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

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

Is this an article I should be showing to my neurologist or pain management doctor?
 
I also had a normal MRI. Should I ask my doctor for a PET scan now?

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

Is this an article I should be showing to my neurologist or pain management doctor?
Hi Womble
This is very much an early finding that needs replication, not something that would be helpful in the clinic. I think it's too early to show to your neurologist or pain management doctor, though if the findings are independently replicated those replications would be worth mentioning. I'm afraid it would be another step again (probably a big one) from establishing that neuroinflammation is important in the illness to actually having a treatment.

One to watch for the future, though.
 
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.
 
Another possibility is that the chronic neuroinflammation is chronic because of a problem with the microglia, and not because of any stimulus outside the brain, and again in that case a microglial inhibitor might be appropriate. Though of course, you need your microglia to get active some of the time, that's what they are there for.

Guess we need the 'Big If' of replication sorted first!
When I first got hit with encephalitis and subsequently M.E. I was seeing Dr Romeo Mariano in Monetary, CA, a psychiatrist who also practices neuroendocrinology. He was the first one to recognise my symptoms and pegged me 100% for brain. inflammation.

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.
 
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.

thanks for sharing your story. Lumbar punctures are said to be painful when gone well, feel sorry that yours went bad, the pain must have been bad, hope they atleast treated your pain???

So are u undertaking any treatments for this neuro inflammation? Im guessing some antidepressants would have anti inflammatory effects as well as certain anticonvulsants??
 
@Womble

I also had various MRIs and MRAs which came back clear, but then went on to get a SPECT scan where it showed massive hypoperfusion. Much like
@CallieAndToby stated, the doctor said he has never seen a case so bad, especially in a 28 year old. He said it was akin to mid-late stage Alzheimer's or dementia. However, as satisfying as it was to me to have validation of my problems it didn't help with any treatments.

I then brought these results, along with the white blood cells in my spinal fluid found from a lumbar puncture, back to the neurologists that I saw at Yale (who told me I was a psychiatric patient) and they completely dismissed it. They told me that a SPECT and PET are completely unreliable and "will change if you have a bad hair day" They again referred me to a psychiatrist, this time because "your obsessed with symptoms"
 
All this makes me think its a waste of time to go to doctors to try to get help. I still can't fathom why proof of problems is dismissed as irrelevant, seen in the general population or psychiatric. I just don't get it.

It's sad.
 
I agree with that, but there are other possibilities. Certainly, if you can treat the underlying cause of the chronic inflammation that would be best, but people have suggested tackling the 'downstream' neuroinflammation with microglial inhibitors. I can't remember where I saw that but did find this recent study:
Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation

I'm not suggesting this is a treatment for ME/CFS or any other case of neuroinflammation, but it does suggest another route to treatment, even if it wasn't treating the cause.
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 have only tried a few items on that list and have found ganoderma lucidum (reishi) to be the most obviously effective. As an extra bonus, reishi also appears to increase NK cell cytotoxicity.
 
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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.
Another reason I get infuriated at the arrogant twits explaining that "Aren't you glad you have Obamacare/it would be so much better with single payer!1!". They like hearing themselves talk, but helping YOU is not anywhere on their mental map.

You need a family member to help you fuss with insurance. It can be done, but probably not while having an encephalitic condition. I know I can't manage that level of bureaucratic combat.
 
@CallieAndToby

I'm interested in the facts hat your insurance covered some IVIG. If I may ask, what was it for specifically? Parvo? I also had/have encephalitis and would love to get IVIG for my parvo and m. Pneumoniae but I need a doctor to order it which has been impossible so far. I was admitted to Yale for 4 days and they sent me packing with a diagnosis of depression.
 
@Womble

I also had various MRIs and MRAs which came back clear, but then went on to get a SPECT scan where it showed massive hypoperfusion. Much like
@CallieAndToby stated, the doctor said he has never seen a case so bad, especially in a 28 year old. He said it was akin to mid-late stage Alzheimer's or dementia. However, as satisfying as it was to me to have validation of my problems it didn't help with any treatments.

I then brought these results, along with the white blood cells in my spinal fluid found from a lumbar puncture, back to the neurologists that I saw at Yale (who told me I was a psychiatric patient) and they completely dismissed it. They told me that a SPECT and PET are completely unreliable and "will change if you have a bad hair day" They again referred me to a psychiatrist, this time because "your obsessed with symptoms"
Wow, I'm speechless.

How much evidence do they need before they recognize this as a legitimate medical problem?

But yeah, it doesn't sound like any treatments are on the horizon for this, despite this new evidence.
 
Hi Womble
This is very much an early finding that needs replication, not something that would be helpful in the clinic. I think it's too early to show to your neurologist or pain management doctor, though if the findings are independently replicated those replications would be worth mentioning. I'm afraid it would be another step again (probably a big one) from establishing that neuroinflammation is important in the illness to actually having a treatment.

One to watch for the future, though.
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.
 
Wow, I'm speechless.

How much evidence do they need before they recognize this as a legitimate medical problem?

But yeah, it doesn't sound like any treatments are on the horizon for this, despite this new evidence.
I honestly believe that conventional doctors, as good as they may be (and neurology is the ivory tower), just aren't aware that conditions like this exist. The only reason any doctors are studying it is because they are outside the box thinkers. If a neurologist hasn't read about this in a book then we must be making it up.

For what it's worth- when I met with the doctor who reviewed my SPECT I asked him if he could take a guess at what he thought this pattern showed. He said it most definitely did not look like chronic fatigue syndrome but also said it didn't look like acute inflammation. His opinion was mitochondrial disease. However, take into account that my brain symptoms seem to be in the top 1%
 
I honestly believe that conventional doctors, as good as they may be (and neurology is the ivory tower), just aren't aware that conditions like this exist. The only reason any doctors are studying it is because they are outside the box thinkers. If a neurologist hasn't read about this in a book then we must be making it up.

For what it's worth- when I met with the doctor who reviewed my SPECT I asked him if he could take a guess at what he thought this pattern showed. He said it most definitely did not look like chronic fatigue syndrome but also said it didn't look like acute inflammation. His opinion was mitochondrial disease. However, take into account that my brain symptoms seem to be in the top 1%
Most doctors no little about it unless it's affected them directly or a family member. Sad isn't it.
 
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.
 
Another fantastic article Simon. This really is such an interesting area of research and its remarkable how it pulls together many of the other strands that have been discussed for so long in ME/CFS research and those that are only just emerging. I'll be very interesting to see whether any studies confirm these findings as it could be a great finding. Perhaps the reason ME/CFS has been such a difficult nut to crack is because of the relatively low level inflammation being proposed here.
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.
I think if this were to be confirmed the next step would be trying to understand what perpetuates it and I don't doubt that the first port of call for many would be the recent research push towards investigating autoimmunity...
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.
I had severe mono as a teen (10 weeks bedridden, I even passed out a few times due to it), I thou recovered from that only to then be hit with ME 10 or so years later. I do have severe ME just like I had severe mono so I can see a corellation ..but why the gap in my case? If it was going to give me severe ME why didnt it do so then?

I though came to the conclusion that I my body was primed in some way before the mono and hence why I got so very sick then.. (I never got colds as a child) .. so I think there is something going on with that TH1/TH2 and something is causing an imbalance before we even get ME (or mono)
 
Im sure I have some kind of brain inflammation going on .. and it seems many things can trigger it eg chemicals, working my brain too hard etc.

Yesterday I was trying to work on a letter but then had to stop due to the feeling I was getting inside my head, this happens to me a lot if Im doing constant thinking on something. 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).

This morning (maybe due to working on letter yesterday), I couldnt text a message on my mobile phone.. forgot how to work it as in how to put a space between words. I ended up contacting people to ask them how to text.
 
Thank you for your reply, I'm asking because inflammation would mean celldeath (right?) and I know it sounds (and looks, I sent you the link to a video) ridiculous but I think mine are recuperating which wouldn't be possible if...well.....dead. The same thing is happening throughout my body but it manifests differently (brain; májor pressure, eyes; trembling, and so on).
As Simon has said, inflammation doesn't necessarily lead to cell death, but even if cells are killed, new ones can grow - even neurons. It was long believed that new neurons did not grow in adulthood, but now we know that they can. There is some info on this here.
 
As Simon has said, inflammation doesn't necessarily lead to cell death, but even if cells are killed, new ones can grow - even neurons. It was long believed that new neurons did not grow in adulthood, but now we know that they can. There is some info on this here.
As long as there are healthy stemcells anything can be replaced.