What is the evidence base for non-infectious precipitating factors?

This question arose in a local support group so I won't give any details except that the broad context is pwME vs insurer so any resources likely to convince an insurer and their lawyers particularly welcome.

The question:

It's frequently mentioned that ME typically starts after an infection but that it can also start after other events including physical trauma such as an accident or surgery.

What's this physical trauma claim based on? Epidemiological studies? Patient surveys? Clinicians' impressions?

I found a couple of older studies based on pwME answering questionnaires:

Precipitating factors for the chronic fatigue syndrome (1997)
https://pubmed.ncbi.nlm.nih.gov/9201648/

Possible Triggers and Mode of Onset of Chronic Fatigue Syndrome (2011)
https://www.tandfonline.com/doi/abs/10.1300/J092v10n02_02

Does anyone know of anything more recent, or better?

Are there any mechanistic hypotheses out there that try to explain how physical trauma could cause ME (apart from the vague 'any sort of stressor')?

Edit: added bolding to highlight key question.

 

From my understanding (clinically) is that traumatic brain injury (TBI) can disrupt neural pathways depending on where the injury occurred and severity.

Also the accident that caused the TBI often required surgery and so an anaesthetic was required and often a lot of medication that may (or may not) be toxic to the brain is also administered. There may also be hypoxic damage to the brain from blood loss (which also damages brain tissue).

Brain injury and ME/CFS- literature review on neuroimaging (2011)
https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-020-02506-

The latest paper on reduced limbic perfusion in ME/CFS has references discussing how they are looking at other fatiguing neurological illnesses like TBI and comparing them to ME/CFS (2021)

https://mdpi-res.com/d_attachment/t...graphy-07-00056.pdf?version=1635757992#page12

Here is a clinician discussing his impressions about environmental effects on the brain and neuroimaging (2011)
http://www.itcoba.net/29HY11A.pdf

I take a view that it is a combination of many factors cause ME/CFS outside infection, I think the literature is still evolving around this as neuroimaging is advancing. There are still many unknowns

 

I don't honestly think there is any tangible evidence for ME being triggered by non-infectious factors.

I cannot think of any very plausible mechanism. That does not mean it does not occur but I think vague ideas about disrupting neural circuits or perfusion should be treated with scepticism. At present there is no evidence or viable theory.

People talk of post-concussion syndrome but I am unclear how that relates to ME.

 

What about surgery just by itself, without preceding injury, could that be plausibly linked?

Or the anaesthetic drugs and/or other medications used? Maybe via a similar route to the one they've found in GWI, where some people can't clear certain substances from their system? I suppose nobody's looked at this in ME?

 

I think a link to surgery itself, or anaesthesia, can probably be discounted. If it occurred it would have been reported by now, considering the hundreds of millions of anaesthetics that have been given.

They haven't actually found a route in GWI, although the link to genes involved in cholinergic effects is interesting. Everything is possible but I think one has to be realistic. Something like 30% of gulf war veterans were ill. Out of hundreds of millions of people having anaesthetics we have heard of reports of ME as far as I know. There ought to be a few hundred by pure chance.

There is a literature on long term effects of anaesthetic and there I one evidence of cognitive decline but nothing resembling ME brain fog a far a I am aware. The main concern I that they can accelerate dementia.

 

I think that the problem is that for many ME patients, if they became ill 1 to 3 months after an acute infection, it was not considered as being post-infectious onset or documented as such. Whereas with long Covid, it is acknowledged that it can occur 1 to 3 months after infection.

I became ill three months following an infection, which itself was 3 months after a bad flu. I had some symptoms starting in the second month which corresponded with what long Covid patients report (chest pressure and ache, tiredness) and then developed into full blown ME. It helped me realize I was a post infectious patient to see the reporting of onset pattern for long Covid be so similar.

 

Maybe the most plausible connection between physical trauma and ME, if indeed there is one, would be via the immune system? Any physical trauma or surgery by definition involves tissue damage which in turn must activate the immune system, creating opportunities for something to go wrong.

 

I've only read a couple of posts above but GWAS comes to mind - GWAS may provide a clue to the underlying cause(s).

Anyone heard when Chris Ponting's GWAS study is due to start - enrolling, sampling ---- whatever?

 

Studies on ME epidemiology are sparse but the old idea was that trauma could reactivate a virus or let a virus that was contained run rampant.

It is not a controversial idea. Microbes reproduce and spread unless they are contained. If the immune system is busy dealing with a separate infection or there is mechanical damage E. coli will infect the bladder and cause disease or candida will give you thrush or a bacteria that always lives on your leg will cause erysipelas.

It should not make a difference to a court case. If someone is well before an accident and sick after that should be all that counts.

 

Not in any known sense as far as I know. Yes, macrophages will pass into an area of tissue damage but they do that every day to tidy tissues up. By activating the immune system people usually mean stimulating a specific antigen response and there is no reason to think that would happen.

Immunological problems are not known to follow trauma in any other context, with perhaps the rare exception of sympathetic ophthalmia.

I am not aware of any evidence for that.

With any attempt to link things as causes in medical problems it is always a good idea to remember the hundreds of millions of times the link has not been made as well as the single case where it seems it might!

 

Dr.Byron Hyde

Non-Infectious M.E. Type Disease: I have not discussed noninfectious M.E.-type disease. Similar M.E phenomena can occur due to CNS injuries from toxic chemical injury. I have seen this in police officers who have fallen into toxic chemical ponds in pursuit of those suspected of criminal activity. I have seen it in farmers repeatedly exposed to pesticides and herbicides, in hospital and industrial workers and in military personnel in contact with toxic chemicals, specifically toxic gases. I will discuss these at a later date as Secondary M.E. They do have one thing in common, and that is they also have a diffuse CNS injury as noted on brain SPECT scans. The diagnosis is made by history, as the actual cases are very difficult to diagnose due to the inability to assess brain levels of toxins in a live patient. Often these Secondary M.E. diseases are more severe than the infectious M.E. cases.

 

Ravn IIRC i have oft read the 'trauma/surgery etc can cause/initiate ME/CFS' thing in ME Association literature, i think it might even be in the purple book but i dont have energy to look it up sorry. I could be wrong but i'm pretty sure I've heard Dr Shepherd say it in interviews too. So asking them/him via MEA fb might throw up something your group member would find helpful.

I have for sure seen, over the yrs, plenty of people saying things like 'My ME was caused by a routine surgery'. But personally I have always thought that as with so many things, until we have a better understanding of the actual mechanism, we will never be sure.

"after it therefore because of it" is a huge problem that is very difficult for human nature to over-ride. Both for recovery/improvement and for onset/deterioration.

One thing i will say is that i have no doubt that surgery can provoke 'chronic fatigue'. I had a major, but fairly routine surgery when i was in my 20s, (about 5yrs before ME onset) & had a terrible time getting over it, i felt utterly exhuasted all the time, it took me about 8mnths to get back to full strnegth/stamina again.

But there again i am 'post hoc propter hoc'-ing, because it might have been due to something entirely different, just coincidentally happened after the surgery.

 

When I did microbiology in the 70s we were taught that E. coli was commensal but could cause infection if it was given a chance. Neisseria can live happily in the nose but cause meningitis if it reaches the brain. Similarly Staph.sp live on the skin but if the skin is broken or thin due to age they can break through the body's barrier and cause erysipelas.

The belief was that infection can come from a microbe that is already present rather than all infections being caused by contact with a new one.

 

I've never received a diagnosis of ME, although I believe I fit the criteria. I have actively avoided a diagnosis. If I have it I am not aware of it being triggered by a virus.

In my case I had an intermittent long-term GI bleed. It went on for several years. By 2013 I had been referred to three different hospitals, had various tests all coming back negative. I think some of the tests weren't even actually carried out because the negative test results were absurd - the bleeding was so severe and so obvious. By this time I had almost constant tachycardia, came close to fainting regularly, had bouts of severe chest pain, couldn't walk upstairs normally. I had to go up a step at a time and it would take 20 minutes to reach the top. I discovered after buying my GP records that the first hospital I was referred to had said my serum iron was under range three years before the cause of the blood loss was found. But I suffer from lots of inflammation (for various historical reasons) and inflammation keeps ferritin levels up. So, nobody saw any problem with my blood tests despite ferritin reducing in five consecutive blood tests over three years. They never repeated the iron panel so never saw the low serum iron again.

I think by 2013 I was suffering from chronic hypovolaemia and needed a blood transfusion but I never got one. I fixed my own low iron/ferritin but it took a long time. I was also suffering from untreated secondary hypothyroidism during this time. I treat that myself as well. I have never completely recovered from all the blood loss. I've replaced what I can in terms of nutrients, and I'm healthier than I was when the cause was found (a copiously bleeding polyp in my colon). But I've never managed to recover completely.

 

All of those are true but I don't see them having relevance to a possible link between injury and ME.

 

The SPECT thing has never been validated and for that reason alone I am sceptical about Dr Hyde's ability to gather reliable evidence. A history of toxin exposure may be of interest but whether or not it is the cause remains speculation. In other conditions we have much stricter criteria for deducing a causal relationship (although not it seems in psychological medicine much).

 

Best answer I could give to the question is "none", I guess?

We don't know what the trigger is in post-infectious cases, just that there's an association with some viruses. If it's also reasonable to say that asymptomatic infection is possible with those viruses, it makes it difficult to be sure about anything else.

If it were me trying to get insurance, I'd focus on the fact of the illness rather than the cause of it. And if they insisted on a cause I'd say it was a virus, because (a) it probably was, and (b) it would be hard for an insurance company doctor to prove that it wasn't.

 

It might be insurance against injury from a specific cause though - surgery or accident etc.

 

OMF published (check out their annual symposium presentations) data on metal toxicity which didn't appear to show any link.

There's some interesting stuff here* by Jonathan "They haven't actually found a route in GWI, although the link to genes involved in cholinergic effects is interesting."
So if a pesticide increased the risk of developing ME/CFS then the GWAS (Chris Ponting's) study might give a hint.

Strikes me that claims like ME/CFS is due to "X", e.g. pesticides, can persist since there no evidence what the underlying problem is. On the face of it, if it were due to pesticides then the Norwegian prevalence study (showing young women in their teens to be most likely to get ME/CFS) doesn't seem to fit. Also, I'm not aware of a link to particular employment sectors - surely there would be one if pesticides were implicated.

*
https://www.s4me.info/threads/what-...ious-precipitating-factors.27964/#post-422126

 

I agree with Ravn about immune activation rather than the cause of that activation being the trigger for ME. Some people might be primed to enter the ME state, and it doesn't matter whether it's a microbe or physical injury (even microtears from normal exercise); what matters is that some immune cells activate and release cytokines, which triggers the ME mechanism, which then locks us in that abnormal state.

Finding hard evidence of a causative factor for ME would be difficult, since we can't even prove that an individual has ME. There might be many people claiming to have developed ME symptoms after getting EBV, but even that isn't hard proof of a connection.