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

I had and still have seizures, massive, massive dissociation, psychosis, memory and cognitive problems, occasional halleucinations and intense headaches. I've had white blood cells show up in my spinal fluid, slowing on my EEG and hypoperfusion on my SPECT. I also have fatigue, PEM and all of the physical symptoms ME people do. However I have yet to find one doctor (functional medicine or neurologist) who has any clue what is going on with me. I have tried like hell to get checked out for all types of autoimmune encephalitis but I can't find a doctor willing to try
 
This is what Drugs.com says about ketamine.
And what, pray tell, does drugs.com say about aspirin, a drug that kills hundreds of people a year?
Ketamine has been around for decades and is well proven to be safe when properly administered. It could help this poor woman immediately.
I hope no one here is relying on drugs.com for more than incidental information.

Ketamine is not in the same class as aspirin. It's safe in the same way that shoulder-fired missiles are safe: some conditions apply ;-)
 
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 was just going to post about this! Thanks, Nielk.
 
Thanks. They are actually finishing trials with a nasal spray cousin-kin-drug to ketamine as we speak, for MDD. My doctor said we'll most certainly try it when it comes out. I would do anything for relief at this point and the cousin-drug (name escapes me) doesn't have the side effects.......
Did you mean the side effects on kidneys? If so, did you mean methoxetamine (mxe)?
 
I was mulling over this again last night and wonder whether this 'multiple paths to the same destination' could indeed be very plausible. Think about the studies from the last few years certain ones such as the initial (and still ongoing) work with rituximab could point to the autoimmune path which we've already discussed, this would explain why some people seem to get a major and long lasting result from this drug (some of the initial trial patients are still healthy, as is Maria Gjerpe who campaigned for further work with the drug) while other got little to no help from it or even suffered more after the treatment. I wonder whether it may be a case of 'breaking the cycle' so to speak wherein B-cells may be producing the antibodies which stimulate the immune cells of the brain hence triggering symptoms.

Similarly I've heard many people sing the praises of certain antivirals in helping their recovery yet others get no help from them although admittedly without there being any specific pathogen that we know of, antivirals are never going to show the same effectiveness when compared to something such as rituximab which is somewhat more specifically targeted...

Obviously I'm making far too many assumptions here but it's an interesting line of thought and could explain why some treatments seem to have such an all or nothing effect.
I'm pretty sure that this is a more than plausible scenario and could also explain the mixed results/failure to date to identify a biomarker.

We have a syndrome defined solely on the basis of a collection of non-specific symptoms and now what appears to be evidence of neuroinflammation of a type seen in a wide range of other conditions (with presumably a variety of etiologies - autoimmune, trauma, metabolic, stress, pathogen related, and even aging).

Its not too unlikely that with a slightly different mix of symptoms or demographic (e.g. an older age group) that each of us could have received a different diagnosis.
 
And what, pray tell, does drugs.com say about aspirin, a drug that kills hundreds of people a year?
Ketamine has been around for decades and is well proven to be safe when properly administered. It could help this poor woman immediately.
Not sure why you mention aspirin. You were talking about ketamine, and I thought it fair to post some info on it so that people can make informed decisions.
 
Given the high cost of these PET scans and possible associated methodological issues that might result in progress in replicating and expanding these findings being slower than we would like, I've been interested in finding other 'markers' of neuroinflammation that may provide less direct but converging evidence.

I've found a few but am grateful for being alerted to another potential marker in peripheral blood (PBMC's).

Microglial activation is now widely believed to underpin neuropathic pain syndromes (often widespread 'central' pain sensitisation which is unrelated or out of proportion to an initial peripheral injury). Various peripheral messengers (associated with damage, pathogens or cellular/metabolic stress) activate CNS microglia via toll like receptors (TLR's) resulting in the release of pro-inflammatory cytokines such as IL1-b. It appears that peripheral TLRs act similarly to those in the brain with the potential that activated brain TLR's may be reflected by activated TLR's in the periphery.

This paper seems to confirm this with peripheral IL1-b levels elevated in chronic pain patients in response to TLR agonists compared to pain free controls suggesting that the TLR/glial pathway in chronic pain patients is 'primed'. Note 'unstimulated' PBMC IL1-b levels didn't differ between patients and controls.

Increased Responsiveness of Peripheral Blood Mononuclear Cells to In Vitro TLR 2, 4 and 7 Ligand Stimulation in Chronic Pain Patients

In summary, TLR agonists (TLR2, TLR4, and TLR7) were found to cause elevation in IL-1β release that could significantly differentiate from chronic pain sufferers on opioids, chronic pain sufferers not on opioids and pain-free participants. This study is the first in providing evidence in human cells that TLRs are more responsive in chronic pain sufferers. As we were able to significantly differentiate three groups on the basis of their IL-1β output, it appears this response of in vitro stimulation of isolated immune cells with TLR agonists may serve to be a potential test for identifying biomarkers for chronic pain from readily accessible peripheral blood samples. (bolding added)
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0044232

Wouldn't it be nice if similar 'biomarkers' of microglial activation/neuroinflammation could be identified in' readily accessible peripheral blood samples' in ME/CFS patients? Its not as if we're now short of biobanks.
 
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.
 
I had and still have seizures, massive, massive dissociation, psychosis, memory and cognitive problems, occasional halleucinations and intense headaches. I've had white blood cells show up in my spinal fluid, slowing on my EEG and hypoperfusion on my SPECT. I also have fatigue, PEM and all of the physical symptoms ME people do. However I have yet to find one doctor (functional medicine or neurologist) who has any clue what is going on with me. I have tried like hell to get checked out for all types of autoimmune encephalitis but I can't find a doctor willing to try
Yea it sounds like we are the same age and have the same things going on and the same stories. I was diagnosed with a sub-acute variation of autoimmune encephalitis, then dropped by my doctors at NYU. With that diagnosis insurance still won't approve treatment. So I'm left with nothing and no-where to turn. I am so very sorry, all I can say is I understand. I have horrific fatigue and PEM as well. I saw two top CFS specialists but they couldn't help and I had violent reactions to everything they tried, I also have extreme sensitivity to all medication and supplements.
 
Yea it sounds like we are the same age and have the same things going on and the same stories. I was diagnosed with a sub-acute variation of autoimmune encephalitis, then dropped by my doctors at NYU. With that diagnosis insurance still won't approve treatment. So I'm left with nothing and no-where to turn. I am so very sorry, all I can say is I understand. I have horrific fatigue and PEM as well. I saw two top CFS specialists but they couldn't help and I had violent reactions to everything they tried, I also have extreme sensitivity to all medication and supplements.
I have all exactly the same. I even went down to the John Hopkins ER because they are supposed to have an encephalitis specialty inside of their neurology dept but they turned me away.
Sounds like we have a chronic encephalitis on top of ME
 
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thatwouldbechronicencephalitisontopofchronicencephalitisthen
 
Yea it sounds like we are the same age and have the same things going on and the same stories. I was diagnosed with a sub-acute variation of autoimmune encephalitis, then dropped by my doctors at NYU. With that diagnosis insurance still won't approve treatment. So I'm left with nothing and no-where to turn. I am so very sorry, all I can say is I understand. I have horrific fatigue and PEM as well. I saw two top CFS specialists but they couldn't help and I had violent reactions to everything they tried, I also have extreme sensitivity to all medication and supplements.
I have all exactly the same. I even went down to the John Hopkins ER because they are supposed to have an encephalitis specialty inside of their neurology dept but they turned me away.
Sounds like we have a chronic encephalitis on top of ME
Well so far we've figured out you can't go to the following for help with encephalitis: Mayo, Yale, Shands, NYU, and John Hopkins............ Nobody locally has any clue what to do. Also, do you think the inflammation and / or autoimmunity to the brain is causing the neuro-psychiatric symptoms? I've tried psych. meds for 10 years and not a single one has helped. The NYU doctors said if you have inflammation and in my case they called it "severe and extensive", psych. meds can't penetrate and help not until inflammation is brought down. I tried minocycline and had wicked side effects at 1/4 of 50 mg, within a week 4 separate times I developed: c-diff, yeast, and UT infections, also gave me bad insomnia and tiredness.
 
Yea it sounds like we are the same age and have the same things going on and the same stories. I was diagnosed with a sub-acute variation of autoimmune encephalitis, then dropped by my doctors at NYU. With that diagnosis insurance still won't approve treatment. So I'm left with nothing and no-where to turn. I am so very sorry, all I can say is I understand. I have horrific fatigue and PEM as well. I saw two top CFS specialists but they couldn't help and I had violent reactions to everything they tried, I also have extreme sensitivity to all medication and supplements.
I have all exactly the same. I even went down to the John Hopkins ER because they are supposed to have an encephalitis specialty inside of their neurology dept but they turned me away.
Sounds like we have a chronic encephalitis on top of ME
Well so far we've figured out you can't go to the following for help with encephalitis: Mayo, Yale, Shands, NYU, and John Hopkins............ Nobody locally has any clue what to do. Also, do you think the inflammation and / or autoimmunity to the brain is causing the neuro-psychiatric symptoms? I've tried psych. meds for 10 years and not a single one has helped. The NYU doctors said if you have inflammation and in my case they called it "severe and extensive", psych. meds can't penetrate and help not until inflammation is brought down. I tried minocycline and had wicked side effects at 1/4 of 50 mg, within a week 4 separate times I developed: c-diff, yeast, and UT infections, also gave me bad insomnia and tiredness.
Have to retract my statements about NYU, have not been dropped. I am just unbelievably stressed and frustrated and the distance from them makes it harder.

@Aerose91 can you send me a PM?

Also, when taking an antibiotic how do you prevent things like yeast infections and c-diff? Seems to always be a problem for me. I take 3 different really nice probiotics.
 
I have a feeling the inflammation though is throughout the body. I have the lower back pain and neck pain now and ct scans show my spine is fall of bone spurs and shrunken disc spaces etc i said to my doc im just getting bloody old and he said that my back was alot older then me.

I cant help but wonder if all the inflammation i have had from cmv etc has played a big part. I did read a few articles implicating infections as triggers for ankylosing spondylitis, and saw cmv implicated a couple of times?? The increased tnf and il6 which is shown in cfs/me and cause of alot of inflammation is also the big causes in auto immune diseases. Maybe it depends on where this inflammation hits is what we are left with??
 
One of the doctors I saw told me that all fatigue is due to inflammation so being body wide would make sense
 
One thing that supports the brain inflammation theory as well is the frequency of low ADH in us. I initially had encephalitis and learned that encephalitis commonly knocks out ADH in people; not sure why that particular hormone but that would give precedence to the theory that our hypothalamus is part of the brain that is effected. I would like to learn more about this correlation