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

[Seven7]

Why if there is so much recognition on dysautonomia there is no more studies on drugs in that area? I went from bed bound to walking a mile in 3 days when treated! I am sill sick but at least I kept my job and can have a decent live with vassocontrictors. Not cure but can keep a lot of people going while they figure this thing out.

 

[DanME]

Why if there is so much recognition on dysautonomia there is no more studies on drugs in that area? I went from bed bound to walking a mile in 3 days when treated! I am sill sick but at least I kept my job and can have a decent live with vassocontrictors. Not cure but can keep a lot of people going while they figure this thing out.

That is a very good question. I would like to see a focus on OI and some further treatment studies. OI symptoms are partly treatable and getting rid of of them can have a huge impact on the quality of life. I would like to see a blood volume study to quantify this problem in ME patients once and for all.

 

[Isabelle]

The talk about sensory processing reminded me of an article I read about sensory processing disorder (SPD) in children. I was interested because some of the symptoms the children experienced were ones I was struggling with—sensitivity to sound, light etc. Also how this sensitivity could change from day to day. Some days I can’t stand the sound of a vacuum; other days it doesn't bother me quite as much. The study detected abnormalities in the microstructure of white matter tracts in the posterior aspect of the brain that connected auditory visual and tactile systems for sensory processing. SPD is a neurodevelopmental disorder so whether this relates to ME/CFS I don’t know.

http://www.ucsf.edu/news/2013/07/10...ical-basis-sensory-processing-disorders-kidsi

 

[rosie26]

The year of my flu sudden severe onset ME, my brother learnt at age 39 he had contracted Hep C from a blood transfusion after a motorbike accident that broke his thigh bone at 18 years old. He was put on interferon treatment. His heavy fatigue symptoms sounded exactly like mine, but his was controlled, for me it was uncontrolled.

I really think interferon plays a role in ME in my view, there is a very heavy immune feel to the fatigue. There is no mistaking how different it is to normal fatigue in my experience.

 

[Jonathan Edwards]

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.

I agree. One of the things that I think became clear during the CMRC meeting was that although alpha interferon and TNF can both cause fatigue that does not mean that either of them have anything to do with fatigue in MEs.

I am not quite sure what Dr Newton means by all fatigue being the same. It might mean that what people complain of is the same but in fact it seems that there are differences between the symptoms in situations with known causes. She seems to be implying that there is some final common pathway, but I am unclear how we can know that.

What I find difficult to understand is the relevance of giving rituximab to PBC patients to ME fatigue. If rituximab works in PBC it will be working through an effect on some abnormal B cells causing a disease that includes fatigue. But we know that lots of diseases that include fatigue are not caused by B cells, including cancer and interferon alpha injections. We do not know if B cells are involved in ME. So the results of treating PBC cannot tell us anything about whether ME would benefit. ME might benefit because it is due to abnormal B cells, but it will not benefit just because fatigue has the same final common pathway - because that is clearly not B cells, it would have to be something further down the line, maybe triggered through effects of antibodies in some cases but completely different things in others.

 

[A.B.]

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

Thanks, that is very interesting. Especially the part about EPA preventing depression during IFN-α treatment.

How much EPA did the mentioned CFS patient take?

While the ultimate goal is finding a cure for ME/CFS, I wish there were also studies that simply attempted to find a few cost effective and relatively safe treatments that improved quality of life.

 

[Sasha]

While the ultimate goal is finding a cure for ME/CFS, I wish there were also studies that simply attempted to find a few cost effective and relatively safe treatments that improved quality of life.

That's the explicit goal of Item #10 on the Open Medicine Institute's MERIT programme (a list drawn up over the course of a two-day conference of international ME experts in 2012 including @charles shepherd):

http://openmedicineinstitute.org/research-initiatives/mecfs-merit/

1. Treatment: Phase 3: Natural and Over-the-Counter Substances
   • Goal: Examine the potential benefit of several over-the-counter/natural therapies in a vetted scientific setting. Substances examined will include Moringa oliefera, GcMAF, Vit B12, and artemesin.
   • Importance: This project will be a first application of vetted scientific method and molecular science to non-pharmacologic substances that have had anecdotal benefits reported, thereby setting a standard for mainstream measurement of ME/CFS.

So far they've successfully crowdfunded a trial of B12 which is presumably either about to start or ongoing, and received a large donation that enabled them to start a trial of Moringa oliefera, which ran into problems when the manufacturer changed the formulation (I don't know the status of that trial).

You're right, we need both the "cure" trials and the "mitigation" trials.

 

[Sasha]

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.

One of our big problems, of course, is that most of us come up normal on all traditional tests. On paper, I look Olympic! In reality, I'm pretty much bedbound/housebound.

With microglia, are we getting near to a test that would either be an ME-specific biomarker (perhaps in combination with other things) or at least an objective sign of organic illness, even if it's not specific to ME? Either would have value.

If so, when there are tests that aren't traditional, is it generally the case that they're only done in research labs and that clinicians wouldn't be able to order them?

 

[Snow Leopard]

And within the medical field the sad truth is that most of my colleagues seem to be too dim to get the point - even the top flight immunologists. A lot of people seem to have a mental block about what tends to be called 'complex system dynamics'. Part of it I think is complacency. People think they know disease causation - genetics and environment. And it is only really on a forum like this that you can say 'rubbish' to people. If a practicing scientist says rubbish to anyone he will get no more grants from then on.

That reminds me of this comment on 'intellectual freedom' from phdcomics:

http://www.phdcomics.com/comics/archive.php?comicid=1436

And as an emeritus professor...

Seriously though, the aim isn't to convince the public as a whole, but simply influence those who are willing to listen. While appealing to the dominant belief is the easy way to publishing something, originality, or especially the expression of suppressed thoughts can often resonate with readers.

I'd write an article for a publication like Huff Post myself but I doubt many would listen to me as I don't come from any sort of position of authority.

 

[Jonathan Edwards]

One of our big problems, of course, is that most of us come up normal on all traditional tests. On paper, I look Olympic! In reality, I'm pretty much bedbound/housebound.

With microglia, are we getting near to a test that would either be an ME-specific biomarker (perhaps in combination with other things) or at least an objective sign of organic illness, even if it's not specific to ME? Either would have value.

If so, when there are tests that aren't traditional, is it generally the case that they're only done in research labs and that clinicians wouldn't be able to order them?

I doubt that we are close to a way of demonstrating a change in microglial behaviour on a diagnostic test. The Japanese PET study might point in the right direction but I found it hard to interpret. One thing that struck me, triggered by Maria Fitzgerald's presentation at the meeting, is that it may be wrong to think in terms of 'microglial priming'. It may be that we should be thinking purely of microglial numbers.

The reason for saying this is that it is hard to see why microglia should persistently over-express certain receptors over a period of months and years. They might do if constantly stimulated by autoantibodies from bone marrow, I agree, but that would not be 'priming' so much as just stimulating. I guess it is conceivable that something like gene methylation might occur during an initial insult and then persist. But I find that pretty implausible because a lot of people report remissions and relapses - either short or long term. A much simpler explanation would be that after an initial insult there is recruitment of microglia to certain areas and that microglial lifespan is long enough, in terms of months or years, for this to explain persistence of 'central sensitisation'. This might seem to give the same predictions for remission and relapse as a shift in receptor expression but it would be a simpler explanation and would allow for further up and down changes in receptor expression on top to help explain relapse and remission.

I do not think we need to worry about new tests not being available to clinicians. When a new test is shown to be of genuine diagnostic value the relevant clinicans will insist on having it and it will become available. If there was a PET scan that reliably diagnosed ME (which would have been proven to be a 'real disease' by the fact that the scan was reliable) it would become universally available within a matter of months.

 

[Snow Leopard]

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?

The CDC Wichita study (one of the decent CDC studies led by Shelly Reyes) said that 30% had reported a current diagnosis of depression. Jason's Chicago study reported a current diagnosis rate of Axis 1 disorders (after a structured interview with a psychologist) of 55%, but that includes other things like sleep disorders, eating disorders etc too. Both of these studies used the Fukuda criteria on a randomly selected community based sample. The rest of the population based studies aren't of high enough quality to mention...

 

[Jonathan Edwards]

And as an emeritus professor....

... I am researching exactly what I want in fact, or at least trying to help things along, and it is looking rather promising.

While appealing to the dominant belief is the easy way to publishing something, originality, or especially the expression of suppressed thoughts can often resonate with readers.

The sad fact is that the importance of random elements in disease causation is not original. It is the textbooks. It is just too difficult for a lot of people to understand. Those that understand don't need telling. Truth moves forward by results. We need some results. Then everyone else joins the bandwagon. And one can do an interview for New Scientist and Science. But to be honest we did that last time on the random bit and I think it just annoyed people - because they couldn't understand!

 

[Leopardtail]

The CDC Wichita study (one of the decent CDC studies led by Shelly Reyes) said that 30% had reported a current diagnosis of depression. Jason's Chicago study reported a current diagnosis rate of Axis 1 disorders (after a structured interview with a psychologist) of 55%, but that includes other things like sleep disorders, eating disorders etc too. Both of these studies used the Fukuda criteria on a randomly selected community based sample. The rest of the population based studies aren't of high enough quality to mention...

So nothing that specifically checks depression in isolation. Unless the researcher validates the diagnosis, I would be suspicious. Too many GPs diagnose clinical depression when in fact their patient is just cross or frustrated. Tanks for the info Snow

 

[Sasha]

I doubt that we are close to a way of demonstrating a change in microglial behaviour on a diagnostic test. The Japanese PET study might point in the right direction but I found it hard to interpret. One thing that struck me, triggered by Maria Fitzgerald's presentation at the meeting, is that it may be wrong to think in terms of 'microglial priming'. It may be that we should be thinking purely of microglial numbers.

Is that something that can be tested for? If so, is anyone looking at that?

I do not think we need to worry about new tests not being available to clinicians. When a new test is shown to be of genuine diagnostic value the relevant clinicans will insist on having it and it will become available. If there was a PET scan that reliably diagnosed ME (which would have been proven to be a 'real disease' by the fact that the scan was reliable) it would become universally available within a matter of months.

That's very good to hear!

 

[Snow Leopard]

So nothing that specifically checks depression in isolation. Unless the researcher validates the diagnosis, I would be suspicious. Too many GPs diagnose clinical depression when in fact their patient is just cross or frustrated. Tanks for the info Snow

The numbers in the Jason study are legit, contact him if you want more details, he is usually happy to explain things.

http://condor.depaul.edu/ljason/

 

[charles shepherd]

That is a very good question. I would like to see a focus on OI and some further treatment studies. OI symptoms are partly treatable and getting rid of of them can have a huge impact on the quality of life. I would like to see a blood volume study to quantify this problem in ME patients once and for all.

Very valid points

I have tried to set up a UK clinical trial looking at the use of midodrine - but without success so far

Peter Rowe gave a very good summary of the current state of knowledge regarding the use of drug interventions for orthostatic intolerance and orthostatic hypotension (OI and OH) in ME/CFS at his Workshop at the IACFS/ME conference in San Francisco in March

My on-line summary:

http://www.meassociation.org.uk/201...sme-conference-in-san-francisco-1-april-2014/

contains some information on what was said but you might find it interesting to look at the notes that Peter prepared to go with what was a really useful Workshop that focussed on practical patient management of OI and OH.

Not sure if they are on-line anywhere.

 

[MeSci]

The reason for saying this is that it is hard to see why microglia should persistently over-express certain receptors over a period of months and years. They might do if constantly stimulated by autoantibodies from bone marrow, I agree, but that would not be 'priming' so much as just stimulating.

Could you remind me/us how priming can occur?

I do not think we need to worry about new tests not being available to clinicians. When a new test is shown to be of genuine diagnostic value the relevant clinicans will insist on having it and it will become available. If there was a PET scan that reliably diagnosed ME (which would have been proven to be a 'real disease' by the fact that the scan was reliable) it would become universally available within a matter of months.

Aren't PET scans expensive? So much emphasis is placed on affordability in the NHS and probably other health systems, especially at the moment, that short-term cost concerns might put doctors off referring people for PET scans, might they not?

I have been refused cheaper scans in recent years - liver/abdominal ultrasound and bone mineral density, and they are relatively inexpensive, I think.

 

[charles shepherd]

Thanks, that is very interesting. Especially the part about EPA preventing depression during IFN-α treatment.

How much EPA did the mentioned CFS patient take?

While the ultimate goal is finding a cure for ME/CFS, I wish there were also studies that simply attempted to find a few cost effective and relatively safe treatments that improved quality of life.

Study Design and Recruitment
Two hundred seven patients with HCV were screened, 162 of them consented to participate and were randomized to the study, and all of them completed the 2-week trial; 152 participants were followed throughout the 24 weeks of IFN-α treatment and were included in the analysis. For allocation of the participants following simple double-blind randomization procedures, a computer-generated list of random numbers was used. The identical capsules were prepacked in bottles and consecutively numbered according to the randomization schedule by an independent nutritionist.

Figure S1 in Supplement 1 provides a flow chart summarizing study recruitment. Ten subjects discontinued the IFN-α treatment; they did not differ from the completers in any demographic features, including gender, age, married status, education years, and past history of depression. While the noncompleters did have significantly higher baseline scores than completers in depressive symptoms (Hamilton Rating Scale for Depression [HAMD]: 8.6 ± 3.65 versus 4.5 ± 4.49; p = .018) and neurovegetative symptoms (Neurotoxicity Rating Scale [NTRS]: 52.9 ± 41.74 versus 26.9 ± 29.58; p = .010), they were equally distributed among the three groups (EPA, n = 4; DHA, n = 3; placebo, n = 3).

The subjects were randomly assigned in double-blind fashion to EPA, DHA, or placebo, administered for 2 weeks before starting IFN-α therapy. Specifically, 2 weeks before the initiation of IFN-α therapy (week –2), patients started receiving a daily treatment of five identical capsules of EPA (3.5 g/day), DHA (1.75 g/day), or placebo (high oleic oil) in single or divided administration. The experimental capsules contained concentrated EPA (700 mg), DHA (350 mg), or high oleic oil (800 mg); they weighed 1000 mg, were deodorized with orange flavor, and were supplemented with tertiary-butyl hydroquinone (.2 mg/g) and tocopherols (2 mg/g) as antioxidants. The sources of EPA, DHA, and oleic acids were, respectively, anchovy fish body oil (purchased from AK BioTech, Ulsan, Korea), algal vegetable (purchased from DSM Nutritional Products, Basel, Switzerland), and safflower oil (purchased from Aarhus Karlshamn, Hull, England).

The recruited participants were evaluated at weeks –2 (when omega-3 fatty acid prophylactic intervention started) and 0 (when the prophylactic intervention stopped and IFN-α therapy started) and during weeks 2, 4, 6, 8, 12, 16, 20, and 24 of IFN-α therapy to assess the occurrence of major depressive episode with the structured Mini-International Neuropsychiatric Interview. Sociodemographic factors, including gender, age, education, and marital status, as well as the past psychiatric history, substance use history, and family psychiatric history, were recorded at the initial assessment. Severity of depressive symptoms and of neurovegetative symptoms were measured using, respectively, the 21-item HAMD (48), rated by trained psychiatrists, and the self-administered NTRS (49), both administered at weeks –2, 0, 2, 4, 6, 8, 12, 16, 20, and 24. The NTRS is a checklist questionnaire that has been frequently used for the evaluation of neuropsychiatric symptoms related to cytokine therapy; the items are categorized into general symptoms, nonpainful somatic symptoms, and painful somatic symptoms, with each item rated from 0 to 10 on a visual analog scale, and the final score ranging 0 to 390 (15, 49, 50, 51). During IFN-α therapy, allowable concomitant medications included acetaminophen and other nonsteroidal anti-inflammatory agents for pain symptoms and fever; granisetron or ondansetron for nausea; lorazepam for severe anxiety; and zolpidem for insomnia. The results of routine biochemical laboratory examinations, the occurrence of adverse effects, and any reason for IFN-α discontinuation were recorded.

 

[MeSci]

The CDC Wichita study (one of the decent CDC studies led by Shelly Reyes) said that 30% had reported a current diagnosis of depression. Jason's Chicago study reported a current diagnosis rate of Axis 1 disorders (after a structured interview with a psychologist) of 55%, but that includes other things like sleep disorders, eating disorders etc too. Both of these studies used the Fukuda criteria on a randomly selected community based sample. The rest of the population based studies aren't of high enough quality to mention...

1. How did these findings compare to controls, or were there no controls?
2. Depression and other mental disorders are greatly overdiagnosed, and once such a diagnosis has been made, most subsequent illness reported by patients is put down to these, often incorrect, diagnoses. I think that my records still say 'panic attack' for my 2007 episode of severe hyponatraemia!

 

[Leopardtail]

The numbers in the Jason study are legit, contact him if you want more details, he is usually happy to explain things.

http://condor.depaul.edu/ljason/

Yes I am aware he's thorough but as you pointed out, he did not separate depression from sleep disturbance. I would think close to 50% of people with ME have that as a primary issue.