UK Research Collaborative Conference in Newcastle: 13th - 14th October

[MeSci]

Thanks - I should have included this one as it also supports a role for basal ganglia:

Abstract
Reduced basal ganglia function has been associated with fatigue in neurologic disorders, as well as in patients exposed to chronic immune stimulation.

Patients with chronic fatigue syndrome (CFS) have been shown to exhibit symptoms suggestive of decreased basal ganglia function including psychomotor slowing, which in turn was correlated with fatigue. In addition, CFS patients have been found to exhibit increased markers of immune activation.

In order to directly test the hypothesis of decreased basal ganglia function in CFS, we used functional magnetic resonance imaging to examine neural activation in the basal ganglia to a reward-processing (monetary gambling) task in a community sample of 59 male and female subjects, including 18 patients diagnosed with CFS according to 1994 CDC criteria and 41 non-fatigued healthy controls. For each subject, the average effect of winning vs. losing during the gambling task in regions of interest (ROI) corresponding to the caudate nucleus, putamen, and globus pallidus was extracted for group comparisons and correlational analyses.

Compared to non-fatigued controls, patients with CFS exhibited significantly decreased activation in the right caudate (p = 0.01) and right globus pallidus (p = 0.02). Decreased activation in the right globus pallidus was significantly correlated with increased mental fatigue (r2 = 0.49, p = 0.001), general fatigue (r2 = 0.34, p = 0.01) and reduced activity (r2 = 0.29, p = 0.02) as measured by the Multidimensional Fatigue Inventory. No such relationships were found in control subjects.

These data suggest that symptoms of fatigue in CFS subjects were associated with reduced responsivity of the basal ganglia, possibly involving the disruption of projections from the globus pallidus to thalamic and cortical networks.

Ignore this if someone else has already raised it, but I am still well behind in this thread.

The CDC criteria aren't very good, are they? Do they include PEM and not include depressive symptoms? Poor response to a task like this suggests depression to me. I have a strong positive response to winning in a competitive context, but when I was depressed I didn't.

 

[MeSci]

The other thing that struck me about Mr Edwards' cogitations is this notion that functional neurological symptoms must be caused by beliefs because they reflect lay people's understanding of the functioning of the nervous system as opposed to what is known in the medical literature about anatomy and physiology. So in his presentation slides and Bayesian hysteria paper he gives an example of a type of functional blindness where the patient develops tunnel vision which is inconsistent with the laws of optics but consistent with Joe Shmoe's intuitions / naive beliefs about the workings of the eye and the brain. In the ME/CFS field we have been subjected to similar hypotheses put forward by some psychiatrists and persons who are B.A. in English Lit and Sociology graduates but who have for some reason decided to write book chapters about ME and who have argued that this illness exists only as an expression of cultural memes / mass hysteria, that without cultural contagion this condition wouldn't exist. But when you think about it, that can't be so. The cardinal symptom of this disease--PEM--which is experienced by millions of people across the world, many of whom had this before media coverage, the internet and support groups is in no way in line with lay people's beliefs about the effects of exertion or the timing of those effects (for some of us with ME, we feel alright while doing the actual activity and the crash/exacerbation of all symptoms starts 24-48 hours AFTER the activity). The immune and autonomic symptoms of PEM are not consistent with what humans believe about exercise, nor is PEM part of any normal human experience or any human language. Only if you are uneducated about ME/CFS and you think this illness is about constant exhaustion or tiredness can you believe that beliefs could cause this illness. In reality this very important key symptom totally defies belief and seems totally alien and improbable. Most of us here struggled for years to make sense of what was happening to us, to understand the causal relationship with exertion that happened a day or more ago, had never met anyone who had ever experienced such a thing, had no language to describe our experience and when we did try to explain it to family or doctors all we got were blank stares and abuse.

So true. How many of us thought that these mysterious episodes of worsened health were actually due to repeated viral infections, and kept visiting our GPs/PCPs and getting the usual 'virus' spiel from them, and didn't know that it was doctor-speak (at least in the UK) for 'I don't know'? It took me many years to make the connection with prior activity, let alone predict it! I think I had to read it or hear it somewhere before I 'got it'.

It takes almost superhuman self-discipline sometimes to resist the urge to do things, and is a source of daily frustration, but ultimately enables us to do more overall. It is criminal, to my mind, to try to make us unlearn such hard-won wisdom, and can cause serious harm.

 

[charles shepherd]

Sorry, but it's just not realistic to assume that here in the UK a drug that:

1 is very expensive

2 is quite complex to administer

3 has the potential to cause very serious (even fatal) side-effects

4 is being used in a condition that could affect as many as 250,000 people

is going to get a product license and a recommendation from NICE for use on the NHS on the basis of the results from one phase 3 clinical trial carried out in Norway…….

 

[Sasha]

Sorry, but it's just not realistic to assume that here in the UK a drug that:

1 is very expensive

2 is quite complex to administer

3 has the potential to cause very serious (even fatal) side-effects

4 is being used in a condition that could affect as many as 250,000 people

is going to get a product license and a recommendation from NICE for use on the NHS on the basis of the results from one phase 3 clinical trial carried out in Norway…….

I think you're right but I think people are interested in why. Suppose the Norwegian trial had 1,000 patients. Would that do it? Or is it to do with concerns about whether weird patients get recruited in Norway? Or what?

 

[BurnA]

I think you're right but I think people are interested in why. Suppose the Norwegian trial had 1,000 patients. Would that do it? Or is it to do with concerns about whether weird patients get recruited in Norway? Or what?

Exactly Sasha. I know what you are saying @charles shepherd but I don't understand the logic.

If this was a cancer drug that saved 50% of patients in a trial run by a major pharma co. in the US would we be having this conversation.

Why are more trials required in some cases than others ? Is this defined anywhere ?

 

[Marky90]

Sorry, but it's just not realistic to assume that here in the UK a drug that:

1 is very expensive

2 is quite complex to administer

3 has the potential to cause very serious (even fatal) side-effects

4 is being used in a condition that could affect as many as 250,000 people

is going to get a product license and a recommendation from NICE for use on the NHS on the basis of the results from one phase 3 clinical trial carried out in Norway…….

Hi Charles

Sorry but I dont`t see point 1 as a real issue.. (?) Rituxumab is cheaper than a lot of cancer medication, and I know doctors use those experimentally after a convincing phase 2 trial e.g.

Point 2 and 3 are of course relavant when deciding whether to give rtx or not, but why would one need another trial if the norwegian phase three shines light on how one administer the drug, and how one best deals with side effects?

Just my cents..

 

[Bob]

Remember that this isn't cancer. It's CFS/ME. So there's little logic involved, when it comes to the authorities. Instead, there's prejudice and ignorance. Like it or not, we might have to fight for rituximab in the UK, for historic and political reasons. Charles isn't making the rules... He's planning ahead, thinking about what we need to set in motion now, for the best possible outcome somewhere down the line. If we have more then one clinical trial that provides positive evidence for rituximab, then that gives us a better chance of convincing the authorities.

 

[Jonathan Edwards]

I hope you're right, @Jonathan Edwards!

This is promising:

http://sro.sussex.ac.uk/7047/1/Neil...eroceptive_Responses_to_Inflammation_2009.pdf

But I notice nothing correlated with levels of IL-6, so the proposed link between inflammation and engagement of the interoceptive network is a bit indirect. Bit of a worry, as PWMEs will not have the benefit of being classed into groups of vaccinated vs. unvaccinated, so everything will have to depend upon actual cytokine levels (or indirect inference based on whether they just exerted themselves or not).

You're not at all concerned that the interoceptive network is viewed as the origin of many of the "somatic" complaints that accompany states of psychological distress? And as the initiator of a cycle that includes increased levels of cytokines in these conditions? (IL-6 is big in these models, I believe?)

I actually think that cytokine measures as they are at present are not really good enough to conclude anything from and poor correlations are not surprising. In RA, which is the paradigmatic cytokine driven disease cytokine levels in serum were never much help. We used other things like CRP. A major possibility is that cytokines are often secreted and recognised very locally - in the liver in RA and maybe around nerve endings in ME.

At the moment everyone researching ME is struggling, whether they are studying psychological factors or cyokines or antibodies or what. Most of what is being published is just dress rehearsal for the real stuff when we find the right things to measure and will in time be forgotten without trace. One approach is to say if we cannot measure things reliably shut down the lab and go home. The other is to keep trying the best available measures and hope that along the way it becomes clear what a better thing might be to do. When I first did a Western blot to identify a new protein you had to screw your eyes up to see a band - but there did seem to be a band. With another three months work we had a band like a stripe on a zebra. One could very easily pull the Edwards project to bits - as a colleague of mine did last week - but you never know what you will learn, like the three year time cut off in the Hornig cytokine study. And it turned out my colleague was bullshitting anyway when I looked up their objection!

 

[jimells]

Doctors don't see patients as customers and so don't go the extra mile to be nice to the patient to hold on to them.

Most of the doctors I've had to deal with in the US seem to see patients as a nuisance, especially if they are poor. In a society where money mediates everything this is a sensible approach to financial survival. Every economic unit has to make something, and for the medical industry, their main product is insurance claims. If they could produce claims without the bother of patients, that would be ideal.

 

[jimells]

Also, on the surface it looks like the wealth of the one percent in the UK is much more conservative in terms of philanthropy.

Here's an example of how philanthropy works in the US:

A guy named Harold Alfond started Dexter Shoe Company and it became successful, expanding to four or five factories and hundreds of employees in rural Maine. In 1993 he sold the company to Warren Buffet for half a Billion dollars in stock. Eight years later Warren Buffet closed all the factories and fired most of the workers, after they trained the Chinese on how to use the equipment, now located in China.

These people were so cheap that their main factory in Dexter didn't even have a break room for the four or five hundred employees - they were forced to eat at their workstation or in their cars in the parking lot. But this is only right, since employees were there to work, not to have breaks. I worked at Dexter as an independent computer consultant, so I had a nice warm cubicle to eat my lunch in.

After selling the company the Alfond family became "philanthropists", spreading around money and buying love. They would donate money for new schools and hospitals and so on, but only if Alfond's name was on the building, of course. So now everyone in the State of Maine loves Harold Alfond, since it's so courageous and generous to give away money squeezed from poorly-paid workers.

And no one gives a single thought to the hundreds of employees tossed to the curb, the folks who actually constructed the buildings and operated the machines and acquired repetitive motions injuries and now have no way to feed their families.

 

[Snowdrop]

@jimells I have no doubt at all that that is true in general about big money private or corporate.

 

[Bob]

Capitalism... Discuss...



(This thread is rather diverse in its scope!)

 

[Snowdrop]

For anybody who is still capable of reading nonfiction books on the subject of society and economics I would suggest names like Martha Nussbaum, Joel Bakan, and Naomi Klein.

 

[Snow Leopard]

Would you apply the same logic to the value of just one RCT if this was applied to CBT or GET, or any other form of behavioural or psychologically based treatment in ME/CFS ? !

For me it depends on the quality of the research and the magnitude of the result.

 

[nandixon]

Incidentally, one of the poster presentations at Newcastle covered the cinical trial of Rituximab in primary biliary cirrhosis:

https://clinicaltrials.gov/ct2/show/NCT02376335

a condition which has some interesting overlapswith ME/CFS, that is now taking place in Newcastle

Some additional info about this trial was recently published here:

RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial

Background
.....
.....The severity of fatigue that patients describe is associated with the length of time that the acidosis is present and the recovery time back to the baseline pH. [Ref 13] As a result of these observations, we hypothesise that the antimitochondrial antibodies which are seen in over 90% of people with PBC lead to over-utilisation of anaerobic pathways through their activity against pyruvate dehydrogenase (PDH).
.....

B-cell biology
.....
Anti-PDH antibody total and individual isotype levels and antibody functional inhibitory capacity will be studied on day 0 and at the primary end point (12 weeks after therapy). Antibody levels will also be correlated with long-term fatigue status during the secondary follow-up period to 12 months..... In the analysis phase, impact of rituximab on fatigue in PBC will be correlated with changes in individual autoantibody isotype responses and with PDH-inhibitory capacity of serum.

 

[charles shepherd]

This is the MEA report on the whole conference:

http://www.meassociation.org.uk/2015/10/global-mecfs-research-22-october-2015/


Two days in Newcastle | reflections on ways forward for global ME/CFS research| 22 October 2015
Dr Charles Shepherd reports and reflects on the second UK CFS/ME Research Collaborative conference held in Newcastle on 13 and 14 October, 2015.
Following on from our conference at Bristol University in 2014, Professor Julia Newton and the multidisciplinary research group at Newcastle University hosted this year’s conference.

Once again, the conference attracted a large number of researchers from here and abroad, clinicians, medical students – four of whom were funded by the MEA – and charity representatives. The presentations, workshops and discussions concentrated on neuropathology, autonomic nervous system dysfunction, clinical trials, including Rituximab, patient-reported outcomes and sleep.

Especially encouraging was the high standard of research being presented, as well as the way in which we are moving forward with a biomedical model of causation that involves infection, immune system dysfunction – including cytokine involvement, and resulting in low-level neuroinflammation. This type of neuroimmune model of causation could explain some of the key symptoms in ME/CFS and in turn lead to effective forms of treatment.

Please note that several of the presentations contain pre-publication research findings – so it is not possible to report on them in any detail at this stage.

 

[Gijs]

Always nice to see a conference but after 20 years with ME/CFS i am very disapointed with the results they produce. Don't get me wrong i am happy with these doctors but i have the feeling they never going to a find the cause of this disease or produce an objective test. I think this generation of ME/CFS patiënts have lost their lives and never will be better. Even Rituximab is not going to be a solution. Sorry, i am not so optimistic but i am very thankful that doctors are looking and doing their best!

 

[charles shepherd]

Comment from UK neurologist, Professor Leslie Findley, on the Edwards et al MRC funded research involving fMRI to investigate the pathophysiology of post-exertional malaise in ME/CFS:

Prof Leslie Findley, medical advisor says: “We are pleased to note that the MRC approved and funded the Sussex Research Study, which will examine simultaneously brain responses using such techniques as functional magnetic resonance imaging, and inflammatory responses in a cohort of people with CSF/ME.

The object of the research is to answer the hypothesis that the symptoms of CFS/ME relate to maladapation in brain responses, and are maintained by abnormal inflammatory responses.

Clearly if this hypothesis was proven, it would be consistent with the WHO’s view that CFS/ME should be considered as a primary neurological (ie, brain) disorder.”

 

[Gijs]

Comment from UK neurologist, Professor Leslie Findley, on the Edwards et al MRC funded research involving fMRI to investigate the pathophysiology of post-exertional malaise in ME/CFS:

Prof Leslie Findley, medical advisor says: “We are pleased to note that the MRC approved and funded the Sussex Research Study, which will examine simultaneously brain responses using such techniques as functional magnetic resonance imaging, and inflammatory responses in a cohort of people with CSF/ME.

The object of the research is to answer the hypothesis that the symptoms of CFS/ME relate to maladapation in brain responses, and are maintained by abnormal inflammatory responses.

Clearly if this hypothesis was proven, it would be consistent with the WHO’s view that CFS/ME should be considered as a primary neurological (ie, brain) disorder.”

Don't forget bloodflow problems to the brain! I still doubt it is a primary neurological disorder.

 

[duncan]

Do we have an idea of what "...maladapation in brain responses..." might be referring to?

If they mean maladaptation - which I am hoping they do and I have not lost another very cool word to memory issues - the question stands: What is our brain responding in a faulty manner to?

Perhaps this is part of the exploration? That the goal is not identifying the trigger, just identifying the faulty mechanism, i.e., brains, at play?