The symptom signaling theory of ME/CFS involving neurons and their synapses

[Jonathan Edwards]

If we accept a comparison to something like a "ongoing sickness response", then I see no reason to also not see a similarity to the PVF that EBV causes in many people, but why is EBV particularly good at doing that?

The immune response to EBV is quite different from and more prolonged than that for most infections. It involves a 'civil war' between activated B cells and cytotoxic T cells. The virus infects B cells and threatens to produce a generalised quasi-neoplastic polyclonal proliferation. It takes cytotoxic cells recognising EBV a while to expand and bring the infected B cell pool under control.

For most viruses the febrile period with major viraemia lasts no more than a few days. The febrile response in EBV infection can last a month. Immune cell expansion is sufficient to produce splenomegaly in a proportion. So the propensity to produce a protracted sickness response is not very surprising.

The link to MS is probably different in that the risk of MS continues long term, it seems, and is not directly linked to the infection period. That to me suggests that the quasi-neoplastic proliferative state of B cells remains a subclinical state that allows otherwise forbidden B cell clones to expand during future immune responses.

 

[jnmaciuch]

I think there is also a huge search space for mechanisms that would affect both the brain and muscle. We don't necessarily have to explain muscle pathology via brain or brain pathology via muscle

 

[EndME]

The immune response to EBV is quite different from and more prolonged than that for most infections. It involves a 'civil war' between activated B cells and cytotoxic T cells. The virus infects B cells and threatens to produce a generalised quasi-neoplastic polyclonal proliferation. It takes cytotoxic cells recognising EBV a while to expand and bring the infected B cell pool under control.

For most viruses the febrile period with major viraemia lasts no more than a few days. The febrile response in EBV infection can last a month. Immune cell expansion is sufficient to produce splenomegaly in a proportion. So the propensity to produce a protracted sickness response is not very surprising.

Is the suggestion then simply that EBV is more likely to cause some problems in neurons/synapses because the febrile response takes longer, or will there be 2 separate arguments for why EBV is good at causing PVF and good at causing ME/CFS?

 

[poetinsf]

Most/many ME/CFS patients respond (in some cases dramatically) to the dopamine system stabilizer drugs (Abilify, Rexulti, Vraylar, OSU-6162), indicating that there are postsynaptic signaling issues (@forestglip) causing symptoms.

Brain chemicals not only effect synaptic signaling, but they can also affect brain immune system. Microglial cells in particular have multiple dopamine receptors and there are several papers that say that dopamine downregulates microglial cells, even deactivating activated ones. So, the dopamine response doesn't necessarily indicate the signaling issue. It could indicate hypersensitive neuroimmune system issue just as well.

But like psychiatric drugs, the effect ends when you stop taking them or when they poop out. If the poop out/tolerance phenomenon wasn’t so common then these drugs would be good treatment options for many.

There are ways to increase dopamine naturally. I'm sitting in my back porch as I type this hoping that more natural light, and being outdoors all day long, would promote dopamine.

 

[Kiristar]

Perhaps AIDS (before it was adequately treated) might also be a good comparison to highlight. This is an example of a persistent virus that causes widespread immune dysfunction, a popular theory in ME/CFS and Long Covid research.

Yet several physicians (Peterson, Klimas etc.) commented that AIDS patients only developed the same degree of debilitating symptoms as in ME/CFS around 2 months before their death. Meanwhile it caused opportunistic infections, rare cancers, muscle wasting, damages blood vessels, and dementia.

So even if we assume some non-brain pathology like a virus in ME/CFS it must be extraordinary good at causing symptoms without destroying or disrupting other functions in the body.

I'm top end of severe grade but slowly deteriorating and recently have started to develop opportunistic infections.

 

[poetinsf]

I think we shouldn't exclude the possibility that there is damage occurring, a few reasons why:

1) As has been alluded to ME/CFS like fatigue is also seen in CNS injury:

Concussion fatigue is caused by the brain immune activation rather than the injury itself. Though it's possible that ME/CFS could be caused by similar injury, it's more likely that the brain immune activation is responsible.

I'm not sure if concussion fatigue patients suffer from PEM either. I don't mean rapid fatiguability which make them more tired than healthy people for the same amount of exertion. I mean by PEM the bottom falling out when crossing the threshold of exertion.

 

[Yann04]

I'm top end of severe grade but slowly deteriorating and recently have started to develop opportunistic infections.

Yeah. I dunno if I should call it opportunistic.

But I have a chronic bacterial infection in my toe since like a year thats unresponsive to treatment.

I’m pretty sure this wouldn’t happen if wasn’t v severe.

 

[EndME]

Concussion fatigue is caused by the brain immune activation rather than the injury itself. Though it's possible that ME/CFS could be caused by similar injury, it's more likely that the brain immune activation is responsible.

I'm not sure if concussion fatigue patients suffer from PEM either. I don't mean rapid fatiguability which make them more tired than healthy people for the same amount of exertion. I mean by PEM the bottom falling out when crossing the threshold of exertion.

Many people with post-concussion syndrome suffer from something akin to PEM and I don't think anybody has any idea on what the cause of post-concussion syndrome is.

 

[leokitten]

I definitely understand your desire to prioritize the neurological angle, but I’ve had some discussions with coworkers and classmates with more of a neuroscience focus over the years about this exact possibility and the answers to “what’s the next step if ME/CFS turns out to be in the brain?” have left me pretty disappointed. It’s far off in a way that most other biomedical research isn’t—a fact that I didn’t fully comprehend until I was walked through the limited set of neurological phenomena that could be measured [edit: especially without an animal model] and the even more limited conclusions that could be drawn from any of it. The few examples of successes with migraine and epilepsy are mostly due to the triggering phenomena in both cases being substantially different to the sort of “broken loop” mechanism proposed here.

If it does turn out to be a broken neurological feedback loop, we’d more or less end up in a “throw psychiatric medications at a wall and see what sticks” scenario.

Yep if it turns out to be a neurological CNS illness that is frankly indistinguishable from being neuropsychiatric we are all well and truly fucked, period. This would be devastating

 

[ME/CFS Science Blog]

But I have a chronic bacterial infection in my toe since like a year thats unresponsive to treatment.

Anecdotally I heard that the problems are mostly with bacterial infections, not so much with viral infections in severe ME/CFS. But I don't know if that is a consistent pattern.

 

[jnmaciuch]

Anecdotally I heard that the problems are mostly with bacterial infections, not so much with viral infections in severe ME/CFS. But I don't know if that is a consistent pattern.

I’ve heard the same

 

[jnmaciuch]

A friend of mine is a PT and he's said the exact same thing. He was shocked to hear that I spend most of my time sedentary given the state of my muscle mass.

That’s almost exactly what my doc said as well, and she was shocked that I hadn’t had sports injuries as a kid. The fact that it always seems to be worst in the muscles I used recently was a big clue as well. My PT asked if I was sneaking in an extra leg day and couldn’t believe when I said I had only walked 20 minutes.

 

[Utsikt]

My physio was surprised at how much muscles I’ve got after being bedbound for a year and walking 50m at most a day.

I don’t understand why that would be surprising to them, because it’s what I hear from every single severe (not extreme) patient: I can do it, but the consequences of doing it are bad.

 

[EndME]

I don’t understand why that would be surprising to them, because it’s what I hear from every single severe (not extreme) patient: I can do it, but the consequences of doing it are bad.

I think it's suprising because one might expect more muscle wastage from inactivity. That's independent of whether one can do something or not with payback.