Invest in ME/Prof Jonathan Edwards statement on UK Rituximab trial, 30 July

[Sasha]

@Jonathan Edwards - I wondered if you had come across the possibility that POTS (which so many of us have) could be an autoimmune issue and whether you thought that the possible effects of rituximab in ME/CFS might be related to that. I just came across these studies on a blog today:

http://www.cortjohnson.org/blog/201...erance-implications-chronic-fatigue-syndrome/

 

[Jonathan Edwards]

@Jonathan Edwards - I wondered if you had come across the possibility that POTS (which so many of us have) could be an autoimmune issue and whether you thought that the possible effects of rituximab in ME/CFS might be related to that. I just came across these studies on a blog today:

http://www.cortjohnson.org/blog/201...erance-implications-chronic-fatigue-syndrome/

I think we mentioned this study before. I would like to see the results repeated by another team. I was a bit puzzled by the immunofluorescent results I seem to remember. My intuition is that in ME an autoimmune response would be to something less specifically related to cardiovascular responses. I would caution against the idea that bits of evidence for something being autoimmune always 'add up'. If there is autoimmunity to one target then it is probably less likely that there autoimmunity to another target. If it was Colonel Mustard in the Library it probably wasn't Professor Plum in the Conservatory as well, if you see what I mean!

 

[sproggle]

Huge raising of awareness for ME and Invest in ME/UCL's rituximab clinical trial project

"We are aiming to visit all 92 English Football League Stadiums in under 92 hours in support of Invest in ME (www.investinme.org) and to raise money and awareness for the Rituximab Trial (www.ukrituximabtrial.org) The event begins on April 16th 2014, if you would like to sponsor us see tabs on the right, thanks for visiting. Follow us on Facebook: www.facebook.com/92forME and Twitter @92forME"

https://twitter.com/92forme
http://www.justgiving.com/teams/strobl

Currently Day 4 of 6 days

 

[Legendrew]

@Jonathan Edwards

I, and I'm sure many others, would be very interested to hear you take on a recent paper regarding the potential findings of low-level encephalitis in ME/CFS patients relative to controls (assuming of course you haven't already commented on it previously). This study was only 9 patients and 10 controls meaning it obviously needs replication, although it throws up some very interesting results. It will certainly be interesting to see how it could connect with the research into autoimmunity and ME/CFS.

http://www.ncbi.nlm.nih.gov/pubmed/24665088

(The recent Phoenix Rising article here brought this to my attention)

 

[Jonathan Edwards]

@Jonathan Edwards

I, and I'm sure many others, would be very interested to hear you take on a recent paper regarding the potential findings of low-level encephalitis in ME/CFS patients relative to controls (assuming of course you haven't already commented on it previously).

Thanks Andrew,
I don't seem to be able to get the full text yet. The abstract seems to show a difference that could be clinically relevant but there are no statistics (which worries me a bit). It could be an interesting finding. I think I will need to have another look when the full paper is available through the College Library system.

 

[Kati]

Thanks Andrew,
I don't seem to be able to get the full text yet. The abstract seems to show a difference that could be clinically relevant but there are no statistics (which worries me a bit). It could be an interesting finding. I think I will need to have another look when the full paper is available through the College Library system.

@Jonathan Edwards i have sent you a message, check your inbox.

 

[Snow Leopard]

I too am curious to hear Jonathan's thoughts on that paper. (Nakatomi et al.)

Update, I'm good thanks re: access to the paper.

 

[Firestormm]

I don't have access to that one either. But I too am curious to hear Jonathan's thoughts on that paper. (Nakatomi et al.)

Oh I have it. Don't bloody understand much of it - but I have it

@Jonathan Edwards if you would like a copy I can send you it

 

[Jonathan Edwards]

Thanks to all, I have the full text of the brain imaging paper and have had a look at it.

I have to say that, as for a lot of these studies, I am a bit puzzled by the results. I am also not very impressed by the introductory and concluding remarks. The authors talk of 'neuroinflammation'. To my mind a serious biomedical scientist or pathologist is not going to talk of 'neuroinflammation', which sounds to me like a lay-term concoction made to sound scientific. I would be interested in microglial activation or increased capillary permeability or cellular infiltration - all of which come under the general heading of inflammation - but I have never heard of some specific entity called 'neuroinflammation' and I am pretty sure it is a pseudo-idea.

The key point is that inflammation is a general term for a whole cluster of processes that has become rather old fashioned now that we know about the processes themselves. And if one of the processes occurs without the others that is not a 'sign of inflammation' so much as one of the processes without the others. So if this was full blown inflammation it could be picked up on ordinary MRI scans, or CT, and in fact it would be likely to produce specific clinical signs. If the thalamus is really inflamed you are usually unconscious or something pretty close to it. The authors talk as if neuroinflammation was something you get in multiple sclerosis and Parkinson's disease as well but I don't think there is any reason to think anything comparable is going on in the three conditions. It sounds to me like very muddled thinking.

Another point is that the hot spot on the scan in the ME case is very similar to the hot spot in the normal case but just a bit bigger. A normal brain should have no 'inflammation hot spot'. So it looks as if the authors are measuring something that you get in normal people to some degree and a bit more in ME. That would be interesting, but not inflammation. Moreover, the hot spot does not really look like an inflammatory response. It is the wrong shape. If you see a black object on the lawn you may think it is a crow, but if you then see it has four legs you change your mind. If this is an inflammation crow it looks to me like to have four legs.

And lastly, the authors give some very tight correlation patterns between scan readings in specific areas and symptoms but do not give a whole set of data - they just seem to have chosen the data that correlates well. That is the first mistake to make in statistical handling of data - to pick out the good bits and forget the rest. I would also like to see much more raw data in scatter plots so that one could see the real results rather than some predigested interpretation.

As for all these studies I am prepared to believe that I have underestimated, but there are certain issues here that make me reserve judgement. If this sort of detail does not look right then one always wonders about the main finding. The main finding of brighter hot spots in ME patients might indicate some change in brain function giving an important clue to what is going on, but calling it 'neuroinflammation' does not help and whatever it is normal people have about half the same thing going on.

 

[Marco]

Thanks to all, I have the full text of the brain imaging paper and have had a look at it.

I have to say that, as for a lot of these studies, I am a bit puzzled by the results. I am also not very impressed by the introductory and concluding remarks. The authors talk of 'neuroinflammation'. To my mind a serious biomedical scientist or pathologist is not going to talk of 'neuroinflammation', which sounds to me like a lay-term concoction made to sound scientific. I would be interested in microglial activation or increased capillary permeability or cellular infiltration - all of which come under the general heading of inflammation - but I have never heard of some specific entity called 'neuroinflammation' and I am pretty sure it is a pseudo-idea.

The main finding of brighter hot spots in ME patients might indicate some change in brain function giving an important clue to what is going on, but calling it 'neuroinflammation' does not help and whatever it is normal people have about half the same thing going on.

Dear Prof Edwards

A candid assessment of this paper is welcome given that there's an unfortunate tendency (I'm probably more guilty than most) to jump on often preliminary findings particularly when they appear to provide some validation/confirmation bias.

Having said that there are a number of fairly high impact journals that might take exception to the description of neuroinflammation as a 'pseudo-idea'.

For example (to name a few):

Journal of Neuroinflammation

http://www.springer.com/biomed/neuroscience/journal/12974

"According to the Journal Citation Reports, the journal has a 2012 impact factor of 4.351, ranking it 59th out of 252 journals in the category "Neurosciences".[1]"

Neuroimmunology and Neuroinflammation

http://www.nnjournal.net/

and one just launched :

Neurology: Neuroimmunology & Neuroinflammation

As for normal people having the same thing going on, in addition to glial cell 'neuronal scaffolding' functions and their ongoing CNS immune functions in sampling for/responding to 'PAMPS, DAMPS/alarmins' it appears that CNS glia also play an ongoing role in neuronal apoptosis/pruning. As a mere punter it does sound to me that no CNS glial activity might be a 'bad thing'.

Methodological, interpretational and presentational issues are fair game but I'm not convinced that the concept of 'neuroinflammation' is now controversial.

 

[Marco]

Sorry if the above sounded over-critical - it wasn't meant to.

I think it fair to say, from what I've read on the subject, that 'neuroinflammation' has become a blanket term relating to CNS immune responses perhaps to distinguish this broad area from peripheral inflammatory processes or neuropathy. But CNS immune response may be many and varied, pathological or protective and to refer to 'neuroinflammation' as a 'pathology' ignores this context.

So if 'neuroinflammation' is confirmed in ME/CFS it would only be the first step in specifying the exact processes involved including determining whether it plays a significant role in the pathophysiology of the condition, is a downstream artifact of some other process or may indeed be an appropriate and protective response.

So yes I have to agree that the term lacks specificity.

 

[bambi]

I agree with Prof. Edwards that this study lacks quality and significance.

Additionally, neuro-inflammation is unspecific and associated with microbes, viruses, autoimmunity, neuro-generative disease, brain trauma, mental diseases ect. - it is unspecific and will not help us in any way.

Furthermore, I would like to draw your attention to previous studies done by the same author's. It say's a lot about their intent and quality of research in general. In my not so humble opinion you can throw this paper in the rubbish pin.

For example,

Abstract
Neurocognitive impairment is a feature of childhood chronic fatigue syndrome (CCFS). Several studies have demonstrated reduced attention control in CCFS patients in switching and divided attention tasks. In students, the extent of deterioration in task performance depends on the level of fatigue. Poor performance in switching and divided attention is common in both fatigued students and CCFS patients. Additionally, attentional functions show dramatic development from childhood to adolescence, suggesting that abnormal development of switching and divided attention may be induced by chronic fatigue. The brain structures associated with attentional control are situated in the frontal and parietal cortices, which are the last to mature, suggesting that severe fatigue in CCFS patients and students may inhibit normal structural and functional development in these regions. A combination of treatment with cognitive behavioral therapy and antidepressant medication is effective to improve attentional control processing in CCFS patients. Studies identifying the features of neurocognitive impairment in CCFS have improved our current understanding of the neurophysiological mechanisms of CCFS.

Abstract
OBJECTIVES:
Cognitive function was investigated in patients with childhood type chronic fatigue syndrome (CCFS) using the modified advanced trail making test (mATMT).

METHODS:
mATMT was performed on 19 patients with CCFS and 25 healthy controls of comparable age and sex. The effectiveness of combined treatment with cognitive behavioral therapy (CBT) and pharmacotherapy and its relationship to cognitive function was investigated by evaluation of Chalder's fatigue scale and behavior state before and after treatment for 6 consecutive months.

RESULTS:
All three tasks (motor skill, selective and alternative attention, and spatial working memory) of the mATMT, especially the difference in reaction time of the alternative attention task, could discriminate CCFS patients from control subjects with 70.5% accuracy (P=0.007). CCFS patients showed significantly lower alternative attention and Chalder's fatigue score before treatment (P=0.037 and 0.002, respectively). A significant improvement in performance status scores was found during the 6 months follow-up period with combined treatment with CBT and medication (P<0.001). Improvement of their cognitive symptoms was significantly correlated with improvement of alternative attention (r=0.653, P=0.002).

CONCLUSIONS:
Higher-order level cognitive dysfunction affects CCFS pathogenesis. Alternative attention performance evaluated by the mATMT may be used to monitor improvement in patients with CCFS. Combined treatment with CBT and medication may be effective to improve poor attention characteristics associated with CCFS.

Abstract
AIMS:
Tyrosine hydroxylase (TH) and GTP cyclohydrolase I (GCH) are the rate-limiting enzymes for the biosynthesis of catecholamines and tetrahydrobiopterin (BH4), respectively. Since catecholamines and BH4 are thought to be involved in the pathophysiology of CFS, we explored the genetic factors that influence CFS development and examined the possible association between the SNPs of the TH and GCH genes and the various characteristics of CFS patients.

MAIN METHODS:
After drawing venous blood from CFS patients and controls, genomic DNA was then extracted from whole blood in accordance with standard procedures. Digestion patterns of the PCR products were used for genotyping the SNPs of GCH (rs841; C+243T) and TH (rs10770141; C-824T). We also performed questionnaires consisting of fatigue-scale and temperament and character inventory scale (TCI) to CFS patients.

KEY FINDINGS:
Our results demonstrated that the allele differences for the GCH and TH SNPs were not associated with CFS patients. We did find that the GCH gene with the C+243T polymorphism affected harm avoidance, while the TH gene with the C-824T polymorphism affected persistence in the CFS patients. The concept of persistence has been linked to specific personality, such as perfectionism, in CFS.

SIGNIFICANCE:
Our results suggest that the biosynthetic pathways of the monoamine neurotransmitters that are mediated by TH and GCH might be associated with the CFS clinical findings, because persistence is one of the typical personality traits observed in CFS and patients with major depressive disorder exhibit a higher harm avoidance score.

 

[Marco]

I agree with Prof. Edwards that this study lacks quality and significance.

Additionally, neuro-inflammation is unspecific and associated with microbes, viruses, autoimmunity, neuro-generative disease, brain trauma, mental diseases ect. - it is unspecific and will not help us in any way.

Given that the syndrome is defined by a collection of non-specific symptoms and is in all likelihood heterogenous and without doubt with multiple triggers, isn't this exactly the sort of mechanism we should be looking for rather than 'X' virus or autoimmunity for example as the cause in all patients? The search for specific biomarkers or 'the' cause hasn't exactly yielded much in several decades.

Furthermore, I would like to draw your attention to previous studies done by the same author's. It say's a lot about their intent and quality of research in general. In my not so humble opinion you can throw this paper in the rubbish pin.

For example,

Somewhat of a selective sample. They've covered a lot of ground including a very large study which ties in nicely with the concept of neuroinflammation which I discussed in some detail here :

http://www.cortjohnson.org/blog/201...deficits-present-in-chronic-fatigue-syndrome/

The ME/CFS as a developmental disorder paper (a speculative but plausible enough explanation as it goes) wasn't their finest hour in my opinion with several flaws including small sample size and they refer to patients with a 'hypo-responsive' CNS whereas their previous studies (as per the link above) had identified two distinct sub-groups 'hypo' and 'hyper' responsive which appear to be absent from their model and discussions. As for any efficacy of antidepressants any conclusions are confounded by the fact that several of the small cohort were simultaneously taking meds that target the autonomic nervous system plus of course antidepressants are now known to act (possibly predominantly) as anti-inflammatory. As for CBT, too many researchers outside the field are happy to accept the claimed benefits at face value.

Here's a more complete listing or prior publications by one of the authors (Kuratsune) which gives more of a feel for the scope of their studies :

http://www.researchgate.net/profile/Hirohiko_Kuratsune/publications

 

[bambi]

I have to add a thought in defense of this team in Japan.

In order to understand what this team from Japan most likely is researching, you have to understand the social framework of Japan. Japanese kids and young adults are under enormous social pressure to succeed in school and university to get a good degree and good well paid jobs. The result is that most kids and young adults in Japan study horrendous hours.( A brain which is studying 16 hours a day and is constantly stressed to preform well is most likely inflamed) This social pressure to succeed is deeply rooted in Japanese culture and hard to understand if one has not lived it. The result is that a large number of kids and young adults suffer from chronic stress induced depression. The suicide rate among kids and young adults in Japan is the highest in the world.

Japan’s suicide rate is notoriously high. For the past decade it’s been above 30,000 a year. Overwhelmingly, suicide is an adult phenomenon—but not exclusively, and the clinical depression that generally underlies it, Shukan Asahi finds, is steadily trickling down the age scale. Hokkaido University professor Kenzo Denda, author of a book on children’s depression, has published research showing that one elementary school child in 12 suffers from the condition. Among junior high school students the rate is one in four.
http://www.japantoday.com/category/...ns-depression-and-suicide-a-worsening-problem

Read the comments to this article!

It is most likely that the term CFS in Japan is researched in this context and has very little to do with ME.

Another example how the broad term and diagnosis CFS can be misunderstood - or misused ……

 

[Marco]

I have to add a thought in defense of this team in Japan.

In order to understand what this team from Japan most likely is researching, you have to understand the social framework of Japan. Japanese kids and young adults are under enormous social pressure to succeed in school and university to get a good degree and good well paid jobs. The result is that most kids and young adults in Japan study horrendous hours.( A brain which is studying 16 hours a day and is constantly stressed to preform well is most likely inflamed) This social pressure to succeed is deeply rooted in Japanese culture and hard to understand if one has not lived it. The result is that a large number of kids and young adults suffer from chronic stress induced depression. The suicide rate among kids and young adults in Japan is the highest in the world.



Read the comments to this article!

It is most likely that the term CFS in Japan is researched in this context and has very little to do with ME.

Another example how the broad term and diagnosis CFS can be misunderstood - or misused ……

You may have a point there. I've noticed that the incidence rates of 'childhood CFS' reported in Japanese studies tend to be surprisingly high plus they also appear to find an approximately 50/50 gender split which might be interesting in itself but doesn't appear to be reported elsewhere.

On the other hand I believe the neuroinflammation study used both Fukuda and ICC to select the cohort which is as good as it gets at present.

 

[Kati]

I think it would be naive to think that ME does not occur outside of north America or Europe. It does.

Regarding neuroinflammation vs glial activation, how do you prove glial activation and could Dr Watannabe use the term?

Various reasons could make it impossible:
- editors restriction
- unproven assumtion

i am not entirely sure, but could it be that glial activation can only be measured in post mortem?

 

[Jonathan Edwards]

Dear Kati,
If you cannot be sure there is glial activation you certainly cannot be sure there is neuroinflammation if the evidence for neuroinflammation is glial activation!!

ME may be a heterogeneous rag-bag but it is not going to be much use finding it is associated with a heterogeneous rag-bag phenomenon like inflammation that you find in a whole host of diseases with unrelated symptoms. We need to find clearly defined biological pathways, like glial activation, or a rise in a particular cytokine that are associated with at least a subset of patients and try to identify the causal link. This study may do just that, but it would be helpful to present it in specific terms. Twenty years ago nobody would have written a paper about an association with a rag-bag idea. This is a trend that has grown up with rag-bag journals that publish for profit.

 

[Kati]

Thank you @Jonathan Edwards indeed, narrowing down subsets, and separating ME patients from Lyme, mold and toxic exposure, slow onset vs viral onset. Then you have a group of patients with ME who will, years later go on to have one or more auto-immune/ rheum condition such as RA, Sjogren's or SLE.

i don't think we're there yet and moreover, ME cohorts are being mixed with patients with idiopathic fatigue and depression and even PTSD in Veterans.

There is so much work that needs done, and so little funds and just a handful of poorly supported experts around the world, with little to no funding to conduct proper research.

 

[Snow Leopard]

My major criticism of the above study is that it is not specific with regards to depression, in fact they found a correlation with respect to reported depressive symptoms and the patterns they found.

 

[Kati]

My major criticism of the above study is that it is not specific with regards to depression, in fact they found a correlation with respect to reported depressive symptoms and the patterns they found.

But depression is totally expected, and healthy, isn't it? We have inflammed brains. We are sick. We are living with grief and loss and constant fights with the health care system, disability insurance and the rest of it. What do you expect, this is normal!

Lupus patients have psychiatric presentations. I bet that rheumatology patients experience depression- living with constant pain is horrible for the brain.