What evidence is there that ME/CFS is more autoimmune than chronic infection?

[Sidereal]

Thanks for the link.

Lipkin informally released his research results a long time before his paper was actually published. That's why there were articles like the one I read, even though no paper was yet available at the time. However, it's possible I guess that the article might have got it wrong.

I just found this very similar Feb 2015 ME/CFS cytokine paper by Lipkin, Hornig, Klimas, Montoya et al. If you look at Fig 1 of that study, they found IL-1β raised in for short-duration ME/CFS, and reduced for long-duration ME/CFS. However, that was in the blood, not cerebrospinal fluid.

Yes, a similar pattern was found for other cytokines too which is why I doubt sickness behaviour can explain symptoms in long-term ME patients.

 

[Hip]

Yes, a similar pattern was found for other cytokines too which is why I doubt sickness behaviour can explain symptoms in long-term ME patients.

If you look above, I explained why blood and CSF levels of IL-1β are irrelevant when it comes to the vagus nerve.

The vagus nerve is the most important activation pathway for sickness behavior. It's the level of IL-1β within this nerve itself which is all important, in Michael VanElzakker's vagus nerve infection hypothesis of ME/CFS.

 

[Sidereal]

If you look above, I explained why blood and CSF levels of IL-1β are irrelevant when it comes to the vagus nerve.

The vagus nerve is the most important activation pathway for sickness behavior. It's the level of IL-1β in this nerve itself which is all important, in Michael VanElzakker's vagus nerve infection hypothesis of ME/CFS.

Is there any evidence for this hypothesis?

The trigeminal nerve is important in sickness behaviour too. Dr Goldstein had a lot of success using meds he believed modified it.

 

[Hip]

Is there any evidence for this hypothesis?

Michael VanElzakker wants to get post-mortem studies done on ME/CFS patients, to see if the vagus nerve is indeed infected as his hypothesis posits. That is the only way to test the theory, he says.

Hopefully there will be a post-mortem study on this soon.

 

[Hip]

The trigeminal nerve is important in sickness behaviour too. Dr Goldstein had a lot of success using meds he believed modified it.

Absolutely.

My guess is that sickness behavior which is activated via the trigeminal nerve might explain how you can experience all the symptoms of ME/CFS from a chronic undetected jaw bone infection (osteomyelitis). The whole jaw is innervated by the trigeminal nerve, so conceivably, inflammatory cytokines from a jaw bone infection could be activating sickness behavior via the trigeminal nerve.

There is a thread on this forum here about one patient whose ME/CFS appeared to be due to jaw bone infection: he said he recovered once he had surgery to clear out this infection from his jaw bone.


Dr Goldstein's use of naphazoline eye drops to stimulate the trigeminal nerve in the eye socket were very interesting. A subset of patients felt dramatically better after such stimulation. Again, it perhaps indicates the involvement of sickness behavior in ME/CFS.

 

[Sidereal]

Dr Goldstein's use of naphazoline eye drops to stimulate the trigeminal nerve in the eye socket were very interesting. A subset of patients felt dramatically better after such stimulation. Again, it perhaps indicates the involvement of sickness behavior in ME/CFS.

In one of the earlier books, he also talked about using TRH (thyrotropin releasing hormone) to modulate the trigeminal nerve.

 

[Hip]

In one of the earlier books, he also talked about using TRH (thyrotropin releasing hormone) to modulate the trigeminal nerve.

I see that TRH can be bought from body-building hormone and peptide suppliers: TRH (Thyrotropin releasing hormone) | PeptideSciences.com

I recently tried naphazoline eye drops, but without noticing any effects. Though unfortunately I had a lower dose solution (0.01% rather than the 0.1% used by Goldstein). I did put 4 drops in each eye, though, to try to make up for the weaker solution.

 

[cmt12]

Are you guys open to the idea that all triggers for ME can be grouped and generalized as 'a perceived threat'? Either internal through the immune system (infections, vaccinations) or external through CNS (extreme stress or trauma).

 

[SOC]

PEM is not a feature of sickness behavior, and is the unique identifying feature of ME/CFS. How does this fit with the ME = sickness behavior theory?

Michael VanElzakker hypothesizes that many of the symptoms of ME/CFS simply arise out of sickness behavior. In other words, our ME/CFS symptoms are sickness behavior. Sickness behavior and ME/CFS symptoms are one and the same. I am going for reiterative overkill here to get the point across!

Saying that many of our symptoms arise out of sickness behavior is hardly the same thing as saying sickness behavior and ME/CFS symptoms are one and the same. Far from it. Many is not all.

Many of the symptoms of autoimmune disease arise out of sickness behavior, but that doesn't mean sickness behavior and autoimmune disease are one and the same, or that all the symptoms of autoimmune disease are attributable to sickness behavior. Sickness behavior is a part of the symptom set, not a definition of the condition.

Fatigue is a symptom of ME/CFS; it is not ME/CFS itself. Sickness behavior is a symptom of ME/CFS; it is not ME/CFS itself. Many of our symptoms arise out of OI. That does not make OI and ME/CFS symptoms one and the same.

I'll agree with VanElzakker that many of our symptoms can probably be traced to sickness behavior related to cytokine abnormalities. Treating the sickness behavior symptoms may help us. I also think many of our symptoms can be traced to OI and OI treatments can help us. There are other ME/CFS symptoms, PEM being the biggest, that are not associated with either sickness behavior or OI. Those still need to be explained in some kind of unified theory of ME/CFS.

 

[Hip]

PEM is not a feature of sickness behavior, and is the unique identifying feature of ME/CFS

Are you sure? Have any formal studies been performed on cancer patients with severe sickness behavior fatigue, to see if they might exhibit some PEM? I imagine many cancer patients in that position of extreme fatigue will not necessarily be out and about testing their fitness levels.

If you look at this article on cancer, it says:

When a healthy person is tired by day-to-day activities, their fatigue can be relieved by sleep and rest. Cancer-related fatigue is different. Cancer patients get tired after less activity than people who do not have cancer. Also, cancer-related fatigue is not completely relieved by sleep and rest and may last for a long time.

The text in bold certainly sounds like cancer patients have exaggerated fatigue after exercise, which is PEM-like.

Also this article on cancer says:

Some signs of cancer-related fatigue are:

• Prolonged, extreme tiredness after an activity
• Feeling weak, tired, weary, or exhausted even after sleeping
• Arms and legs feel heavy and hard to move
• Too tired to complete normal daily activities
• Having trouble concentrating, thinking clearly, or remembering
• Feeling frustrated, irritable, and upset about the fatigue and its effects
• Not taking part in normal day-to-day activities
• Putting less energy into personal appearance
• Spending more time in bed or sleeping

Again, the text in bold sounds like cancer patients have PEM-like responses to exercise or activity.


If you want to see my hypothesis of how the sickness behavior cytokine IL-6 might cause PEM, see this post. This is just my own tentative idea of how PEM might arise, not Michael VanElzakker's, but it's based around his theory.

Saying that many of our symptoms arise out of sickness behavior is hardly the same thing as saying sickness behavior and ME/CFS symptoms are one and the same. Far from it. Many is not all.

I agree. I was only shouting out "sickness behavior and ME/CFS symptoms are one" as a pedagogic simplification for Adreno's benefit. Just to try to get the point across as simply as possible. But if you look at my earlier posts, you will see my explanations are more nuanced. If Michael VanElzakker is correct, many ME/CFS symptoms could indeed simply be sickness behavior symptoms; but not all.

I think OI likely does not result from sickness behavior. My hunch is that a separate mechanism other than sickness behavior is responsible for OI. In the case for POTS, for example, which a recent study showed was associated with adrenergic receptor autoantibodies, it might be an autoimmune process that kicks this off.

Our hypothalamic-pituitary-adrenal (HPA) axis symptoms might (at least in part) be sickness behavior symptoms, though, as sickness behavior involves HPA activation.

 

[Mij]

Are you sure? Have any formal studies been performed on cancer patients with severe sickness behavior fatigue, to see if they might exhibit some PEM? I imagine many cancer patients in that position of extreme fatigue will not necessarily be out and about testing their fitness levels.

I wonder if continuous light exercise or over activity would render the cancer patient worse 10yrs down the road. hnm, I don't think so. It is cumulative over doing (every day living, cooking, showering etc) alone that can make us permanently worse.

I wonder if cancer patients lose their balance, stagger or mumble words after walking or standing for too long?

PEM is not measured by fitness levels, so whatever, some of us are able to exercise and feel fit/fine whilst we're doing it, but going over the threshold (an added 10 mins of activity) can bring on PEM.

Even though there are similarities or overlap does not mean that they represent the same etiological or pathobiological process.

 

[Hip]

I think you may be missing the thrust of the argument here, @Mij.

The question here is whether or not PEM appears in sickness behavior, and whether it can be explained by the mechanism of sickness behavior.

If PEM is part of sickness behavior, then you would expect PEM-like effects to arise in other diseases that feature sickness behavior. Looking at cancer as an example of a disease in which significant sickness behavior occurs, it appears that PEM-like effects do indeed occur. So that's the end of the story.

Now I grant you there may be some differences between ME/CFS PEM and the PEM-like effects in cancer, and these differences may arise from the different causes of the sickness behavior: likely viral infection in ME/CFS, and a tumor in cancer.

 

[SOC]

Are you sure? Have any formal studies been performed on cancer patients with severe sickness behavior fatigue, to see if they might exhibit some PEM? I imagine many cancer patients in that position of extreme fatigue will not necessarily be out and about testing their fitness levels.

If you look at this article on cancer, it says:

The text in bold certainly sounds like cancer patients have exaggerated fatigue after exercise, which is PEM-like.

Also this article on cancer says:

Again, the text in bold sounds like cancer patients have PEM-like responses to exercise or activity.

No, it sounds like exercise intolerance (which is a different beast), along with sickness behavior and depression. That's not PEM. Cancer patients often benefit from exercise, so PEM seems highly unlikely. It's a much bigger stretch to claim cancer patients have PEM (not exercise intolerance) that everyone studying cancer has missed, than to suggest that cancer patients don't have PEM.

If you want to see my hypothesis of how the sickness behavior cytokine IL-6 might cause PEM, see this post.

That post sounds like you are conflating exercise intolerance and fatigue with PEM. They are not the same thing. Exercise intolerance and fatigue are well-known symptoms of many different conditions and may well be related to sickness behavior. PEM is not the same thing. That's why it's identified as a separate symptom. If all we had was exercise intolerance and fatigue, that's what Ramsay, and the authors of the CCC and the ICC would have said.

This is just my own tentative idea of how PEM might arise, not Michael VanElzakker's, but it's based around his theory.

Yes, I think we need to be clear that VanElzakker is not saying ME=sickness behavior. He hypothesizes that some of our symptoms may be sickness behavior, and I agree, but even that is unproven.

If Michael VanElzakker is correct, many ME/CFS symptoms could indeed simply be sickness behavior symptoms; but not all.

Then we agree.

 

[Mij]

@Hip

http://www.ncbi.nlm.nih.gov/pubmed/23497361

A narrative review on the similarities and dissimilarities between myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and sickness behavior.
Morris G1, Anderson G, Galecki P, Berk M, Maes M.
Author information

Abstract
It is of importance whether myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a variant of sickness behavior. The latter is induced by acute infections/injury being principally mediated through proinflammatory cytokines. Sickness is a beneficial behavioral response that serves to enhance recovery, conserves energy and plays a role in the resolution of inflammation. There are behavioral/symptomatic similarities (for example, fatigue, malaise, hyperalgesia) and dissimilarities (gastrointestinal symptoms, anorexia and weight loss) between sickness and ME/CFS. While sickness is an adaptive response induced by proinflammatory cytokines, ME/CFS is a chronic, disabling disorder, where the pathophysiology is related to activation of immunoinflammatory and oxidative pathways and autoimmune responses. While sickness behavior is a state of energy conservation, which plays a role in combating pathogens, ME/CFS is a chronic disease underpinned by a state of energy depletion. While sickness is an acute response to infection/injury, the trigger factors in ME/CFS are less well defined and encompass acute and chronic infections, as well as inflammatory or autoimmune diseases. It is concluded that sickness behavior and ME/CFS are two different conditions.

 

[voner]

Enteroviruses seem to be present in gut lining in quite a lot of normal people much of the time and I agree that it is possible that in ME there is some higher rate of carriage PLUS some unusual response. I am a bit doubtful about this being due to cytokines affecting the vagus because to get cytokine you usually need some sort of cellular change in the tissue like some macrophage activation. Dr Chia's biopsies look extremely normal in structure.

Jonathan,

for us neophytes, would you expand on your statement about Dr. Chi is biopsies looking extremely normal in structure? dr. Chia is one clinician who has taken his own time and money to investigate a possible tirgger/cause of ME/CFS, only to be ignored by the research community and I've often wondered why.

 

[Mij]

@Hip

http://www.biomedcentral.com/1741-7015/11/64/table/T1

 

[Mij]

Michael VanElzakker hypothesizes that many of the symptoms of ME/CFS simply arise out of sickness behavior. In other words, our ME/CFS symptoms are sickness behavior. Sickness behavior and ME/CFS symptoms are one and the same. I am going for reiterative overkill here to get the point across!

The fact that sickness behavior symptoms also appear in cancer and other diseases actually helps prove the point: because the fatigue, brain fog, etc symptoms in these other diseases like cancer are very similar to ME/CFS. So that kind of helps demonstrate the assertion that VanElzakker is making: that sickness behavior symptom and ME/CFS symptom are one and the same.

As you can see in the above table, they are not one of the same at all!

 

[Hip]

Thanks for quoting that study, @Mij. It's actually a very good study by Michael Maes et al, and one which I have read before. The study does an excellent job of comparing the symptoms of sickness behavior and ME/CFS.

Let me quote from the Maes study:

Both sickness behavior and ME/CFS show a phenomenological overlap, both presenting with fatigue, malaise, hyperalgesia, sleepiness, neurocognitive symptoms and mood symptoms.

Post-exertional malaise following mental and physical activities, a characteristic symptom of ME, probably also occurs during sickness behavior.

I don't however think the conclusion of that study, that "sickness behavior and ME/CFS are two different conditions" is a good one though. Yes, as mentioned, there are aspects of ME/CFS that cannot be explained by the sickness behavior mechanism. But that does not logically imply that sickness behavior may not be the cause of a large bulk of ME/CFS symptoms.

As you can see above, they are not one of the same at all!

As I mentioned just above, I was only shouting out "sickness behavior and ME/CFS symptoms are one" as a pedagogic simplification. I am fully aware this is not entirely true.

No, it sounds like exercise intolerance (which is a different beast),

Well the fact that cancer patients get "prolonged, extreme tiredness after an activity" seems quite PEM-like to me. We are not talking about not being able to do exercise (exercise intolerance), but rather the extreme tiredness that occurs for a prolonged period after exercise/activity.

It would require I think more detailed research to determine how similar the ME/CFS and cancer post-exertional symptoms are. But I think there is enough there to suggest that PEM may well be a sickness behavior symptom.

In the Maes study quote above, they think that PEM probably also occurs during sickness behavior.

 

[Mij]

I don't however think the conclusion of that study, that "sickness behavior and ME/CFS are two different conditions" is a good one though. Yes, as mentioned, there are aspects of ME/CFS that cannot be explained by the sickness behavior mechanism. But that does not logically imply that sickness behavior may not be the cause of a large bulk of ME/CFS symptoms.

I think you could be more clear when you are referring to symptoms or PEM. My original comment was referring to PEM and it's long term permanent effects, not an adaptive reaction such as sickness behaviour.

 

[Hip]

@Mij
Much of the last two pages have been focused on discussing vagus nerve infection / sickness behavior as a possible theory of ME/CFS. When SOC brought up the subject of PEM, it was within this context of this sickness behavior discussion.

This vagus nerve infection / sickness behavior theory of ME/CFS is the only one so far that, theoretically at least, explains the entire disease process from initial infection, all the way up to the final end symptoms (or at least most of the symptoms).