What is your personal theory or understanding of ME/CFS?

[Hip]

However there is quite a lot of research showing that psychological stress causes increased microglial activity and neuroinflammation:

Psychological stress unfortunately is a poorly defined concept: one person facing a stressor may cope admirably, and in fact even thrive and get a buzz from that stressor; you only need to look at people engaging in high risk sports to appreciate that. I used to do things like that when young and healthy: I'd seek out the buzz from facing risky activities, like for example irresponsible boy-racer driving.

Whereas for another person, the same stressor may be highly perturbing and nerve-wracking, and even mentally damaging.

A great deal depends on the brain's ability to cope with stress, and when people say something is stressful, it depends as much on their brain make-up as it does on the external life stressor itself. The same stressor can be an exhilarating buzz for one person, and a nightmare for the next.


Whether it is a buzz or a nightmare can depend on genetics, but also in my experience, on infectious pathogen status.

When I caught the virus that later seemed to triggered my ME/CFS, it first caused a chronic sore throat and some other chronic physical symptoms, but at around two months after first contracting the virus, it induced some really horrible neuropsychological symptoms: significant anxiety (generalized anxiety disorder), anhedonia, loss of desires, blunted affect (weak emotions), depression, worsening memory. There was increased fatigue, but not yet what would consider ME/CFS.

And as this virus spread to friends and family (my chronic sore throat appeared to be constantly shedding the virus), I observed it was able to trigger these same mental symptoms in a number of people, especially severe generalized anxiety disorder. So my response to the virus was not unique or idiosyncratic. Although most people had milder mental symptoms than I did.


Once my brain had been affected by this virus, my ability to cope with any stressors plummeted. Whereas before I'd enjoyed facing challenging stressors, all of a sudden, my brain and mind just could not cope with these.

The effects of this virus on the brain (possibly mediated via a neuroinflammatory immune response) dramatically altered the way I handle stress. Consequently I started avoiding any form of stressor, because I felt my mind was just not able to cope. I was not working at the time, so fortunately it was easy to cocoon myself away from all stressors; but if I had been working, I am sure it would have been a disaster, and I would have come tumbling down in flames, as I would not have been able to cope with anything, and my work colleagues would have probably perceived me as having a nervous breakdown.

This is I think what happens when people have a nervous breakdown: the cliche of nervous breakdown is someone in a high flying job, doing very well, then all of a sudden they find they cannot cope, and are totally stressed out by everything — whereas before they loved the challenging stressors.

The cliche explanation of the average man in the street is that his stressful job itself caused the nervous breakdown; but your average man in the street will often create some psychological explanation for such events, because that's all he understands. He does not have the background in biology to understand the complexities of the body and brain.

But most likely these people caught some sort of infection, perhaps asymptomatically so that they do not even know that they contracted a new microbe, and then that pathogen starts altering their brain mechanics, and suddenly makes them vulnerable to stress and unable to cope with stressors. Hence the "nervous breakdown".



But going back to your statement that increased psychological stress causes increased microglial activity and neuroinflammation: depending on how the study was conducted, if you are simply asking people whether they feel stressed, and then measuring neuroinflammation, that's a flawed study because as explained, whether you feel stress or not from a stressor depends on the health of your brain, which may in turn depend on the infections in your body and your immune response to them.

Thus if you find in a study that people who report high stress have neuroinflammation, that does not prove that the stressors caused the neuroinflammation; it may be that a chronic viral infection caused the neuroinflammation, which in turn leads to inability to cope with stressors, and thus a constant feeling of being stressed.

 

[xak53]

CFS isn't defined by "mere fatigue" either. And SPECT scans don't actually show CNS change, they show changes in blood flow. You also see changed in SPECT scans in patients with depression. The consensus is that SPECT scans aren't very useful in diagnosing CFS (or ME).

The reality is that ME is an invalid etiology because there isn't generally any inflammation, and a lot of the time there isn't even any myalgia. The reason for using the term CFS is that it doesn't imply any etiology, but it definitely isn't "just fatigue".

SPECT SCANS.
Single-photon emission computed tomography, abbreviated SPECT or SPET, is a nuclear medicine imaging test. It is used to obtain 3-D images of many body systems, however, the one used specifically for ME/CFS is a brain scan. At present time, the use of SPECT brain scans for ME/CFS is mostly in clinical studies of the pathophysiology of ME/CFS. It is not needed for diagnosis nor is it used as a treatment.
So yes you are right.

REGARDING INFLAMMATION IN M.E.

• 
  
  
  • SARAH KNAPTON SCIENCE EDITOR

31 JULY 2017 • 8:00PM
Chronic fatigue syndrome is an inflammatory disease which could soon be diagnosed through a simple blood test, scientists have said.

Researchers at the Stanford University School of Medicine discovered that people suffering the symptoms of CFS show spikes in 17 proteins produced by the immune system. The bigger the rises, the more severe the condition.

Chronic fatigue syndrome, which is also known as myalgic encephalomyelitis or ME, affects around 250,000 Britons and is characterised by extreme tiredness, muscle pain, sleep disorders, headaches and flu-like symptoms.

Because it often occurs following an illness, infection or traumatic event, such as a car accident, scientists have suspected that it could be that the immune system failing to shut down properly. Antivirals and anti-inflammatories have also helped some people.

But for decades the illness was largely dismissed by sceptics as ‘yuppie flu’ because no cause could be found.

The new research is the first to show a concrete reason for the condition: chronic inflammation, driven by the immune system. Inflammation is the body’s way of responding to an invader and the reason that people feel so groggy when combating a cold or the flu.
When comparing patients the investigators found that the concentrations of 17 of the cytokines were linked with disease severity and 13 triggered inflammation.

So I feel this is a questionable area of study at this point.

 

[Hip]

@xak53, when you quote someone like you did, their comments are placed between [ QUOTE ] and [ /QUOTE ] markers (which create the orange box once you post your comment). Your own text should be outside of these two markers. Hope that helps.

 

[femtosecond99]

But going back to your statement that increased psychological stress causes increased microglial activity and neuroinflammation: depending on how the study was conducted, if you are simply asking people whether they feel stressed, and then measuring neuroinflammation, that's a flawed study because as explained, whether you feel stress or not from a stressor depends on the health of your brain, which may in turn depend on the infections in your body and your immune response to them.

Thus if you find in a study that people who report high stress have neuroinflammation, that does not prove that the stressors caused the neuroinflammation; it may be that a chronic viral infection caused the neuroinflammation, which in turn leads to inability to cope with stressors, and thus a constant feeling of being stressed.

Have a look at my previous post, and you'll see the studies were looking at mice (the same mice that Duncan seems to be accusing of being responsible for their own stress response), so I don't think it wasn't reporting bias.

My CFS was the same as yours...triggered by what appeared to be a viral infection, then I wasn't able to cope with stress. But I suspect pre-existing stressors were the main cause of the subsequent CFS rather than the viral infection (or perhaps a combination).

The way stress seems to work is that at a certain point the brain shuts off the energy supply, resulting in an inability to deal with any type of stressor. Of course you'll see a similar response if you have a long-term viral infection, so it's hard to know for sure, but in CFS there doesn't appear to be any such infection (at least, not after the initial infection). There is sometimes chronic EBV, but that only happens sometimes, and may be a reactivation due to the CFS rather than the other way around.

 

[duncan]

The way stress seems to work is that at a certain point the brain shuts off the energy supply, resulting in an inability to deal with any type of stressor

Conjecture. Proof please, and preferably from non-psych sources.

in CFS there doesn't appear to be any such infection (at least, not after the initial infection).

Not quite accurate - there are plenty of cases where there is evidence of continued infection. I can speak to Lyme at length, and I am sure there are others here that can address enteroviruses and EBV etc.

 

[femtosecond99]

Conjecture. Proof please, and preferably from non-psych sources.

We've known this since Selye's experiments in the 50s. For more research review, see:

http://dx.doi.org/10.1037/0033-2909.133.1.25 (see full text).

Not quite accurate - there are plenty of cases where there is evidence of continued infection. I can speak to Lyme at length, and I am sure there are others here that can address enteroviruses and EBV etc.

There isn't really any good evidence of persistent chronic lyme infection. (Yes there is a study into Macaques, but it hasn't been replicated, and there are quite a few criticisms of it). One study doesn't constitite proof. I mentioned EBV in my comment above...it only appears in some patients, and seems to be reactivation. Antivirals certainly don't help (according to research by Strauss, Montoya, Lerner and others).

 

[duncan]

There isn't really any good evidence of persistent chronic lyme infection.

Sure there is. Does the name Vicky Logan mean anything? There are many more where that came from. Also, check C6 references as it has been used repeatedly to demonstrate continued infection.

(Yes there is a study into Macaques, but it hasn't been replicated, and there are quite a few criticisms of it).

Embers just released the results of a second primate study that validate the 2012 effort.

One study doesn't constitite proof

Oh dear. There are many studies that demonstrate persistent Borrelia infection, including a recent effort by Marques at the NIH employing xenodiagnosis.

Antivirals certainly don't help (according to research by Strauss, Montoya, Lerner and others).

Antivirals have been reported to help a subset of patients.

We've known this since Selye's experiments in the 50s.

A lot of things we thought were true in the 1950's have since been shown to be nonsense, including a swath of Freudian theory. A lot of things we thought were true in the '70's have since been demonstrated to be nonsense - including Lyme having a viral cause.

 

[femtosecond99]

Embers just released the results of a second primate study that validate the 2012 effort.

By the same person, and the criticisms were towards this latest study. It will be interesting to see if it can be replicated by someone else.

a recent effort by Marques at the NIH employing xenodiagnosis.

Do you have a reference for that?

Antivirals have been reported to help a subset of patients.

But clinical trials show no benefit over placebo, even in that subset.

A lot of things we thought were true in the 1950's have since been shown to be nonsense. A lot of things we thought were true in the '70's have since been demonstrated to be nonsense - including Lyme having a viral cause.

That's why I included a more recent review as well.

 

[duncan]

Do you have a reference for that?

For Marques and Xeno? - just google it.

As for wanting another proof of persistent infection, check out research by Johns Hopkins and Northeastern and Tulane - Zhang, Lewis and Embers respectively.

 

[femtosecond99]

For Marques and Xeno? - just google it.

"
RESULTS:
Xenodiagnosis was well tolerated with no severe adverse events. The most common adverse event was mild itching at the tick attachment site. Xenodiagnosis was negative in 16 patients with posttreatment Lyme disease syndrome (PTLDS) and/or high C6 antibody levels and in 5 patients after completing antibiotic therapy for erythema migrans. Xenodiagnosis was positive for B. burgdorferi DNA in a patient with erythema migrans early during therapy and in a patient with PTLDS. There is insufficient evidence, however, to conclude that viable spirochetes were present in either patient."

Not exactly convincing evidence of ongoing infection.

 

[Hip]

Have a look at my previous post, and you'll see the studies were looking at mice (the same mice that Duncan seems to be accusing of being responsible for their own stress response), so I don't think it wasn't reporting bias.

I had a quick look at the review paper you linked to, and there seem to be a significant flaw in all the studies it reviewed, which would seem to negate their conclusion that psychological stress in mice leads to neuroinflammation.

The problem is that the studies used Iba-1 (ionized calcium‐binding adaptor molecule 1) as their means to detect microglial activation and thus neuroinflammation.

However, this paper points out that Iba-1 binds to both quiescent microglia as well as activated microglia, and thus Iba-1 does not appear to be a reliable means of detecting activated microglia. By contrast, the paper says PK11195 exclusively detects activated microglial cells. The paper says:

Another problem for neuropathological studies is that the immunohistochemical markers (HLA‐DR and Iba‐1) label both quiescent and amoeboid microglia; therefore, it is difficult to assess microglial activation.

To overcome the subjective nature of these studies, alternative methods to quantify microglial activation include the use of markers such as [3H]‐PK11195, [3H]‐PBR28 and CD11b, which (unlike HLA‐DR and Iba‐1) are up‐regulated exclusively on the surface of activated microglial cells

Since microglia are also involved in learning, what your stress studies may have detected in simply the consolidation of information in the mices' brains, after exposure to these events that were designed to cause stress. I am not denying the possibility that psychological stress might ramp up neuroinflammation, but the review paper you provided does not reliably prove that.

CFS there doesn't appear to be any such infection (at least, not after the initial infection)

In the enterovirus subset, there is no doubt that a chronic enterovirus infection exists in the muscles of ME/CFS patients. You cannot detect this infection by blood PCR, but it will show up if you perform PCR on biopsied muscle tissue.

If you would like to glance at all the early research done in the UK in this post, and perform a browser Find on the word "muscle", it will pick out the studies in which patients were found PCR positive for enterovirus in their muscles.

So there is no doubt enterovirus can and does form chronic infections in the tissue in ME/CFS. Dr Chia's research extended this finding to the intestines, where you also find chronic enterovirus infection in ME/CFS. And all three brain autopsies looking for enterovirus in ME/CFS patients found it there, whereas none of the control brains were found infected.

These chronic infections found in ME/CFS are not regular enterovirus infections, but non-cytolytic enterovirus infections — a form of the virus that was only recently discovered in the last 15 or 20 years.

So I am not sure where you are getting your information from when you say that there is no infection after the initial acute infection in ME/CFS.


The evidence for chronic herpesvirus infections in ME/CFS is weaker: as with enterovirus ME/CFS, you find elevated IgG antibodies to herpesvirus in ME/CFS patients, but it is open to interpretation whether that represents a hidden infection in the tissues or not. Dr Lerner detected cytomegalovirus infection by PCR on ME/CFS patient heart muscle samples, but that was just one very small study.

 

[femtosecond99]

Since microglia are also involved in learning, what your stress studies may have detected in simply the consolidation of information in the mices' brains, after exposure to these events that were designed to cause stress. I am not denying the possibility that psychological stress might ramp up neuroinflammation, but the review paper you provided does not reliably prove that.

Yes, there definitely needs to be studies looking into PK11195 during stress. However given that we know that stress affects the immune system, it wouldn't really be a great surprise if there was neuroinflammation from psychological stress.

In the enterovirus subset, there is no doubt that a chronic enterovirus infection exists in the muscles of ME/CFS patients. You cannot detect this infection by blood PCR, but it will show up if you perform PCR on biopsied muscle tissue.

I don't think we can say that, when it is only Chia who has found this. Has it been replicated by anyone else? Muscle infection would be unlikely to explain PEM...it would most likely be permanent pain.

 

[duncan]

Xenodiagnosis was well tolerated with no severe adverse events. The most common adverse event was mild itching at the tick attachment site. Xenodiagnosis was negative in 16 patients with posttreatment Lyme disease syndrome (PTLDS) and/or high C6 antibody levels and in 5 patients after completing antibiotic therapy for erythema migrans. Xenodiagnosis was positive for B. burgdorferi DNA in a patient with erythema migrans early during therapy and in a patient with PTLDS. There is insufficient evidence, however, to conclude that viable spirochetes were present in either patient."

You don't get it. Just as it's the cumulative effect of evidence for those that do not believe in persistence, it is the same for those that do. There is ample evidence for BOTH sides. The problem is, once you take the position that persistence cannot exist post CDC-recommended treatment protocols, all one needs is one exception - and there are literally countless exceptions. It's like saying no mountain exists higher than 1,000 meters - all one needs to do is point to one. When you can point to two or three or a hundred or more - you get the idea.

The concept of persistent Bb infection has plenty of evidence. Period. So, too, is there evidence of persistent infection in other diseases.

So, is that indisputable proof that active infections are at the root of ME/CFS? No. But to discount them by suggesting there is little to no evidence is inaccurate.

 

[Hip]

I don't think we can say that, when it is only Chia who has found this.

Long before Chia, back in the 1990s, there were 7 different British studies that found enterovirus in the muscles. These studies are listed here.

Dr Chia's work replicated and extended what we already know: that ME/CFS is associated with chronic enterovirus infection.

However given that we know that stress affects the immune system, it wouldn't really be a great surprise if there was neuroinflammation from psychological stress.

I would expect the opposite: we know that under times of stress, the immune response is temporarily turned down (by cortisol release), presumably to divert all energy into the animal's fight for survival and dealing with the stressful situation. It would make little sense for the body to ramp up immunity in times of stress.

Even if neuroinflammation were increased under stress, you would have to prove that psychological stress can cause chronic and permanent neuroinflammation; if there were just transient neuroinflammation from stress, then that would not on its own likely lead to disease.

Antivirals certainly don't help (according to research by Strauss, Montoya, Lerner and others).

When you say antivirals don't seem to help, that's not the conclusion of Montoya's clinical trial of Valcyte for the herpesvirus subset of ME/CFS:

Randomized clinical trial to evaluate the efficacy and safety of valganciclovir in a subset of patients with chronic fatigue syndrome

And Lerner's trial of Valtrex or Valcyte for herpesvirus ME/CFS, although without a control group, nevertheless found that one group of patients in the study with pure herpesvirus infection made substantial improvements after 2 years treatments, whereas another group in the study which had herpesvirus plus confections made lesser improvements.

If the benefits of Valcyte had been placebo, you would have expected both groups to have the same results.


And in the enterovirus subset, interferon has produced some substantial improvements, that lasted as long as 14 months in some cases, before patients relapsed. Unfortunately interferon often does not work a second time, as the body creates antibodies to the interferon.

Dr Chia also conducted an informal study using a control group on the immunomodulator oxymatrine (he had no funding for a formal study). He found 30% of enterovirus ME/CFS patients will make substantial improvements.

And Chia's before and after stomach biopsies on these oxymatrine patients found that as they improved, the amount of enterovirus in their stomach tissues was substantially reduced.

 

[duncan]

We've known this since Selye's experiments in the 50s. For more research review, see:

http://dx.doi.org/10.1037/0033-2909.133.1.25 (see full text).

Hmmm, I thought I had requested non-psych sources.....

 

[Hip]

Muscle infection would be unlikely to explain PEM...it would most likely be permanent pain.

In chronic coxsackievirus B myocarditis, you get the same non-cytolytic enterovirus infections in the heart muscle as you find in ME/CFS patients' skeletal muscles.

In the case of CVB myocarditis, it has been shown that the enteroviral infection seems to precipitate an autoimmune attack on the mitochondrial of the heart muscle cells. This causes a dramatic loss of energy output from the heart muscle.

Thus it is not beyond the realms of possibility that the same think might happen in ME/CFS patients' infected muscles.

 

[femtosecond99]

Long before Chia, back in the 1990s, there were 7 different British studies that found enterovirus in the muscles. These studies are listed in this post.

Dr Chia's work replicated and extended what we already know: that ME/CFS is associated with chronic enterovirus infection.

Later work by those scientists showed that the same viruses are present in healthy people:

http://www.me-cfs-treatment.com/more-information/background-to-guidelines/

(Not sure of the refs, but if you're interested in this stuff it's probably quite easy to find them).

I would expect the opposite: we know that under times of stress, the immune response is temporarily turned down (by cortisol release), presumably to divert all energy into the animal's fight for survival and dealing with the stressful situation. It would make little sense for the body to ramp up immunity in times of stress.

That's not quite true. Cortisol doesn't turn down the immune system, it shifts it from Th1 (intracellular) to Th2 (extracellular) response.

Even if neuroinflammation were increased under stress, you would have to prove that psychological stress can cause chronic and permanent neuroinflammation; if there were just transient neuroinflammation from stress, then that would not on its own likely lead to disease.

I'm not saying that psychological stress causes CFS to persist. I was just pointing out that it's one possible cause of neuroinflammation.

When you say antivirals don't seem to help, that's not the conclusion of Montoya's clinical trial of Valcyte for the herpesvirus subset of ME/CFS:

The results were not statistically significant.

If the benefits of Valcyte had been placebo, you would have expected both groups to have the same results.

It could also have been that the treatment had no effect, and both groups gradually improved but the more ill group just took longer to improve.

 

[duncan]

I'm not saying that psychological stress causes CFS to persist.

This strikes me as a bit awkward of an observation. Did you mean to say, "I'm not saying psychological stress causes CFS."? Almost by definition, CFS usually persists, unless perhaps you are conflating ME/CFS with chronic fatigue?

I'm not saying that psychological stress causes CFS to persist. I was just pointing out that it's one possible cause of neuroinflammation.

You've probably got that backwards.

 

[femtosecond99]

This strikes me as a bit awkward of an observation. Did you mean to say, "I'm not saying psychological stress causes CFS."? Almost by definition, CFS usually persists, unless perhaps you are conflating ME/CFS with chronic fatigue?.

It seems pretty clear that stress is a trigger for CFS. Whether ongoing stress is a factor that causes it to persist after the stress has ended is another question entirely. Many CFS patients didn't have ongoing stress (I didn't), so my own opinion is that it's not (but it will certainly make it worse).

 

[duncan]

Whether ongoing stress is a factor that causes it to persist after the stress has ended is another question entirely.

?

Ah, you mean after the precipitating stress has been replaced by another stress? Lots of stress here...Some might suggest that to feel all this stress all this time that neuroinflammation should be on the table as a contributing cause of that stress.

I think your position has many contributors reversed. In my view this is a common deficit in psych arguments because they fall into that whole nest of nasties associated with Cartesian Dualism. These deficits, in my experience, have elements in common with religionists.

I suggest you look at the objective indicators, and remove yourself as much as possible from subjective vantages. Again, I could run all the way between the goal posts with Borrelia alone - and that represents merely a single pathogen.