than "living"!
The roadmap does not really detail many scientific hypotheses for ME/CFS etiology. It touches on a few theories, but the roadmap focuses more on factors you can address that might improve health, like gut issues, viral infection, useful drugs and supplements, etc.
I have not seen a comprehensive list of theories, but @sometexan84 posted quite a few theories in this post, which I will copy here:
To that list you could add:
There are probably many others, but that's all I can think of off hand.
There are a few more ME/CFS hypotheses on this MEpedia page.
The roadmap does not really detail many scientific hypotheses for ME/CFS etiology. It touches on a few theories, but the roadmap focuses more on factors you can address that might improve health, like gut issues, viral infection, useful drugs and supplements, etc.
I have not seen a comprehensive list of theories, but @sometexan84 posted quite a few theories in this post, which I will copy here:
- B2 adrenergic receptor dysfunction (Klaus Wirth, Carmen Scheibenbogen)
- Cell Danger Response (Robert Naviaux)
- Enteroviral infection hypothesis (John Chia, Byron Hyde, Melvin Ramsay)
- IDO Metabolic Trap (Robert Phair)
- Ken Lassesen's "gut" model (Ken Lassesen)
- Mackay-Tate hypothalamus hypothesis (Mackay A, Tate WP)
- Methylation cycle (Rich Van Konynenburg)
- Nitric oxide hypothesis (NO/ONOO cycle) (Martin Pall)
- Nitrogen metabolism (Christopher Armstrong)
- Omega 3 fatty acid (Basant Puri)
- RCCX Theory (Sharon Meglathery)
- Vagus Nerve Hypothesis (Michael VanElzakker)
- Viral Cardiomyopathy (Martin Lerner)
- Hypercoagulation theory (David Berg, Joseph Brewer)
- Cortene's hypothesis (Lucinda Bateman, Cortene inc)
To that list you could add:
- Autoimmune theory of ME/CFS
- Mitochondrial dysfunction theory (Myhill group, and others)
- Immune priming theory (Prof Hugh Perry, Dr Jarred Younger
- Endotoxin tolerance theory (Prof Michael Maes)
- Leaky gut causing translocation of the bacterial toxin LPS (Prof Michael Maes)
- Microbiome dysfunction theory
- Channelopathy theory (Chaudhuri and Behan)
- Hydrogen sulfide theory (Marian Dix Lemle, Dr Kenny De Meirleir)
- Slow sepsis theory of ME/CFS (Dr David Bell)
- Hypothalamic dysfunction theory (Dr Jacob Teitelbaum)
- Central sensitivity syndrome theory
- Craniocervical instability theory (Jeff Wood, Bjorn Bragee)
- Sluggish lymph fluid theory (Dr Raymond Perrin)
- Mold or biotoxin exposure + viral infection dual-factor theory (Erik Johnson)
- Chronic mold infection in nasal or sinus cavities (Dr Joseph Brewer)
- Abnormal red blood cell shape (Dr Leslie Simpson)
- Chronic herpesvirus infection (EBV, CMV, HHV-6, etc) which dates back to the 1984 Lake Tahoe outbreak
- Viral hit and run theory (acute viral infection causes permanent physical damage causing ME/CFS )
- Bacteria toxins from kidney dysbiosis theory of ME/CFS (Dr Igor Markov)
There are probably many others, but that's all I can think of off hand.
There are a few more ME/CFS hypotheses on this MEpedia page.
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Thank you Hip!
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Raise your hand if you had to Google what "Moribund" was...
Word-of-the-day toilet paper? Hip? ... no?
Word-of-the-day toilet paper? Hip? ... no?
I put my hand up! I had to Google that word myself!
Although I have a reasonable vocabulary, since getting ME/CFS, I've sort of semi-forgotten what many words mean exactly, especially words you do not use everyday.
So sometimes a word will pop into my head, suggesting itself as the right word for the context, but I am never confident I can remember the precise meaning of the word, so I usually just check in on my Mac's built in dictionary, or on Google, which only takes a split second.
Although I have a reasonable vocabulary, since getting ME/CFS, I've sort of semi-forgotten what many words mean exactly, especially words you do not use everyday.
So sometimes a word will pop into my head, suggesting itself as the right word for the context, but I am never confident I can remember the precise meaning of the word, so I usually just check in on my Mac's built in dictionary, or on Google, which only takes a split second.
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@Hip @Pyrrhus @nerd @sometexan84 @AnyOneOnTheForumWhoWouldLikeToAnswer would love to hear from all.
I am curious which of the theories on this list you would consider the top 3 or so most common triggers for ME/CFS.
It also seems like some items on the list are more likely downstream consequences of a primary trigger?
I am curious which of the theories on this list you would consider the top 3 or so most common triggers for ME/CFS.
It also seems like some items on the list are more likely downstream consequences of a primary trigger?
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could machine learning gather up all of this and turn it into a possible integrated theory of Everything?
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Hey, why didn't I make the cut! Fine, I didn't want to share anyway 
@sometexan84 I would love to have your thoughts, please, if you are willing 🤗. Didn't mean to make it exclusive.
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Lol, you edited it to include me!!!! Very thoughtful!
Hey can I make it fun and give mine, but also guess what those other three would say??
Hey can I make it fun and give mine, but also guess what those other three would say??
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My Top 3 would be...
@Pyrrhus I think would say...
@Hip I think would say...
"There is anecdotal evidence which supports many of these theories. Some theories I find to be interesting. But SOME theories I find to be VERY interesting. But alas, until there is scientifically proven evidence, we just do not know"
- Enteroviral infection hypothesis (John Chia, Byron Hyde, Melvin Ramsay)
- Ken Lassesen's "gut" model (Ken Lassesen) and Microbiome dysfunction theory, which I think are similar
- Autoimmune theory of ME/CFS
- and any that talk about Sickness Behavior
@Pyrrhus I think would say...
- Enteroviral infection hypothesis (John Chia, Byron Hyde, Melvin Ramsay)
- Mackay-Tate hypothalamus hypothesis (Mackay A, Tate WP)
- And anything that says viral infection in the brain and/or has been systemically spread
- Probably thinks highly of this: Chronic herpesvirus infection (EBV, CMV, HHV-6, etc) which dates back to the 1984 Lake Tahoe outbreak
- Ken Lassesen's "gut" model (Ken Lassesen) or that Microbiome one..
- He may actually be a fan of this one: Cortene's hypothesis (Lucinda Bateman, Cortene inc)
- Also prob anything viral in brain or systemic
@Hip I think would say...
"There is anecdotal evidence which supports many of these theories. Some theories I find to be interesting. But SOME theories I find to be VERY interesting. But alas, until there is scientifically proven evidence, we just do not know"
For my understanding,all this is not the cause ,but the consequences.and I truly meanwhile believe because we are searching for a cure of the consequences and not looking at and treating the cause, we fail .and this applies to every chronic illness and western medicine.
The viral load is real in ME,,but viruses feed on stress and toxins and are a result of outfections (in my believe)
But that's just me,and my believe
The viral load is real in ME,,but viruses feed on stress and toxins and are a result of outfections (in my believe)
But that's just me,and my believe
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In other words: We have to distinguish the etiology from the pathogenesis. The interesting point is where both cross over, e.g. when CFS/ME begins after a mononucleosis-type infection, which still seems to be the most commonly identified "trigger", even though mononucleosis isn't specific for an EBV infection and can happen with other viruses as well.
To shortly address the pathogenesis, I think the vagus nerve explains a lot of it. The work of Dr. Michael VanElzakker was an eye-opener to me for how consistent the perceived symptoms are with the CNS dysregulation by vagus nerve stimulation and by immunological triggers such as microglia activation. This explains why many people have such consistent illness experiences but inconsistent perceived etiologies and biomarkers. Physical trauma and tumors, for instance, can trigger similar symptoms, so basically the same syndrome but with different therapeutic requirements.
It also explains why it is so easily dismissed as psychosomatic. The range of contributors to vagus nerve stimulation is huge. Biologically, women are more sensitive to this stimulation. The whole idea of attributing the perceived illness from women as psychosomatic stems from this misconception. They aren't hysteric at all. They are just more sensitive and men can be sensitive as well. This shows how nonsensical and biomedically inconsistent the whole idea of psychosomatic disease really is. It has never existed.
Of course, anxiety disorders can exist, but they do not explain the translation from psychological stimulus to physiological disease. On the contrary, the vagus nerve causes anxiety. That's why psychology shouldn't be mentioned in either context of etiology or pathogenesis.
Since I and other patients (e.g. @Martin aka paused||M.E. ) exhibit viral immune activation that is highly associated with EBV and possibly other gamma herpes infections, and since my first exercise intolerance symptoms began after ca. 6 months of mononucleosis, I think highly of gamma herpes viruses participating in the etiology. As far as I can tell, other viral etiologies such as SARS-CoV-2 might just reactivate EBV asymptomatically. This would also explain why many Post-Covid patients don't experience COVID-19 symptoms, don't build antibodies against it, but do experience infection symptoms.
One way in that a chronic herpes virus reactivation might transpire is a repeated reactivation and long infection time which leads to a growing number of latently infected cells. The sheer number of cells would reduce the threshold of how much stimulation (by oxidative stress and other viral infections) the virus needs to begin the signaling of the reactivation phase. The immune system would never recover because every tiny impulse would cause a reactivation (i.e. PEM). The pathogenesis and perceived illness would just be a physiological response to the repetitive reactivation, to protect the body from its potential damage, which, by the way, is also mediated by the vagus nerve.
Nevertheless, EBV alone can't explain why the immune system stops responding properly to stimuli (as seen in Neuro-COVID). Something must contribute to a subclinical chronic infection first (at least in a significant amount of patients). Genetics, immune priming (the original antigenic sin), sociocultural (e.g., depression, PTSD), and environmental factors (e.g., mold toxins, drug use, diet, physical trauma) must also contribute to it. Otherwise, the epidemic spread would be more clear. If it was supposed to be genetic only, it would be more clear within family trees. But it rather seems to be a mix.
I'm also fascinated by the idea of a dual infection, e.g. a herpes, zoster, or enterovirus triggering the pathogenesis that is mediated by another virus and overshadows its pathology. So it wouldn't matter if you already have a reservoir of HHVs, EBV, or CMV, they would just be opportunistic co-pathogens.
I'm not convinced by the microbiome theories. I think the microbiome is a correlative factor, just as basic blood, etc. It's interesting that a lack of butyrate-forming bacteria is associated with CFS/ME though. If they are able to identify distinct pathogenic bacteria, I'd change my view. Viral infection in the gut, however, is a completely different topic.
The Cortene theory is similar to my "GABA trap" hypothesis. It could explain microglia activation. What's still missing here is evidence for how this presumed dysregulation is maintained. Is it just a sustained dysregulation after a physiological and healthy response to a pathogen or is the pathogen still dormant and just waiting for another chance, e.g. by another infection that allows it to reactivate?
Another of my always-favorite theories I basically adopted from the field of MG is the chronic infection of the thymus or thymocyte progenitors from the bone marrow. It could explain why the immune system isn't able to recover from childhood infections and why the lymphocyte profiles are off. But the results on this subject aren't very consistent yet. Time will tell if they can reproduce the cytokine profiles and the double-positivity of CD8+CD4+ lymphocytes. If that's the case, the thymus would be the first place to look. These double-positives might be knocked out by EBV in the thymus when they are still thymocytes, so they can't mature properly into single-positives.
This and more, to sum it up in the following list:
To shortly address the pathogenesis, I think the vagus nerve explains a lot of it. The work of Dr. Michael VanElzakker was an eye-opener to me for how consistent the perceived symptoms are with the CNS dysregulation by vagus nerve stimulation and by immunological triggers such as microglia activation. This explains why many people have such consistent illness experiences but inconsistent perceived etiologies and biomarkers. Physical trauma and tumors, for instance, can trigger similar symptoms, so basically the same syndrome but with different therapeutic requirements.
It also explains why it is so easily dismissed as psychosomatic. The range of contributors to vagus nerve stimulation is huge. Biologically, women are more sensitive to this stimulation. The whole idea of attributing the perceived illness from women as psychosomatic stems from this misconception. They aren't hysteric at all. They are just more sensitive and men can be sensitive as well. This shows how nonsensical and biomedically inconsistent the whole idea of psychosomatic disease really is. It has never existed.
Of course, anxiety disorders can exist, but they do not explain the translation from psychological stimulus to physiological disease. On the contrary, the vagus nerve causes anxiety. That's why psychology shouldn't be mentioned in either context of etiology or pathogenesis.
Since I and other patients (e.g. @Martin aka paused||M.E. ) exhibit viral immune activation that is highly associated with EBV and possibly other gamma herpes infections, and since my first exercise intolerance symptoms began after ca. 6 months of mononucleosis, I think highly of gamma herpes viruses participating in the etiology. As far as I can tell, other viral etiologies such as SARS-CoV-2 might just reactivate EBV asymptomatically. This would also explain why many Post-Covid patients don't experience COVID-19 symptoms, don't build antibodies against it, but do experience infection symptoms.
One way in that a chronic herpes virus reactivation might transpire is a repeated reactivation and long infection time which leads to a growing number of latently infected cells. The sheer number of cells would reduce the threshold of how much stimulation (by oxidative stress and other viral infections) the virus needs to begin the signaling of the reactivation phase. The immune system would never recover because every tiny impulse would cause a reactivation (i.e. PEM). The pathogenesis and perceived illness would just be a physiological response to the repetitive reactivation, to protect the body from its potential damage, which, by the way, is also mediated by the vagus nerve.
Nevertheless, EBV alone can't explain why the immune system stops responding properly to stimuli (as seen in Neuro-COVID). Something must contribute to a subclinical chronic infection first (at least in a significant amount of patients). Genetics, immune priming (the original antigenic sin), sociocultural (e.g., depression, PTSD), and environmental factors (e.g., mold toxins, drug use, diet, physical trauma) must also contribute to it. Otherwise, the epidemic spread would be more clear. If it was supposed to be genetic only, it would be more clear within family trees. But it rather seems to be a mix.
I'm also fascinated by the idea of a dual infection, e.g. a herpes, zoster, or enterovirus triggering the pathogenesis that is mediated by another virus and overshadows its pathology. So it wouldn't matter if you already have a reservoir of HHVs, EBV, or CMV, they would just be opportunistic co-pathogens.
I'm not convinced by the microbiome theories. I think the microbiome is a correlative factor, just as basic blood, etc. It's interesting that a lack of butyrate-forming bacteria is associated with CFS/ME though. If they are able to identify distinct pathogenic bacteria, I'd change my view. Viral infection in the gut, however, is a completely different topic.
The Cortene theory is similar to my "GABA trap" hypothesis. It could explain microglia activation. What's still missing here is evidence for how this presumed dysregulation is maintained. Is it just a sustained dysregulation after a physiological and healthy response to a pathogen or is the pathogen still dormant and just waiting for another chance, e.g. by another infection that allows it to reactivate?
Another of my always-favorite theories I basically adopted from the field of MG is the chronic infection of the thymus or thymocyte progenitors from the bone marrow. It could explain why the immune system isn't able to recover from childhood infections and why the lymphocyte profiles are off. But the results on this subject aren't very consistent yet. Time will tell if they can reproduce the cytokine profiles and the double-positivity of CD8+CD4+ lymphocytes. If that's the case, the thymus would be the first place to look. These double-positives might be knocked out by EBV in the thymus when they are still thymocytes, so they can't mature properly into single-positives.
This and more, to sum it up in the following list:
- Double HSV-herpes infection as in Alzheimer's (incomplete but applicable as a general idea) [forum link]
- EBI2/EGR/NF-kB-mediated early EBV reactivation theory by Jonathan Kerr [forum link]
- Possible extension of this theory: Overgrown viral reservoir and immune exhaustion theory
- Many other theories that orient around EBV or HHV, e.g. the one of Dr. Prusty
- MG-like thymus infection theory
- Mast cell activation theory (Dr. Tina Peers)
- CNS infection and microglial activation theory (Dr. Michael VanElzakker)
- Original zoster infection sin
- Monocyte polarization theory as in Post-COVID (Dr. Bruce Patterson, Dr. Ram Yogendra et al.)
- Antibody cross-reactivity from viral antigens by genetically dysfunctional immune system and antigen presentation (basically autoimmunity)
- Various novel parasite findings that have never been followed up (e.g. Cryptostrongylus pulmoni)
- Viral infection of bacteria in the body (completely speculative, e.g. infection of borrelia or microbiota)
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I think EV triggers EBV just like SarsCoV2.
But I still can't explain what PEM is. Why it occurs after looking at the phone when you're very severe. And as long we have no convincing EVIDENCE (I don't mean a fancy hypothesis like hypoxia that leads to a decreased mito output) we can't explain at least ME. Whatever is wrong in CFS without PEM doesn't internet me at all and I would ask everyone to use the ICC for diagnosis to rule out other illnesses that are “fatiguing”.
The reactivation as PEM doesn't convince me bc it happen far too quickly. PEM can hit like a stroke. No virus can replicate so fast.
So yes, I do believe in pathogens. But I think the hallmark symptom is still pretty much unprove
But I still can't explain what PEM is. Why it occurs after looking at the phone when you're very severe. And as long we have no convincing EVIDENCE (I don't mean a fancy hypothesis like hypoxia that leads to a decreased mito output) we can't explain at least ME. Whatever is wrong in CFS without PEM doesn't internet me at all and I would ask everyone to use the ICC for diagnosis to rule out other illnesses that are “fatiguing”.
The reactivation as PEM doesn't convince me bc it happen far too quickly. PEM can hit like a stroke. No virus can replicate so fast.
So yes, I do believe in pathogens. But I think the hallmark symptom is still pretty much unprove
None of the theories I mentioned involve replication of a virus. These infected cells already exist somewhere, can manage to evade the immune system, just as EV can evade immune recognition in the GIT. They only need a trigger and the altered protein synthesis, metabolic signaling and immune suppression will hit you within an hour.
It's also possible that when things appear to progress even quicker, within minutes, that a contributing factor overshadows it. If the nervous system is involved and is overstimulated during the asymptomatic reactivation phase, the symptoms would quickly shift into the symptomatic area. During the initial reactivation, latent-lytic viruses push immune suppression to its maximum. At the same time, this immune suppression serves as a reactivation signal for all sorts of viruses.
In a healthy person, this would temporarily lead to overactivity of the nervous system and suppressed stress response, but not to infection symptoms. Only in the later stage, this phase shifts to symptomatic infection but it can remain completely asymptomatic in heathy individuals. In ME, if you follow these theories, the large amount of cells would create a stronger metabolic change from an already dysregulated and damaged baseline. The cells would immediately go into self preservation mode, pushing ROS, restricting mitochondrial activity, which the vagus nerve senses and which leads to a sustained hypometabolic and hyperimmunological response, which feels like being sick.
The symptoms of PEM could be very well explained by the CNS/NTS, at least how I experience them. These are valid theories because they are at least partially backed by supportive findings such as microglia activation. In my opinion, PEM is related to the pathogenesis or pathophysiology, not the etiology.
Where I agree is that most studies unfortunately don't look at ME in a phase-dependent manner. You might get completely contradicting results by looking at PEM vs. well paced patients outside of PEM. This might also explain the poor reproducibility of the immunological markers. It should be part of every study questionnaire if the patient currently perceives PEM symptoms and should be statistically adjusted.
It's also possible that when things appear to progress even quicker, within minutes, that a contributing factor overshadows it. If the nervous system is involved and is overstimulated during the asymptomatic reactivation phase, the symptoms would quickly shift into the symptomatic area. During the initial reactivation, latent-lytic viruses push immune suppression to its maximum. At the same time, this immune suppression serves as a reactivation signal for all sorts of viruses.
In a healthy person, this would temporarily lead to overactivity of the nervous system and suppressed stress response, but not to infection symptoms. Only in the later stage, this phase shifts to symptomatic infection but it can remain completely asymptomatic in heathy individuals. In ME, if you follow these theories, the large amount of cells would create a stronger metabolic change from an already dysregulated and damaged baseline. The cells would immediately go into self preservation mode, pushing ROS, restricting mitochondrial activity, which the vagus nerve senses and which leads to a sustained hypometabolic and hyperimmunological response, which feels like being sick.
The symptoms of PEM could be very well explained by the CNS/NTS, at least how I experience them. These are valid theories because they are at least partially backed by supportive findings such as microglia activation. In my opinion, PEM is related to the pathogenesis or pathophysiology, not the etiology.
Where I agree is that most studies unfortunately don't look at ME in a phase-dependent manner. You might get completely contradicting results by looking at PEM vs. well paced patients outside of PEM. This might also explain the poor reproducibility of the immunological markers. It should be part of every study questionnaire if the patient currently perceives PEM symptoms and should be statistically adjusted.
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Agreed but unproven.
May I ask how you experience it?
That's what I wanted to say!
May I ask how you experience it?
That's what I wanted to say!