Post-exertional malaise in ME/CFS | Medical Research Council announces new neuroimaging research | 16 October 2015

Our medical adviser, Dr Charles Shepherd, comments on post-exertional malaise (PEM) and the new Medical Research Council (MRC)-funded neuroimaging study that was announced at the Research Collaborative Conference in Newcastle on Tuesday October 13.


WHAT IS PEM?


Post-exertional malaise (PEM), or post-exertional symptom exacerbation, describes a delayed and significant exacerbation of ME/CFS symptoms that always follows physical activity and often follows cognitive activity.

PEM is a highly characteristic clinical and diagnostic feature of ME/CFS.

In some respects, PEM is an illness within an illness.


WHAT CAUSES PEM?


The cause of PEM remains uncertain. However, clues are starting to emerge. So gaining a better understanding of the underlying pathophysiological mechanisms involved could help to improve at least one aspect of ME/CFS management.


EXISTING RESEARCH INTO PEM


The MEA regards PEM as a research priority. Consequently, the MEA Ramsay Research Fund been funding two research studies in this area:

1 Professor Jo Nijs et al in Brussels have been looking at the role of autonomic dysfunction in PEM, in particular the parasympathetic response to exercise. Professor Nijs presented some of the unpublished results to this study during the plenary session on autonomic nervous system dysfunction at the Research Collaborative Conference. The autonomic nervous system – which is not under conscious control, hence the name – has its control centres in the brain. Through a network of sympathetic and parasympathetic nerves, it passes messages to heart, blood vessels, bowel and bladder to regulate (by speeding up or slowing down) a wide range of body functions.

2 Dr Amolak Bansal et al at St Helier Hospital, Surrey have been looking at what happens to immune function before and after a cognitive challenge (completed) and an exercise challenge (not yet done).

So we already have some clues from these and other studies to indicate that the immune system and autonomic nervous system are involved in PEM.


THE MISSING LINK?


But what might be happening elsewhere in the brain?

There is a growing consensus that ME/CFS may be an illness that is triggered by infection, which then causes the release of cytokines – immune system chemicals that produce flu like feelings, pain and malaise following any infection. This normal acute immune system response, which is unfortunately known as sickness behaviour/response, then continues in the form of low level immune system activity, continued cytokine production, and activation of immune cells in the brain called microglia. This is a model of causation involving on-going low-level neuroinflammation which is supported by a recent Japanese PET neuroimaging study by Nakatomi et al:

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

And, if there is already low-level immune system activation, linked to activation of the microglia/low level neuroinflammation, could an exercise challenge with cytokine production, exacerbate the existing microglial activation and cause an increase in symptoms?

From a theoretical point of view, exercise can stimulate cytokine production (ie IL1, IL6 and TNF) and people with ME/CFS show an exaggerated immune response to exercise:

www.medizin.uni-tuebingen.de/transfusionsmedizin/institut/eir/content/2014/94/article.pdf

So, in theory, the answer is yes…..


THE NEW RESEARCH


What has not been done so far in the investigation of PEM is to look at what happens to brain networks before and after an exercise challenge in ME/CFS – which is where this new study fits in.

Three scientists – Dr Mark Edwards, a neurologist at the Motor Neurosciences and Movement Disorders Unit, UCL Institute of Neurology, Dr Neil Harrison from the University of Sussex and Dr James Kilner at University College London – will be carrying out this study.

Dr Harrison has already shown how acute inflammatory and infective challenges can cause activation in parts of the brain (e.g. following vaccination with typhoid vaccine: www.nature.com/npp/journal/v40/n4/full/npp2014222a.html or during interferon treatment for hepatitis.

Twenty people with ME/CFS and 20 age- and sex- matched controls will have a baseline functional MRI scan and blood samples taken (for immune system activation measurements).

They will then have specialised exercise to induce PEM.

There will also be a fairly difficult cognitive challenge using what is known as the Stroop test.

The scans and blood tests will be repeated 24 hours later.

In relation to the fMRI scans, these will look in particular for evidence of activation in key brain structures such as the dorsal insula.

Overall, I believe this is a very sound and welcome piece of research that should help to increase our understanding of what is happening in the brain in PEM.

Thanks are due to Professor Hugh Perry, a member of the Research Collaborative Board and Chair of the Neurosciences Board at the MRC, for his determination to see high quality research into the neuropathology of ME/CFS taking place.


TRANSCRIPT OF THE PRESENTATION FROM DR EDWARDS, PREPARED BY RUSSELL FLEMING, CAN BE FOUND HERE



COMMENTS BY PROFESSOR JONATHAN EDWARDS ON THE PHOENIX RISING WEB FORUM


Now we know what we are talking about. It looks brilliant to me. Neil is superb and he clearly has a big input. It is all about inflammatory and neural pathways and specifically about PEM so all that stuff about Oxford criteria can go in the bin. Presumably they will even correlate findings with the degree of PEM. This is proper science. They have even thought of the confounding problems of what people will be thinking because they are in an experiment – and will control for that be switching around the order of events.

I think this is a seriously important move forward in the science. The right people are focusing in on the most likely place to find some clues. And the cytokines and things will be measured as well it sounds like. It fits with the point made on both sides of the Atlantic that we should be studying people during PEM and looking at the abnormal response to exercise rather than just looking at PWME at any old time.

With this and the people connecting to David Brooks repeating the Japanese PET study I think there is the best chance yet of actually pinning down what is going wrong in the ME brain.

I think this is a seriously important move forward in the science. The right people are focusing in on the most likely place to find some clues. And the cytokines and things will be measured as well it sounds like. It fits with the point made on both sides of the Atlantic that we should be studying people during PEM and looking at the abnormal response to exercise rather than just looking at PWME at any old time.

With this and the people connecting to David Brooks repeating the Japanese PET study I think there is the best chance yet of actually pinning down what is going wrong in the ME brain.

And there is no suggestion that this is money pinched from the ME pot. Edwards and Harrison got this grant through the open application system. There was no special pleading, no internal politics. It would have gone up against applications for MS or Alzheimer’s or whatever. ME has actually become a fashionable disease to study I suspect. I would double the £600,000 personally.

Full discussion here: http://forums.phoenixrising.me/index.php?threads%2Fuk-research-collaborative-conference-in-newcastle-13th-14th-october.36515%2Fpage-19#post-651365

Dr Charles Shepherd
Hon Medical Adviser, ME Association
Board member, UK CFS/ME Research Collaborative
16 October 2015

PS The MEA funded 4 medical students to attend the RC conference. We also helped to fund the cost of bringing two overseas speakers – Øystein Fluge and Jo Nijs – to the conference.