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Neuroinflammation in Patients with CFS/ME: PET study

Seven7

Seven
Messages
3,446
Location
USA
I beg to disagree, if it would be the inflammation the factor then 100% of us who have inflammation would have the psy issues too.

I am 100% sure I have brain inflammation. I do not have anxiety and I have never been depressed (evaluated by neuropsy and all).
 

anciendaze

Senior Member
Messages
1,841
lnester7, I believe that 100% do have neuroinflammation, but many are able to cope. Part of the reason would be that the inflammation affects different nerves, and part that some are more careful about checking themselves before they act on impulses. This would go along with evidence that cognitive processing is slower in ME/CFS patients. Those who don't check as carefully probably end up in a different category with a more solid psychiatric label.
 

Sea

Senior Member
Messages
1,286
Location
NSW Australia
I beg to disagree, if it would be the inflammation the factor then 100% of us who have inflammation would have the psy issues too.

I am 100% sure I have brain inflammation. I do not have anxiety and I have never been depressed (evaluated by neuropsy and all).

I think it depends entirely on where the damage is done. People with brain injuries from accidents have variable outcomes (including depression) depending not only on the extent of damage but also which part of the brain is damaged.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
To date I have seen no evidence in ME that I recall of damage to the myelin around nerves. There is evidence of brain-associated inflammation and immune infiltration however. Should the myelin sheaths be damaged then it would most likely be a diagnosis of MS not ME.

However, myelitis does not have to involve damage to myelin according to wikipedia, maybe someone should look into this further:

http://en.wikipedia.org/wiki/Myelitis
 

lansbergen

Senior Member
Messages
2,512
I think myelitis can be transient and does not always cause demyelination.

Not every itis causes large amount of tissue destruction.
 

Gijs

Senior Member
Messages
697
To date I have seen no evidence in ME that I recall of damage to the myelin around nerves. There is evidence of brain-associated inflammation and immune infiltration however. Should the myelin sheaths be damaged then it would most likely be a diagnosis of MS not ME.

However, myelitis does not have to involve damage to myelin according to wikipedia, maybe someone should look into this further:

http://en.wikipedia.org/wiki/Myelitis

Many people with ME have UBO's showing up in MRI. Little white leasies. This can be due to inflamation.
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I think myelitis can be transient and does not always cause demyelination.

Not every itis causes large amount of tissue destruction.

Yes, that is my understanding. Myelitis may involve functional impairment of myelin, or neuronal action, but not necessarily demyelinization.

PS On M.E. there is another reason its not a good acronym, although the name is fine. I had Measles Encephalitis when I was 7. That is also M.E.

I think @SOC pointed out that Encephalitis might be a better term than Encephalomyelitis.
 

Hip

Senior Member
Messages
17,992
The ME/CFS neuroinflammation study discussed in this thread found microglia and/or astrocyte activation in the brain, indicating state of brain inflammation; the interesting thing is that you also get this inflammatory state of chronic microglial activation in other diseases, including:

Hepatitis C [1]
Lyme neuroborreliosis [1]
Systemic lupus erythematosus [1]
Schizophrenia [1]
Bipolar disorder [1]

The first three, hep C, Lyme and lupus, have fairly similar symptoms to ME/CFS, such as fatigue and brain fog.


Russell L. Blaylock has written an accessible overview on how chronic microglial activation raises glutamate and generally causes problems in the brain:

Microglial Activation and Neurodegeneration by Russell L. Blaylock, MD

@Marco has written an article about how raised glutamate from neuroinflammation may be the cause of many ME/CFS symptoms, especially the sensory gating symptoms of ME/CFS, like increased sound sensitivity:

Glutamate - One More Piece in the Chronic Fatigue Syndrome Puzzle?
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I heard this test cost about 1 million yen.

That would be about ten thousand dollars or in the vicinity. That sounds a little high, though it might not be high for cutting edge research testing. Its not like existing facilities would be structured to do experimental tests cheaply.

If this becomes a standardized commercial test it should be much cheaper.
 

biophile

Places I'd rather be.
Messages
8,977
Anthony Komaroff on the E in ME

I was going to start another thread, but what I wanted to post is an implication of this thread.

http://www.meactionuk.org.uk/Komaroff-Summary-San-Francisco-March-2014.htm

Based on this video:


Some good bits, but I found this comment interesting:

In the brain research section of his highlights, Komaroff discussed the work of Marcie and Mark Zinn from Stanford, whose qEEG (quantified electroencephalogram) studies demonstrated a remarkable ability to distinguish CFS from healthy controls; he also spoke about the Japanese studies showing an activation of key brain immune cells (microglia and astrocytes) using PET scans, noting that "past studies have demonstrated reduced cortical blood flow, reduced glutamate - an important neurotransmitter-reduced serotonin transporter and increased dopamine biosynthesis".

On the issue of neuro-inflammation, Komaroff said: "There is, and you've heard it repeatedly in the last three days, a theory that CFS might reflect an ongoing activation of immune cells in the brain, not in the periphery, but in the brain" and he went on to discuss the Japanese study that clearly showed an increased signal, giving evidence of immune activation in multiple areas of the brain, the intensity of the signal correlating with cognitive impairment.

In the Question and Answer session, Komaroff was asked if neuro-inflammation was not encephalomyelitis, to which he replied: "Yes. If it were confirmed by multiple other investigators it would, for me, say that there is a low-grade, chronic encephalitis in these patients, that the image we clinicians have of encephalitis as an acute and often dramatic clinical presentation that can even be fatal has - may have - blinded us to the possibility that there may be an entity of long-lasting - many years long - cyclic, chronic, neuro-inflammation and that that underlies the symptoms of this illness", commenting that it was "entirely plausible and these data are consistent with it".
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
@Hip

Thanks Hip. That early blog kicked off a long (and ongoing) series of blogs considering a possible neuroinflammatory basis for ME/CFS.

A key issue I had to ponder was mechanisms whereby a wide range or peripheral 'stressors' (given the reported heterogenous onset in ME/CFS) could result in the same chronic, low grade and difficult to detect central neuroinflammation.

One potential mechanism is the model of 'spreading neuroinflammation' in complex regional pain syndrome (CRPS) :

Given that CRPS is a condition for which a neuroinflammatory process has been proposed and, unlike in ME/CFS or FMS, the initial trigger in many cases is unambiguous, CRPS may provide a more constrained environment in which to explore a potential neuroinflammatory model of other complex multi-system syndromes including ME/CFS and FMS.

Neuroinflammation or neuroinflammatory tracks that spread through the nervous system alter neurotransmission and coding, causing higher order functional changes in the nervous system including, perhaps, deficits in higher level brain tasks such as executive functioning. It’s important to note that these neuroinflammatory tracks may not necessarily result in easily detected structural changes to the nervous system (e.g. demyelination of nerves or gross structural changes to the brain). Functional or dynamic lesions that may also contribute to the pathology may be undetectable using neuroimaging technologies such as traditional MRI scans.

Plus autoimmunity may be a key mechanism to explain why only a small minority of patients develop CRPS (or ME/CFS following a common viral infection) :

The key concept here is that the development of autoimmunity to specific neuroautoantigens may be the initiating event for many cases of CRPS. Psychological stressors, physical trauma, infectious agents, and/or genetic susceptibility could all play a role in the breakdown of self-tolerance, and the onset of an autoimmune response. This set of etiological linkages fits well with documented clinical experience with CRPS (Mitchell 1872; Birklein et al. 2000). Psychological stressors and immunologic priming have been linked to the enhanced activation of microglia to nervous system injury (Frank et al. 2007; Hains et al. 2010).”

http://www.cortjohnson.org/blog/201...lgia-mecfs-spreading-neuroinflammation-model/
 

RustyJ

Contaminated Cell Line 'RustyJ'
Messages
1,200
Location
Mackay, Aust
Why has the possibility of myelin damage been ruled out? Just because there is no corroberating evidence in the case of ME doesn't mean it doesn't happen. There really hasn't been much effort to research neurological issues in ME.

There is some evidence that hypoperfusion (well-documented in ME) leads to myelin damage; also leads to neuroinflammation (in rats):

Permanent, bilateral common carotid artery occlusion in the rat: a model for chronic cerebral hypoperfusion-related neurodegenerative diseases.

Also a possible treatment option?:

Huperzine a improves chronic inflammation and cognitive decline in rats with cerebral hypoperfusion.
 

Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
Why has the possibility of myelin damage been ruled out? Just because there is no corroberating evidence in the case of ME doesn't mean it doesn't happen. There really hasn't been much effort to research neurological issues in ME..

Prasher et al (1990) used evoked potentials to show that sensory nerve conduction (which is impaired in demyelinating diseases such as MS) is normal in 'ME' whereas event related potentials (the cortical response to stimuli) show abnormalities related to 'gating in' or attentional processes which may reflect cognitive problems.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1014138/pdf/jnnpsyc00513-0063.pdf

Not necessarily definitive but I don't see the need to demonstrate gross structural abnormalities when discussing neuroinflammation.
 

RustyJ

Contaminated Cell Line 'RustyJ'
Messages
1,200
Location
Mackay, Aust
Not necessarily definitive but I don't see the need to demonstrate gross structural abnormalities when discussing neuroinflammation.

I agree. However my response was intended as a contribution to the discussion on the aptness of using the term 'myelitis'. It may well be that there is not only different damage sites in the brain, but different causes, in patients.

Further to this, Richard A. Van Konynenburg mentions that in me/cfs the body's capacity to repair normal degradation of myelin is hampered. Also he mentions that the myelin damage causes “white spots” in MRI examination of the brain. I don't know what his references were.

With respect to me/cfs it appears to be more accurate to say that not enough research has been done to determine if there is myelin damage or not, rather than to say there is no damage.
 

Hip

Senior Member
Messages
17,992
my response was intended as a contribution to the discussion on the aptness of using the term 'myelitis'.

Note that the term myelitis does not mean inflammation of myelin, but rather means inflammation of the spinal cord.

Myelitis derives from Greek word myelós which refers to the spinal cord.

Similarly:
Encephalitis = inflammation of the brain.
Encephalomyelitis = encephalitis + myelitis = meaning inflammation of the brain and spinal cord.

Though of course damage to myelin can occur as a result of inflammation such myelitis or encephalitis.



This is an interesting list of Greek and Latin medical prefixes and suffixes:

List of medical roots, suffixes and prefixes - Wikipedia, the free encyclopedia

Once you learn a few of these, you can often half guess the meaning of medical terms.

You can see from this list that the prefix myel(o)- actually means "of or relating to bone marrow or spinal cord." So this prefix in fact has two meanings.

Not to be confused with the prefix my(o)- which means "of or relating to muscle," as in the term myalgic, meaning muscle pain.
 
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Marco

Grrrrrrr!
Messages
2,386
Location
Near Cognac, France
I agree. However my response was intended as a contribution to the discussion on the aptness of using the term 'myelitis'. It

Hi Rusty (and thanks to Hip for clarifying the full interpretation of 'myel').

Correct me if I'm wrong but wasn't the term myalgic encephalomyelitis first coined following the Royal Free outbreak? From the few original papers I've read I don't recall any physiological/histological evidence to support 'myelitis' in these folks.

Very happy to be told otherwise though.
 

Hip

Senior Member
Messages
17,992
Hi Rusty (and thanks to Hip for clarifying the full interpretation of 'myel').

Correct me if I'm wrong but wasn't the term myalgic encephalomyelitis first coined following the Royal Free outbreak? From the few original papers I've read I don't recall any physiological/histological evidence to support 'myelitis' in these folks.

That's a good point: how did they know in the 1950s that there was brain and spinal cord inflammation in ME/CFS, so as to be able to call it "myalgic encephalomyelitis"?

In two published studies about the Royal Free Hospital outbreak in London 1955, the authors already described the condition as "encephalomyelitis" (but without using the "myalgic"), so even in this 1955 outbreak, they must have known it involved brain and spinal cord inflammation. The two Royal Free Hospital outbreak papers are these:

Epidemiological aspects of an outbreak of encephalomyelitis at the Royal Free Hospital, London, in the summer of 1955

An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955

From the second paper cited above, I quoted a text extract below which seems to provide possible physical evidence of brain inflammation: it details a postmortem brain examination of one of the Royal Free ME/CFS patients who committed suicide using the barbiturate drug Carbrital.

In the brain of this patient they actually found demyelination; however they diagnosed this as the patient having an early stage of multiple sclerosis, in addition to simultaneously having what we now call ME/CFS.

In this brain autopsy, the main abnormality they found, in addition to the typical multiple sclerosis brain lesions, was to quote: "one section taken from the hypothalamus which showed intense perivascular cuffing."

Perivascular cuffing means the accumulation of lymphocytes or plasma cells in a dense mass around the blood vessel, and this perivascular cuffing is indicative of inflammation or of an immune reaction.

So this is possible evidence of brain inflammation in ME/CFS, back in the 1950s. Although the authors stated that it is more probable than the intense perivascular cuffing in the hypothalamus represents an unusual reaction associated with multiple sclerosis.

Presumably though there must have been other good indicators of brain and spinal cord inflammation in these Royal Free outbreak patients for this outbreak to be described as encephalomyelitis.


It is interesting that another ME/CFS brain autopsy published in 1994 found what appeared to be coxsackievirus B infection in the hypothalamus and brainstem of the patient. So here we see a hypothalamus infection again implicated in ME/CFS. Reference: here. Full paper here.

@Marco, from the perspective of sensory gating dysfunction, the brainstem infection is very relevant, since "studies on rats show the brain stem, thalamus, and primary auditory cortex play a role in sensory gating for auditory stimuli." Reference: here.



Here is the text from the Royal Free Hospital ME/CFS 1955 outbreak study (terms in bold are defined in the glossary below):
"The second fatality, due to acute “carbrital” poisoning [ie, suicide], occurred in a woman, aged 32, who had the epidemic disease seven months before death, and who had had definite clinical evidence of organic disease of the central nervous system for the last seven months of her life.

In her case it was considered on clinical grounds that she had disseminated sclerosis as well as the epidemic disease. Post-mortem examination revealed small circumscribed grey or yellowish plaques in the white matter of the cerebral hemispheres, mainly paraventricular in distribution. In the brain stem and in the spinal cord, particularly in the cervical segment.

Microscopical examination showed multiple small well or fairly well demarcated areas of demyelination with associated microglial and astrocytic proliferation and a variable degree of gliosis. There was no evidence of primary neuronal damage, and no viral cell-inclusions were seen. Occasional cellular foci composed of lymphocytes and cerebral histiocytes, mainly perivascular in distribution, were present in the leptomeninges overlying the brain, but this was not a marked feature except in one section taken from the hypothalamus which showed intense perivascular cuffing.

The distribution and character of the lesions in the central nervous system, with the exception of the changes in the hypothalamus, were typical of disseminated sclerosis, and a histological diagnosis of disseminated sclerosis in a fairly early phase was made. The lesion in the hypothalamus in this case may represent the of a superadded [ie, additional] viral encephalitis, but such an explanation is conjectural, and it is more probable than the intense perivascular cuffing represents an unusual but not unknown reaction associated with disseminated sclerosis.
"

Source: page 901,
An Outbreak of Encephalomyelitis in the Royal Free Hospital Group, London, in 1955


Glossary or Medical Terms Used

Epidemic disease = the term the authors use to refer to the ME/CFS outbreak at the Royal Free Hospital.

Gliosis = nonspecific reactive change of glial cells in reactiveesponse to damage to the central nervous system (CNS). In most cases, gliosis involves the proliferation or hypertrophy of several different types of glial cells, including astrocytes, microglia, and oligodendrocytes. In its most extreme form, the proliferation associated with gliosis leads to the formation of a glial scar.

Viral cell-inclusions (aka: viral inclusion bodies) = abnormal structures which appear within the cell nucleus, the cytoplasm, or both, during the course of virus multiplication.

Disseminated sclerosis = another name for multiple sclerosis.

Histiocyte = a tissue macrophage or a dendritic cell.

Perivascular cuffing = the accumulation of lymphocytes or plasma cells in a dense mass around the vessel. An indication of inflammation or of an immune reaction.

Plasma cells (aka: plasma B cells, plasmocytes, and effector B cells) = white blood cells that secrete large volumes of antibodies.
 
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