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

[DanME]

Maybe we should call it "infection response of the brain" or just "infection behaviour". Sickness behaviour or response is too close to sick behaviour.

 

[A.B.]

Maybe we should call it "infection response of the brain" or just "infection behaviour". Sickness behaviour or response is too close to sick behaviour.

Infection response of the brain isn't good. This is not something triggered by the brain. It's the immune system taking control of the body (which includes the brain). This goes contrary to popular view that the brain ultimately controls everything.

And sickness response isn't limited to infections.

 

[lansbergen]

I agree with Mesci and DanielBt but with the reservation the immune response is not only cytokines.

 

[DanME]

I agree with all of that. Not only infections, not only the brain, not only cytokines.

So we are stuck with sickness response. Nevertheless I don't like sickness behaviour. It seems to be too focused on the brain, mood changes and individual behaviour.

 

[A.B.]

Here is a nice article about the effects of cytokines:

Mood Changes With Cytokines Animals and human volunteers given cytokines usually undergo mood and behavioral changes. Animals sleep excessively, lose interest in their surroundings, stop exploratory behavior, appear fatigued and lethargic. Human volunteers, after their first or second injection of cytokine, invariably experience flu like symptoms such as aching muscles and joints, malaise, fever, chills, headache and fatigue. With daily doses of cytokine, the aches and pains, headache, fever and malaise only last about a week.

If cytokines have been given to animals or humans for more than seven consecutive days, then body temperature usually goes back to normal even in the face of continued cytokine administration. Cytokines don't appear able to keep body temperatures raised for extended periods of time. Consequently fever is not a reliable sign of chronic (i.e. long term) immune system activation. This is an extremely important observation, since fever is universally assumed by both professionals and lay people to be the most reliable and consistent sign of immune system activation available. Clearly, it is not. Fever is only a reliable sign during the first week or so of immune system activation.

Cytokines given chronically (i.e. more than 10 days) result in a different set of symptoms. Fever is usually not present. Varying combinations of neuropsychiatric symptoms are usually more prominent, such as, fatigue, loss of interest in things, apathy, inability to concentrate, poor attention span, headache, irritability, anxiety and depression. In most subjects, the symptoms are mild, but in almost all the experiments, between 10 and 50% of the subjects report severe and debilitating symptoms.

http://www.cytokines-and-depression.com/chapter5.html

Cytokines and sickness response can also elegantly explain why comorbid mood disorders are associated with poorer prognosis in many illnesses. They're just an index of illness severity, rather than some mind-body effect as claimed by psychobabblers. Treating comorbid mood disorders does not, to my knowledge, improve the prognosis, which is also what one would expect if this cytokine hypothesis was true.

 

[MeSci]

Here is a nice article about the effects of cytokines:
http://www.cytokines-and-depression.com/chapter5.html

Interesting, although I find this odd:

Varying combinations of neuropsychiatric symptoms are usually more prominent, such as, fatigue

AFAIK, fatigue is a physical symptom. I know that depression can cause fatigue - at least it is said to - or is it that a third factor causes both the depression and the fatigue? But for most of us here, fatigue is not psychiatric.

 

[MeSci]

I suffer from solute diuresis after exertion - haven't yet analysed when it starts, but suspect that it is the day before my PEM appears.

With perfect timing, I have developed solute diuresis this afternoon, after a tiring weekly shop yesterday.

So it will be PEM tomorrow, I expect, although I was already feeling quite grotty on and off yesterday and today.

Can I have some saline, please...?

 

[A.B.]

AFAIK, fatigue is a physical symptom. I know that depression can cause fatigue - at least it is said to - or is it that a third factor causes both the depression and the fatigue? But for most of us here, fatigue is not psychiatric.

I don't think psychiatric fatigue exists. It's just fatigue. The terminology is a bit unfortunate, but the focus is on psychiatric illness. In any case, the article is very good. It's not the usual psychobabble!

 

[Marco]

But to be a bit more imaginative, I wonder if some of it has to do with salience. I spend a lot of time working on theories of perception (nothing to do with my interest in ME). It seems likely that what we rather quaintly call 'making a logical decision' is a bit more like a ladies Bingo session or a cattle auction where the person who shouts just before the hammer goes down wins. All sorts of possible ideas compete in our heads, both in terms of just what we see when we look out of the window and in terms of deciding whether to buy a house for hundreds of thousands of pounds. The system works quite well because each pathway is constantly recalibrating its 'bidding strategy' in the light of experience. And the choice of what comes through as relevant, salient or 'the right decision' can be fine tuned using synchronisation that gives preference to certain cells firing.

I suspect that when the system is sensitised by local cytokine or whatever the salience regulation mechanism goes all to pot. From the sensory point of view all you can do is go to bed and cover your head with the eiderdown. From the 'executive function' point of view decision making goes to pot and you rapidly realise it is better not to try. On the autonomic side regulatory loops may get overloaded with signals and go for an 'escape valve' response such as collapsing on the floor with 'grey-out'.

Many thanks. That's an interesting choice of words.

Biological pathways aside, I've long considered that the symptoms of ME/CFS could be explained as a disruption of the normal filtering mechanisms that distinguish signal from noise - in effect a problem of sensory information processing. The continuous bombardment of unfiltered sensory input could very easily (another unwelcome generalisation?) lead to frequent bouts of overload.

Interestingly, one large Japanese study of childhood CFS found two distinct sub-groups where brain responses to visual stimuli were tested using a paradigm that involved picking out a small number of 'target' stimuli from a large number of 'non-target'. One sub-group had a suppressed response with an extended time to respond (latency). The other sub-group had an abnormally enhanced response (amplitude) to the non-target stimuli. These responses are interpreted as relating to attention.

On the same test PTSD patients show a similar enhanced response - but only to the target stimuli - which makes sense in terms of salience as sensory cues that are closely related to the original trauma elicit a strong response. This sub-group of CFS patients had a nervous system which was over-responding to any stimulus.

Not surprising that the 'trip switch' kicks in from time to time.

 

[Marco]

Esther Crawley is actually getting involved in complex modelling in this way. It sounds as if her husband is a statistician.

Hopefully not the same statistician who advised on the PACE trial who didn't appear to know the meaning of the word 'kurtosis' or when and when not to use statistics such as the mean and standard deviation which are based on the assumption of a normal distribution.

ETA : Sorry. Must have sounded like a terrorist there

 

[MeSci]

Interestingly, one large Japanese study of childhood CFS found two distinct sub-groups where brain responses to visual stimuli were tested using a paradigm that involved picking out a small number of 'target' stimuli from a large number of 'non-target'. One sub-group had a suppressed response with an extended time to respond (latency). The other sub-group had an abnormally enhanced response (amplitude) to the non-target stimuli. These responses are interpreted as relating to attention.

Was this a one-off test? The reason I ask is that I, and I suspect many other ME sufferers, will do fine on such a test on a good day but badly on a bad day. Thus could the study just have found people at different stages of their severity cycle?

I know I have posted this link before but I don't think it can be over-emphasised:

http://cfstreatment.blogspot.co.uk/2013/03/who-took-id-out-of-cfids.html

Extract:

Natelson found that that there was no consistent immune dysfunction. Some studies indicated that there were increased pro-inflammatory cytokines, others found increased anti-inflammatory cytokines.

Given the fact that one of the hallmarks of CFIDS is waxing and waning symptoms, this "inconsistency" should not have come as a surprise. The immune dysfunction that characterizes CFIDS is that it both under- and over-responds. Immune, as well as neuro-endocrine, swings are the inevitable outcome of the loss of homeostasis that lies at the heart of the illness.

 

[alex3619]

The science on the immune parameters is being sorted out, hopefully anyway. We now know that given the testing protocols used in the past its likely there will be different results. These are to some extent artifacts of the testing/study protocols.

There does now seem to be different NK cell function in moderate and severe patients. There is also an unsubstantiated claim that isolated NK cells are fine, its cells in serum that are not working. Further the ability of NK cells to migrate via chemotaxis appears to be damaged in ME. So if you test isolated NK cells, they are fine. Cells in patient serum/plasma are not.

What test you do strongly effects the outcome. How sick the patient is does too.

A lot of this was covered at the IiME mid-year.

I do not doubt there are complicated homeostatic mechanisms involved though. There is evidence that elevated inflammatory pathways and anti-inflammatory pathways go together. However I am mindful of the point, was it from Jonathon?, that many of these "inflammatory" molecules do not actually cause inflammation. It can be misleading.

I would like to see more of what we saw at Stanford earlier in the year - one large patient cohort, many studies. Results can then be compared on the same patients.

 

[Marco]

Was this a one-off test? The reason I ask is that I, and I suspect many other ME sufferers, will do fine on such a test on a good day but badly on a bad day. Thus could the study just have found people at different stages of their severity cycle?:

As far as I can recall it was a one off test so it's entirely possible that the results may reflect fluctuating symptoms/severity at the time.

On the other hand I have a theory that these two sub-groups (under and over-responsive) may actually reflect disease severity/progression with the over-responsive stage progressing to under-responsive. The same progression has been suggested for ADHD.

 

[charles shepherd]

Changing the subject re UKRC conference….

One of the benefits of studying how fatigue and other ME/CFS like symptoms are being caused in other situations is that this can also provide clues about treatments that may be worth pursuing

In the case of the MRC funded study which is looking at how some people with hepatitis virus C develop fatigue and other flu-like symptoms during treatment with interferon alpha, Professor Carmine Parante described the results from a clinical trial using an omega 3 PUFA (polyunsaturated fatty acid) to see if this reduced the incidence of depression

And it did:

http://www.ncbi.nlm.nih.gov/pubmed/24602409

Abstract
BACKGROUND:
Interferon (IFN)-α therapy for chronic hepatitis C virus infection is frequently associated with depression. The routine prophylaxis with antidepressants might expose patients to adverse effects, hence, the need for alternative preventive interventions. Omega-3 polyunsaturated fatty acids are safe and effective essential nutritional compounds used for the treatment of depression, putatively through an anti-inflammatory action. In addition, lower erythrocyte levels of omega-3 polyunsaturated fatty acids have been associated with an increased risk of IFN-induced depression.
METHODS:
We conducted a 2-week, double-blind, placebo-controlled trial comparing eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and placebo for the prevention of IFN-α-induced depression. A total of 162 patients consented to participate and were randomized to the study. All of the patients completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis.
RESULTS:
Compared with placebo, the incident rates of IFN-α-induced depression were significantly lower in EPA-treated but not in DHA-treated patients (10% and 28%, respectively, versus 30% for placebo, p = .037). Both EPA and DHA significantly delayed the onset of IFN-induced depression (week of onset: 12.0 and 11.7, respectively, versus 5.3 for placebo, p = .002). EPA and DHA were both well tolerated in this population. EPA treatment increased both EPA and DHA erythrocyte levels, but DHA only increased DHA erythrocyte levels.
CONCLUSIONS:
EPA is effective in the prevention of depression in hepatitis C virus patients received IFN-α therapy. Our study confirms the notion that anti-inflammatory strategies are effective antidepressants in the context of depression associated with inflammation.


We don't know if EPA supplementation can reduce ME/CFS like symptoms where interferon alpha is being used to treat hepatitis C infection but it is interesting to note that there is one small clinical trial of EPA which found some benefit in people with ME/CFS:

http://www.ncbi.nlm.nih.gov/pubmed/15117099

Abstract
Lateral ventricular enlargement has been reported in chronic fatigue syndrome, while cerebral neurospectroscopy has recently indicated that essential fatty acid treatment may be of value in this condition. An essential fatty acid supplement rich in eicosapentaenoic acid (EPA) was therefore given daily to a female patient with a 6-year history of unremitting symptoms of chronic fatigue syndrome. Cerebral magnetic resonance scanning was carried out at baseline and 16 weeks later. The EPA-rich essential fatty acid supplementation led to a marked clinical improvement in her symptoms of chronic fatigue syndrome, starting within 6-8 weeks. Accurate quantification of the lateral ventricular volumes in the baseline and 16-week follow-up registered images of high-resolution magnetic resonance imaging structural scans showed that the treatment was accompanied by a marked reduction in the lateral ventricular volume during this perio



So the use of EPA supplementation is an intervention that probably deserves further assessment

Incidentally, when people with ME/CFS are keen to try using a supplement, I point out that EPA (along with carnitine) is one supplement where there is some limited evidence of benefit. Feedback I have received from people who use EPA indicates that some of them certainly feel it is of benefit

 

[Leopardtail]

I think that Sonia tweeted:


I see that as a comment that we need to understand more about what we mean by fatigue and how it might change with different diseases.

If I were to de-generalise Prof Newton's statement and quote specifics she says that fatigue associated with ME/CFS is similar to that in PBC and that fatigue associated with Sjogeren's is similar to PBC. Iff fatigue is associative then ME fatigue is similar to Sjogren's.

But I think there are two different questions
1) Is fatigue a single concept or is it a grouping of different things that could have different mechanisms (even if triggered by the same thing). I wonder are mental and physical fatigue different.
2) Is fatigue the same in all things or just a selection. I think Prof Newton was looking at Rituximab for treating PBC. So there could be common mechanisms.

My guess is that in the questionnaire they use they are profiling different elements of fatigue.

From a sample of 1 (not very scientific I know) a friend who had ME symptoms (never formally diagnosed) and then cancer had different fatigue. After the cancer treatment things like the pain associated with ME went as did the PEM which I think of as part of fatigue.

I think the important thing to keep in mind is that the mechanism by which the sensation of fatigue might be triggered (the end of the pathway) likely is common to many illnesses it would make little biological sense for it to be different. The bigger question is what starts the cascade - in other words the cause of the fatigue.

Where that research might be useful, is in distinguishing signalling mechanisms from causal ones, thereby delivering a better focus for research.

 

[Leopardtail]

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.

True Alex.

and we also have to account for the fact that many hormones are produced in a pulsatile fashion. E.g. Thyroid Stimulating hormone is released in a short burst, paused, released again etc.... This makes reliable accurate measuring something of a challenge.

The types of hormone you refer to are:
Endocrine: delivered from glands through blood to remote organs
Autocrine: messaging between parts of a cell
Paracrine: diffused to nearby cells
Juxtacrine: delivered through channels to adjacent cells.

Intracrine is a variation on endocrine where the signal is received inside the cell not on its surface...

One could also argue that the cyokines such as the interleukins in immunology and leptin in fat metabolism are hormones.

 

[Leopardtail]

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.

Charles,

There is much talk of 'depression' in CFS, but that's just not me, and most of the people I know with it are remarkably happy given their quality of life.

Is there any reliable data on prevalence?

 

[Leopardtail]

I agree with Charles that the answer is a definite yes. My impression is that ten years ago there were a few individual scientists scattered over the world, each with their own private theory about ME. Now we have a body of scientists, many coming in from careers in other related fields, who are all talking the same language and they pretty much agree on what sort of a problem we are dealing with. There is some sort of persistent problem in the brain and spinal cord, and maybe in many other organ systems, of a sort that can be at least influenced by, and may well in some cases be caused by, a disturbed immune response. Perhaps most importantly we now understand how such a problem can be explained by changes in cells like microglia at a level that would be invisible on traditional tests.

Understanding every step of a disease process is a lot to ask, but it may not be necessary. It may be interesting to ask; do we know as much about ME now as we did about rheumatoid arthritis when we started finding powerful new treatments in the 1990s? The answer may be not quite, but it is not so far off. We have a good idea what processes we might want to target in treatment and as soon as we find a treatment working we will know we were on the right lines. We may already be in that situation.




Interestingly, Professor Holgate and many others at the CMRC conference answered this question by turning it on its head. In other branches of medicine we now realise that 'a proper diagnosis' is not really what we looking for. We want to be able to know exactly what is going wrong for each person individually. The buzz word is personalised medicine but the reality is just common sense.

In the last twenty years I looked after people with rheumatoid arthritis I never bothered to think what the name of their diagnosis was. Each person had a different range of problems and I dealt with them as seemed sensible for that person. If you are in a restaurant you have to order pizza Romana or Fiorentina, but at home you may put anchovy on dad's pizza but not on the kids' pizzas. You may put more cheese of Jack's and no salt on your own. If you know enough about what you are doing in cooking and medicine the labels no longer matter.

But you are right in that we do need some basic agreed categories - you need to know what a pizza is. The scientists at the CMRC meeting seemed to agree that we should allow the category to be quite broad because we do not want to leave anybody out just because they do not tick some box on a form. And I think we have as good an idea of what we mean by ME as we do for 'inflammatory arthritis' which would be the pizza word in my old clinic.

I think ME, or MEs, are a group of processes in which there is some persistent microscopic change in the brain and spinal cord (probably with some common features and some difference between cases) that gives rise to fatigue, myalgia and post-exercise malaise, and which are not covered by other categories (often with more macroscopic structural or inflammatory change) such as lupus or MS. That is all we need to go on to start developing new treatments because we know a lot about the possible mechanisms that might be involved.

My memory is that Charles Shepherd has been quite keen on the term Myalgic Encephalomyelopathy. I would agree but I suspect neither of us would think it something worth arguing over, since disease names are often a bit arbitrary. But with this proviso it seems to me more and more that Ramsay's name of Myalgic Encephalomyelitis was not so bad. It is no worse than osteoarthritis, which is not really an -itis at all.

I though at the time there are eight kinds of diabetes with two major 'super types'. They have different treatments but are all called 'diabetes'.
This approach is needed with ME though more effort is needed to sort out those subtypes.

 

[Leopardtail]

I think the time line for new treatments is impossible to predict. Sometimes it seems things take forever and sometimes one is amazed how much things have changed in a few years. The main thing is that the momentum seems to be gathering.

I don't think criteria matter. I know this seems strange to patients but in my RA research I never bothered with any criteria. I followed the biological processes I could measure and the patients' symptoms and signs. Strictly speaking you need a different set of criteria for every experiment because each experiment asks a different question. What matters is that we all know who needs help and that we need to find out which people might be helped one way and which people another way. A key point made at the conference is that criteria for research have nothing whatever to do with criteria for patient care. I know it sounds odd but it is a basic truth about medical research.

Are criteria not used to ensure sample quality in research in other fields?

 

[Leopardtail]

I'm interested in @Jonathan Edwards's distinctions between symptoms and underlying pathologies (if I have recalled his posts correctly - apologies if not, but I have only just managed to struggle to the end of this thread and resisted posting too many replies in case others had already made the same comments).

I sense that we have similar views in that there are two main ways to treat an illness, and they both have value and can be used together if required. Also that the way we categorise illnesses is flawed, as illnesses with similar symptoms can have different underlying causes/pathology and illnesses with different symptoms (e.g. ME and RA) can have similar or even the same underlying causes/pathology.

For some time I have been sceptical about dividing what now appear to me to be related illnesses (my particular interest is gut dysbiosis as an underlying cause/pathology) into a veritable dictionary of different names based largely on symptomatology.

I also have doubts about the wisdom of treating some symptoms (e.g. fatigue in ME) in ways that may actually exacerbate or perpetuate the illness in the longer term.

So simple symptom treatment for, e.g. headache or high blood pressure can sometimes usefully be provided.

But the underlying causes for these symptoms may be very different, and to improve longer-term outcomes, different approaches and disease categories need to be applied. And some short-term interventions can make things worse in the longer-term.

And, as you say, everyone is different and needs to be treated as such.

I am struck by the differences between the modern, 'Western' paradigm of illness and, for example, Chinese medicine and Ayurveda, and think that we may benefit from taking the best from a range of approaches whilst discarding the wrongheaded stuff from the different approaches. They probably all have good and bad aspects.

Hope this makes sense!

It made sense to me I think. What strikes me is that measuring fatigue alone has little use, it's too common a symptom, but the balance of pain vs fatigue may indicate something different in research. Some symptoms however are much more variables such as Polyuria, Bowel problems and so on...