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
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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
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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."
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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
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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."
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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.

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'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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Did he say what that direct action might be? A "friend" wants to know.

His opinion was anti-psychotic medication and steroids. Needless to say I moved on to another doctor

 

@Aerose91 How silly of me to get a wee bit hopeful. After all, you did say "psychiatrist".

 

in rats.

Trigeminal nerve stimulation actives dura mast cells and increases vascular permeability

Int J Immunopathol Pharmacol. 2013 Jul-Sep;26(3):597-600.
Impact of capsaicin on mast cell inflammation.
Frydas S1, Varvara G, Murmura G, Saggini A, Caraffa A, Antinolfi P, Tete' S, Tripodi D, Conti F, Cianchetti E, Toniato E, Rosati M, Speranza L, Pantalone A, Saggini R, Di Tommaso LM, Theoharides TC, Conti P, Pandolfi F.
Author information
Abstract

Mast cells are inflammatory cells, and they are prominent in inflammatory diseases such as allergy and asthma. Mast cells possess high-affinity receptors for IgE (FcERI) and the cross-linking of these receptors is essential to trigger the secretion of granules containing arachidonic acid metabolism (such as prostaglandin (PG) D2, leukotriene (LT) B4, and LTC4), histamine, cytokines, chemokines, and proteases, including mast cell-specific chymases and tryptases. Activation of mast cells provokes the secretion of cytokines and mediators that are responsible for the pathologic reaction of immediate hypersensitivity. Sensory nerve stimulation by irritants and other inflammatory mediators provokes the release of neuropeptides, causing an increase in vascular permeability, plasma extravasation and edema. Trigeminal nerve stimulation actives dura mast cells and increases vascular permeability, effects inhibited by capsaicin. Capsaicin causes release of sensory neuropeptide, catecholamines and vasodilation. Several studies have reported that capsaicin is effective in relief and prevention of migraine headaches, improves digestion, helps to prevent heart disease, and lowers blood cholesterol and blood pressure levels. The findings reported in these studies may have implications for the pathophysiology and possible therapy of neuroinflammatory disorders.

http://www.ncbi.nlm.nih.gov/pubmed/24067456

 

@osisposis i pretty sure i got olfactory damage also.

sorry to hear that AbbyDear.

 

Good question. If it is sickness behaviour then it would be the same basic idea of activated microglia (and astrocytes). Whether the level of neuroinflammation/activation would be the same, I don't know.

As for fever, that turns out to be a separate pathway from sickness behaviour - though again fever is a host response, not something caused by the pathogen: turns out we can generally take the heat better than bugs. One amazing thing I learned on an immunology course I did recently is that reptiles - who are cold-blooded so can't control their body temp - will move to a hotter area if they are sick, say 40 degC, same as a mammalian fever. And experiments have shown moving to the higher temp improves their survival rates.

Half true?

Simon, do you mean sickness behaviour as in promoting rest, or sickness behaviour as in immune response here?

The fever response (according to my understanding) tends to kick in after several days of infection and failure of the immune system to deal with the problem. As you indicate microbes are more temperature sensitive than our cells and the immune response uses fever to weaken them. It is because it may indicate a more severe infection that medics are concerned by it.

The info re reptilian response to infection was in interesting tit bit, may I ask where you picked that up?

Leo

 

Thanks . And if you are talking about mecfs research on neuroinflammation, I totally agree it should be a priority.

Great question


I think for all of this, the first step needed is replication by the original authors using their improved design, which I understand has already started or will soon do so. Then other Qs come into play, including how it compares with other chronic illnesses and with acute infection. As Tony Komaroff said, what's needed is independent confirmation by multiple different labs. I wouldn't normally blog on such a small study, but as the findings tie in with so many other theories, and as an improved version of the study is already planned, I think this study deserves more attention.


Re encephalitis, I took my cue from Tony Komaroff:



As for encephalomyelitis, the microglial and astrocytes that showed up as activated in the brain PET scan are also present in the spinal column, so it's plausible they too are activated - that would need a different PET scan to investigate. Again, this would be low-grade which as I understand it is not what is normally meant by encephalomyelitis. There again, my understanding was that Ramsay used encephalomyelitis because he thought that would explain the clinical symptoms he found (he didn't have direct evidence).

If the neuroinflammation evidence checks out Ramsay may have been on exactly the right lines - that's the only point I'm trying to make. I wouldn't want to push it too far, esp as this is a study on only 9 patients and didn't even look at the spinal column.

We must talk before I write my next blog! Hugh Perry's hypothesis is about microglial priming, so that people have an exaggerated immune response.


got a link for that, would like to follow up?

still working on replies to others, got to go lie down and rest....

More importantly how this compares with depression in order to put the psychiatric dogma to sleep permanently..

 

The fever response (according to my understanding) tends to kick in after several days of infection and failure of the immune system to deal with the problem.

My own understanding is that fever is actually one of the early responses to infection - part of the innate immune system.

This page appears to support this, e.g. this bit:

Innate immunity also comes in a protein chemical form, called innate humoral immunity. Examples include the body's complement system and substances called interferon and interleukin-1 (which causes fever).

If an antigen gets past these barriers, it is attacked and destroyed by other parts of the immune system.

 

My own understanding is that fever is actually one of the early responses to infection - part of the innate immune system.

This page appears to support this, e.g. this bit:

The page is slightly misleading (re fever at least). In so far as we are born with innate immunity it obviously comes first in two respects. Aspects of it also kick in a little quicker than the th1 system. What's described as innate immunity includes most b-cell activity, natural killer cells etc as well as fever.
Fever actually commences after NK cells, T-cells etc and is primarily an endocrine response to infection. We don't fever ever time we get a cold due to it being the bodies 'emergency response'.

It was the length of time about which I had my doubts.

 

Neuroinflammation and Comorbidity of Pain and Depression


http://pharmrev.aspetjournals.org/content/66/1/80.abstract

 

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.

"Learned responses" that's a great way to put it. I have been saying I operate solely on logic. I would feel horrible for a child that has to go through this because they haven't had a chance to learn the correct behaviors and responses to things.

I never get periods of OK brain function though. Never fluctuates, ever, not even 1%

 

"Learned responses" that's a great way to put it. I have been saying I operate solely on logic. I would feel horrible for a child that has to go through this because they haven't had a chance to learn the correct behaviors and responses to things.

I never get periods of OK brain function though. Never fluctuates, ever, not even 1%

By OK brain capacity I mean times when I can think at 30% or more of normal capacity, rather than times when I am at 1%.

 

Dr Younger listed potential microglial inhibitors that he thinks may be worth investigating at the Stanford and IACFS/ME conferences. Other than naltrexone I don't think most have been studied in fibromyalgia or ME but I think several are very promising. For example, I know many people are using minocycline for its neuroprotective qualities. The list is split into prescription drugs and supplements (primarily from chinese medicine.)
The full list is at http://forums.phoenixrising.me/inde...-me-21-march-day-two.29098/page-3#post-443598

I'm doing great on minocycline. Don't want to jinx it, but i've had a significant increase in activity, no PEM (so far), clearer head, no pain, no POTs-like symptoms.
Some of the improvement maybe could be attributed to buhner herbs i am also taking, but i noticed the shift to lack of PEM and lack of POTs-like symptoms particularly after taking minocycline.
I have been on other lyme Abx for a year, and am now into my third week on mino.

It stuffs up sleep, but i'm managing that with some add-ons.

Fingers crossed this bout of better health continues. One often looks like a dickhead when touting a cure after a couple of weeks of remission, but it's clear i have improved since minocycline.

Fantastic beaverfury, I'm glad to hear you're improving.

 

Nobody know if this study will be replicated ??

 

Is the article available as a PDF?

 

This is a study that describes how I felt at worst and during every relapse. My most recent one pretty bad and I described it to a doctor saying: it feels upon waking up as if my brain was full of some sort of yellow pus which has to get out but wont. It makes my head soinning at first and then impacts the most basic funtions from sleeping, eating and peeing to standing speaking, holding anything in my hands. It is all tragic that makes me laugh at times how bad can it be this time? I seem to develop more and more symptoms with most recent addition tightness round my throat and problems swallowing as well as getting food into my stomach it all seem to go up involuntary (yes some muscles freak up and soasm while some other seem to stop working). Basically my brain seems to be so inflammed that it stop to function and so my body shuts down. All due to another silly docile virus my kid brought home. Any help for temporary flare ups in brain inflammation? Which btw was not recognised by basic blood tests CRP was very low but I had low grade fever. Merry Xmas everyone.