Science at the UK CMRC Conference, 1-2 Sept 2014

[charles shepherd]

My CFS doctor seemed to believe that some pathogens retreat into CSF or other areas where they can no longer be detected via the usual tests. I'm not sure whether this is merely a suspicion or a proven phenomenon. In the case of Sophia Mirza at least, there was infection of the spinal cord.

To be strictly accurate:

The presence of dorsal root ganglionitis in the post mortem specimens we have reported on here in the UK (Journal of the Neurosciences - abstract below) is likely to have been caused by an infection - but not necessarily a current infection, and it may be a past infection that is not relevant to ME/CFS

I would also point out the dorsal root ganglia lie outside the spinal cord and are anatomically part of the peripheral nervous system

Pathology of Chronic Fatigue Syndrome: Pilot Study of Four Autopsy Cases
DG O’Donovan1, 2, T Harrower3, S Cader2, LJ Findley2, C Shepherd4, A Chaudhuri2
1Addenbrooke’s Hospital Cambridge UK
2Queen’s Hospital Romford Essex UK
3Royal Devon & Exeter Hospitals UK
4Honorary Medical Advisor to ME Association UK
Chronic Fatigue Syndrome / Myalgic Encephalomyelitis is a disorder characterised by chronic exercise induced fatigue, cognitive dysfunction, sensory disturbances and often pain. The aetiology and pathogenesis are not understood.
We report the post mortem pathology of four cases of CFS diagnosed by specialists.
The causes of death were all unnatural and included: suicidal overdose, renal failure due to lack of food and water, assisted suicide and probable poisoning.
Selected portions of tissue were made available by the various Coroners in the UK and with the assent of the persons in a qualifying relationship.
The cases were 1 male, and 3 female. Ages (years) M32, F32, F43 & F31.
One case showed a vast excess of corpora amylacea in spinal cord and brain of unknown significance but Polyglucosan Body Disease was not supported by clinicopathologial review. No ganglionitis was identified.
One case showed a marked dorsal root ganglionitis and two other cases showed mild excess of lymphocytes with nodules of nageotte in the dorsal root ganglia.
This raises the hypothesis that dysfunction of the sensory and probably also the autonomic nervous system may lead to abnormal neural activity eg hyperalgesia & allodynia rather than anaesthesia and may explain some of the symptoms of CFS / ME such as pain, hypotension, hyperacusis and photophobia. However, the syndrome may be heterogeneous.
Nevertheless, the precise relationship of fatigue, which may be either peripheral or central, to abnormalities in the peripheral nervous system (PNS) needs to be studied.
The differential diagnosis of ganglionitis should be investigated in CFS / ME patients hence Varicella Zoster, Lyme disease, HIV, Sjogren’s disease, paraneoplastic sensory ganglionopathy should be excluded by appropriate history and tests.
Thorough histopathological study of cases coming to autopsy may help to confirm or refute the hypothesis, that CFS is a disease process, and whether the symptomatology may be explained by inflammation of the sensory and autonomic divisions of the PNS.
A specific CFS / ME brain and tissue bank in the UK is proposed.​

 

[Sasha]

Sonya Chowdhury (AfME) talking about the conference (and Dr Lipkin's Wednesday presentation here):

http://www.actionforme.org.uk/get-informed/news/our-news/ceo-blog-asking-the-what-if-questions

 

[alex3619]

Good points. We may be mixing up different situations. However, I think the answer is probably simpler - that cytokines are not intended to work in free solution blood, even if that is where they were first found. They will be billions of times more potent acting locally in tissues. That may not be universally true but my experience has always been that looking for cytokines in blood tells you nothing much.

Many of the general public are probably that hormones mean endocrine hormones. I think there are now five classes of hormones, including autocrine (acting on the same cell) and paracrine (acting locally on close cells). When I was first looking into these things, circa 1993 or so, I ran into a wall. The literature was confused, and contradictory, and new hormones were continually discovered.

I am not up to date on this at all, but it would surprise me if we knew all the hormones. We also do not know all the actions of hormones, we keep discovering more, even for older hormones. We also do not know how these things interact. The human body is hideously complex. The brain is one of the most complex things we are studying in science. There is very much more to learn, but that is the point of science ... to keep chipping away at our ignorance on important but measurable and testable issues.

I am in full agreement that its very hard to deal with locally acting hormones, to measure and assess them, from global blood tests. There is spacial diffusion and degradation (which means you have to factor in degradation products and pathways). There is also temperal diffusion ... hormones can peak at certain times, due to circadian or other factors, and blood levels may represent only one small time window if the hormone degrades rapidly (such as PGD2), or if its a slowly degrading hormone then the blood test is a time average. Yet peak and trough hormone levels are critical, particularly in local tissues.

Trying to figure this out with respect to my own now disproven model was why I went back to uni to finish my biochem degree.

If you look at all of these papers, add them to IiME and Stanford studies this year, and so on, there is a big picture emerging. We have some of the pieces. I hope we will continue to put in more pieces until we can see the big picture ... soon.

On the PACE trial there are multiple logical and mathematical issues, including statistical misuse. It is disturbing to some advocates that obvious flaws are ignored. It is also the case, and has been pointed out before, that these kinds of studies cannot be blinded, and therefore are not Gold Standard under EBM.

 

[Dolphin]

Thanks to all for the info on the conference. I am very interested in the PACE Trial so would be interested in more information on:

Sonya Chowdhury @SonyaChowdhury · Sep 2
Peter White discussing PACE trial. Outlining a case study to start
https://twitter.com/SonyaChowdhury/status/506736480178700288

Can anyone remember any details of the case study.

 

[Dolphin]

Peter White: PACE trial

I think I can only describe Dr White’s presentation as out of place. He presented a single slide of outcomes in the PACE study and claimed that it showed clearly that two treatments worked. He then spent the rest of his talk saying how unreasonable it was that patients did not gratefully accept this conclusion, indicating that this was an attack on science (if I remember rightly).

I have not scrutinised the PACE trial in detail but my understanding is that it was an unblinded trial and that, indeed, for such treatments it could only be unblinded. What Dr White seemed not to understand is that a simple reason for not accepting the conclusion is that an unblinded trial in a situation where endpoints are subjective is valueless. Even where there is traditional double blinding you have to be very careful. My old boss at UCL who is a clinical trials expert, immediately pointed out to me in a recent discussion that the crucial weakness even of a randomised double blind placebo controlled trial of something like rituximab in ME is that if either the researchers or the patients get a hint as to what treatment they have (from some minor side effects maybe) the whole thing becomes uninterpretable. Methodological problems for ME trials are almost insuperable. Open efficacy studies are not worth embarking on.

I think it was unfortunate that Dr White suggested that people were being unreasonable over the interpretation of the PACE study. Fortunately nobody seemed to take offence.

The contrasting results particularly with CBT of the general lack of improvement in objective measures but lots of improvements reported in subjective measures suggests response biases could well be very important.

Like Esther12, I can't agree that it was fortunate that nobody took offence. If somebody had taken offence he might then have been challenged.

 

[Sasha]

Like Esther12, I can't agree that it was fortunate that nobody took offence. If somebody had taken offence he might then have been challenged.

I took that remark about it being fortunate as possibly tongue in cheek but I'd also have liked someone to have challenged him on the issue of the post-hoc change to the planned principal outcome measure of PACE to something very strange indeed, and on his attitude that to request data on the planned measure is somehow anti-scientific.

Did anyone, in fact, raise either of those issues with him from the floor? Did he get any questions at all?

Given the extent to which his presentation seemed out of place I'm wondering if he just looked too irrelevant to bother with, but it seems a missed opportunity.

 

[snowathlete]

...This is where I come back to a comment I have made before, that the idea that cytokines are either ‘inflammatory’ or ‘anti-inflammatory’ looks now to be unhelpful. I am not convinced that we are even looking for true ‘inflammation’ of the sort I know in rheumatoid arthritis. The key message from these studies for me was that you can get severe fatigue with just one cytokine that is not directly involved in cell migration or tissue swelling. Interferon alpha may not be the right one for MEs but it illustrates the fact that there are several options.

Thanks for this Jonathan,
I always have symptoms, but I do get flares a lot of the time. I had one start a couple of days ago and I said to my wife, "I've got loads of inflammation today," to which she said "how do you know?". I had to pause for a minute and try to answer that question. I don't have any obvious tissue swelling or anything like that, but I can just feel the there is some kind of very ramped up response going on and this results in more severe symptoms. Testing I've had done has shown I have high cytokines/chemokines, IL-6, -8, MIP-1BETAs, TNFs, etc, and I think this is what I am feeling, but I can't show you tissue swelling or anything like that; it seems hard to understand what it all means because of their various interactions, but I can feel their effect for sure.

 

[Marco]

"He then spent the rest of his talk saying how unreasonable it was that patients did not gratefully accept this conclusion, indicating that this was an attack on science (if I remember rightly)."

A quick perusal of the responses submitted to The Lancet by some members of PR plus Graham et al's excellent animated expositions of the PACE results should give some indication of how 'unreasonable' the response was and whether or not it was 'an attack on science' (sic).

 

[Jonathan Edwards]

Good thinking.

I have no doubt brain and muscles are both involved.

What do you think will happen when axon ends are attacked?

I need to get back to this.

I am not quite sure if you really mean attacking axon ends. Axons in tissues feed muscle end plates and such like. Attack on muscle endplates is what you have in myasthenia gravis and I doubt we are in that territory. You would see changes on electromyography. But what I think might be more what you are thinking of is attack on sensory nerve endings. Maybe not, but that is what interests me.

Let us say that a lymph node is innervated both by efferent (motor) fibres that might modulate immune responses via perhaps catecholamines or even acetyl choline (in the thymus), damage to which I doubt would give any symptoms, and by afferent sensory nerves that can signal to the brain the local cytokine levels in the lymph node. That should not be hard since cytokines alter prostaglandin levels and prostaglandins sensitise nerve endings. These nerve endings (not axon ends but sensory ends) might be affected by antibodies or anything you like. If so they would signal trouble directly to the brain, or maybe indirectly through spinal cord reflexes.

This is where my other interest starts to become relevant. I spend most of my time studying the biophysical basis, not of ME, but of conscious perception. We say that sensory fibres from tissues are 'pain' fibres. (Others are touch etc but we are interested in 'bad' signals.) But the signal a sensory fibre sends is not in itself a pain. It is just a signal. It is the brain that, if feeling inclined, invents a pain when it gets this signal. But note that signals coming in to the brain get sent off to several places for different purposes. It is like when you send in an application form for a job and it gets sent to four members of staff who you might work with, human resources to make sure you tick the admin boxes, occupational health to make sure you won't die and CRB to make sure you are not a criminal. The brain does the same for vision for instance. Any dot of light coming in gets sent off to bits that deal with colours, with edges, with shapes, with objects, with shadows of objects and so on.

My suspicion is that what we call pain fibres send in messages that the brain interprets in all sorts of ways depending on what it thinks the general situation is. And it generates not just pains but other feels from the same signals. So if pain fibres in a tooth root are stimulated you feel toothache. But you also cannot face going to that film you really wanted to see. You cannot get to sleep. You really don't want supper even. And this all comes from a 'pain' fibre, which is really a much more sophisticated 'nociceptor'. In fact in lymph nodes there may be little or no pain when there is still enough signal to make you give the film tickets to your neighbour. It is not that these are unconscious signals like temperature regulators that just go through hypothalamus. They give us 'sensations', but our idea that if bad these will be 'pains' may be very oversimplified.

So I am very interested in the idea that the brain gets to know there is immune mischief going on without needing any blood cytokine levels. It has a hotline from the spleen and lymph nodes maybe. And moreover it has microglial amplifiers sitting on the hotline connection pathways if the signals keep coming and the signals that keep coming may be set off by the same things that get microglia excited - or they may be different, or overlap. TNF may put the boot in but I am tempted to think that it is interferon gamma gently turning the thumbscrews that may be the real culprit. And it may turn the same thumbscrews on muscle fibres as well - so it is very hard to pin down exactly 'where' the problem is. It is everywhere but everywhere invisible and local. - Maybe?

 

[Jonathan Edwards]

Did anyone, in fact, raise ...

Perhaps I should just say that we were having a very good conference with lots of fascinating science from people who were extremely self critical and fielding good probing questions. Two or three contributions were out of context and these were just ignored. To my mind that sends the most powerful message.

 

[Sasha]

Perhaps I should just say that we were having a very good conference with lots of fascinating science from people who were extremely self critical and fielding good probing questions. Two or three contributions were out of context and these were just ignored. To my mind that sends the most powerful message.

Fair enough!

 

[ukxmrv]

Perhaps I should just say that we were having a very good conference with lots of fascinating science from people who were extremely self critical and fielding good probing questions. Two or three contributions were out of context and these were just ignored. To my mind that sends the most powerful message.

You really make my day when you say this. Thank you Professor Edwards for all your incredible work in reporting back from the conference and your diplomacy.

 

[Scarecrow]

Peter White: PACE trial

I think I can only describe Dr White’s presentation as out of place. He presented a single slide of outcomes in the PACE study and claimed that it showed clearly that two treatments worked. He then spent the rest of his talk saying how unreasonable it was that patients did not gratefully accept this conclusion, indicating that this was an attack on science (if I remember rightly).

Thank you. That's the biggest laugh I've had all day.

I think it was unfortunate that Dr White suggested that people were being unreasonable over the interpretation of the PACE study. Fortunately nobody seemed to take offence

Tumbleweed, anyone?

 

[Joss]

The differential diagnosis of ganglionitis should be investigated in CFS / ME patients hence Varicella Zoster, Lyme disease, HIV, Sjogren’s disease, paraneoplastic sensory ganglionopathy should be excluded by appropriate history and tests.

Does that mean that a bad case of chicken pox in early adult life can cause ganglionitis? Sorry for my idocy in this respect - not up to the concentration thing.

 

[charles shepherd]

Does that mean that a bad case of chicken pox in early adult life can cause ganglionitis? Sorry for my idocy in this respect - not up to the concentration thing.

Joss - Good question Simple answer is yes.

My ME started off with a very nasty dose of chickenpox + an encephalitic component that caused cerebellar damage.

I don't know if I have dorsal root ganglionitis but it's possible that this is so because I get a lot of sensory problems in my lower limbs when I have an occasional really bad patch.

But DRG can also occur in Sjogren's Syndrome - so it could be autoimmune. Interestingly, some of these SS patients have symptoms consistent with a peripheral neuropathy. A lot of them also have debilitating fatigue - which is why we are using this disease to try and find a biomarker for fatigue.

We have a lot to learn about the neurology of ME/CFS!

 

[Tuha]

A lot of scientific text - difficult to understand for someone with no scientific background and bad english.
But I have one "simply" question - can we say that after this conference (and other ME/CFS conferences of this year)
we moved further with understanding, diagnosing, treating,....ME/CFS. The last months there were many positive news and enthusiasme from ME/ CFS conferences and I would also like to be optimistic like always but I am not even sure if we are able to diagnose ME/CFS correctly. I just ask myself where we are in our fight - can we expect in a short time at least a propre diagnose? this would be probably my question if I would be at the conference

 

[NK17]

@charles shepherd I'm very happy to hear that we have an awful lot to learn about the neurology of ME.

I had a nasty case of mono at 14 and then got hit by chickenpox at 16, 30 years later I find myself with a ME diagnosis and many of the neuro symptoms of Sjogren and MS (just to name a few autoimmune diseases), but my case remains a mystery for the 2 neurologists that I was lucky to see and even more lucky to get respect from.

I've the typical non focal white matter punctate lesions of ME (as per ICC), the ones which get dismissed as non specific.

I've been turned inside out in the past 3 years. Amongst the tests I had were a lumbar puncture, a minor salivary gland biopsy @ the SICCA clinic @ UCSF (one of the international clinics where they do a really thorough job to diagnose Sjogren Syndrome), 2 EMGs, 4 MRIs, 1 punch skin biopsy for possible small fiber neuropathy and all sorts of blood work up.

No clear marker of Lupus, Sjogren, MS have been found so far.

Still there's no doubt in my mind that many cases of ME involve the CNS and as Dr. Gavin Giovannoni states on his MS blog, what we can see and what we see on MRIs is just the tip of the iceberg, what he calls NEDA no evident disease activity, is a cardinal concept which I think should be brought into ME clinics or Centers of Excellence, the ones we desperately need to have.

 

[charles shepherd]

A lot of scientific text - difficult to understand for someone with no scientific background and bad english.
But I have one "simply" question - can we say that after this conference (and other ME/CFS conferences of this year)
we moved further with understanding, diagnosing, treating,....ME/CFS. The last months there were many positive news and enthusiasme from ME/ CFS conferences and I would also like to be optimistic like always but I am not even sure if we are able to diagnose ME/CFS correctly. I just ask myself where we are in our fight - can we expect in a short time at least a propre diagnose? this would be probably my question if I would be at the conference

Tuha - The simple answer is a very definite yes and having attended (and helped to organise this conference) as well as the Invest conference in May, and the IACFS/ME conference in San Francisco conference in March, I really do believe that the tide is starting to turn and that the biopsychosocial model of abnormal illness beliefs, behaviours along with CBT and GET is no longer sustainable. There are now a considerable number of really good scientists and clinicians getting involved with this illness who accept that we have a complex multi system DISEASE with a biomedical basis. So while there is no 'miracle cure' round the corner, I think we are now heading for a situation where we can start to look at treatments matched to clinical and pathological phenotypes (subgroups of patients) that really will make a difference to the lives of peole with ME/CFS. So please switch to optimistic from now on!

 

[charles shepherd]

@charles shepherd I'm very happy to hear that we have an awful lot to learn about the neurology of ME.

I had a nasty case of mono at 14 and then got hit by chickenpox at 16, 30 years later I find myself with a ME diagnosis and many of the neuro symptoms of Sjogren and MS (just to name a few autoimmune diseases), but my case remains a mystery for the 2 neurologists that I was lucky to see and even more lucky to get respect from.

I've the typical non focal white matter punctate lesions of ME (as per ICC), the ones which get dismissed as non specific.

I've been turned inside out in the past 3 years. Amongst the tests I had were a lumbar puncture, a minor salivary gland biopsy @ the SICCA clinic @ UCSF (one of the international clinics where they do a really thorough job to diagnose Sjogren Syndrome), 2 EMGs, 4 MRIs, 1 punch skin biopsy for possible small fiber neuropathy and all sorts of blood work up.

No clear marker of Lupus, Sjogren, MS have been found so far.

Still there's no doubt in my mind that many cases of ME involve the CNS and as Dr. Gavin Giovannoni states on his MS blog, what we can see and what we see on MRIs is just the tip of the iceberg, what he calls NEDA no evident disease activity, is a cardinal concept which I think should be brought into ME clinics or Centers of Excellence, the ones we desperately need to have.

Interesting

Both Professor Peter Behan (a distinguished UK neurologist with a longstanding interest in ME/CFS) and I have a number of patients who predate the onset of their illness to a herpes virus infection (chickenpox or shingles). Our impression is that these patients have a more severe, protracted and complex illness.

I think it would also be true to say that there are people with what might be best described as an atypical form of ME whereby they have unusual neurological features and/or symptoms, lab findings that are suggestive of autoimmune conditions such as SS or lupus, and sometimes it is therefore very difficult to provide a good diagnostic label for what they are presenting with.

 

[lansbergen]

I am not quite sure if you really mean attacking axon ends. Axons in tissues feed muscle end plates and such like. Attack on muscle endplates is what you have in myasthenia gravis and I doubt we are in that territory. You would see changes on electromyography.

I mean axons and not only at the neuromusculair junction but also in the brain.

I considered MG but based on what I know from the liturature it does not fit well enough to my liking.

But what I think might be more what you are thinking of is attack on sensory nerve endings. Maybe not, but that is what interests me.

That too but at the moment I am more interested in the axons.

That should not be hard since cytokines alter prostaglandin levels and prostaglandins sensitise nerve endings. These nerve endings (not axon ends but sensory ends) might be affected by antibodies or anything you like. If so they would signal trouble directly to the brain, or maybe indirectly through spinal cord reflexes.

I have no doubt prostaglandins are involved. And COX2

We say that sensory fibres from tissues are 'pain' fibres. (Others are touch etc but we are interested in 'bad' signals.) But the signal a sensory fibre sends is not in itself a pain. It is just a signal. It is the brain that, if feeling inclined, invents a pain when it gets this signal. But note that signals coming in to the brain get sent off to several places for different purposes.

And when routes are blocked that will work not as good anymore.

My suspicion is that what we call pain fibres send in messages that the brain interprets in all sorts of ways depending on what it thinks the general situation is. And this all comes from a 'pain' fibre, which is really a much more sophisticated 'nociceptor'.CSF findings were also interesting in that IFN gamma and IL-17a tended to be lower.They give us 'sensations', but our idea that if bad these will be 'pains' may be very oversimplified

Yep

So I am very interested in the idea that the brain gets to know there is immune mischief going on without needing any blood cytokine levels. It has a hotline from the spleen and lymph nodes maybe. And moreover it has microglial amplifiers sitting on the hotline connection pathways if the signals keep coming and the signals that keep coming may be set off by the same things that get microglia excited - or they may be different, or overlap. TNF may put the boot in but I am tempted to think that it is interferon gamma gently turning the thumbscrews that may be the real culprit. And it may turn the same thumbscrews on muscle fibres as well - so it is very hard to pin down exactly 'where' the problem is. It is everywhere but everywhere invisible and local. - Maybe?

I have not thought about a hotline but I think I need more interferon gamma now then is assumed normal.

In my opion part of it certainly is local.