First Direct Evidence of Neuroinflammation - 'Encephalitis' - in ME/CFS

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Simon McGrath reports on the new study that indicates low-grade encephalitis in ME/CFS ...

A small study with just nine patients has captured the attention of patients and researchers alike after reporting direct evidence of inflammation in the brain of ME/CFS patients. The finding was one of the highlights picked out by Professor Anthony Komaroff in his IACFS/ME conference round up.


Neuroinflammation may be behind ME/CFS symptoms
Photo credit: Canstock, www.canstock.com


Back to the future

What makes this study so fascinating is that it provides tantalising evidence supporting not only of current views that inflammation in the brain is central to understanding the disease, but also of Melvin Ramsay's original name of 'myalgic encephalomyelitis'.

Encephalomyelitis is inflammation of the brain and spinal column, and critics of the name pointed to the lack of direct evidence for inflammation of either. This study only looked at the brain, not the spinal column (so could only find encephalitis), but the immune cells found to be activated in the brain are also present in the spinal column.

The study



Dr. Yasuyoshi Watanabe
To see if there is immune activation in the brain, researchers need to look inside the brain -- which is not so easy if you want patients to still be alive when your study is done.

The scientists in this study, led by Dr. Yasuyoshi Watanabe from the RIKEN institute in Japan, used PET & MRI imaging to peer into the brain.

What make this study work is the use of tiny quantities of a radioactive tracer that binds to specific proteins that appear on activated microglia (the main immune cells of the brain) but crucially doesn't bind to non-activated microglia. The marker also binds to activated astrocytes, which play an immune role in the brain. The brains of nine ME/CFS patients meeting both Fukuda and International Consensus Criteria were compared with those of 10 healthy controls.

The results showed that neuroinflammation markers were higher for patients than controls across many brain areas including the thalamus, the pons and the midbrain. They also found that the severity of symptoms correlated with the degree of inflammation in multiple brain regions, particularly for cognitive functioning.

It was the correlation between a biological finding -- neuroinflammation -- and clinical problems that Komaroff found so exciting about this work, because it suggests a biologically plausible explanation for the symptoms of ME/CFS:


"[If replicated] 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 that long-lasting -- many years long -- cyclic chronic neuroinflammation is underlying the symptoms of this illness."


Representative PET scans showing activated microglia in a CFS/ME patient.
Key to brain regions: AMY, amygdala; CC, cingulate cortex; HIP, hippocampus; MID, midbrain; THA, thalamus; and PON: pons.
Photo credit: Image courtesy of RIKEN

Intriguingly, the midbrain, thalamus and amygdala -- all regions where cognitive problems correlate with neuroinflammation -- are also all part of neural circuits involved in awareness, arousal and attention. Concentration problems are typical of ME/CFS, and one of the problems found most consistently in laboratory testing.

Harvard Professor Tony Komaroff on these PET findings, and their potential importance
Starts at 30' 10", Q&A re encephalomyelitis @ 37'.


Replication needed
While tantalising, these findings are far from conclusive, as the authors acknowledge. The study has only nine patients, albeit diagnosed with ICC criteria. The tracer used to identify activated immune cells produces a very 'noisy' signal, giving rather indistinct readings, and the overall level of neuroinflammation was relatively low.

Although cognitive issues correlated with neuroinflammation in several areas, generally other symptoms, including fatigue, did not significantly correlate with inflammation.

There was almost no sign of inflammation in the prefrontal cortex, the region of the brain most involved in higher cognitive functions, that might be expected to be a problem in ME/CFS. And there was a potential technical weakness in the way the study was run.

Commenting on the neuroinflammation, Komaroff emphasised the need for replication:

"If it were confirmed by multiple other investigators ... these data are consistent with [encephalitis], but I would feel more strongly if other labs using same technology came up with the same result."
The good news is that the authors of this study are already working on a new study using the same patients but with a newer and more sensitive tracer to pick up neuroinflammation. They will address the earlier technical issue, and to make the study more powerful they will also be looking at neurotransmitter activity in the brain, following up their previous findings of neurotransmitter abnormalities.

Hopefully independent groups will try to replicate this finding too - and in the U.K., Dr. Charles Shepherd of the ME Association has already said it would welcome applications to fund a replication attempt.

Microglia -- key to ME/CFS?


Microglial cells (green)
Photo credit: Gary Shaw, Wikimedia, CC 3.0 licence
So neuroinflammation -- specifically activation of microglia -- correlates with cognitive problems, but how might microglial activation cause the problem?

The most plausible answer is through what is termed 'sickness behaviour' -- a characteristic set of responses to infection, including fatigue, malaise joint and muscle pain and problems concentrating -- which might just sound familiar to ME/CFS sufferers. ('Sickness behaviour' is a lousy name for biological phenomenon, as Dr. Dan Peterson has noted).

Microglia are known to play a key role in regulating sickness behaviour, and that's a big reason this study has attracted so much attention in ME/CFS.

'Sickness Behaviour' is driven by biology: infection leads to a rise in pro-inflammatory cytokines in the blood, triggering activation of brain microglia and their production of cytokines. This triggers sickness behaviour.
The fatigue, malaise, problems concentrating, etc., of sickness behaviour help us survive an infection by forcing us to rest so our body can devote all its resources to the energy-greedy immune system.

However, sickness behaviour is normally a short-lived response to an acute infection, designed to temporarily divert resources to ensure a swift recovery. If that doesn't happen, e.g., if there is a chronic infection, or the process goes wrong, for instance, if microglia remain activated after an infection has been cleared, then sickness behaviour can itself be a problem. ME/CFS may be an example of this.

Cytokines in the spotlight
Cytokines are a key trigger for sickness behaviour, and researchers have often found elevated cytokines in patients, but the findings have been inconsistent and in small studies. The new studies reported on by Dr. Jose Montoya at the Stanford conference and Dr. Mady Hornig at the IACFS/ME conference are helping to firm up these findings in huge cohorts.

Probably the most important piece of work on the role of sickness behaviour -- and cytokines -- in ME/CFS came from the landmark "Dubbo" studies.

The researchers found that about 12% of those with glandular fever and two other infections developed CFS after six months. And crucially, what predicted the length of the illness (and chance of developing CFS) wasn't psychological factors, but the severity of the initial 'acute illness', or sickness behaviour.

The researchers also showed that those with more active genes for the pro-inflammatory cytokine Interferon-gamma had a more severe sickness behaviour (and longer illness) than those with regular versions, linking cytokine response to sickness behaviour and ME/CFS.

The Dubbo study did not look at inflammation in the brain, but the authors did speculate that the cause of CFS could be long-term activation of microglia and astrocytes. And that is exactly what was found in this new PET imaging study.
As with all research findings, replication is essential, and a new version of the Dubbo study is currently under way in Sydney, Australia.

The new imaging study from Japan has found provisional evidence of activated astrocytes and microglia cells (both types of glial cell) in the brain of ME/CFS patients. This is support for the suggestion from the Dubbo team that ME/CFS develops from certain infections as a result of activation of brain microglia.

Dr. Michael VanElzakker's recent vagus nerve infection hypothesis also features glial cells heavily. And recently Professor Hugh Perry, who has studied microglial cells in neurodegenerative diseases such as Parkinson's disease, proposed that primed microglia and sickness behaviour lie at the heart of ME/CFS.

Neuroinflammation and Sickness Behaviour the final common path in ME/CFS?

It may prove to be that 'neuroinflammation' -- i.e., activated microglia in the brain/spinal column -- is a common endpoint of numerous triggers, including glandular fever (EBV), other infections, vaccines -- or even, as Dr. Lipkin has proposed, disturbances in the microbiome.

Discovering if this is the case -- and firming up the finding of neuroinflammation is key -- could be a big step forward in understanding and then treating ME/CFS. And those it is still very early days, it is possible this approach could eventually show that Dr Ramsay was right about 'encephalomyeltitis'.

Watch out for a new blog on sickness behaviour, microglia, cytokines and their role in ME/CFS, coming soon.



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Comments

Have any of you read the book "Brain on Fire" by Susanna Cahalan? It describes her journey with a rare autoimmune disease resulting in inflammation in the brain called anti-nmda receptor autoimmune encephalitis. Top NY neurologists did not believe that she was sick. Her brain MRI, EGG and bloodwork were all normal. (sounds familiar?) Even a brain biopsy came back normal. They thought that she was just psychotic and should be institutionalized.

She was lucky that she finally met a doctor who actually "listened" and found antibodies in her cerebrofluid. he started treating her with immunotheraphy - Rituximab and steroids which eventually nursed her back to health.

Although this seems to be an acute disease, ME has a lot of similarities and it is evident that inflamation in the brain whether chronic or acute is not easily diagnosed.
I read that book and felt it may have some interesting clues
 
Many years ago I had the type of brainfog where I couldn't manage to think from one word to the next. When the brainfog was very severe, my chronic-headache-from-hell would go ballistic if I actually tried to think - i.e. remember a name or answer a simple question. I've often thought that this was the result of neural inflammation.
What did you do to improve your brain condition?
 
Many, many things including lots of time. Some of them, in no particular order -
REST
Omega 3, at least 3,000 a day - don't remember if that is iu or mg

I'm exhausted at the moment - will come back later when thinking better
 
I think its very important her to pay close attention to the conclusions of the study. It states that immune activation could be causing the SYMPTOMS of the disease. That is very far from stating that an Etiology of enduring cause has been found. For example and underfuctioning immune system could case relentless low level infection and permanent activation, as could poor mito function.
This confirms what we already know - immunity is problematic and that the name ME is as good as any...
 
Acta Neuropathol. 2014 Apr;127(4):459-75. doi: 10.1007/s00401-014-1261-7. Epub 2014 Feb 20.
Olfactory bulb involvement in neurodegenerative diseases.
Attems J1, Walker L, Jellinger KA.
Author information
Abstract

[
Olfactory dysfunction is a common and early symptom of many neurodegenerative diseases, particularly of Parkinson's disease and other synucleinopathies, Alzheimer's disease (AD), and mild cognitive impairment heralding its progression to dementia. The neuropathologic changes of olfactory dysfunction in neurodegenerative diseases may involve the olfactory epithelium, olfactory bulb/tract, primary olfactory cortices, and their secondary targets. Olfactory dysfunction is related to deposition of pathological proteins, α-synuclein, hyperphosphorylated tau protein, and neurofilament protein in these areas, featured by neurofibrillary tangles, Lewy bodies and neurites inducing a complex cascade of molecular processes including oxidative damage, neuroinflammation, and cytosolic disruption of cellular processes leading to cell death. Damage to cholinergic, serotonergic, and noradrenergic systems is likely involved, since such damage is most marked in those diseases with severe anosmia. Recent studies of olfactory dysfunction have focused its potential as an early biomarker for the diagnosis of neurodegenerative disorders and their disease progression. Here, we summarize the current knowledge on neuropathological and pathophysiological changes of the olfactory system in the most frequent neurodegenerative diseases, in particular AD and synucleinopathies. We also present neuropathological findings in the olfactory bulb and tract in a large autopsy cohort (n = 536, 57.8 % female, mean age 81.3 years). The severity of olfactory bulb HPτ, Aβ, and αSyn pathology correlated and increased significantly (P < 0.001) with increasing neuritic Braak stages, Thal Aβ phases, and cerebral Lewy body pathology, respectively. Hence, further studies are warranted to investigate the potential role of olfactory biopsies (possibly restricted to the olfactory epithelium) in the diagnostic process of neurodegenerative diseases in particular in clinical drug trials to identify subjects showing early, preclinical stages of neurodegeneration and to stratify clinically impaired cohorts according to the underlying cerebral neuropathology.

/QUOTE]

http://www.ncbi.nlm.nih.gov/pubmed/24554308


J Clin Invest. 2014 Mar 3;124(3):1228-41. doi: 10.1172/JCI71544. Epub 2014 Feb 24.
Immune cell trafficking from the brain maintains CNS immune tolerance.

http://www.ncbi.nlm.nih.gov/pubmed/24569378

Front Neurosci. 2014 Apr 29;8:92. eCollection 2014.
Neurogenic and non-neurogenic functions of endogenous neural stem cells.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4010760/



J Neurosci Res. 2012 Sep;90(9):1693-700. doi: 10.1002/jnr.23054. Epub 2012 Jun 5.
Olfactory dysfunctions in neurodegenerative disorders.
Ruan Y1, Zheng XY, Zhang HL, Zhu W, Zhu J.


http://www.ncbi.nlm.nih.gov/pubmed/22674288
 
Biofilms in Chronic Rhinosinusitis February 2014
1
TITLE
:
Biofilms in Chronic Rhinosinusitis
SOURCE: Grand Rounds Presentation,
The University of Texas Medical Branch in Galveston, Department of Otolaryngology
DATE: February 19, 2014
RESIDENT PHYSICIAN:
Angelia Natili, MD
ATTENDING PHYSICIAN
AND DISCUSSANT
:
Bruce Leipzig, MD
SERIES EDITOR: Francis B. Quinn, Jr., MD, FACS
ARCHIVIST: Melinda Stoner Quinn, MSICS
http://www.utmb.edu/otoref/Grnds/2014-02-19-biofilm-sinus-Natali/biofilm-2014-02.pdf
 
Thanks. Yes, as Tony Komaroff pointed out, encephalitis is normally an acute, dramatic and sometimes fatal condition - whereas these results point to a much lower level of inflammation which simply hasn't been considered by many.

That is the big question (and I thought you might suggest autoimmunity :)). One possibility is that there is an ongoing stimulus, such as a chronic infection - or autoimmunity. Another possibility is that something has gone wrong with regulation of microglia and astrocytes, so that they become 'stuck' in an activated position, so that the neuroinflammation continues long after the original stimulus has been cleared - the 'hit and run' scenario. The Dubbo group propose this possibility, and it is the severity of the initial illness that somehow sets of excessively prolonged activation of microglia in the brain.

My illness started out with a serious encephalitis so pronounced that through the thicket of the encephalitis I knew immediately, well, within a short time, what it was. I couldn't speak properly so I faked it. Several of my daughter's neurologists (she had a serious childhood illness) sat and conversed with me for long periods. I think they were trying to figure it out. I never told them I was ill. Newly divorced, I didn't want to lose custody to her party guy dad. Yes, he was a lot of fun until responsibility set in and he couldn't handle it. My own doctors ignored the ongoing encephalitis. Boy, do I ever have some skeery stories about being mentally impaired and hiding it. Still am impaired. Don't like it. This new research is exciting! I wish I could still understand the new research, but my head has holes! Iz
 
Acta Neuropathol. 2014 Apr;127(4):459-75. doi: 10.1007/s00401-014-1261-7. Epub 2014 Feb 20.
Olfactory bulb involvement in neurodegenerative diseases.
Attems J1, Walker L, Jellinger KA.
Author information
Abstract
are those papers all ME related?
 
I think they could, it might depend on how you got to this point. I got ill from WDB/water damaged building/home exposure, my sinuses/brain route was very involved and I know my olfactory system is damaged, I'm guessing beyond self repair. sorry, not up to much writing at this time. new here but been around long time, been researching about 8+ years.
 
Boy, do I ever have some skeery stories about being mentally impaired and hiding it.
I sympathize with you completely on this. Nothing harder than fighting the hardest battle a human can possibly fight while trying to keep normal daily activities appear unaffected. I don't know which is worse, the torture of feeling yourself slip into psychosis and having no power to help it, or having that happen at the same time you're around people that think you're lying anyway and trying to hold a dinner conversation.
 
I sympathize with you completely on this. Nothing harder than fighting the hardest battle a human can possibly fight while trying to keep normal daily activities appear unaffected. I don't know which is worse, the torture of feeling yourself slip into psychosis and having no power to help it, or having that happen at the same time you're around people that think you're lying anyway and trying to hold a dinner conversation.
You might like to read my blog: http://forums.phoenixrising.me/index.php?entries/masks.680/

Its not only that we feel driven to pretend to be normal. Its that we can operate on learned responses, even speech. Ask me how I am and unless I have lost enough cognitive function that either I cannot understand you or cannot speak any more, then I can give a reply. Its just not a considered reply unless my brain is operating at an OK level.

An amusing side note is that some people think I am too far gone to notice what they say. They forget I get short periods of OK brain capacity ... and then I rethink what they said. Presuming I can even remember it of course.;)
 
Biofilms are getting more and more attention. A biofilm in one spot could lead to heart attack or stroke. In another it could lead to neurological damage. One cause, different locations, different consequences.

Biofilms in the vasculature of the brain, for example, could constantly trigger a brain inflammatory response. Say, that sounds like something ...
 
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Its similar to POTS in which you know you get that urge that you NEED to go and lay down (or you know something bad will occur) but with the brain thing instead its the urge that you know you need to stop doing something which is making you think too much and rest the brain (highly uncomfortable).
I definitely feel increased brain inflammation when I read or think too much. The POTS analogy is accurate. Stopping the activity at hand isn't an option; it's mandatory. Even then, once over that line it can take hours or days to recover from the buzzing, increase fog, and pain.

I know that my brain is inflamed - I feel it, I hear it, and I live with it daily.
He did state, however, that brain inflammation is a much different monster than inflammation in the body and described trying to stop it as akin to "trying to stop a speeding train without any brakes" He said that no matter what the initial offender, once microgliol activation reaches a certain level it can go on for the rest of your life unless direct action is taken.
Did he say what that direct action might be? A "friend" wants to know.;)