Discussion - Does ME involve brain inflammation?

[Jonathan Edwards]

Moderator note:
The subject of brain inflammation in ME arose in this thread about a Netflix series.

The discussion started with the following quote in post #32 from a doctor visiting a patient with ME shown in the film when explaining the word 'encephalomyelitis' in name ME may not be appropriate:

There are a subset of patients who did have inflammation in the brain.
But the vast majority of people with chronic fatigue don't.

The validity of this statement was questioned by @JenB (post #41) and @Jonathan Edwards responded (post #82). His response is copied below.
....................................................................................................................

There are a subset of patients who did have inflammation in the brain.
But the vast majority of people with chronic fatigue don't.

There may not be sufficient proof of the positive, but I've never seen positive proof of the negative. (Is there? I checked with a neuroscientist and he said there is not.)

I wish doctors understood logic, probability, statistics and causal inference. I wish the public (and TV documentary producers) didn't mistake doctors for scientists.

There is cast iron proof @JenB. I wonder who your neuroscientist is? Is he someone also trained in clinical neurology, histopathology, immunology and with extensive clinical experience of looking after people with encephalitis, as in lupus? (Like me.) Neuroscientists have got used to talking of 'neuroinflammation' in the context of everything from Parkinson's to Alzheimer's. This takes the meaning of inflammation completely away from the original meaning as used in the term encephalitis.

Inflammation, as in encephalitis, is a process where increased dilatation and permeability of blood vessels leads to increase in flux of fluid and cells followed by tissue restructuring. The term actually means the 'flaming' of the redness due to dilatation. You cannot see that in a brain and dilatation is not necessarily the most important factor so clinical encephalitis is really about the manifestations of increased permeability.

Even slight increase in permeability of blood vessels in the brain produces swelling with either impairment of consciousness or abnormal brain function such as severe mood change or loss of sensory or motor capabilities. Lupus encephalitis neatly illustrates all the stages of pathology. Even slight changes with increased water content lead to mood change, drowsiness (not fatigue) and then coma. If there is local change with cellular influx then you get what looks like a stroke.

These changes are easy to pick up clinically. There are also now easy to pick up on MRI. In people with ME they are not there. The guy is on cast iron ground. We know for sure that the majority of people with ME do not have encephalitis. They might have some microglial activation but that is not encephalitis. Negative MRIs are not absence of evidence, they are evidence of absence.

I understand logic, probability, statistics and causal inference very well, Jen. I am also both a doctor and a scientist. I think you need to make sure you are not mistaking absence of evidence that someone knows what they are taking about for evidence of absence!

 

[MSEsperanza]

Neuroscientists have got used to talking of 'neuroinflammation' in the context of everything from Parkinson's to Alzheimer's. This takes the meaning of inflammation completely away from the original meaning as used in the term encephalitis.

I am particularly interested in this, so anticipated apologies in case this is going off-topic a bit.

I wonder whether I understood you properly,@Jonathan Edwards: Do you think that only encephalitis deserves to be called "inflammation in the brain"? Shouldn't we distinguish between any kind of inflammation in the brain and inflammation of the brain? E.g., vasculitis, an inflammation of blood vessels, may occur in the brain, but is not the same as encephalitis, right?

They might have some microglial activation

What kind of "microglial activation" could that be? Could it also be a stage anterior to inflammation of smaller tissue, comparable with an allergic reaction which does not always induce inflammation, or sometimes induces inflammation only in very small parts of the skin or mucosa?

There are also now easy to pick up on MRI.

I remember when I had been suspected to have MS, I was taught that MS was a chronic inflammation of the CNS, and only a flare/ relapse was an acute inflammation, which can best be shown on MRI because an inflamed brain's blood-brain-barrier becomes permeable and lets contrast agent inside the brain which a non-inflamed brain won't do. Thus, when you have an MRI done in a remitting phase, there will be no signs of an acute inflammation, but increased lesions in a particular order still are suspect for a chronic inflammation.

I haven't understood yet how this fits in with progressive and secondary progressive MS, in which no flares = no acute infections occur, but in which CNS inflammation produces lesions as well?

[eta: some typos]

 

[Jonathan Edwards]

Do you think that only encephalitis deserves to be called "inflammation in the brain"? Shouldn't we distinguish between any kind of inflammation in the brain and inflammation of the brain? E.g., vasculitis, an inflammation of blood vessels, may occur in the brain, but is not the same as encephalitis, right?

Cerebral vasculitis would come under encephalitis I think. Vasculitis is a form of inflammation in which the cellular infiltrate remains focused on the vessel rather than moving out into the tissue parenchyma. The distinction between that and other forms of local inflammation can be blurred.

What kind of "microglial activation" could that be? Could it also be a stage anterior to inflammation of smaller tissue, comparable with an allergic reaction which does not always induce inflammation, or sometimes induces inflammation only in very small parts of the skin or mucosa?

Microglial activation could mean anything where microglia are expressing or secreting molecules more than usual. People find microglia showing evidence of activation in almost all types of brain pathology, regardless of whether there is true in floatation. This is not related to allergy, which is mast cell based. Allergy mostly does produce inflammation. Local skin allergy like urticaria is the paradigm of acute inflammation in a sense. Allergy can produce things like bronchospasm without overt inflammation but mostly it is inflammatory.

I remember when I had been suspected to have MS, I was taught that MS was a chronic inflammation of the CNS, and only a flare-up was an acute inflammation, which can best be shown on MRI because an inflamed brain's blood-brain-barrier becomes permeable and lets contrast agent inside the brain which a non-inflamed brain won't do. Thus, when you have an MRI done in a remitting phase, there will be no signs of an acute inflammation, but increased lesions in a particular order still are suspect for a chronic inflammation.
I haven't understood yet how this fits in with progressive and secondary progressive MS, in which no flare ups = acute infections occur, but in which CNS inflammation produces lesions as well?

MRI will show increased water content during acute inflammation. In chronic inflammation the water content may return to normal and the changes are of increased cell numbers and structural changes like scarring. MRI changes are different and may be less obvious but with modern machines are still easy enough to see. In progressive forms of MS there will be areas in various stages of evolution from acute to chronic changes all overlapping in time. There are no acute infections in MS that we know of, just bursts of cellular infiltration into the brain from the blood vessels.

 

[Jonathan Edwards]

Not sure if this is of any relevance here but........
The Neuroinflammatory Etiopathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5314655/

(have only skimmed thro.....not sure if this trying to push the 'Central Sensitisation' theory(?))

I am afraid that is just every-babble.

 

[alex3619]

We know for sure that the majority of people with ME do not have encephalitis.

Yes, this is correct. However there is some evidence that some are encephalitis survivors. According to surveys, with inherent bias, up to 70% of encephalitis survivors are partially disabled, and that is just from the "recovered" pool. Up to 40% appear fully disabled.

There is a subset in ME who are encephalitis survivors, and according to Ian Lipkin et. al. these have a different cytokine profile, and he called them atypical ME. As I am an encephalitis survivor I wonder if I am in that group. Doctor Charles Shepherd is also an encephalitis survivor I believe.

Now this does not mean that post-encephalitis deserves its own diagnostic category, nor that it is accurate to speak of inflammation in the brain.

There is now growing evidence of similar pathology in post-sepsis, post-burns, and post-viral-infection-M.E. This is currently under scrutiny from ME researchers and sepsis researchers. Its entirely possible that most post-physical-trauma survivors have a similar pathology (such as with Lyme and cancer and chemo), and the evidence is mounting. We are not at anything like proof yet, and a lot is hypothesising, but its an issue that deserves to be watched.

However if the chronic microglial activation hypothesis is confirmed, with Stanford replicating the Japanese finding, what would it be classed as? Many are calling it inflammation. Should it more accurately be called a neuroimmune disorder without mentioning inflammation if this finding is confirmed?

 

[Jonathan Edwards]

However if the chronic microglial activation hypothesis is confirmed, with Stanford replicating the Japanese finding, what would it be classed as? Many are calling it inflammation. Should it more accurately be called a neuroimmune disorder without mentioning inflammation if this finding is confirmed?

Good points @alex3619. I think it should probably be called microglial activation - that would be precise and unambiguous. It does not need to be called immune, even if it might come under the broad spectrum of innate immune pathways. Macrophage activation after a broken leg is not normally called immune - very much along the lines you were discussing.

 

[alex3619]

it should probably be called microglial activation - that would be precise and unambiguous

I do think clear and unambiguous is usually a very good choice.

 

[MSEsperanza]

Cerebral vasculitis would come under encephalitis I think. Vasculitis is a form of inflammation in which the cellular infiltrate remains focused on the vessel rather than moving out into the tissue parenchyma. The distinction between that and other forms of local inflammation can be blurred.



Microglial activation could mean anything where microglia are expressing or secreting molecules more than usual. People find microglia showing evidence of activation in almost all types of brain pathology, regardless of whether there is true in floatation. This is not related to allergy, which is mast cell based. Allergy mostly does produce inflammation. Local skin allergy like urticaria is the paradigm of acute inflammation in a sense. Allergy can produce things like bronchospasm without overt inflammation but mostly it is inflammatory.



MRI will show increased water content during acute inflammation. In chronic inflammation the water content may return to normal and the changes are of increased cell numbers and structural changes like scarring. MRI changes are different and may be less obvious but with modern machines are still easy enough to see. In progressive forms of MS there will be areas in various stages of evolution from acute to chronic changes all overlapping in time. There are no acute infections in MS that we know of, just bursts of cellular infiltration into the brain from the blood vessels.

Thank you, @Jonathan Edwards. Once again, your answers are very helpful. And once again, I am too slow to ask further, more specified questions right now. I will come back to some points maybe in related threads.

Only two points for now (even though they might be more relevant for the thread on the central MEpedia page: https://www.s4me.info/threads/the-mepedia-page-on-myalgic-encephalomyelitis.5342/page-4#post-96789 )

- I understood that In ME, there seem to be no signs of inflammation in any part of the brain. Are there, then, only historical and pragmatical reasons for keeping the term "ME"?

- In a patient with urticaria, would you find any signs of inflammation in the blood or skin 12-24h after the visible signs on the surface of the skin are gone? (I have to confess that I am not entirely convinced that inflammation in the brain, be it locally very restricted and only temporary, could not play a role in ME, thus the comparison with urticaria).

 

[Jonathan Edwards]

- I understood that In ME, there seem to be no signs of inflammation in any part of the brain. Are there, then, only historical and pragmatical reasons for keeping the term "ME"?

- In a patient with urticaria, would you find any signs of inflammation in the blood or skin 12-24h after the visible signs on the surface of the skin are gone? (I have to confess that I am not entirely convinced that inflammation in the brain, be it locally very restricted and only temporary, could not play a role in ME, thus the comparison with urticaria).

The use of the term encephalitis is entirely historical - based on Acheson's inappropriate assumption that ME must be similar to polio encephalomyelitis. It is a pity because it is such a red herring. But archaic names are not unusual. Systemic lupus erythematous means 'a generalised red version of the flesh-eating wolf that is tuberculosis of the face'.

The inflammation of urticaria is mediated by histamine and kinins rather than cytokines and you are unlikely to pick up much of a signal in blood. If you biopsy the skin after 24hrs you will almost certainly find some extra white cells, but not many.

But if you had the equivalent of urticaria in your brain you would be unconscious, or at least seem to have had a stroke. A sudden increase in fluid, as you get in the skin in urticaria, leads to a rise if pressure and also malfunction of the tissue locally. Very mild change in the brain in lupus produce confusion, mood change, drowsiness of a sort that does not look at all like ME. Something may well be going wrong in the brain in ME but I think it is almost certainly misleading to think of it as a form of inflammation.

 

[lansbergen]

to have had a stroke. A sudden increase in fluid, as you get in the skin in urticaria, leads to a rise if pressure and also malfunction of the tissue locally

Well when I was very severe, during flares I had something what I called a waterhead.

 

[Inara]

drowsiness of a sort that does not look at all like ME

Now that you mention drowsiness a second time, and I find myself thinking the same...

In certain rare situations (on an airplane, stomach/gut biopsy, after getting certain medicines) I go into an interesting state, which starts with drowsiness and develops into a form of "drowsiness" where I can't think, I can't open my eyes for long, I can barely speak...including paralysis of the right leg and general heavy weakness. I observed oxygen helps.

Now I made a comparable experience during a tilt table test. I hypothesize that the brain isn't "supplied" properly (which would fit the PET findings I guess).

My impression was I am not alone with these experiences, but that others with ME know this too. So even if it may not be typical for ME, I think it can be part of ME.

And what about "mini-strokes"?
My mother had a "mild stroke" when she was relatively young, and another family member had several strokes.

 

[Trish]

Brain inflammation and microglial activation in ME is also discussed on this thread.

 

[lansbergen]

But if you had the equivalent of urticaria in your brain you would be unconscious

When I was very severe I could go in a state I did not respond to anything. It could happen when I was sitting upright and stayed in that position. I was not the only one who had that.

 

[Cinders66]

I remember Prof Komaroff saying that there could be low grade or mild “ encephalitis” going on. Perhaps he comes from a specialism where this isn’t his expertise but it’s not just patients saying it.
I’m not wedded to the name. What I found troublesome in the netflix clip around this, was Jamison’s dr seeming to act as if we don’t know anything about this misnamed Illness it could be anything and I’m going to look at YOU and find stuff and treat YOU as if a) there wasn’t a common illness group Jamison belonged to which science was researching with abnormalities found b) if the dr looked with his standard tests he’d find things to get J better.

 

[Alvin]

These changes are easy to pick up clinically. There are also now easy to pick up on MRI. In people with ME they are not there. The guy is on cast iron ground. We know for sure that the majority of people with ME do not have encephalitis.

This sentence leads to this question, one of the current theories is that depression is caused by neuroinflammation, what are your thoughts on this (afaik it does not show up on MRI)

 

[wdb]

Where should the bar be set in terms of evidence justifying the claim/implication that brain inflammation is present ?

Would it be set too high to say ME brains should be able to be differentiated from controls under blind conditions using some medical imaging or measuring procedure ?

 

[Cinders66]

This sentence leads to this question, one of the current theories is that depression is caused by neuroinflammation, what are your thoughts on this (afaik it does not show up on MRI)

I think the type of neuroinfllammation being thought to be there in depression,schizophrenia and ME brains shows up on PET scans. Doing PET scans to assess microglial activation was suggested as an avenue for ME CFS by the MRC right back around 2003, it just hasn’t been done much. I think it’s already been established as part of the MS picture.

 

[Jonathan Edwards]

This sentence leads to this question, one of the current theories is that depression is caused by neuroinflammation, what are your thoughts on this (afaik it does not show up on MRI)

Neuroinflammation is one of those trendy babble words that is now applied to anything that might have something to do with brain. If the tests show nothing there is no reason to call it inflammation. I think people with depression tend to have slightly higher CRP levels blood. There are all sorts of reasons why that might be and neuroinflammation would be bottom of my list. I am always ready to learn more but I don't buy it at present.

 

[Jonathan Edwards]

Where should the bar be set in terms of evidence justifying the claim/implication that brain inflammation is present ?

Would it be set too high to say ME brains should be able to be differentiated from controls under blind conditions using some medical imaging or measuring procedure ?

I don't think that is too high. For the conditions we know with brain inflammation a policeman could tell the difference, as my old boss used to say. At least an senior neurology or radiology trainee should be able to tell in an exam without a crib. ME is not a subtle problem. I cannot see that we are going to explain it with changes so subtle nobody can be sure if they are there.

 

[Forbin]

I remember Prof Komaroff saying that there could be low grade or mild “ encephalitis” going on.

BMC Neurol. 2005 Dec 1;5:22.
A Chronic Fatigue Syndrome - related proteome in human cerebrospinal fluid.
Baraniuk JN1, Casado B, Maibach H, Clauw DJ, Pannell LK, Hess S S.
http://www.biomedcentral.com/1471-2377/5/22

Anthony Komaroff summarized the findings of that paper before the Massachusetts CFIDS Association, saying:

“A whole group of proteins, in the brain, were found in 1/3 to 1/2 of patients with Chronic Fatigue Syndrome vs. none of the patients who were healthy - highly significant differences, statistically. And what those molecules - and others that I haven’t shown you for lack of space - say is that there is a low-grade inflammation going on in the brain. There is something in the brain that the immune system doesn’t like, doesn’t want to be there, it wants to get rid of, and that’s being reflected in these proteins in the spinal fluid.”

Slide from Dr. Komaroff's presentation:


Quote starts at 4:14



----------------------

This paper...
Distinct Cerebrospinal Fluid Proteomes Differentiate Post-Treatment Lyme Disease from Chronic Fatigue Syndrome
...found mildly elevated spinal fluid protein levels in about a quarter of the ME/CFS patients in the study and in none of the controls. [ 46–93 mg/dl (with a median of 59 mg/dl) ]