Could nerve damage or retrograde microtubule based transport in axons explain the delay associated with PEM?

I made a few comments about this kind of idea on this thread, but I wanted to explore the idea a little more and see what others thought - you can perhaps tell me if it's unlikely then why.

The reasoning is the delay often reported with PEM lines up quite well with the timings associated with the transport of proteins along the axons of neurons, to and from nerve endings, sites of injury and the cell body.

It also lines up well with a delay associated with nerve damage, from the actual time of damage to the neuron losing electrical properties and degradation of the axon.

 

This paper:

Axonal transcription factors signal retrogradely in lesioned peripheral nerve - Ben-Yaakov et al 2012

describes a signaling axis involving the phosphorylation of the transcription factor STAT3 at the site of nerve injury (sciatic nerve crush), which is then transported retrograde from the site of injury to the nucleus of DRG neurons using the dynein/microtubule machinery. There is a delay from the time of injury, to the transcription factor appearing in cell bodies at the DRG that is dependent on the distance the nerve crush injury is from the cell body. At 4cm away it takes ~6 hours, 5cm away takes 8 hours. STAT3 supposedly has roles in promoting cell survival, axon growth, maybe IL-6 production etc. It seems that this kind of injury mechanism is applicable also to motor neurons and maybe other neuron types.

In this paper:

Voluntary exercise increases axonal regeneration from sensory neurons - Molteni et al 2004

they describe that exercise in a rodent model leads to increased neurite growth in DRG neurons taken from the mice and grown in culture. It appears this growth happens irrespective of transcription, but there are also transcriptional changes and I wonder if these exercise associated transcriptional changes might be mediated in a similar kind of way (with a similar kind of delay).

 

There appears to be a process called Wallerian(-like) degeneration of nerves which also follows a similar time delay pattern. After nerve damage (eg crush), the neurons can retain electrical activity for (according to wikipedia) 24-36 before the axon degenerates and macrophages infiltrate the tissue to start clearing debris. I'm not sure why there is this delay, maybe it also involves accumulation of proteins normally being transported along the axon at the site of injury.

Perhaps this injury repair mechanism also applies at the most distal ends of the nerves close to or including eg NMJs. A period of nerve ending damage followed after a delay by weakness and macrophage activity, followed by a gradual process of repair and reinnervation, that could maybe explain why nerve staining patterns may look odd as in Wuest's study.

Also possibly relevant that acute nerve damage can take highly variable amounts of time to heal eg 3-6 months or longer - possibly relevant to the duration of typical recovery from post viral fatigue? I've been openly speculating and handwaving for parts of this but wanted to get the thoughts out.

 

Are you proposing this theory to explain PEM? Or ME/CFS? How would it explain PEM lasting 3-4 days and then returning to the baseline? Nerve damages take longer to recover, I would think. If you mean the damage triggers ME/CFS, how would it explain ME/CFS lasting decades? And how would peripheral nerve damage explain the symptoms of ME/CFS?

 

I think the proposal is more the timing of initiation of PEM after an action which triggers it and then some recovery time if there is no subsequent triggering event?

The reference to damage may or may not be directly relevant but gives examples of these timings. I wonder if there could be experiments triggering PEM using muscles linked to nerves of differing lengths?

 

I think this hypothesis would fail due to lack of evidence of delay correlating with distance from the muscles that were exerted. AFAIK, most PWME report fairly consistent delays, while the nerve damage hypothesis would involve a wide range of delays.

 

Would nerves get damaged? Genuine question, I've no idea.

Major muscles suffer attrition all the time in healthy active people, but they're built for it and recover very quickly.

Is there a phenomenon like that in nerves, as opposed to the familiar compression injuries that cause symptoms like numbness, pain and tingling?

 

Yes exactly that's the thinking here.

I can't give good answers to these fair questions I'm afraid I can only speculate. I don't know of course whether the smaller PEM events like over a few days and the disastrous huge relapses type PEM are just degrees of the same phenomenon or not. For me PEM is something I might recover from if I get lucky but I never count on it. Maybe it's just a question of degrees of damage/ whatever the effect is.
3) Maybe more lasting damage/effect to sensory nerves involving nociception, or some ongoing immune system interaction with nerve endings in peripheral tissue that get kicked up when you exercise. 4) If NMJs are affected maybe a feeling of weakness. Sensory nerves are affected maybe misreporting of muscle usage leading to malaise. autonomic problems from autonomic ganglia or nerve endings.

Maybe, but I'm not sure this bit is too problematic. PEM time delay for me personally is not consistent but might be for others. If exercise in ME mainly affects neurons at or close to their terminals in muscle for instance then the distance would always be the same. If it involves damage then the delay could be similar wherever it happens if it depends on the accumulation of certain proteins at that site, that would otherwise always be passing through.

Yep, I don't know either! There's no obvious neurodegenerative clinical phenotype of course. I don't know also whether if something like that was happening there would be really obvious signs detectable in the blood for instance - but then if it only happens during PEM it could be easy to miss?

 

I personally doubt that PEM can relate to nerve damage with retrograde degeneration. People with ME/CFS would have abnormal neurophysiology findings and they don't. If signals can alter nerve responsiveness at the DRG I don't really see any need for anything to travel up or down an axon. The afferent end can also be locally sensitised in the tissue it supplies.

 

Fair enough but I'm not suggesting there's retrograde degeneration, but a delay between an event such as damage at the neuron terminals and a phenotype occuring possibly mediated by this retrograde movement. You might be right about sensitisation at the DRG but does it necessarily need to happen like that? The two clues from acetylcholinesterase with GWS and nerve staining from Wuest could be completely wrong, but could be suggestive of damage at the synapses.

 

The answer to the general question of nerve sensitisation post-damage, either the nerve endings or in the DRG is yes and it doesn't require nerve crush like the cheap and dirty animal models you see published (the 'damage' stimulus can be milder). I am trying to write about this right now. This is one of the few pathological phenomena that precisely matches PEM kinetics and there are specific sensisation mechanisms that I have in mind.

I have no idea about 'retrograde microtubule based transport' specifically though.

Diseases that cause peripheral neuopathy also cause ME/CFS-like syndromes including PEM and brain fog specifically and I feel this begs the question...

 

"No abnormal neurophysiological findings"

I'm not sure that's correct. The fact that neurophysiological findings or symptoms aren't part of the diagnostic criteria doesn't mean they don't exist.

And there would be much more to report than these findings, if my neurophysiological abnormalities were the 'norm', and I think they could be for at least a subgroup.

 

It isn't a matter of diagnostic criteria. If there were significant neurophysiological abnormalities then it is reasonably certain that somebody would have reported them in the literature. People with fibromyalgia are said to have small fibre neuropathy but even there I don't think electrophysiology shows anything very substantial because the diagnosis relies on biopsy.

 

I just posted an abstract showing that half of all ME/CFS patients can’t walk a straight line without losing their equilibrium. Is that not a neurophysiological finding? I was one of those patients before I lost the ability to walk and even sit. I have/show many other abnormalities.

I think you might be underestimating how extremely biased neurologists are.

I vividly remember neurologists telling me I was “not this or that, some things are definitely off, but,..." meaning they couldn’t categorize me within any existing diagnosis — of course, that's because they simply ignore ME/CFS. So, it is about diagnosfic criteria, because that's what matters most to the neurologist, they need to put you in a box. If there is no box then you and your neurophysiological findings are lost.

 

Perhaps more likely to be temporary, though if there was more permanent damage to types of sensory neurons that don't directly lead to an obvious loss of touch sensation would that really be detectable with neurophysiology techniques? I don't know the extent of what's possible with these techniques, though I get the impression from the discussion here and the other thread that if there was a sensitisation of DRG neurons then these techniques either wouldn't be able to detect that or haven't yet been tested.

This seems to be an atypical symptom in ME but my first ever symptom on day 1 lasting for the first month(s) was loss of fine motor control. I remember doing GCSE exams struggling to hold a pen. partial loss of sensation at things like finger tips or feet, or even my whole leg going slightly numb is quite common for me but not a symptom I ever really see people mention.

Very interesting cheers! Sounds like maybe you're implying that damage that has occured at one time - that might even have since been long healed - could lead to a more permanent sensitisation? Either way look forward to seeing this.

 

I was meaning objective electrophysiology.

 

About neurologists being biased:
Recently I saw one of those. First year neurologist.
I told him in the shortest way possible what brainfog meant to me.
Final year uni student, I had to drop out and started working as a telephonist, that's all I could do.

In the letter to the GP he wrote: fluent speach, language function impressed; intact.
No attention at all to the real problem.
Adding more iatrogenic damage.

 

It depends on what you mean by electrophysiology, you can't easily probe what we're talking about with needles. You can block the signals in the spine and measure different responses in the brain and if it is muscle afferents we are talking about, we can also measure the differential effect on motor cortex and corticospinal excitability through stimulation and measurement of the resulting muscle evoked responses. No one has bothered to do this in ME/CFS probably because neurologists simply don't understand it and most exercise physiologists aren't interested in ME/CFS.

Maybe, but that (permanent damage) doesn't explain the PEM kinetics either, but generalised sensitivity.