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Question re: the ICC Criteria and Ion Transport issues

Gingergrrl

Senior Member
Messages
16,171
Autoantibodies can cause ion channels to function improperly, leading to improper ion levels. Viruses such as enteroviruses can make specific proteins, called "viroporins", that punch holes in membranes, leading calcium ions to leak into the intracellular space. These are just two examples.

Thank you and this all makes sense to me.

But the reverse situation is also possible: improper ion levels can cause problems with voltage-gated ion channels. If the ion levels inside or outside the membrane are disturbed, it will change the difference in electrical charge between the inside of the cell membrane and the outside of the cell membrane. (i.e. "voltage") This change in voltage will affect the voltage-gated channels.

Maybe the change in voltage will make the voltage-gated channels more sensitive. Maybe it will make them less sensitive. And in some cases, it can cause the voltage-gated channel to get stuck in either the open or closed position. These situations are, of course, temporary channelopathies in the voltage-gated channels. When the ion levels return to normal, the channelopathies will disappear.

I'm not sure that I understand this part though and I bolded one part in particular above that I wanted to ask you. What makes an ion channelopathy temporary vs. permanent? (in my case the calcium channel). Is there any chance that the autoantibodies that I have that attack the N-type calcium channels could be temporary vs. permanent?! (or do the temporary reasons not include autoantibodies)? I was trying to understand your two paragraphs above re: the temporary situations but didn't quite get it :xeyes:

I've had significant improvement from autoimmune treatments which I started in 2016 & 2017. None of my doctors are questioning that autoimmunity is behind my core issues and I had eleven autoantibodies before I started treatment (if I include the two thyroid/Hashi's Abs but really those are separate). The odd thing is that while almost all of my autoantibodies went down after treatment, the calcium channel autoantibody did NOT go down. It went from 0.05 to 0.06 (on Mayo testing) which means that it basically stayed the same in spite of my vast improvement in muscle weakness, breathing, POTS, and other core symptoms. My main doctor was not totally sure what to make of this but he thought possibly that the test was picking up on the quantity of autoantibodies but that they were no longer pathogenic.

Did any of you all have any bouts of Raynaud syndrome or ptosis or both drooping eyes lids (not to be confused with twitching eyelids but that too if you have it)?

I had some symptoms of Raynauds when I was at my most ill but I never officially had that diagnosis. But my hands, feet, and nose would get extremely cold to the point that it was painful (and I was not in the snow or super cold conditions)! I have never had ptosis or drooping eye lids at any point in my illness.
 

Pyrrhus

Senior Member
Messages
4,172
Location
U.S., Earth
I'm not sure that I understand this part though and I bolded one part in particular above that I wanted to ask you. What makes an ion channelopathy temporary vs. permanent? (in my case the calcium channel). Is there any chance that the autoantibodies that I have that attack the N-type calcium channels could be temporary vs. permanent?!

Thank you for your question. First, I should clarify that I am using the definition of "channelopathy" used by Chaudhuri and Behan, who use the word "channelopathy" to refer to any problem with ion channels.

If the cause of the channelopathy is temporary, as in a short-lived infection, then the channelopathy will probably be temporary. If the cause of the channelopathy is permanent, as in a genetic mutation, then the channelopathy will probably be permanent.

So are channelopathies caused by autoantibodies temporary or permanent? I don't have a concrete answer to this, as it depends upon whether the cause of the autoantibodies is temporary or permanent. And we don't have a good grasp of what causes autoimmunity, so we can't know whether a given autoimmunity is temporary or permanent.

The odd thing is that while almost all of my autoantibodies went down after treatment, the calcium channel autoantibody did NOT go down.

That is fascinating! Perhaps the calcium channel antibodies were caused by something different, something that did not respond to IVIG? It's hard to figure out what's going on here, as we still don't understand exactly how IVIG works against autoimmunity. But if you ever figure it out, please let me know!

Hope this helps, somewhat.
 

Gingergrrl

Senior Member
Messages
16,171
So are channelopathies caused by autoantibodies temporary or permanent? I don't have a concrete answer to this, as it depends upon whether the cause of the autoantibodies is temporary or permanent. And we don't have a good grasp of what causes autoimmunity, so we can't know whether a given autoimmunity is temporary or permanent.

Thank you and my doctors believe the autoimmunity was triggered by the EBV virus (in my case) in case that makes any difference. I am under the assumption that it is now permanent although I would love to be wrong.

That is fascinating! Perhaps the calcium channel antibodies were caused by something different, something that did not respond to IVIG? It's hard to figure out what's going on here, as we still don't understand exactly how IVIG works against autoimmunity. But if you ever figure it out, please let me know!

I apologize and was actually talking about Rituximab when I said that the calcium channel autoantibodies did not go down. I did two years of IVIG as well and the two overlapped in the middle. Basically, I started IVIG mid- 2016, started Rituximab mid- 2017 (overlapped with IVIG), stopped IVIG mid- 2018, and continued Rituximab to the present day (but am now only getting it 2x/year for maintenance).

Hope this helps, somewhat.

Definitely, thank you! I know that all of this is just at the theoretical stage right now and no one knows the true mechanism behind of any of it (as far as I know).
 

Inara

Senior Member
Messages
455
But the reverse situation is also possible: improper ion levels can cause problems with voltage-gated ion channels. If the ion levels inside or outside the membrane are disturbed, it will change the difference in electrical charge between the inside of the cell membrane and the outside of the cell membrane. (i.e. "voltage") This change in voltage will affect the voltage-gated channels.
I didn't think about this - but it makes perfect sense, i.e. it is logical! Thanks for explaining.
So your voltage-gated ion channels can be perfectly fine, but as soon as the ion levels outside and/or inside of the cell get disrupted such that the "working voltage levels" are changed, you can get problems with the voltage-gated ion channels. I.e. if ligand-gated calcium channels are dysfunctional (or if viruses open them) such that they can change calcium ion levels in the cell, this may involve the voltage-gated ion channels as a consequence, too.

Thinking this further this could also imply a fluctuating nature - sometimes a changed calcium flux will rise intracellular calcium too much - which then might also influence the voltage-gated ion channels - sometimes it won't, depending on the substance that bound to the receptor probably? (There's still a changed calcium signal which may have other downstream effects.)

Maybe the change in voltage will make the voltage-gated channels more sensitive. Maybe it will make them less sensitive. And in some cases, it can cause the voltage-gated channel to get stuck in either the open or closed position. These situations are, of course, temporary channelopathies in the voltage-gated channels. When the ion levels return to normal, the channelopathies will disappear.
Is it already known in which situations an ion channel gets more or less sensitive or stuck in a position? (I know that thapsigargin "knocks out" IP3 receptors, but it's not a natural substance in the body, so this doesn't count.) And what time frame is meant with "stuck in a position"? E.g. some viruses send substances that open IP3Rs so that the endoplasmic reticulum is emptied with calcium so that calcium channels on the cell membrane open through which the viruses then can send their DNA/RNA - but the ones I read about weren't voltage-gated calcium channels. Are these influenced, too, in such or other situations? So here "stuck in a position" would mean as long as the virus takes to inject its DNA/RNA? Are there situations where the channel gets stuck permanently, and wouldn't lead this to death?
 

stetson28

If it aint broke don't fix it...but.
Messages
49
Location
Richmond Virginia
I have Raynaud's and twitching eyes phases (i.e. days of twitching, and then someday it disappears for a while). Why?

Sometimes I just do weird random mental mapping and cross-referencing overlapping common symptoms among many different disease forms. I love the discussion on viral retroviral quorum sensing and viroprins. But I was also curious to see if people were symptomatically blowing through potassium and magnesium at a high rate possibly alkalosis, assuming parathyroid and vit d / k2 levels were appropriate.
 

L'engle

moogle
Messages
3,200
Location
Canada
@stetson28 Do you find vitamin k2 helpful? I have been taking it in small amounts. Either that or vitamin A has helped me but they both have negative effects if I take them very much. I think for several years my system was actively flushing out magnesium, because the phases of needing mag would alternate with longer phases where I couldn't tolerate any magnesium without insomnia and in fact had to take in calcium in large dietary quantities to get any sleep. This finally stopped(hopefully for good) in the spring when I took vitamin A and MK-4 version of k2. I think the stores of magnesium may have gotten so low over the years that now very little vitamin d has a huge effect in terms of magnesium need. This is all just conjecture though, no proof of anything beyond life ruining symptoms.
 
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82
Would this relate to muscle weakness or some other symptom?
Well, theoretically, yes. But I am not sure that their evidence supports their assertions. I have simply relayed what they said.

TBH, this is where I prefer the IOM papers. They took a much more realistic view of what evidence we have (and what assertions we can't support right now).

Ion channel problems would make a lot of sense to me personally for what goes on with me, although I can't rule out that some of it comes from not-ME health issues. But I can't prove any of it from the literature or from tests (I didn't have any such tests, if I even knew what the right tests were).

I would like to see more papers on this. Replication studies are good. :)
 
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82
Do you know what the ICC criteria is used for (if not for research studies)? I've never seen it used as a clinical diagnostic criteria by a doctor. When is it used (or is it not currently being used)?
I believe the ICC are used in research studies sometimes. I do not know whether it's used clinically anywhere.

Dr. Lucinda Bateman says the CCC and ICC are too long and complicated for doctors to use. As we have no specialty certification program, I would tend to agree with her. The only other criteria I know that are this complicated are for Ehlers-Danlos syndrome, and only specialists can diagnose this (and some of them still get it wrong and use only one aspect of the criteria).
 
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82
I remember seeing at least one paper showing an ion channelopathy in ME/CFS. But it is one thing observing a pathophysiology like this, but quite another to connect it to specific symptoms.

Sure, there are some studies.
https://www.ncbi.nlm.nih.gov/pubmed/15790422
https://www.ncbi.nlm.nih.gov/pubmed/10790725
https://www.ncbi.nlm.nih.gov/pubmed/26399744
https://www.ncbi.nlm.nih.gov/pubmed/16610953
https://www.ncbi.nlm.nih.gov/pubmed/27099524

I have not looked at them all in detail to see how consistent the findings or how good the methods.
 

Pyrrhus

Senior Member
Messages
4,172
Location
U.S., Earth
I apologize and was actually talking about Rituximab when I said that the calcium channel autoantibodies did not go down.

Thanks for the clarification. This clarification actually makes it much easier to formulate an hypothesis to explain your observation. Since the Rituximab wiped out the B-cells that produce the autoantibodies, but the calcium channel autoantibodies came back, perhaps the cause of the calcium channel autoantibodies is still around.

So your voltage-gated ion channels can be perfectly fine, but as soon as the ion levels outside and/or inside of the cell get disrupted such that the "working voltage levels" are changed, you can get problems with the voltage-gated ion channels.

Yes!

Thinking this further this could also imply a fluctuating nature

Yes!

Is it already known in which situations an ion channel gets more or less sensitive or stuck in a position?
And what time frame is meant with "stuck in a position”?

If you’re asking about voltage-gated channels, the dynamics of opening and closing the channel can be complicated to explain. I will use T-type calcium channels as an example. T-type calcium channels have three positions, “open”, “closed”, and “inactivated”.

Normally, the ion levels inside and outside the cell membrane result in a voltage of about 70mV and the T-type calcium channel is in the “closed” position. When this voltage drops to around 55mV, the channel switches to the “open” position and Ca2+ ions start passing through the channel. As the ions pass through the channel, the voltage drops even further. After about 15-30 milliseconds in the “open” position, the channel switches to the “inactivated” position and ions stop flowing through the channel. Eventually the voltage returns to its original voltage of around 70mV and the channel returns to the “closed” position.

Now, if something disturbs the ion levels and the voltage becomes greater than 70mV, the channel will be less sensitive to electrical signals. If something disturbs the ion levels and the voltage becomes less than 70mV (but more than 55mV) then the channel becomes more sensitive to electrical signals. If something disturbs the ion levels and the voltage becomes less than 55mV, then the channel will become stuck in the “inactivated” position until the ion levels return to normal levels.

Are there situations where the channel gets stuck permanently, and wouldn't lead this to death?

There are many animal toxins that get the ion channels stuck in a position, leading to paralysis and even death:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210452/

Hope this helps.
 
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Gingergrrl

Senior Member
Messages
16,171
I didn't think about this - but it makes perfect sense, i.e. it is logical! Thanks for explaining.

I wish I could understand this part but I don't :( (and don't waste time trying to explain it to me, I just wish I knew more science).

Well, theoretically, yes. But I am not sure that their evidence supports their assertions. I have simply relayed what they said.

I agree that I have absolutely no idea if those statements in the ICC Criteria (re: ion transport issues) are backed up by evidence or studies. I had assumed that everything in the ICC criteria was back up as proven fact but this is making me question the criteria.

I believe the ICC are used in research studies sometimes. I do not know whether it's used clinically anywhere.

Thanks and I do not know either.

Thanks for the clarification. This clarification actually makes it much easier to formulate an hypothesis to explain your observation. Since the Rituximab wiped out the B-cells that produce the autoantibodies, but the calcium channel autoantibodies came back, perhaps the cause of the calcium channel autoantibodies is still around.

I really don't know if the calcium channel autoantibodies "came back" as you stated or if the number never went down to begin with? I have done the Mayo testing twice but did not do it in the middle of treatment (so it would just be a guess).

My doctor suspects that there are many mechanisms in which high dose IVIG and Rituximab work in addition to killing B-cells. He also thinks it is possible that while many of my autoantibodies went down (5+ of them went down on the Cell Trend panels in addition to anti GAD65 went down on the Mayo Panel), that maybe the blood tests are picking up on the number or quantity of the autoantibodies but this does not reflect if they are still pathogenic or causing symptoms. I hope that makes more sense then whatever I wrote earlier!
 
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82
I agree that I have absolutely no idea if those statements in the ICC Criteria (re: ion transport issues) are backed up by evidence or studies. I had assumed that everything in the ICC criteria was back up as proven fact but this is making me question the criteria.
Ah, sorry. Just because I feel uncertain doesn't necessarily mean you should, too. :)
 

Inara

Senior Member
Messages
455
I was wondering the following:
In Periodic Paralyses, it is said to be typical to get attacks after an activity, during rest. I read that it can take days or weeks to recover from such an attack. Although I exhaust pretty fast, now and then I am surprised how well I can get through an activity when needed (e.g. sitting in a waiting room, talking with people), but then afterwards a worsening sets in (which can remain for longer) - maybe this worsening is an "attack". Could this be explained by a channelopathy/ion transport problems?
 

Gingergrrl

Senior Member
Messages
16,171
Ah, sorry. Just because I feel uncertain doesn't necessarily mean you should, too. :)

No apologies needed and my uncertainty about the link between the ICC criteria and ion channelopathies are not b/c of anything that you said!

I was wondering the following: In Periodic Paralyses, it is said to be typical to get attacks after an activity, during rest. I read that it can take days or weeks to recover from such an attack. Although I exhaust pretty fast, now and then I am surprised how well I can get through an activity when needed (e.g. sitting in a waiting room, talking with people), but then afterwards a worsening sets in (which can remain for longer) - maybe this worsening is an "attack". Could this be explained by a channelopathy/ion transport problems?

That is an interesting question (but I don't know the answer :nerd:) ... When I was very sick (prior to finding the right treatments) the trigger for me was always instant and was always brought about by exertion and never by resting.

Once I crossed an invisible line (standing up from wheelchair, using my muscles, even just walking a few steps across the room), it could trigger an episode that included a severe POTS reaction, shortness of breath, chest pain, and gasping for air. This reaction was never delayed and never brought about by rest (in my own case). All of that is now gone even though I will never have the muscle strength and stamina that I did pre-illness. And I still don't know what happens if I stop Rituximab allowing my B-cells to grow back vs. keeping them at zero.
 

Inara

Senior Member
Messages
455
In my case, POTS is always there; but you mean in your case it got instantly worse with activity? ("My" POTS gets worse, too, after I've done too much, but it's not like a wall that hits me, um, usually.) My worsening can set in with activity, too, and usually does, but more comes after activity and even more when I finally find rest. I look mostly normally functional to the outside, because nobody sees what happens afterwards.
 

Gingergrrl

Senior Member
Messages
16,171
In my case, POTS is always there; but you mean in your case it got instantly worse with activity?

I think you are asking me @Inara (and apologies if you are not :xeyes:)... Prior to the proper treatments, my entire illness, including POTS, got instantly worse with physical activity.

("My" POTS gets worse, too, after I've done too much, but it's not like a wall that hits me, um, usually.)

For me, there was an invisible line and once I crossed it, the symptoms were instant. It is hard to explain but basically, if I did not cross the line, I was okay but once I crossed it, the reaction was instant and never delayed. It was also progressive from Jan 2013 to mid 2016 when I began IVIG and then Rituximab in mid 2017. I really am scared to think how far it could have gone without those treatments.

My worsening can set in with activity, too, and usually does, but more comes after activity and even more when I finally find rest.

For me, lying flat without physical activity was the only thing that could reverse an episode once it started. If an episode had not been triggered, than there was no need for me to lie flat to regain my ability to breathe and use my muscles. Either I had crossed the invisible line triggering the episode or I had not. It was never delayed and it was never brought on by rest, only by physical exertion. But the exertion could be walking from bedroom to bathroom without wheelchair or trying to open my front door. I was completely disabled by the time I started the right treatments BUT I never had cognitive symptoms, flu-like symptoms, or delayed reactions that match with "PEM".

I look mostly normally functional to the outside, because nobody sees what happens afterwards.

I look mostly normal and functional now and this switch truly began in May 2018 exactly nine months after starting Rituximab. I had many improvements from IVIG but I could not walk without a wheelchair, drive my car, or be independent until mid 2018. Prior to that, no one would have ever thought that I looked normal or functional vs. now almost everyone would think that I look normal and functional unless you look really closely or are with me 24/7.
 

Gingergrrl

Senior Member
Messages
16,171
I do not see muscle fatigability mentioned anywhere in the ICC. I could be missing it... So not required in CCC, not described ICC at all (I think)

I copied this quote by JenB from another thread re: hEDS b/c I didn't want to take it off-track and it seems to fit with our discussion in this thread. In that thread, JenB said that the ICC Criteria does not include muscle fatiguability which shocked me.

I was shocked that the ICC included ion transport issues (which is why I started this thread to learn more about that) and now I am shocked again that it does not include muscle fatiguability (which was an absolute core issue for me prior to treatment).

Is that how everyone understood the ICC Criteria? I am finding all of this very confusing :confused:

@Inara @Foxglove @duncan @Pyrrhus
 
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82
I would not necessarily see it as not including muscle fatiguability, although it could be a bit wooly. ICC says this regarding PEM:
A. Postexertional neuroimmune exhaustion (PENE pen’‐e): Compulsory  This cardinal feature is a pathological inability to produce sufficient energy on demand with prominent symptoms primarily in the neuroimmune regions.

Characteristics are as follows:  
1. Marked, rapid physical and/or cognitive fatigability in response to exertion, which may be minimal such as activities of daily living or simple mental tasks, can be debilitating and cause a relapse.  
2. Postexertional symptom exacerbation:e.g.acute flu‐like symptoms, pain and worsening of other symptoms.
3.Postexertional exhaustion may occur immediately after activity or be delayed by hours or days.  
4. Recovery period is prolonged, usually taking 24 h or longer. A relapse can last days, weeks or longer.  
5. Low threshold of physical and mental fatigability (lack of stamina) results in a substantial reduction in pre‐illness activity level.
So we have in point 1, physical and/OR cognitive fatiguability in response to exertion
but in point 5, low threshold of physical AND mental fatiguability.

Fatiguability is reducing ability to carry out work (activity) over time. Thus to me it implies weakness (muscle weakness is not required in point 1 but seems to be required in point 5.). Although it doesn't specifically say that so I suppose fatiguability from other sources could potentially be included (e.g. joint instability).

Muscle weakness could feasibly be included in points 2 and 3 but not well explained--though "flulike symptoms" is generally understood to include a debility that's perhaps a sort of immunological rather than neurological muscle weakness, and "exhaustion" could potentially include this, too, as serious exhaustion, heat exhaustion, and so on, would make a person weak

This is probably why some people prefer the very old definitions, or obscure definitions modified from those, as they explained the muscle weakness more clearly.

Fukuda, I think it was, specifically said "not asthenia" and "not somnolence" (not weakness and not sleepiness) which I think is straight-up wrong in the first instance, and wrong at least at some times or for some patients in the second instance. The field has been struggling to recover ever since, IMO.

However, the IOM report specifically mentions "weakness" in the PEM section.