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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since it's in my laywoman's knowledge also the area that controls body temp I'm wondering what the brain would look like during a regular fever with a mild flu

 

since it's in my laywoman's knowledge also the area that controls body temp I'm wondering what the brain would look like during a regular fever with a mild flu

regular flu with a mild fever, also ;-)

 

I agree 110% with the conclusion of this article. I would love to get into a study like this!

 

great article, Simon. Thank you

 

Very nice. Thanks Simon

 

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.

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 within ME/CFS, especially given the vast number of conditions associated with autoimmune encephalitis (although admittedly what is being proposed here is an altogether different beast). The interesting thing here is that the ongoing response doesn't appear to be causing gross pathological damage which would likely manifest with somewhat more specific symptoms.

Interesting stuff indeed.

Also I agree that 'Sickness behavior' is a terrible term for such a well acknowledged physiological phenomenon; perhaps one day we'll move to something a little more appropriate like 'Cytokine induced behavioral alteration'.

 

Wow, love this! Thank you for sharing!

 

Maybe we will end up calling this disease microgleitis.

 

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.

 

Simon, what about the possibility of accumulation of environmental toxins in the brain promoting low level inflammation?

 

Thanks. Yes, as Tony Komaroff pointed out, encephalitis is normally an acute, dramatic and sometimes fatal condition - whereas these results point to a much lower level of inflammation which simply hasn't been considered by many.

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

Interesting, this ties in with how I think that Lyme can share so many similar symptoms, In lyme it is proven that there is a chronic mild encephalitic state of the brain and nervous system, so maybe CFS is derived from this state of inflammation and with each person a possible different underlying cause i.e. Infection, or in some cases auto immune attack? Alongside possible methylation issues that cause someone to be stuck in a set of symptoms where the body cannot resume normal processes again, depleted glutathione and dysregulated immune system, also explains many other things as well..

There are also many other components and tie ins that I have looked into for all of these disease states and it is in some ways incredibly complex but this seems to be a clinical presentation rather then the fundamental root cause. Now if only there was a way to find specific points of dysfunction for each case and work on reversing the vicious cycle for each person. This would be a great discovery, there is still much work to be done!

Thanks again for this wonderful information!

Todd

 

Simon, what about the possibility of accumulation of environmental toxins in the brain promoting low level inflammation?

This would definitely play a huge component, anyone dealing with chronic illness will have impaired enzyme and physiological activities and all kinds of inflammatory immune system markers, and other sources of impairment. Heavy metal toxicity impairs the basic functioning of the bodily systems and can definitely contribute to a worsening of someones condition, or possibly in some cases the root issue.

A chelation would work great here, however nutritional re balancing and getting the body to detox at a rate of its own seems best, removing amalgams and avoiding high metal toxins would be the safest route, every chelation protocol has its inherit risks and is not worth it in some cases where a person is already so toxic and overwhelmed.. Restoring methylation processes, and glutathione production, alongside a high veggie diet and some lean grass fed meats would work well to get the system re balanced on its own accord. Andy Cutler has a very well known metal de tox protocol which is the only one I would ever trust myself.

 

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.

Well I think it's fairly well known I'm a fan of the autoimmune hypothesis but the interesting thing with this form of neuroinflammation is that there are a plethora of ways to arrive at the same state, as you mention. If this research holds true during replication (and I know that's a very big if!) then we could perhaps be looking at differing sub-groups. It's only logical that if autoimmunity is perpetuating your neuroinflmmation that the treatment would be different than if it was a virus causing it and the same goes for nearly ever different event that could perpetuate it.

 

since it's in my laywoman's knowledge also the area that controls body temp I'm wondering what the brain would look like during a regular flu with a mild fever

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.

 

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.

Yes to all the possibilities you mention ... I am not familiar with the theory proposed by the Dubbo group, wondering if it is any way similar to what Michal Schwartz talks about here - I find this talk, and her work in general, absolutely fascinating. In this scenario there is a communication breakdown btw microglia and the rest of the immune system, esp blood macrophages (and there can be dozens or hundreds of possible reasons for this breakdown). In any case blood monocytes are needed and constantly being recruited to repair damage in the brain - and they are summoned by the activated microglia.

here are my old notes from her talks, some of it may well be relevant to ME:

She talks about using immune cells to repair injured CNS/brain. By using BLOOD macrophages (as opposed to microglia/macrophages already present in the CNS) and T lympocytes – CD4 positive T cells, they managed to reverse spinal cord injury, PTSD and MD, and stress induced anxiety in mice.

She talks about those 'imported' M2-type activated macrophages (from blood) being protective and healing in cases of spinal cord injury and neurodegeneration etc.

• T-cells that recognise brain antigen (mentioned myelin specifically) are protective
• Affinity and regulation is what differentiates T-cells that are autoimmune in pathogenic way and those that are protective
• Part of what those good T cells are doing is recruitment of BLOOD monocytes to sites of injury
• In injured brain: resident macroglia do the first response job (get activated/inflammed) and by staying activated they recruit blood monocytes to come help. Those newcomer monocytes will then calm down activated resident microglia and terminate their response (this doesn't happen in ME, autism etc but just goes on!??), and this process is dependent on IL-10 ! (if no IL-10 this will not happen)

Their theory: chronic neuroinflammatory disease risk factor is present before visible onset (imo it could even be that prenatal events set the stage). Onset happens when the equilibrium is lost, when the immune system stops responding to need. See slide at 38 minutes for possible reasons why (peripheral loss of immunity etc).

They observed lack of brain plasticity and neurogenesis in immune-deficient animals. They had poor memory, high neurotoxicity etc. In aged animals those that have more memory loss are those whose immune system ages fast, with higher levels of supressive regulatory T-cells! By reducing levels of those Reg T cells they were able to boost brain activity and memory in aged mice.

 

Great article, @Simon.

I recently had a brain MRI scan which came up negative for signs of inflammation - presumably the kind of low-level inflammation you're talking about here would be invisible on an MRI?

 

Great article, Simon! Thank you

 

Great write up Simon. We seem to have taken as slightly different although complementary slant in reporting this. I'm not sure I'd agree with the conclusion that this represent 'encephalitis' though - certainly not the encephalomyelitis as envisaged by Ramsey as discussed here :

http://www.cortjohnson.org/blog/201...yelitis-back-future-chronic-fatigue-syndrome/

I wasn't aware that the Dubbo work was continuing which is great news as a predisposition to an enhanced immune response to common infections could be a key component in a 'multi-hit' scenario (conversely this enhanced response could be a symptom of already primed/activated glia - normal aging involves glial priming and the elderly have an often catastrophic enhanced immune reaction to minor stressors). Another possible contributor is SNPs that result in exaggerated microglial activation. One compelling example is a mouse model of obsessive compulsive disorder (obsessive grooming) where knockout mice displaying this behaviour are 'cured' by transplanting immune cells from wild type (and vice versa). Interesting comments above in this context @natasa778


My own personal view is that this model of neuroinflammation can explain all of the symptoms and is the key to understanding ME/CFS. It may aslo reconcile many previous conflicting findings and the inability to date to identify one pathogen or consistent biomarkers.


As @Legendrew says, there is a vast range of possible triggers that could lead to glial priming and activation. Microglia respond to biological messages which can be classified as PAMPS, DAMPS or 'alarmins' – basically messages signaling organic damage, pathogens or endogenous signaling of metabolic stress respectively. Scientists are only starting to list and characterise alarmins but they include ATP and signaling of fatigue and pain takes place via the purinergic receptors (remember the Lights' gene expression findings?). I wouldn't rule out other metabolic markers such as leptin acting as alarmins either.


As posted on another thread ;


Microglia are the critical convergence point for the many diverse triggers that elicit an adaptive immune response (Figure 1). Stroke, hypoxia, and trauma compromise neuronal survival and indirectly trigger neuroinflammation as microglia become activated in response to the insult in an attempt to limit further injury. Infectious agents activate microglia either through damage to infected cells or direct recognition of foreign (viral or bacterial) proteins. Following exposure to neurotoxins such as the mitochondrial complex I inhibitor 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the dopamine analog 6-hydroxydopamine (6-OHDA), or the pesticide paraquat, microglia become activated and primed. Microglial responses to these toxins may contribute to neuronal dysfunction and eventually hasten neurodegeneration (Czlonkowska et al., 1996; Kohutnicka et al., 1998; Liberatore et al., 1999; Dehmer et al., 2000; Vila et al., 2001). In addition, genetic mutations that give rise to increased production of toxic oligomeric, aggregated/truncated, or oxidized protein species promote sustained activation of microglia and may prime the immune system for aberrant responses to subsequent insults. Regardless of the initiating factor, all of these external or internal stimuli have the potential to trigger a self-perpetuating inflammatory response that, if left unresolved, may contribute to death of vulnerable neuronal populations.


My own feeling is that future research should be aimed at replicating and expanding our understanding of this as the central mechanism and common end point resulting from a range of potential triggers. I am slightly biased though !

 

Simon, what about the possibility of accumulation of environmental toxins in the brain promoting low level inflammation?

Like many things, it is a possibility. If the neuroinflammation pans out - and remember this is just one study on 9 patients - the next step will be finding out what causes the neuroinflammation.

Interesting, this ties in with how I think that Lyme can share so many similar symptoms, In lyme it is proven that there is a chronic mild encephalitic state of the brain and nervous system, so maybe CFS is derived from this state of inflammation and with each person a possible different underlying cause i.e. Infection, or in some cases auto immune attack?

. Interesting, I didn't know that about an encephalitic state of the brain in Lyme's. Do you know how they showed that?

I agree that the end point of low-grade chronic inflammation could well be a common feature of several diseases, and that's what a number of people are suggesting. I would see the neuroinflammation as a final common pathway, and the sickness behaviour as the clinical manifestation, but either way it could be that several different triggers, and different diseases end up with a similar endpoint. A slightly more nuanced version of this is that certain common symptoms - in particular fatigue - are the result of a shared pathway, but that more than one pathways are in play,

And glad you liked the piece!

Great article, @Simon.
I recently had a brain MRI scan which came up negative for signs of inflammation - presumably the kind of low-level inflammation you're talking about here would be invisible on an MRI?

Thanks . Yes, a MRI scan would definitely NOT pick this up: although the study did use MRI, it was in conjunction with PET, a technique that detects a radioactive tracer, and in this case a tracer specific for activated microglia and astrocytes.