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Neuroinflammation in Patients with CFS/ME: PET study

Marco

Grrrrrrr!
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Near Cognac, France
Thanks @Hip

My take on re-reading these papers is that the name was a compromise ("The title as a whole, however, fails to indicate that there is involvement of lympho-reticular structures.") used in the Royal Free case due to a 'similarity' to earlier presumed outbreaks of encephalitis which bore some similarity to poliomyelitis (particularly spinal neurological symptoms).

Without having identified an infectious agent any similarity in the clinic presentation associated with these various outbreaks doesn't guarantee that they were in any way linked. Or for that matter that any of them are linked to what is now termed CFS.
 

Hip

Senior Member
Messages
17,949
Without having identified an infectious agent any similarity in the clinic presentation associated with these various outbreaks doesn't guarantee that they were in any way linked. Or for that matter that any of them are linked to what is now termed CFS.

That's true, but personally I think that the nature of ME/CFS will always be changing, decade to decade, even in the future, because the viruses and bacteria in circulation that cause ME/CFS will always be changing. This is especially true of RNA viruses like enteroviruses, which have a much higher mutation rate than DNA viruses like the herpes family viruses. Enteroviruses are also notorious for creating an epidemic outbreak that lasts for a few years, and then disappearing for a long time. Enterovirus are known to form epidemics in this way. By contrast, herpes family viruses such as HHV-6, EBV and CMV never come in epidemics; they remain at steady levels all the time. Only certain types of virus come in epidemics.

So when you hear of an ME/CFS epidemic, you know for certain it cannot possibly caused by a herpes family virus like HHV-6, EBV and CMV, but must be caused by a virus capable of creating epidemics, like enterovirus.


The virus that triggered my ME/CFS, which I detail on my website here, I suggest may be a newly appearing enterovirus, or a new strain of enterovirus, because in some of the 30+ people (family and friends) who caught this virus, it produced unusual symptoms which I could not find in any of the medical literature — symptoms such as a fine-textured crêpe paper-like wrinkling of the skin. My virus also produced potent psychiatric symptoms such as anhedonia, blunted affect, and generalized anxiety disorder (GAD) in a few people, including me; and it triggered mild polymyositis (weak legs) in several people.

I imagine that if my virus spreads widely, and if it causes a high percentage of the ME/CFS cases with this comorbid anhedonia, blunted affect and GAD, then this may change the nature of how we view ME/CFS in future. Perhaps in future, mild polymyositis, anhedonia, blunted affect, and GAD will be considered the norm in ME/CFS, and will become standard symptoms of ME/CFS.

In this way, as the ME/CFS-causing infectious agents in general circulation slowly change over time, due to epidemics, and due to viral evolution by mutation, so will the nature of ME/CFS.
 
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Marco

Grrrrrrr!
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2,386
Location
Near Cognac, France

Hip

Senior Member
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17,949
Dr Chia once mentioned that enterovirus can travel from the stomach to the brain along the vagus nerve in only 3 days, by a mechanism called retrograde axonal transport. So this is how enterovirus may enter the brain in ME/CFS.

Now interestingly, the vagus nerve actually terminates at the brainstem, which might explain why this apart of the brain gets infected — and then becomes dysfunctional.
 
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Dr Chia once mentioned that enterovirus can travel from the stomach to the brain along the vagus nerve in only 3 days, by a mechanism called retrograde axonal transport. So this is how enterovirus may enter the brain in ME/CFS.

Now interestingly, the vagus nerve actually terminates at the brainstem, which might explain why this apart of the brain gets infected — and then becomes dysfunctional.

Dr. Komaroff, in his summary shown on Cort's blog, explained that (as I recall) enterovirus from gut tissue of CFS patients had been grown in mice; Dr. Komaroff hoped more researchers used the specimens.
When I got sick, several others also got it, which seems to confirm that CFS is probably an enterovirus and not herpes? Perhaps it lurks for years in the nervous tissue. I certainly think it is viral as that would explain the immune system up-regulation.
 

Hip

Senior Member
Messages
17,949
Dr. Komaroff, in his summary shown on Cort's blog, explained that (as I recall) enterovirus from gut tissue of CFS patients had been grown in mice; Dr. Komaroff hoped more researchers used the specimens.

That is very interesting, and is similar to an idea that I had myself about a good method for viral identification in ME/CFS.

The virus that triggered my ME/CFS gave me a chronic sore throat, and I noticed that months and even year after catching this virus, I was still infecting others with it, just through normal social interaction. The people I infected then developed some of the same symptoms (some very unusual) that the virus caused in me, so I was certain that the virus they caught was my virus.

It occurred to me that if my saliva or nasal secretions are constantly shedding infectious virus that people can catch from me, it should be possible to pass this infection to rodents as well. My virus is very likely an enterovirus, and enteroviruses are known to be pretty cosmopolitan viruses: that is to say, enteroviruses can infect a range of hosts, not just humans. If you can pass the infection to a rodent using saliva samples, then during the acute phase of the rodent's infection, you can take a blood sample from the rodent, and identify the virus.

Enteroviruses are easy to identify during the acute phase of infection (this phase is the first week after the virus was caught), because in the acute phase, there are high levels of viral particles — and antibodies to these viral particles — in the blood. But after that, once the acute phase is over and the enterovirus enters into its chronic stage, most of the viral particles in the blood disappear, along with the antibodies too, and this virus then exists only as a low level smoldering infection, and is then much harder to detect and identify. This has always been one of the problems with enterovirus research in ME/CFS — the fact that this virus is vey hard to detect in chronic infections.

I am not sure why more researchers don't use this rodent infection method of viral identification in ME/CFS. Many ME/CFS patients have a chronic sore throat, I would imagine that many such patients are frequently shedding infectious viral particles from their sore throat, especially in days or weeks when the sore throat flares up a bit. Since this chronic sore throat symptom of ME/CFS often begins from the time the patient first caught the virus which triggered their ME/CFS, it is likely that the virus shed from the patient's chronic sore throat is indeed the same virus that triggered their ME/CFS.
 
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Messages
19
That is very interesting, and is similar to an idea that I had myself about a good method for viral identification in ME/CFS.

The virus that triggered my ME/CFS gave me a chronic sore throat, and I noticed that months and even year after catching this virus, I was still infecting others with it, just through normal social interaction. The people I infected then developed some of the same symptoms (some very unusual) that the virus caused in me, so I was certain that the virus they caught was my virus.

It occurred to me that if my saliva or nasal secretions are constantly shedding infectious virus that people can catch from me, it should be possible to pass this infection to rodents as well. My virus is very likely an enterovirus, and enteroviruses are known to be pretty cosmopolitan viruses: that is to say, enteroviruses can infect a range of hosts, not just humans. If you can pass the infection to a rodent using saliva samples, then during the acute phase of the rodent's infection, you can take a blood sample from the rodent, and identify the virus.

Enteroviruses are easy to identify during the acute phase of infection (this phase is the first week after the virus was caught), because in the acute phase, there are high levels of viral particles — and antibodies to these viral particles — in the blood. But after that, once the acute phase is over and the enterovirus enters into its chronic stage, most of the viral particles in the blood disappear, along with the antibodies too, and this virus then exists only as a low level smoldering infection, and is then much harder to detect and identify. This has always been one of the problems with enterovirus research in ME/CFS — the fact that this virus is vey hard to detect in chronic infections.

I am not sure why more researchers don't use this rodent infection method of viral identification in ME/CFS. Many ME/CFS patients have a chronic sore throat, I would imagine that many such patients are frequently shedding infectious viral particles from their sore throat, especially in days or weeks when the sore throat flares up a bit. Since this chronic sore throat symptom of ME/CFS often begins from the time the patient first caught the virus which triggered their ME/CFS, it is likely that the virus shed from the patient's chronic sore throat is indeed the same virus that triggered their ME/CFS.

I don't know if any actual researchers read this forum, but if they do, they should contact Dr. Komaroff for more information. I think the viral cultures may still be available.
This definitely started as an epidemic in my college. And if it's an enterovirus, or any kind of virus, which it probably is, then maybe some of the anti-virals can cure it.
I think it's a virus because the symptoms fluctuate every day, as though my body keeps fighting something, but it keeps recurring. I usually get hit by a wave of extreme fatigue in the early afternoon - it feels like I've been injected by a triple dose of morphine, but then the symptoms tend to ease gradually after a couple hours.
 

Hip

Senior Member
Messages
17,949
This definitely started as an epidemic in my college.

What were the symptoms of this infectious epidemic in your college? Where they anything like the symptoms that my virus produced? The symptoms of my virus are listed here.
 
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What were the symptoms of this infectious epidemic in your college? Where they anything like the symptoms that my virus produced? The symptoms of my virus are listed here.

The people getting CFS had some of the ones you mentioned, but in addition some of the more standard ones, like headaches and extreme fatigue. I've had the post-exertional malaise, pressure headaches, and cardiac arrhythmias, which I'd say are the most common symptoms I've seen. The flu-like stuff is mainly in the beginning, though I still can feel achy. I think it depends on where the virus settles.
 

Forbin

Senior Member
Messages
966
There is an interesting 1978 paper by Dr. J. Gordon Parish in which he outlines the early outbreaks of what he terms ENM, or "Epidemic Neuromyasthenia" (which should not be confused with "neurasthenia"). He addresses the naming issue towards the end of the review:

Early outbreaks of 'epidemic neuromyasthenia'
J. GORDON PARISH
M.D., F.R.C.P. (C), D. Phys. Med.

Full PDF here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2425322/

Neither of the names commonly used for the disease is completely satisfactory. 'Epidemic neuromyasthenia' describes the epidemic nature of the disease and the abnormal fatigability of the nervous system and muscles, but the term is liable to be confused with neurasthenia and does not take into account the encephalomyelopathy. 'Benign myalgic encephalomyelitis' does not define the mild systemic form of the disease, which occurs frequently in district epidemics with its characteristic fatigability. The chronic disability revealed by the follow-up of the Los Angeles cases does not justify the title 'benign'. However, until more is known about the underlying pathology of the disease it seems preferable to use the term 'epidemic neuromyasthenia' and qualify the more severe neurological cases with the description 'encephalomyelitic form'.

It contains some other interesting assessments which suggest the involvement of enteric pathogens:
Several epidemics appear to have been triggered off by an outbreak of an infection with enteric organisms or poliovirus which then subsides.

The illness may have resulted from modification of the disease prevailing in the community, namely, poliomyelitis, or from a coincident infection of a central nervous system infection of unknown aetiology.
Thus, the agent responsible for ENM would appear to be able to inhibit the pathological effects of poliomyelitis infection.
The epidemic at Rockville, U.S.A. (Shelokov et al., 1957) was associated with the isolation, from a number of the ENM patients of Bethesda-Ballerup paracolon organisms which appear to have triggered off the disease in the same manners as infection with poliomyelitis virus precipitated other epidemics.

Bethesda-Ballerup paracolon organisms are bacteria.
 
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Ema

Senior Member
Messages
4,729
Location
Midwest USA
I've not read through this whole thread carefully, but the article can be found in the appropriate place if anyone is interested.
 

Aerose91

Senior Member
Messages
1,401
I have a question about this topic: I got ME from encephalitis and it seems like the encephalitis just never went away. However, my doctor told me that neopterin is a measurement of immune activation in your brain and an indicator of microgliol activation.

My neopterin and all other immune activation tests came back completely normal so he surmised that I do not have brain inflammation. However, the only people I've met that share the same symptoms as me are those with autoimmune encephalitis. There must be a missing link somewhere, has anyone else had neopterin tested?
 

Womble

Senior Member
Messages
138
I also had a normal MRI. Should I ask my doctor for a PET scan now?

Also, what are the implications for treatment once this inflammation is discovered?

Is this an article I should be showing to my neurologist or pain management doctor?
 

Annesse

Senior Member
Messages
164
I made the following post on my Facebook page today concerning this study.

NEUROINFLAMMATION AND CHRONIC FATIGUE SYNDROME

New research (study below) has found evidence of neuroinflammation in chronic fatigue syndrome (ME/CFS). In the study, PET scans revealed inflammation in multiple areas of the brain...read mo...re at: http://www.nlm.nih.gov/medlineplus/news/fullstory_146023.html


Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study.
Nakatomi Y1, et. al. J Nucl Med. 2014 Mar 24. [Epub ahead of print]

"Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue...Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms."


The activation of the kynurenine pathway (KP) would explain the neuroinflammation in patients with CFS/ME. The KP degrades the essential amino acid tryptophan in the human body. In patients with CFS/ME, fibromyalgia, autoimmune disease, Alzheimer's, and Parkinson's disease the KP is being upregulated by inflammatory cytokines due to a lack of the enzymes protease and DNase 1. This results in the depletion of tryptophan and the production of neurotoxins.


In the following study the researchers concluded that chronic fatigue syndrome and fibromyalgia appear to meet the criteria of a tryptophan-kynurenine pathway disorder.

Kynurenine Pathway Pathologies: do Nicotinamide and Other Pathway Co-Factors have a Therapeutic Role in Reduction of Symptom Severity, Including Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM).
Blankfield A. Int J Tryptophan Res. 2013 Jul 21;6(Suppl 1):39-45.

"The definition of dual tryptophan pathways has increased the understanding of the mind-body, body-mind dichotomy. The serotonergic pathway highlights the primary (endogenous) psychiatric disorders. The up-regulation of the kynurenine pathway by physical illnesses can cause neuropathic and immunological disorders1 associated with secondary neuropsychiatric symptoms...Chronic fatigue syndrome (CFS) and fibromyalgia (FM) appear to meet the criteria of a tryptophan-kynurenine pathway disorder with potential neuroimmunological sequelae."



The following studies discuss the involvement of the KP in the neuroinflammation found in Parkinson's disease and diabetes.


The Involvement of Neuroinflammation and Kynurenine Pathway in Parkinson's Disease
Anna Zinger, et. al.

"Parkinson’s disease (PD) is a common neurodegenerative disorder characterised by loss of dopaminergic neurons and localized neuroinflammation occurring in the midbrain several years before the actual onset of symptoms...The KP generates several neuroactive compounds and therefore has either a neurotoxic or neuroprotective effect. There are to date several lines of evidence linking some of the KP intermediates and the neuropathogenesis of PD. Moreover, it is likely that pharmacological modulation of the KP will represent a new therapeutic strategy for PD."


Involvement of the kynurenine pathway and neuroinflammation in diabetes.
Pr. Gilles J. Guillemin et. al

"During neuroinflammation, the KP is activated in brain cells... There is accumulating evidence that the excitotoxin quinolinic acid is involved in the neurotoxicity associated with several inflammatory brain diseases such as Alzheimer's disease, Parkinson's disease, motor neuron diseases, multiple sclerosis (MS) and major psychiatric disorders. We also recently found that the KP is dysregulated in diabetes."
 
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Bob

Senior Member
Messages
16,455
Location
England (south coast)
Prof Hugh Perry discussed this study (Nakatomi et al.) in his presentation at the Action for ME symposium for severely affected patients. He seems quite excited by it. His presentation is an easy-to-understand explanation (in lay-person's terms) of the role of 'primed' microglia (in the brain) in chronic illness and potentially in ME/CFS. His discussion of the Nakatomi paper starts at 41mins 31secs:
www.youtube.com/watch?v=7oSEncRbu6E


"So this idea might be that these microglia in these brain regions are primed, and even very low grade infections coming from the peripherals - Signals from low-grade infections could be sufficient to further activate the microglia and induce the symptoms of sickness behaviours."

The following info relates to the video, starting at 41mins 31secs:

Perry discusses the research paper by Nakatomi et al. (i.e. the paper relating to this thread.) I made some brief notes:

Small study - 9 participants.

Differences seen beween patients and controls.

Microglia appear to be more activated in brains of ME/CFS patients

- A strong correlation was found between poor cognitive scores and the amount of activated microglia in the amygdala.

- A correlation was found between levels of depression and the amount of activiated microglia in hippocampus.

- And a correlation was found between pain and the amount of activated microglia in region of the thalamus.



Published paper:

Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study.
Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, Onoe K, Fukuda S, Kawabe J, Takahashi K, Kataoka Y, Shiomi S, Yamaguti K, Inaba M, Kuratsune H, Watanabe Y.
2014
J Nucl Med. 55:945-950.
http://jnm.snmjournals.org/content/55/6/945.full
 
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Folk

Senior Member
Messages
217
I gotta ask, if neuroinflamation is present, what's missing for a closed diagnostic?
 

Folk

Senior Member
Messages
217
I have not heard the expression "closed diagnostic" before? What does it mean?

hehehe
I meant something like "final diagnostic".
Something like, "hmm you have this symptoms, lets check for neuroinflamation... Yeah you have it. That's ME"
 
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