ME/CFS Research (Dr Amolak Bansal) and Management (Dr Charles Shepherd)

[msf]

That`s a great stance, I guess we simply have conflicting opinions on the value of anecdotal "evidence" compared to trial evidence. I agree that there are many questions regarding safety with long term treatment, but it seems to be much more important when rituximab is used with other immunosuppressives.

Or in an already immunosuppressed individual, such as those with SLE. I guess the question is, are people with ME immunosuppressed?

 

[charles shepherd]

Or in an already immunosuppressed individual, such as those with SLE. I guess the question is, are people with ME immunosuppressed?

The immunology of SLE is quite complicated >>

Systemic lupus erythematosus (SLE) is a complex immune disorder in which loss
of tolerance to nucleic acid antigens and other crossreactive antigens is
associated with the development of pathogenic autoantibodies that damage
target organs, including the skin, joints, brain and kidney. New drugs based on
modulation of the immune system are currently being developed for the
treatment of SLE. Many of these new therapies do not globally suppress the
immune system but target specific activation pathways relevant to SLE
pathogenesis. Immune modulation in SLE is complicated by differences in the
immune defects between patients and at different disease stages. Since both
deficiency and hyperactivity of the immune system can give rise to SLE, the
ultimate goal for SLE therapy is to restore homeostasis without affecting
protective immune responses to pathogens.

>>

http://www.lupusresearch.org/research/documents/davidson-targeting-of-the-immune-system-in.pdf

 

[JoanDublin]

Or in an already immunosuppressed individual, such as those with SLE. I guess the question is, are people with ME immunosuppressed?

People with SLE don't actually have a suppressed immune system. Actually it's the opposite in that it is over active and out of control, therefore it attacks healthy cells as well as the bad guys. It's probably more accurate to say it's a dysfunctional immune system. That's why the medications used are designed to suppress the immune system.

I suspect that there are some similar actions going on with M.E. in that the immune system is in overdrive. Lipkins paper last year showed a difference in cytokine producing cells in that they were in overdrive for the first three years or so but after that they appear to lead to an “exhaustion” of the cytokine-producing cells thereafter.

 

[charles shepherd]

People with SLE don't actually have a suppressed immune system. Actually it's the opposite in that it is over active and out of control, therefore it attacks healthy cells as well as the bad guys. It's probably more accurate to say it's a dysfunctional immune system. That's why the medications used are designed to suppress the immune system.

I suspect that there are some similar actions going on with M.E. in that the immune system is in overdrive. Lipkins paper last year showed a difference in cytokine producing cells in that they were in overdrive for the first three years or so but after that they appear to lead to an “exhaustion” of the cytokine-producing cells thereafter.

From the Research (Immunology) section of MEA purple booklet (2016 edition):

Table 4

Infection, immune system activation and inflammation


There is growing interest across a wide range of illnesses in the bidirectional communication between the immune system and the brain and in the role of low-level immune system activation and inflammation in disease causation.

In relation to ME/CFS, this fits in with a model of causation that involves a triggering infection which then causes the release of pro-inflammatory cytokines from activated cells in the innate immune system. This is a perfectly normal immune response to infection and results in a cluster of symptoms known as biomedical ‘sickness behaviour’. The main symptoms include fever, malaise and fatigue, muscle and joint pains, anorexia, coldness and cognitive dysfunction. Many of the characteristic symptoms of ME/CFS are consistent with immune system-activated sickness behaviour that has not been properly switched off.

Some of the immune system research that is summarised in this publication supports the hypothesis of cytokine-mediated low-level immune system activation in ME/CFS in both the blood and the cerebrospinal fluid.

Additional support for this model comes from the observation that people with hepatitis C infection who are treated with interferon alpha often develop debilitating fatigue, sleep disturbance, cognitive dysfunction and other ME/CFS-like symptoms – a finding that is now being investigated by one of the Medical Research Council funded research studies(see section 5.11).

A recent positron emission tomography neuroimaging study from Japan (Nakatomi et al 2014) is consistent with this model of disease causation. It suggests that cytokine-mediated neuroinflammation, possibly associated with activation of the microglia (resident immune system cells in the brain), may affect key structures such as the amygdala, hypothalamus, mid-brain and thalamus and play a role in symptom development. Activation of microglia can also affect neurotransmitter systems that may be involved in ME/CFS.

Additional support relating to the involvement of inflammatory mechanisms comes from studies which have demonstrated that submaximal exercise induces distinct patterns of mRNAs for nociceptive sensor proteins, ion channels and adrenergic and other receptors in peripheral blood leukocytes of ME/CFS patients but not of control patients or other groups (Light et al, 2012; White AT et al, 2012).

For a recent academic review as to how a peripheral viral infection can lead to neuro-inflammation, activation of microglia and the development of fatigue, see Yamato and Kataoka 2015.

 

[duncan]

Anorexia is a main symptom?

Sickness behavior: A perspective promoted by a vet and likely embraced by your neighborhood psych.

 

[msf]

People with SLE don't actually have a suppressed immune system. Actually it's the opposite in that it is over active and out of control, therefore it attacks healthy cells as well as the bad guys. It's probably more accurate to say it's a dysfunctional immune system. That's why the medications used are designed to suppress the immune system.

I suspect that there are some similar actions going on with M.E. in that the immune system is in overdrive. Lipkins paper last year showed a difference in cytokine producing cells in that they were in overdrive for the first three years or so but after that they appear to lead to an “exhaustion” of the cytokine-producing cells thereafter.

I knew someone would get technical on me. The term ´immunosuppression´ seems to be good enough for the authors of this paper:
http://www.ncbi.nlm.nih.gov/pubmed/24471448

 

[Scarecrow]

Anorexia is a main symptom?

Yes, if you have a 'flu like illness / malaise, you typically tend not to have an appetite.

 

[msf]

I see that they referred to immunosuppression in the context of treatment options. I was really just talking about ability to fight off bugs, as referred to in this article: http://www.lupus.org/answers/entry/am-I-at-increased-risk-for-infections

 

[charles shepherd]

Anorexia is a main symptom?

Sickness behavior: A perspective promoted by a vet and likely embraced by psychs.

I share your strong dislike of the term 'sickness behaviour' (as it does imply a psychological rather than a physical or physiological response to infection) but this is the term that is now widely used by the scientific community to describe what is a normal human (and animal) response to an acute infection

And yes, anorexia (= loss of appetite) is part of the normal human and animal response in many cases to a significant acute systemic infection

If you have ever looked after a sick animal with an acute infection you will know that loss of appetite is a very common symptom of their sickness behaviour

 

[duncan]

Some people may distinguish between hunger and appetite. I would suggest that sickness reduces hunger. We are treading unsteady ground where wording matters, precisely because of what Dr. Shepherd just wrote. Accordingly, I would suggest deep-sixing the anorexia reference, especially since in the US it is used interchangeable with anorexia nervosa, but obviously that is Dr. Shepherds call.

 

[Scarecrow]

Some people may distinguish between hunger and appetite. I would suggest that sickness reduces hunger.

Could you expand? I don't understand the distinction that you are drawing.

Accordingly, I would suggest deep-sixing the anorexia reference, especially since in the US it is used interchangeable with anorexia nervosa, but obviously that is Dr. Shepherds call.

Yes, anorexia is often used by lay people when they mean anorexia nervosa but that doesn't alter the fact that the medical definition of anorexia is loss of appetite. It's also one of the optional symptoms in the CCC.

 

[charles shepherd]

Some people may distinguish between hunger and appetite. I would suggest that sickness reduces hunger. We are treading unsteady ground where wording matters, precisely because of what Dr. Shepherd just wrote. Accordingly, I would suggest deep-sixing the anorexia reference, especially since in the US it is used interchangeable with anorexia nervosa, but obviously that is Dr. Shepherds call.

This one is getting a bit pedantic!

If a patient has a medical illness with loss of appetite (which is quite common) I will write anorexia in their medical notes

If patient is not eating adequately, losing weight, and has a psychological problem I might write anorexia nervosa (or AN?) in the medical notes

There is an important difference between the two in medical language…..

 

[Nielk]

For what its worth here is my current opinion on stress in ME and CFS, and this changes over time.

Does stress cause ME or CFS? No.

Can stress increase risk of ME or CFS? Yes.

Can stress exacerbate ME or CFS? Yes.

Is treating stress worthwhile? Maybe. Its a factor that can be treated, so if it seems a big issue for a given patient then they could consider ways of mitigating it. This can include more classic CBT, though how that method has been abused in psychogenic research contributes to our justifiable distrust of CBT claims. What we need to see for any such claims is repeatedly validated objective outcomes. I don't give a damn about subjective or highly interpretable claims. I do not want to feel I can do more. I want to be actually able to do more. However this becomes more blurred when talking about quality of life issues. If someone feels they are better off then they wont be having such a rough time ... but they might not be better off in any objective and verifiable way.

Will reducing stress cure ME or CFS? No.

Will reducing stress improve quality of life for ME or CFS patients? Yes, but with so many caveats that it might be best thought of as "maybe" rather than "yes". Too many alternatives here are overhyped or unjustifiable, but claimed to be effective because money is involved.

Is research into stress and ME or CFS a good idea? When we have an annual research budget of hundreds of millions of dollars then diverting a little into stress research is probably a good idea. For now its a waste of resources unless there is a specific physiological mechanism that is being tested, such as brain metabolites, eicosanoids, etc. Vague and imprecise research is exactly what we do not want at this current stage of research and funding.

One way to find out if stress may be a contributing factor in coming down with ME is to study a very large group of people who have gone through a common stressful/traumatic event. Follow them for years and see if prevalence in that group is higher than the "normal" population.

I don't think that this has been officially done, but if you take the group of survivors of the Holocaust, who have been stressed to the maximum for a few years, I would say that the prevalence of ME, if anything, is lower than the regular population.

I don't think that one can make any conclusions based on the fact of hearsay from some patients that their disease was preceded by a stressful event.

 

[duncan]

Sorry, @Scarecrow and @charles shepherd , the distinction is not mine. Google anorexia and appetite. You will find that the word "appetite" is more associated with behavior; hunger is the physiological response.

This is a problem, this school of thought which emphasizes behavior. I think any community at risk of being co-opted by a psych contingent needs to be vigilant and sensitive to wording.

I hope that does not come across as pedantic.

 

[Scarecrow]

Sorry, @Scarecrow and @charles shepherd , the distinction is not mine. Google anorexia and appetite. You will find that the word "appetite" is more associated with behavior; hunger is the physiological response.

I know that there is a difference between appetite and hunger. I was asking why you were drawing a distinction.

This is a problem, this school of thought which emphasizes behavior. I think any community at risk of being co-opted by a psych contingent needs to be vigilant and sensitive to wording.

Yes but it's possible to be too sensitive.

I do apologise for quoting Wikipedia but here goes:
https://en.wikipedia.org/wiki/Anorexia_(symptom)

Anorexia is the decreased sensation of appetite. While the term in non-scientific publications is often used interchangeably with anorexia nervosa, many possible causes exist for a decreased appetite, some of which may be harmless, while others indicate a serious clinical condition or pose a significant risk.

For example, anorexia of infection is part of the acute phase response (APR) to infection. The APR can be triggered by lipopolysaccharides and peptidoglycans from bacterial cell walls, bacterial DNA, double-stranded viral RNA, and viral glycoproteins, which can trigger production of a variety of proinflammatory cytokines. These can have an indirect effect on appetite by a number of means, including peripheral afferents from their sites of production in the body, by enhancing production of leptin from fat stores. Inflammatory cytokines can also signal to the central nervous system more directly by specialized transport mechanisms through the blood–brain barrier, via circumventricular organs (which are outside the barrier), or by triggering production of eicosanoids in the endothelial cells of the brain vasculature. Ultimately the control of appetite by this mechanism is thought to be mediated by the same factors normally controlling appetite, such as neurotransmitters (serotonin, dopamine, histamine, norepinephrine, corticotropin releasing factor, neuropeptide Y, and α-melanocyte-stimulating hormone).[1]

 

[duncan]

Similarly, sickness behavior encompasses all the requisite physical and organic components.

The difference is that "behavior" - instead of sickness attributes or characteristics or manifestations - opens wide the door for psychs. "Behavior" is their playground.

Same mechanism at play with using "anorexia".

So why do it?

 

[Scarecrow]

I really can't get worked up about the terms sickness behaviour or anorexia. I find them thoroughly inoffensive.

 

[duncan]

I wasn't asking you to date the terms, @Scarecrow.

I was petitioning for precision and accuracy in the face of appropriation of those and other phrases by psychs - many of whom have repeatedly demonstrated they are no friends to an organic etiology to ME/CFS.

Wording matters. We pretend otherwise at our great risk.

 

[Wolfiness]

It is interesting to note that the scientific community has long ago made up its collective mind about the weaknesses and role of anecdotes. Logic and the lessons of history speak very clearly on this issue. But there are forces at work today that want to turn back the clock on scientific progress – they want to bring back anecdotes as a reliable source of medical evidence, essentially returning to the pre-scientific era of medicine. In some cases this is done out of frustration – that controlled scientific data has not validated a prior strongly held belief. In other cases it seems to be a calculated attempt to lower the bar of evidence to admit treatments that have not been validated by solid scientific evidence. In either case, this is not in the best interest of the health of the public.

I agree with this but my experience of how 'CFS' trials are bedevilled by unacknowledged heterogenous subtypes leads me to ask: do the clinical trials that say X happens or Y doesn't acknowledge the possibility of different susceptibilities? This isn't a contention, merely a question.

So, say, when trials find that 'electromagnetic hypersensitivity' doesn't exist because sufferers respond equally to dummy devices. Have these trials determined whether there's a subgroup of people who *are* responding 'correctly' to genuine vs. dummy every time, i.e. that the trial consists of a majority of hypochondriacs and a minority of genuinely affected people? I don't believe that EMH genuinely exists, but my question is whether trials are being well constructed enough to rebut the criticism that they have tested a lot of misdiagnosed people?

 

[BurnA]

One way to find out if stress may be a contributing factor in coming down with ME is to study a very large group of people who have gone through a common stressful/traumatic event. Follow them for years and see if prevalence in that group is higher than the "normal" population.

I don't think that this has been officially done, but if you take the group of survivors of the Holocaust, who have been stressed to the maximum for a few years, I would say that the prevalence of ME, if anything, is lower than the regular population.

I don't think that one can make any conclusions based on the fact of hearsay from some patients that their disease was preceded by a stressful event.

This would be one way of doing it but just to expand on this a bit ( although i want to add i dont agree with the proposal of what i am about to say )

It would be possible that onset (if related to stress ) was down to precisely how stressed you were the days and weeks leading up to a viral infection. If this was the case a prior stressful event may not be sufficient to determine the effects of stress on onset. So what i am saying is we'd need a different study to rule it out completely!