Researcher Interactions Video: Science for ME Q&A with Dr Michael VanElzakker, Oct 2019

In this video Q&A, Andy from our forum, https://www.s4me.info/, talks to Dr Michael VanElzakker, https://twitter.com/MBVanElzakker, a neuroscience researcher of Massachusetts General Hospital and Harvard Medical School about his research into ME/CFS and related topics

His published work can be found listed here, https://www.researchgate.net/profile/Michael_Vanelzakker), and his current work can be supported here, https://because.massgeneral.org/cam...onic-fatigue-syndrome-research-at-mgh/c153689

https://www.youtube.com/watch?v=pFWKo9sqAyM

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https://youtu.be/pFWKo9sqAyM

I have added a comment on the video which has several timestamps allowing viewers to jump to sections that might be of particular interest to them.

ETA: No additional text, just changed layout of post.

 

Anyone able to summarise please??

 

I’ll need to watch again, but thank you Dr Van Elzakker for both your research and being so willing to engage with us patients. Thanks to you too @Andy for all your work on this.

eta sorry, I should have written ‘engage with the forum’ as we’re not all pwme

 

Great stuff. I think he's right that we should pull back a little and think more about the mechanisms.

 

@Sarah94 here is a partial summary, I will need to take a break before I can finish it.


3:00 Mike van Elzakker understands that the current tools will not get at the root cause of ME so is instead looking at brain correlates to ME to try to understand the mechanisms involved in driving the symptoms


5:00 The tools he is using are MRI, FMRI arterial spin labelling, magnetic spectroscopy (metabolites), diffusion tensor imaging looking at water moving along axons, PET with a tagged translator protein which proxy for neuroinflammation, and EEG.

In talks to get an EEG study but has used all of the other tools.

9:00 He is in the middle of gathering data. So the following is preliminary, n= something too small and we are not to get excited.

In the scans pwme's peripheral measures of physiology: HR, blood pressure, pulse ox, inhaled gas exchange, respiration in and out. These should correlate with the measurements in the brain and in pwme they don't correlate as well as well as they do in controls. Which suggests a problem with perfusion in the brain.

13:00 The problem with perfusion is an issue at baseline.

Pwme then do invasive cardiopulmonary test to induce PEM and then they are tested again.

This poor correlation between perfusion in the body and the brain is not worsened by the exercise.

He notes that just because something has not worsened as the symptoms worsened does not mean it cannot be the driver of symptoms.

It is possible that the failure of proper perfusion during exercise may have longer term consequences that take time to kick in.

Mentions a difference between the way PEM was used by Ramsey and the way it is used now. He thinks that there is likely to be a different mechanism between PEM caused by physical and mental exertion even if they share the same endpoint.

Note that he sees not post-PEM change in the brain only means that he sees no change with that measure, it is not the same as saying there is no change in the brain.

18:00 mechanisms

Two plausible models

The first is about IL6 which is an apex cytokine and triggers a lot of pathways.

He notes that one distinction between people who are very fit and people who are decoditioned is that deconditioned people produce more IL6 for a given level of exertion.

(He notes that he is NOT endorsing the idea that ME is deconditioning when saying this.)

After multiple infectious hits people can develop a sensitised afferent signal system for the detection of cytokines. The afferent vagus nerve serves as a diffuse system for detecting inflammation for the brain.

He thinks that a slight increase in the production of IL6 coming into contact with a sensitised system leads to glial activation (20:30)

He knows that some studies in pwme see no change in IL6. But he thinks that these sorts of experiments are difficult because you have to control for an absurd number of variables and you cannot control for the sensitivity of the system. So he does not think that the failure to find this in some experiments means that it cannot be the case.


The second plausible mechanism is to do with the problems of perfusion in the brain. The failure of perfusion will cause a low level ischaemic response which could last from days to a week. This would cause glial activation. This would lead to brainfog and sensory sensitivity. 22min

 

part 2
glutamate and glutamine

Using Magnetic resonance spectroscopy they have seen relatively increased brain levels of glutamate in PEM. These results are preliminary so he says not to run too far with them.

He explains that when activated glia produce neuroexitatory modulators including glutamate. He sees the increase in glutamate as evidence of glial activation.


24:00 there was some discussion of other research showing an increase in glutamate in peripheral blood. He says we have protective mechanisms to stop blood glutamate getting into the brain. He thinks that there is a problem with blood testing for a CNS problem. You have to be careful about making an argument about what is happening in the brain from evidence about what is happening in the blood.

27:00 Tinnitus, there are different models for tinnitus but it could come from glial activation part of the story probably related to the sensory sensitivity and he hopes to look at sensory sensitivity in an EEG study.

29:00 One of his students ? called Paulina presented a poster on cerebral vascular reactivity at Massachusetts General Hospital's clinical research day. She presented baseline data on several autonomic challenges, such as pwme holding their breaths for 30s in the scanner to cause vascular changes in the brain. Recovery and response should correlate with the peripheral measures, but the brains of pwme do not seem to (relative to controls).

31:00 He was asked about vagus nerve stimulation. He issues the usual this is not medical advice warnings. Said that he had talked to pwme who had benefited, and pwme who had not and pwme who had triggered migraines when attempting it.

33:00 He does not thing sterile inflammation is the root cause of ME, but if some of ME is overstimulation from inflammatory regulators, then stimulating the efferent motor vagus nerve (which is anti inflammatory) would work something like a pacemaker.

He thinks this would work symbiotically with mestinon and would like to do the experiment

 

"He notes that just because something has not worsened as the symptoms worsened does not mean it cannot be the driver of symptoms."

This makes sense. If perfusion is worse at base line, it doesn't need to get worse to worsen symptoms during or following exercise. The brain/body just has to tax the impaired the system more. If you have a constricted fuel line, it doesn't have to get more constricted to produce further complications when more fuel is required.

 

@richard7 thank you so much

 

I can see why he things that but decades ago I decided not to go the galantamine route.

 

Many pwme have tried mestinon to no avail.

 

One interesting bit was at the very end when Van Elzakker said he would like to see more fundamental research into possible mechanisms rather than research into ME/CFS per se.

When doctors say all possible tests are negative and don't show anything, these are usually blood tests and the blood is a whole different milieu than what is happening in the nervous system. Things could be happening there without us being able to see it.

I got the impression that Van Elzakker is more excited about developing new techniques to see what's happening in the brain/nervous system rather than yet another test of blood biomarkers in a cohort of ME/CFS patients compared to controls. I thought that was an interesting perspective.

 

That is interesting. My mental PEM comes on quickly after exertion, and resolves much quicker than physical PEM, which is always delayed by at least 14-16 hours and takes a minimum of 48hrs to get back to baseline.

 

Mestinon is pyridostigmine bromide, not galantamine, isn't it?

 

It are both Acetylcholinesterase inhibitors but not the same.

 

part 3
35:00 - 45:00

He pointed out that there is a distinction between the entity of ME and the entity of the diagnosis of ME. For example he said you could call the outbreak at the Royal Free Hospital real ME or Incline Village real ME but he does not know that the two are really the same thing. And whichever one you choose he is sure that there are people watching who do not have the same thing.

He talks about the need to filter out people with symptoms which match the criteria but have other treatable conditions. And explained that using the people defined by the criteria they found that they had too much noise in their research results, so they are now using an experienced doctor who does not rely upon the criteria but takes a thoughtful approach to looking at everything else that might be causing the symptoms.

Having said that he says that they need to both do research on people who all came down with the same trigger (say Incline Village which is being done by other people) and to study people who all came to the same endpoint (meeting ME criteria) from different starting points.

He also said that he thinks that there can be many causes, but he also talked about how pathogens work in communities and how one infection can give another the chance to act. [ I found this bit unclear]


45:00 CCI

Equifinality forest fire may be from many causes but you have the same endpoint.

Asks if people think that CCI is not real ME how many people thought that from seeing Jen Brea in the film Unrest, She saw almost all the top ME doctors in the US and she had idiosyncratic symptoms but that is normal for pwme and all the doctors thought it was ME.

He noted that Byron Hyde thought that patients with EDS were some of the worst ME effected patients. And that the real question is what is it about compression at the brain stem that causes the symptoms of ME. Brainstem nuclei to his mind really important in the inflammatory milieu communicating between inflammatory and central immune systems. He thinks that these brainstem problems can be constantly driven by pathogens, damage or compression and that they drive ME.

47 He says that trigger is less useful as a term than driver.

He thinks it less likely that a defeated pathogen will trigger a long term disregulation. And that it is better to think of something like herpes which even though it is latent and unable to act still causes ongoing cytokine transcription in peripheral ganglia, which will not be detectable in DNA or RNA in peripheral blood.

49 At the moment they can only use the presence of absence of the translator protein to tell if the glia are activated or not. But they know that there are at least 19 different activation states for glia.

They see glia active in many conditions (such as brain injury huntingtons, parkinsons and suicidality) so that they can see activated glia has little discriminatory value. He mentioned that one activation phenotype with high glutamate leads to grand mal seizures and we don't have that so we are presumably a distinct activation phenotype.

Notes that a problem is that most of the research is done in mouse models and mice have much simpler glia.

 

part 4 and the end

52:00 In NIH funded autism research each research subject has a unique anonymous ID and each time that research subject takes part in research the data is uploaded and and shared in between research groups in a relatively raw state and people can get an understanding of how these research subjects over time. He thinks that it is important use something like this to study how pwme change over time.

Need more money for basic research on mechanisms.

The best research we have for neuronimflammation is Nakatomi 2014 in which with the 11C-(R)-PK11195 radio ligand they found elevated translocator protein. What does the translocator protein do? we don't know. Its active during microglia activation, but there are 19 activation states so which one(s)

He thinks activists need to focus on increasing total NIH funding rather than increasing their slice of the a tiny pie. He thinks that a healthy society should be spending a lot more research.

Thinks that NIH does not get enough funding, and kind of believes NIH when they say that they do not get enough good applications. We should ought not be in a scarcity mentality when studying these chronic illness

57:00 People have no idea how poorly mechanisms are understood. If you put running wheel into a rodent's cage it will run for miles and miles. It is unnatural for them to be sedentary and 90-95% of research is done on artificially sedentary rodents and we don't know what effect that has. So we may be missing a huge amount of how these things work in normal situations.

So the tools researchers use to measure patients are not up to task. He is going to do another cytokine study and see that the results for pwme are abnormal and have no idea what it means.

There is a massive need for basic research.

 

I understand why he wants to pull back and look at basic mechanisms, but that is seriously hard to hear for someone who has been sick for decades. Basic mechanisms will be very valuable in the general scientific understanding of the body, but they won’t lead to any help in my lifetime.

 

I feel the same about younger people, @Trish - especially my daughter and grandsons. I just wanted so many to know that we were moving in the right direction before I wasn’t around any more. I’m 3 weeks away from 70 myself. Did it seem to anyone else that he was very dubious about Dr Davis’ approach?

 

I think it's a valid argument in that whatever the explanation is for ME, it is clearly beyond our current scientific understanding as we would otherwise have gotten something tangible.

The fact that we are completely abandoned meanwhile is a different issue altogether and frankly has little to do with research, it is a choice made by institutions involved in medical care and training, a choice made broadly by the medical industry and profession on the frontline, not in labs. It is justified by a lack of convincing research, but that's nothing but a cheap cop-out.

The NIH could definitely do something about it but it is not their rightful responsibility, the CDC bears more and even more for health departments. More than anything, it is having allowed blatant pseudoscience to take hold in the first place that is to blame. The CBT-GET paradigm carries little weight in research, it does not even have a formal testable hypothesis, it does not even qualify as a valid scientific concept. All the weight is carried in clinical practice and deciding to promote a harmful treatment is not guided by research, in favor or against. Here, it is pure ideology, a whole other class of problems that medicine keeps making.

Still disappointing, but I agree that fundamental research is more likely to figure this out eventually.