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

Ive been thinking more about this article and I wonder if the worst the brain issues is, the worst the inflammation in the brain may be?

Another here and I were on the phone today discussing amnesia episodes with him saying how at uni one time he forgot where he lived or who he was and was having to go throu his wallet looking at his cards to try to work it out. Ive had similiar thing happen at times, my brain one time (after a perfume exposure at a petrol station) forgot where I'd lived thou I lived there for 17 years, I was stuck then and couldnt go home.

Another time before I stopped working (no chemical exposure on this occassion), my brain stopped remembering where I was working thou I'd worked there for years.. I couldnt go to work for 3 days due to not knowing where I worked (and was too embarrassed to ring my boss and say "where do I work?").

I'd love for them to do brain scans on us when we are having a severe brain episode when we dont know who we are or know our address or on the very severe ME group who are struggling just to be able to speak as surely even more would show up at such a time (probably quite shocking results!!!). I think my brain issues shift at times with the "inflammation"? not so bad at some times then others.
 
As long as there are healthy stemcells anything can be replaced.
then how long would it take for the entire brain to be replaced....?

I
Another time before I stopped working (no chemical exposure on this occassion), my brain stopped remembering where I was working thou I'd worked there for years.. I couldnt go to work for 3 days due to not knowing where I worked (and was too embarrassed to ring my boss and say "where do I work?").
I'm sorry for actually LOL at this but I did.....and I also think that's some serious concern for real inflammation, which I have luckily not, my cells are fixing themselves and I have the at times overdoses of neurotransmitters to prove it.. (well not really, I asked the neurologist to test me but got snubbed ;()

VanElzakker says it's unlikely to have inflammation without cells moving on to a better place
 
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
ah, That was where I'd seen it - your conference report! Thanks for this.

Here's the study Dr Younger ran for Naltrexone for Fibromyalgia:

Low-dose naltrexone for the treatment of fib... [Arthritis Rheum. 2013] - PubMed - NCBI
CONCLUSION:
The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication.
 
Might encyphalitis be a way of explaining my pain syndrome at least?

When the doctors ask me what kind of pain I'm having, and I just describe it as a "nerve ending pain" or an "inflammation", they act clueless.

Maybe neuro-inflammation would clarify it for them? Cause it feels like my brain is burning, that is literally what it feels like.
This study did look at pain, and while they did find a correlation between the level of pain and the level of inflammation in the thalamus (but not other areas of the brain), this correlation was not statistically significant when the appropriate corrections were applied.

One problem with small studies is that they lack the 'statistical power' to find all but the largest effects. It's possible that a larger study would find a significant correlation with pain (possible too it would find nothing) but these PET studies are horrendously expensive - so it might be hard to get funding for a suitably large study.

Ive been thinking more about this article and I wonder if the worst the brain issues is, the worst the inflammation in the brain may be?
...
I'd love for them to do brain scans on us when we are having a severe brain episode when we dont know who we are or know our address or on the very severe ME group who are struggling just to be able to speak as surely even more would show up at such a time (probably quite shocking results!!!). I think my brain issues shift at times with the "inflammation"? not so bad at some times then others.
They did find that the worse the neuroinflammation, the worse the cognitive problems in several areas of the brain.

However that was comparing between patients, what you are talking about is a longitudinal study looking at changes in each patient over time. That would be a great idea and hopefully something that will happen if this field takes off.
 
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.
 
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@Legendrew

The superoxide scavenger I use also decreases autoantibodies in several diseases.

The positive effect it has on the immune system could be the result of superoxide excess decrease.

In one paper I read it stops superoxide production. If that is true the low SOD2 could get the chance to neutralise the superoxide excess.
 
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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...
in part because after a while the cells the virus is in stop fighting back (or never tried in the first place) and go into rest-mode which makes them indifferent to whether there's a bug or not, they don't work anyway, and why indeed Ampligen par example stops being effective after 3-5 yrs

I'm not even adding I thinks and imho's anymore, wastes of times ;P
 
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Last year I saw a neurologist at NYU, well 2 to be exact. We did a PET scan and found decreased metabolism through-out my brain, the radiologist was so alarmed she paged him and said, "I've never seen anything like this in a 20 - something female, this is what'd I'd expect to see in an elderly patient with severe Alzheimer's". They looked at extensive labs from UM and my pro-inflammatory cytokines were through the roof. They said they thought I had neuro-inflammation and we did CT scan which also came back grossly abnormal. I received a diagnosis of "primary autoimmunity and clinical encephalitis". These are not quack doctors they are NYU NEUROLOGISTS. My insurance covered an 11 day stay at NYU to get IVIG, I had 4 infusions, a lumbar puncture that went bad and that I still don't have results from, ended up with LP leak and stayed in hospital for 11 days - there was nothing more brutal than everything I went through. My insurance company cancelled ivig and have denied all appeals to continue, now my neurologist has dropped me as a result. We have PROOF of inflammation, not just in one spot, all over my fu**ing brain, yet I can't get anyone to help me. I contacted the Autoimmune encephalitis alliance and they recommended some doctor from mayo - I've been there 4 times and was told every time to see a psychiatrist. I do think I have M.E. but I also have terrible depression and OCD and insomnia, the diagnosis eventually became "neuro-psychiatric autoimmune encephalitis" but my records still say clinical encephalitis. Just thought I'd add my story to show and prove that yes we have neuro-inflammation and in my case I have all signs of auto-immunity, unfortunately it's making me deathly ill and I can't find anyone to help me or they don't know what to do; I really thought ivig would help but insurance won't cover it.
CallieAndToby-

Look into Ketamine infusion. There are clinics in New York that will do this for you. It's a cheap, safe drug that repairs fried brain synapses and works very well for depression as well.
 
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.
 
CallieAndToby-

Look into Ketamine infusion. There are clinics in New York that will do this for you. It's a cheap, safe drug that repairs fried brain synapses and works very well for depression as well.
This is what Drugs.com says about ketamine.
 
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.
 
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.
Yep and I consulted with her neurologist but eventually got moved to someone else. Dr. N is the one who diagnosed me with neuro-inflammation. However, I think they're all too busy to help me and I live way too far away. I will say that I don't recall rituximab ever being mentioned by her or them, what I recall is: steroids, PEX, then ivig, and anti-psychotics at first. I don't know that there are a lot of similarities, just meeting patients there I clearly had the worst fatigue and that wasn't a huge complaint with the patients I met.

They have seizures, paranoia, hallucinations, but there are different forms of AE. I am sure that rituximab is used though regularly for AE and I read about a woman who had post-natal depression - then anti-nmda auto-antibodies, Ritux. brought her into complete remission. I think this is a bit off topic b/c it is a discussion about auto-immunity causing neuro-psychiatric illness and I know people don't like to mention that with M.E.

The researchers at NYU and Univ. of Penn believe that many psych. patients, especially those unresponsive to treatment, actually have autoimmunity and neuro-inflammation................. But the biggest question is, how do we treat all these patients? And I guess that's what people are wondering on this message board.
 
Last year I saw a neurologist at NYU, well 2 to be exact. We did a PET scan and found decreased metabolism through-out my brain, the radiologist was so alarmed she paged him and said, "I've never seen anything like this in a 20 - something female, this is what'd I'd expect to see in an elderly patient with severe Alzheimer's". They looked at extensive labs from UM and my pro-inflammatory cytokines were through the roof. They said they thought I had neuro-inflammation and we did CT scan which also came back grossly abnormal. I received a diagnosis of "primary autoimmunity and clinical encephalitis". These are not quack doctors they are NYU NEUROLOGISTS. My insurance covered an 11 day stay at NYU to get IVIG, I had 4 infusions, a lumbar puncture that went bad and that I still don't have results from, ended up with LP leak and stayed in hospital for 11 days - there was nothing more brutal than everything I went through. My insurance company cancelled ivig and have denied all appeals to continue, now my neurologist has dropped me as a result. We have PROOF of inflammation, not just in one spot, all over my fu**ing brain, yet I can't get anyone to help me. I contacted the Autoimmune encephalitis alliance and they recommended some doctor from mayo - I've been there 4 times and was told every time to see a psychiatrist. I do think I have M.E. but I also have terrible depression and OCD and insomnia, the diagnosis eventually became "neuro-psychiatric autoimmune encephalitis" but my records still say clinical encephalitis. Just thought I'd add my story to show and prove that yes we have neuro-inflammation and in my case I have all signs of auto-immunity, unfortunately it's making me deathly ill and I can't find anyone to help me or they don't know what to do; I really thought ivig would help but insurance won't cover it.
CallieAndToby-

Look into Ketamine infusion. There are clinics in New York that will do this for you. It's a cheap, safe drug that repairs fried brain synapses and works very well for depression as well.
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....... I actually live really far from NY, but this is definitely something my mom has been looking into (nasal spray) - say it helps ocd as well.
 
This is awesome, thank you Simon. I remember years ago attempting to convince doctors that my symptoms felt so much like inflammation caused by a CNS infection. Of course they thought it was somatic. When I finally got into a good me/cfs doc, his list of my diagnosis had right up top......Viral Encephalitis. Treating this brought much relief.