First Direct Evidence of Neuroinflammation – ‘Encephalitis’ – in ME/CFS

April 29, 2014

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 lead to ME/CFS symptoms.  credit: Canstock

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

Yasuyoshi Watanabe

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. AMY, amygdala; CC, cingulate cortex; HIP, hippocampus; MID, midbrain; THA, thalamus; and PON: pons. Credit: Image courtesy of RIKEN

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?

microgliawikimedia

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.

sick

‘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 11% 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.

 Simon McGrath tweets on ME/CFS research:

 

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129 comments

{ 129 comments… read them below or add one }

soofke April 28, 2014 at 1:30 pm

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

soofke April 28, 2014 at 1:31 pm
soofke

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 ;-)

Aerose91 April 28, 2014 at 1:36 pm

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

Nico April 28, 2014 at 2:14 pm

great article, Simon. Thank you

Firestormm April 28, 2014 at 2:15 pm

Very nice. Thanks Simon :)

Legendrew April 28, 2014 at 2:17 pm

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'.

Martial April 28, 2014 at 2:43 pm

Wow, love this! Thank you for sharing!

Nielk April 28, 2014 at 3:29 pm

Maybe we will end up calling this disease microgleitis.

Simon April 28, 2014 at 3:37 pm
Legendrew

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.

A.B. April 28, 2014 at 3:44 pm

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

Martial April 28, 2014 at 3:47 pm
Simon

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

Martial April 28, 2014 at 3:52 pm
A.B.

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.

Legendrew April 28, 2014 at 4:17 pm
Simon

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.

Simon April 29, 2014 at 12:31 am
soofke

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.

natasa778 April 29, 2014 at 12:51 am
Simon

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.

Sasha April 29, 2014 at 1:33 am

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?

vli April 29, 2014 at 1:42 am

Great article, Simon! Thank you

Marco April 29, 2014 at 1:49 am

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 April 29, 2014 at 2:34 am
A.B.

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.

Martial

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!

Sasha

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.

soofke April 29, 2014 at 3:37 am

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).

MeSci April 29, 2014 at 3:46 am
Nielk

Maybe we will end up calling this disease microgleitis.

or a gliopathy, as described here?

Snow Leopard April 29, 2014 at 4:01 am
soofke

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

Good question, I'd like to know how the findings of this study compare to that of other medical conditions.

N.A.Wright April 29, 2014 at 5:13 am

Simon, excellent survey of the terrain !

I'm cautious about what the Osaka study actually found – as I wrote on another thead:

"The Osaka City University study is promising but even that need not require actual inflamation of the brain, merely that the usual products of inflammation be present and caused by some as yet unexplained disease process. There's also the possibility that this small Japanese study has revealed something specific to a localised gene variant and replication needs to be done in diverse populations to address that, along with the usual prcesses of replication."

Of course one would hope that nature is abiding by Occam's Razor and the simplest explanation of 'evidence of inflamation = inflamation' is the right one, but in the case of ME I don't think that we can be certain without some very weighty numbers. It's become a sort of accepted coda amongst patients that – "the answer is out there" – and if only researchers had been looking in the right place then 'the answer' to ME would have been found years ago. And again of course that would be ideal because good, focussed and sustained research should be certain of getting the answer. But it may not be like that – ME may just be something that is very difficult to get at, something where there is an awful lot of evidence to be found, but where little or none of the evidence quite means what it is expected to mean.

Simon April 29, 2014 at 5:37 am
Marco

Great write up Simon. We seem to have taken as slightly different although complementary slant in reporting this.

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 !:)

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

Snow Leopard

I'd like to know how the findings of this study compare to that of other medical conditions.

Great question

MeSci

or a gliopathy, as described here?

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

Marco

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 :

Re encephalitis, I took my cue from Tony Komaroff:

Prof Komaroff

"[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."

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

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

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.

As @Legendrew says, there is a vast range of possible triggers that could lead to glial priming and activation….

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

As posted on another thread…

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

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

A.B. April 29, 2014 at 6:06 am

As Tony Komaroff said, what's needed is independent confirmation by multiple different labs.

Will this happen within a year or two though? How much importance does the medical community attribute to these findings? Is this a mere curiosity or highly significant?

Marco April 29, 2014 at 6:25 am
Simon

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

Yes indeed.

Re encephalitis, I took my cue from Tony Komaroff:

I appreciate that and I agree that its an 'itis' but this type of neuroinflammation is also found in conditions such as post concussion syndrome, complex regional pain syndrome, in normal aging (as previously mentioned) neurodegenerative diseases and in what were considered 'classic' psychiatric disorders such as major depression, bipolar and OCD. It may just be semantics but I doubt few would refer to these conditions as reflecting 'encephalitis' even if neuroinflammation is now recognised as playing a central role.

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

http://www.molecularneurodegeneration.com/content/4/1/47


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

Good idea! :)

Simon April 29, 2014 at 6:53 am
Marco

Yes indeed.

:thumbsup:

I appreciate that and I agree that its an 'itis' but this type of neuroinflammation is also found in conditions such as post concussion syndrome, complex regional pain syndrome, in normal aging (as previously mentioned) neurodegenerative diseases and in what were considered 'classic' psychiatric disorders such as major depression, bipolar and OCD. It may just be semantics but I doubt few would refer to these conditions as reflecting 'encephalitis' even if neuroinflammation is now recognised as playing a central role.

Fair point. Just found Charles Shepherd's quote on this:

the presence of neuroinflammation (which our post-mortem group has already reported in relation to dorsal root ganglionitis – part of the peripheral nervous system) does not necessarily mean that encephalomyelitis is present.
A lot of autoimmune and inflammatory diseases, as well as neurological diseases, have a neuroinflammatory component – but the clinical presentation and pathology is not an encephalomyelitis

Lupus for example: http://www.sciencedirect.com/science/article/pii/S0889159108000342

I continue to take the view that ME/CFS has a neuroinflammatory component

But I still don’t think that ME/CFS is going to turn out to be what neurologists and pathologists would regard as an encephalomyelitis. – i.e. extensive inflammation involving the brain and spinal cord

So to avoid confusion I will stick with neuroinflammation. However, I do think that Ramsay's implicit point, that the symptoms indicated a problem in the brain, may eventually prove right.

http://www.molecularneurodegeneration.com/content/4/1/47
Molecular Neurodegeneration | Full text | Does neuroinflammation fan the flame in neurodegenerative diseases

Terrific, another highly relevant paper I need to digest. Thanks ;)

Sean April 29, 2014 at 8:00 am

Thanks for this, Simon.

Melvin Ramsay's original name of 'myalgic encephalomyelitis'.

Could be wrong, but I have a vague memory that Ramsay actually wasn't so enamoured with that name, but reluctantly went with it for various reasons.

Firestormm April 29, 2014 at 8:02 am
Sean

Thanks for this, Simon.

Could be wrong, but I have a vague memory that Ramsay actually wasn't so enamoured with that name, but reluctantly went with it for various reasons.

It was Post-viral Fatigue Syndrome he regretted :)

Sean April 29, 2014 at 8:13 am

Thanks, Firestorm.

Simon April 29, 2014 at 9:58 am
Legendrew

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.

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.

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!

wdb April 29, 2014 at 11:27 am

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

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.

Dolphin April 29, 2014 at 12:22 pm

Another great article, Simon.

Small point:

Phoenix Rising Team


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 typically, 20% 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.

What the study found was:

Prolonged illness characterised by disabling fatigue, musculoskeletal pain, neurocognitive difficulties, and mood disturbance was evident in 29 (12%) of 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronicfatiguesyndrome.

Legendrew April 29, 2014 at 1:06 pm
wdb

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

I'd imagine you would compare the scans of controls and patients alongside one another and it would allow you to clean up a lot of the 'noise', it's far from a perfect way to analyse this kind of data but it lets you see on a qualitative level whether there is any significant difference which is what I believe this study is reporting.

lauluce April 29, 2014 at 1:13 pm

It seems that the pieces of the puzzle are starting to fit

Simon April 29, 2014 at 1:31 pm
wdb

I'm a little concerned about this bit, do you know if the scans were analyzed blind ?

Not sure, but they did prespecify which areas they considered:

Image Data Analysis
All 11C-(R)-PK11195 BPND images were normalized to the Montréal
Neurologic Institute space, smoothed with an isotropic 8-mm
gaussian kernel, and analyzed by Statistical Parametric Mapping 5
software (SPM5; Wellcome Department of Cognitive Neurology) using
a categoric design. The between-group comparison (CFS/ME
patients vs. healthy controls) of 11C-(R)-PK11195 BPND and correlation
analysis of 11C-(R)-PK11195 BPND values and clinical scores
were performed on a voxel-by-voxel basis using t statistics with the
statistical threshold set at a P value of less than 0.005 at the voxel level
and a P value of less than 0.05 with a correction for multiple comparisons
at the cluster level for the entire brain (familywise error). The
regions of interest for the cingulate cortex, hippocampus, amygdala,
thalamus, midbrain, and pons were defined from the Wake Forest
University PickAtlas (21) and applied to the smoothed images.

Does this help? there is more like it….

Dolphin

Another great article, Simon.

Small point:[I got the numbers wrong in the blog :bang-head:]
What the study found was:

re Dubbo study: 253 participants at six months, of whom 28 (11%) met the diagnostic criteria for chronicfatiguesyndrome

Thanks on both counts. I was finishing the blog off yesterday and was having a rough one – I was sure the figure was around 12% but could only find one suggesting 20% so lazily went with that. Blog now corrected.

soofke

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).

Activation of the microglia (or astrocytes) themselves does not cause their cell death. Their activation will lead to other changes which may or may not lead to cell death/apoptosis for other cells – I think it would depend on other things too, such as other signalling molecules in the micro environment.

heapsreal April 29, 2014 at 3:25 pm

its worth looking into memantine as a treatment for inflammation in ME as this drug has been around awhile and can be repurposed, so no having to wait for long trials and studies for its approval, possibly get a doctor now to prescribe it off label.

Memantine has effects on lowering tnf as well as nmda/glutamate, another cause of inflammation. It also helps increase dopamine which is useful for increasing mood and energy, decreasing pain and many other functions. Its also known to increase cortisol in certain parts of the brain which would also enhance energy. The nmda antagonist effects can also improve gaba sensitivity, so maybe help those with that tired wired feeling??

I think its an interesting drug that could be very useful in this reguard??

cheers!!

alex3619 April 29, 2014 at 3:38 pm

I think the evidence of neuro-inflammation, whether or not you consider that to be encephalitis, goes back to 1955. After the outbreaks in Adelaide, Australia, in the late 1940s they did some research. One line of research injected patient blood into animals. In 1955 it was published that the blood in monkeys resulted in particular kinds of spinal lesions, with immune infiltration. That is, I think not coincidentally, the kind of thing they have found in ME autopsy results.

In inflammation there is growing evidence that brain cells do not so much die as become dormant. So long as inflammation persists they do not function. Remove the inflammation and they have restored function. This is still a new and controversial area though.

Womble April 29, 2014 at 3:42 pm

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?

Simon April 29, 2014 at 3:52 pm
Womble

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.

CallieAndToby April 29, 2014 at 3:57 pm

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.

Aerose91 April 29, 2014 at 5:16 pm
Simon

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.

heapsreal April 29, 2014 at 5:20 pm
CallieAndToby

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??

Aerose91 April 29, 2014 at 5:22 pm

@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"

minkeygirl April 29, 2014 at 5:32 pm

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.

searcher April 29, 2014 at 5:40 pm
Simon

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.

HowToEscape? April 29, 2014 at 6:13 pm
CallieAndToby

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.

Aerose91 April 29, 2014 at 9:44 pm

@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 April 29, 2014 at 10:06 pm
Aerose91

@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.

Womble April 29, 2014 at 10:09 pm
Simon

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.

biophile April 29, 2014 at 10:14 pm

Targeting B cells may help with multiple sclerosis, study shows

http://www.sciencedaily.com/releases/2014/04/140424161527.htm

It tested ofatumumab (see http://en.wikipedia.org/wiki/Ofatumumab).

Aerose91 April 29, 2014 at 10:41 pm
Womble

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%

heapsreal April 29, 2014 at 10:56 pm
Aerose91

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.

November Girl April 29, 2014 at 11:03 pm

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.

taniaaust1 April 30, 2014 at 2:49 am
Simon
Legendrew

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)

taniaaust1 April 30, 2014 at 3:12 am

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.

MeSci April 30, 2014 at 3:16 am
soofke

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.

lansbergen April 30, 2014 at 3:20 am
MeSci

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.

taniaaust1 April 30, 2014 at 3:34 am

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.

soofke April 30, 2014 at 7:10 am
lansbergen

As long as there are healthy stemcells anything can be replaced.

then how long would it take for the entire brain to be replaced….?

taniaaust1

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

lansbergen April 30, 2014 at 7:15 am
soofke

then how long would it take for the entire brain to be replaced….?

Ages. But why do you think the whole brain must be replaced?

Simon April 30, 2014 at 7:26 am
searcher

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.

soofke April 30, 2014 at 8:07 am
lansbergen

Ages. But why do you think the whole brain must be replaced?

so the reason people die of Alzheimers is because they don't have ages?

Simon April 30, 2014 at 8:37 am
Womble

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.

taniaaust1

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.

Legendrew April 30, 2014 at 8:49 am

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.

lansbergen April 30, 2014 at 8:55 am

@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.

soofke April 30, 2014 at 9:15 am
Legendrew

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

lansbergen April 30, 2014 at 9:42 am
soofke

why indeed Ampligen par example stops being effective after 3-5 yrs

Well the med I use has not stopped working yet. I still improve slowly.

lansbergen April 30, 2014 at 9:44 am
soofke

so the reason people die of Alzheimers is because they don't have ages?

Do you think the replace cells will not get affected?

soofke April 30, 2014 at 10:42 am

what are you taking?

lansbergen

Well the med I use has not stopped working yet. I still improve slowly.

Mudhole April 30, 2014 at 11:59 am
CallieAndToby

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.

Nielk April 30, 2014 at 12:09 pm

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.

MeSci April 30, 2014 at 12:39 pm
Mudhole

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.

lansbergen April 30, 2014 at 3:24 pm
soofke

what are you taking?

Levamisole

Mudhole April 30, 2014 at 3:31 pm
MeSci

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.

CallieAndToby April 30, 2014 at 7:32 pm
Nielk

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.

CallieAndToby April 30, 2014 at 7:36 pm
Mudhole
CallieAndToby

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.

Tristen April 30, 2014 at 7:52 pm

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.

Aerose91 April 30, 2014 at 8:31 pm

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

HowToEscape? April 30, 2014 at 9:17 pm
Mudhole
MeSci

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 ;-)

vli April 30, 2014 at 9:42 pm
Nielk

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.

vli April 30, 2014 at 10:20 pm
CallieAndToby

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)?

soofke May 1, 2014 at 1:46 am

can anyone lend me 40 bucks? ;D

lansbergen

Levamisole

I hope all goes well and you get well (too)

Marco May 1, 2014 at 2:56 am
Legendrew

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.

MeSci May 1, 2014 at 2:58 am
Mudhole

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.

Marco May 1, 2014 at 3:20 am

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.

beaverfury May 1, 2014 at 6:11 am
searcher

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.

CallieAndToby May 1, 2014 at 7:04 am
Aerose91

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.

Aerose91 May 1, 2014 at 11:38 am
CallieAndToby

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

soofke May 1, 2014 at 12:56 pm

thatwouldbechronicencephalitisontopofchronicencephalitisthen

CallieAndToby May 2, 2014 at 7:27 am
Aerose91
CallieAndToby

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.

catly May 2, 2014 at 7:43 am

Perhaps the use of intranasal insulin, currently being trialed for neuroinflamation in Gulf War Illness, will offer some help for neuroinflamation in ME/CFS.

http://clinicaltrials.gov/show/NCT01802944

CallieAndToby May 2, 2014 at 10:21 am
CallieAndToby
Aerose91
CallieAndToby

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.

Aerose91 May 2, 2014 at 2:48 pm
CallieAndToby

Also, do you think the inflammation and / or autoimmunity to the brain is causing the neuro-psychiatric symptoms?

100% guarenteed

heapsreal May 2, 2014 at 6:16 pm

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??

lansbergen May 2, 2014 at 7:25 pm
heapsreal

I have a feeling the inflammation though is throughout the body.

So do I and the strange thing is improvement went from central to perifere.

Aerose91 May 2, 2014 at 8:41 pm

One of the doctors I saw told me that all fatigue is due to inflammation so being body wide would make sense

Aerose91 May 3, 2014 at 2:54 pm

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

wastwater May 3, 2014 at 7:06 pm
Nielk

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 read that book and felt it may have some interesting clues

Aerose91 May 5, 2014 at 10:50 am
November Girl

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.

What did you do to improve your brain condition?

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