Question re: the ICC Criteria and Ion Transport issues

duncan

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That is my guess as well. At this point, I am given a LEMS (Lambert Eaton Syndrome) diagnosis b/c it is a closer match than ME/CFS but it is not a match in many key criteria. I am not positive for the P/Q type calcium channel autoantibody (the most common in LEMS) and am only positive for the N type. Also most cases of LEMS begin with profound leg weakness which I never had (and the upper body and lung/diaphragm weakness that I had pre-treatment is MUCH more rare in LEMS).

Also, the criteria states that people w/LEMS gain muscle strength with muscle exertion but I was the complete opposite and the more I tried to use my muscles (pre-treatment), the weaker and more fatigued they got. I asked about this in LEMS groups and most people were the same and their muscles got weaker with use (not stronger) so I question where that piece of the criteria even came from o_O?! It was only after successful treatment with IVIG & Rituximab that I was able to increase my muscle strength with PT & Pilates. Prior to treatment this literally was not possible and I could not turn on a shower faucet, open a bottle, or open my patio door by myself.
Many of us have similar patch-work diagnoses stories to tell, don't we? :) We have Chinese Menu diagnostic protocols, with lousy fortune cookies.

Yes, my wife grows weaker, too. There are often two elements at play here, and these may be more peculiur to her channelopathy. There is the defective ion transport mechanism which translates immediately into poor muscle stamina etc. But, there is also the downstream cardiac issues which feed and compound the weakness and exhaustion.

I think it is exciting that IVIG and Rituximab helped you. I love to hear successful treatment protocols. But you still have symptoms, yes?

I agree with this but it seems to vary greatly whether the profound weakness is the legs, upper body, lungs/ breathing, etc.
Nods. I cannot explain this. But it is certainly true.
 
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duncan

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I can't blame her for not wanting to see more doctors and I am glad that you are on top of the research! I wonder if any of her meds for heart failure or Long QT would also be helping with POTS symptoms?
This is possible. I know the one helps inadvertently with her potassium levels. One is a diuretic. She is on so many. One of her problems is digestive and I cannot claim to know if those issues are iatrogenic, ie, caused by all those crazy meds, or lead back to her potassium channelopathy,

Mine was not intermittent and once it started, it was progressive until I began IVIG. But I suspect that is b/c it was autoimmune in my case vs. genetic?
I am facsinated by this. IVIG rebooted your system. No problems since? Of course, this suggests acquired, and I know you know this, but maybe not, right? It still might be genetic? Or you are certain it is autoimmune? Either way, your story is so hopeful that I get a lift inside each time I read your posts.
 
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duncan

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o you mean for the Mayo autoantibody panels or genetic testing?
I mean "they" have only begun to scratch the surface of even qualifying the channelopathies they've discovered so far, and I strongly suspect more discoveries will be coming. Which means more investments into more and better tests to capture diagnoses - covering the spectrum of diagnostics - quicker and more definitively.

I'm just not confident about the time frame. I want to believe sooner than later, but history doesn't necessarily support that.
 

Inara

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I asked about this in LEMS groups and most people were the same and their muscles got weaker with use (not stronger) so I question where that piece of the criteria even came from o_O?!
I call my muscle issues muscle weakness although I'm aware it must be a mild form (compared to others who can't do anything anymore). First muscle issues were in the upper legs - the first thing I had to reduce/nearly end was leg training; now the upper body is also affected (although I always was weak-ish in the upper body). My muscles definitely get weaker (fast) when used. I think it is a shame that one of the main criterium for LEMS is "getting stronger with exertion" (although I seem to remember that it was some strength gain after 10min, and then a weakening) and most LENS people then say, "Well no, my muscles get weaker". There's something really wrong. I do wonder how pravelent this is, which practically means worse diagnostics (i.e. more misdiagnoses).

Anti GAD65 autoantibodies are linked w/several different issues including Diabetes, Stiff Person Syndrome (SPS), and general autoimmunity (even to Hashimoto's Disease which I have).
I didn't know it's linked to general autoimmunity. Shows I need to search more about it. Thanks !

I remember seeing at least one paper showing an ion channelopathy in ME/CFS.
Do you by chance have the title/link?
 

Gingergrrl

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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.
Do you mean that there was a paper showing that an ion channelopathy exists in ME/CFS but that they were not able to link it to specific symptoms (like muscle weakness, etc)?

They do mention ion channel issues in ME/CFS in the original ICC published paper, but the original published paper does not mention ions in the title of section D. So it could be a mistake, but I am not sure.
That is all very strange and I have no idea how to interpret any of it?!

I think the explanations about what’s going on are way too obscure. Occam’s razor- ME is an infectious, inflammatory nervous system disease.
Do you think (for a sub-group) that it could start out infectious and then flip into autoimmunity?

Many of us have similar patch-work diagnoses stories to tell, don't we? :) We have Chinese Menu diagnostic protocols, with lousy fortune cookies.
Yes... that is definitely a good description!

There are often two elements at play here, and these may be more peculiur to her channelopathy. There is the defective ion transport mechanism which translates immediately into poor muscle stamina etc. But, there is also the downstream cardiac issues which feed and compound the weakness and exhaustion.
My understanding of the calcium channelopathies are that they cause muscle weakness, that can be severe and affect the lungs/diaphragm and breathing like in my case prior to treatment, but I haven't heard of them causing cardiac issues. BUT this just may not be known yet since almost 100% of the people in the calcium autoantibody group that I belong to also have POTS.

I think it is exciting that IVIG and Rituximab helped you. I love to hear successful treatment protocols. But you still have symptoms, yes?
I have been really been agonizing lately over how to best describe my current situation and feel like the best description is "partial remission". I will never use the word "recovery" or "cure" re: my case b/c when I stop Rituximab, all of my disabling symptoms could return. In addition, I still take several other meds, I still do not have the muscle stamina that I did pre-illness, and I still cannot climb stairs.

So if "remission" means "pre-illness level" than it is not the right term for me. But I have vast improvement (my breathing is now normal, I can stand, walk without wheelchair, drive, no allergic reactions to food, etc). I continue to strive toward what I would call a full remission but not sure if I will get there (and I don't at all mean that as a complaint and am beyond grateful for my current state, I just wish it could improve a little bit more).

I am facsinated by this. IVIG rebooted your system. No problems since? Of course, this suggests acquired, and I know you know this, but maybe not, right? It still might be genetic? Or you are certain it is autoimmune? Either way, your story is so hopeful that I get a lift inside each time I read your posts.
IVIG re-booted my immune system so I was no longer allergic to food and no longer had anaphylaxis (since 2016). It caused several other improvements but I was not able to walk without a wheelchair and have normal breathing/muscles until Rituximab. The two worked in conjunction with each other in my case. My doctors feel my autoimmunity is acquired BUT it makes sense that I also had some kind of genetic predisposition b/c other people have had my set of triggers (neurotoxic reaction to a med, severe Mono/EBV, and toxic mold exposure) and been able to recover vs. I was not and continued to progressively worsen prior to treatment.

I mean "they" have only begun to scratch the surface of even qualifying the channelopathies they've discovered so far, and I strongly suspect more discoveries will be coming. Which means more investments into more and better tests to capture diagnoses - covering the spectrum of diagnostics - quicker and more definitively.
I agree.

I'm just not confident about the time frame. I want to believe sooner than later, but history doesn't necessarily support that.
I am not confident about the time frame either :(

First muscle issues were in the upper legs
Everything that I read about LEMS says that the upper leg muscles are the first to weaken but this did not happen in my case which makes me question the diagnosis. My legs never weakened and it was all my upper body (arms, neck, lungs, diaphragm, etc).

I think it is a shame that one of the main criterium for LEMS is "getting stronger with exertion" (although I seem to remember that it was some strength gain after 10min, and then a weakening) and most LENS people then say, "Well no, my muscles get weaker". There's something really wrong. I do wonder how pravelent this is, which practically means worse diagnostics (i.e. more misdiagnoses).
I'm sure it must vary greatly for each person but in the group that I participated in, many people said that their muscle weakness was progressive and exertion was not possible and certainly did not strengthen their muscles. I wish I knew if it really was my diagnosis.

I didn't know it's linked to general autoimmunity. Shows I need to search more about it. Thanks !
Anti GAD65 definitely links to general autoimmunity (especially in cases where the person does not have diabetes or Stiff Person Syndrome).

Thank you @Hip and I bookmarked this to read later. It is very possible that I have already read it at some point between 2016 and now but do not remember :D
 

Inara

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Do you mean that there was a paper showing that an ion channelopathy exists in ME/CFS but that they were not able to link it to specific symptoms (like muscle weakness, etc)?
In the paper "Chronic fatigue syndrome is an acquired neurological channelopathy" by Chaudhury and Behan, which Hip linked to above, the authors hypothesize that "dysfunctional ion channels in the cell membranes [are] the key abnormality in CFS which may also be responsible for the altered neuroendocrine functions reported in this condition. In our hypothesis, changes in the neuronal ion channel function from time to time offers a rational basis to explain fluctuating fatigue and related symptoms in CFS." I.e. it was not shown.
 

Gingergrrl

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I looked at the link and it only seems to show an abstract. Is there a way to view the whole paper? @Inara were you able to read the whole paper or just the abstract?

The abstract said:

The fatigue in CFS is distinct from the fatigue of neuromuscular disorders but is similar to that found in disorders of the central nervous system such as multiple sclerosis, Parkinson's disease and multiple system atrophy.
I was curious how they know this (that the fatigue of CFS is different from neuromuscular disorders and more similar to MS, Parkinson's, and Multiple System Atrophy")? Was this based on a study or is it also a hypothesis or speculation? My own illness was definitely more similar to a neuromuscular disorder and I would describe it as muscle weakness/ muscle fatigue vs. overall fatigue, tiredness, or sleepiness.

Cort also wrote an article on it.
I did not get a chance to read this link yet but am looking forward to reading it later when I have more time.
 
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I've just ordered genetic testing, trying to find out anything at all about my magnesium problems. Does anyone know what genes are associated with channelopathies and if there is a magnesium chanelopathy subset? I am getting low magnesium symptoms even with supplementing huge amounts of magnesium. Then if I go over, I get symptoms of high magnesium, which then wear off and are rapidly back into needing more magnesium. It seems the magnesium is perhaps not getting to cells that it needs to and it fluctuating hugely in blood levels, which are supposed to be mostly self regulating but are not in my case. The magnesium need increases hugely with any vitamin d exposure, including quite minimal amounts of sunlight/UV. I can't find answers anywhere. I've ordered genetic testing and hair mineral testing.
 

Moof

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Does anyone know what genes are associated with channelopathies and if there is a magnesium chanelopathy subset?
Some genes are known (Wikipedia has information on the most thoroughly researched ones), but because the science is at such an early stage, many are not. Also, some mutations have been associated with channelopathies but it's not clear yet whether they really are causative. I've got some of these on my WGS report, and I'm guessing quite a lot of people will see the same – the mutations could well be perfectly harmless, but because some of them aren't very common, much more data is needed before researchers can be sure.
 

Pyrrhus

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They do mention ion channel issues in ME/CFS in the original ICC published paper, but the original published paper does not mention ions in the title of section D. So it could be a mistake, but I am not sure.
I believe the authors of the ICC were referring to the (then-preliminary) findings of Staines and Marshall-Gradisnik regarding TRPM3. But I am not sure about that.

n the paper "Chronic fatigue syndrome is an acquired neurological channelopathy" by Chaudhury and Behan, which Hip linked to above, the authors hypothesize that "dysfunctional ion channels in the cell membranes [are] the key abnormality in CFS which may also be responsible for the altered neuroendocrine functions reported in this condition. In our hypothesis, changes in the neuronal ion channel function from time to time offers a rational basis to explain fluctuating fatigue and related symptoms in CFS." I.e. it was not shown.
Further to Chaudhuri and Behan’s hypothesis, I would point out that ion channelopathies can be induced simply by raising the intracellular calcium ion levels, slightly depolarizing the cell membrane.

This may be most dramatically seen with T-type calcium channels, which are often found at the junction between the neuronal cell body and the neuronal axon , and may be important for transmitting electrical signals from the neuronal cell body to the axon. Even slight depolarization induced by elevated intracellular calcium ions can shut down T-type calcium channels entirely.
 

Gingergrrl

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Does anyone know what genes are associated with channelopathies and if there is a magnesium chanelopathy subset?
My understanding (which certainly could be wrong :xeyes:) is that there are calcium, potassium, sodium, and (maybe chloride?) channelopathies but not a magnesium channelopathy. But like I said, this could be wrong so don't quote me on it :nerd:

Thank you @Moof and the link works for me and I just bookmarked it in my browser to read later and also plan to read Cort's blog re: channelopathies.

I've got some of these on my WGS report, and I'm guessing quite a lot of people will see the same – the mutations could well be perfectly harmless, but because some of them aren't very common, much more data is needed before researchers can be sure.
What is a "WGS report"? I'm assuming it is for genetic channelopathies but not autoimmune channelopathies?

I believe the authors of the ICC were referring to the (then-preliminary) findings of Staines and Marshall-Gradisnik regarding TRPM3. But I am not sure about that.
That was my initial guess (that ion transport issues were included in the ICC criteria b/c of the research from the Australian Team) but I wasn't sure.

This may be most dramatically seen with T-type calcium channels, which are often found at the junction between the neuronal cell body and the neuronal axon , and may be important for transmitting electrical signals from the neuronal cell body to the axon. Even slight depolarization induced by elevated intracellular calcium ions can shut down T-type calcium channels entirely.
Wow, I didn't even know about T-type calcium channels?! The ones that I was tested for (for autoantibodies) were the N-type and the P/Q type and I have autoantibodies against the N-type (since first Mayo test in 2016) but not against the P/Q type. I know there is also the L-type but it seems that is tested in research only and there is no commercial test for autoantibodies (that I am aware of).

I tried (without success) to figure out if Propofol (anesthesia) would be safe for me since it is an L-type calcium channel blocker. But since there is no clear answer, I am avoiding it unless it was life or death and will be having Versed/Fentanyl for an upcoming procedure instead which are safe for me.
 

Gingergrrl

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Sorry, a really quick reply (expecting a phone call!): whole genome sequencing. :)
Thanks @Moof and I have heard of WGS but just forgot the term :bang-head:

Can you explain more? And what would raise intracellular calcium ion levels?
I am curious, too :) ... the only thing that came to mind (re: my case) is lowering the pathogenic autoantibody through treatments so that it is not blocking the calcium channel which stops the calcium from entering the cells. Is this part of it?

From the bit I am reading it sounds like little transistors, that allow or prevent ions through when the voltage changes. Weird stuff.
I have not had a chance to read the article or Cort's Blog (hoping to do this soon) but the autoantibody that I have is called VGCC for "voltage gated calcium channel". I know that there are also "ligand" channels which are not voltage gated but I cannot explain much beyond knowing those words (which is a bummer b/c I really want to understand this better some day) and am now gobsmacked that there could be a connection to ME/CFS after all (from the ICC criteria).
 

Pyrrhus

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From the bit I am reading it sounds like little transistors, that allow or prevent ions through when the voltage changes. Weird stuff.
I have not had a chance to read the article or Cort's Blog (hoping to do this soon) but the autoantibody that I have is called VGCC for "voltage gated calcium channel". I know that there are also "ligand" channels which are not voltage gated but I cannot explain much beyond knowing those words
Yup, those are both pretty accurate. Voltage-gated channels open and close depending upon the difference in electrical charge between the inside of the cell membrane and the outside of the cell membrane. (i.e. "voltage") Transistors are a good analogy. The electrical charge on either side of the cell membrane is determined by the concentrations of positive and negative ions on either side of the membrane.

Ligand-gated channels open when a specific molecule (a "ligand") binds to the channel. When the specific molecule separates from the channel, the channel closes again.

Can you explain more? And what would raise intracellular calcium ion levels?
Thanks for the question. As you already know @Inara , many different things can cause a change to intracellular calcium levels. 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.

Now it's easy to see how problems with ion channels ("channelopathies") can cause improper ion levels inside or outside the cell membrane.

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 hope that I answered your question. My apologies if I did not.