Antibodies to ß adrenergic and muscarinic cholinergic receptors in patients with CFS

[Jemima]

I am not in the UK and was tested for MuSK via Mayo Clinic and was negative. I am going to be attempting to test the autoantibodies from Cell Trend (the tests that Dr. Schiebenbogen developed with them) that are only available in Germany. Myasthenia Gravis and MuSK are ruled out in my case but I do have pretty bad muscle weakness and cannot open my front door (or most doors) or do a leg lift exercise in another thread. Am hoping this improves with IVIG.

PS what was the N type antibody test you had?

 

[anciendaze]

PS what was the N type antibody test you had?

I can answer that. She had the Mayo Paraneoplastic panel. You can see the specific test on that web page.

 

[Gingergrrl]

@Jemima, I find your posts very difficult to read but I am going to do the best I can to respond! I do not believe that I have any type of myasthenia gravis b/c I had a full panel for all of the MG and MuSK antibodies and was negative on every single one.

I did well with the first IVIG (minus a debilitating headache) and I had my 2nd IVIG yesterday (no headache so far!) but too early to tell what the overall outcome will be. I have not at a tensilon test and no doctor has mentioned this to me but I did have an EMG to rule out LEMS which found neuropathy of the left phrenic nerve.

I do have low Potassium and have been supplementing since end of 2014 with 20 MEQ daily from my cardio. Thus far every cardiac test (EKG, Echo's, Zio Patch, heart cat scan, etc.) are "normal" and my cardiac diagnoses were IST changed to POTS/dysautonomia. It is the pulmonary tests that I cannot pass and every single one has been abnormal (spirometry, attempted PFT tests, V/Q scan, EMG showing phrenic nerve abnormality, etc).

As far as thyroid, I was diagnosed with Hashimoto's in Oct 2013 but my numbers are all normal on very low dose of Armour. I hope that answered everything!

 

[Gingergrrl]

I can answer that. She had the Mayo Paraneoplastic panel. You can see the specific test on that web page.

Yes that is correct, it was the PAVAL panel from Mayo. All was normal on it except for the Calcium Channel antibody at 0.05 and anything above 0.02 is a definitive positive. Although the ideal result is 0.0 which is what I had for all of the other antibodies. I also tested positive for anti GAD65 antibodies at 1.6 but I believe this was a different panel and not part of PAVAL (but I would need to check my results to confirm).

 

[Jemima]

@Jemima, I find your posts very difficult to read but I am going to do the best I can to respond! I do not believe that I have any type of myasthenia gravis b/c I had a full panel for all of the MG and MuSK antibodies and was negative on every single one.

I did well with the first IVIG (minus a debilitating headache) and I had my 2nd IVIG yesterday (no headache so far!) but too early to tell what the overall outcome will be. I have not at a tensilon test and no doctor has mentioned this to me but I did have an EMG to rule out LEMS which found neuropathy of the left phrenic nerve.

I do have low Potassium and have been supplementing since end of 2014 with 20 MEQ daily from my cardio. Thus far every cardiac test (EKG, Echo's, Zio Patch, heart cat scan, etc.) are "normal" and my cardiac diagnoses were IST changed to POTS/dysautonomia. It is the pulmonary tests that I cannot pass and every single one has been abnormal (spirometry, attempted PFT tests, V/Q scan, EMG showing phrenic nerve abnormality, etc).

As far as thyroid, I was diagnosed with Hashimoto's in Oct 2013 but my numbers are all normal on very low dose of Armour. I hope that answered everything!

Thanks, sorry my typing is not great. You certainly have a complex picture too. The best tests for any kind of sero negative myasthenia is a tensilon test I am surprised they havent done that with your history, maybe the other issues you have make it inappropriate. I have the heart issues of POTS but not The actual OT thingy.

 

[Jemima]

Yes that is correct, it was the PAVAL panel from Mayo. All was normal on it except for the Calcium Channel antibody at 0.05 and anything above 0.02 is a definitive positive. Although the ideal result is 0.0 which is what I had for all of the other antibodies. I also tested positive for anti GAD65 antibodies at 1.6 but I believe this was a different panel and not part of PAVAL (but I would need to check my results to confirm).

Am i to understand in USA there is a panel which tests for all antibodies? here in UK they do one antibody at a time!

 

[anciendaze]

Am i to understand in USA there is a panel which tests for all antibodies? here in UK they do one antibody at a time!

The panel in question covered autoantibodies provoked by various cancers. This is far from "all antibodies". A different panel found the GAD65 antibodies, which are normally associated with type 1 diabetes. Still a different autoantibody panel was run by a rheumatologist, and found antinuclear antibodies. Did I mention antibodies to thyroid, found by an endocrinologist?

We aren't even close to testing for all autoantibodies.

 

[Jemima]

That what I thought!
We all carry hundreds of antibodies.
It would be impossible to scan for all. When you get a positive ANA they may look for a specific but in UK testing for any antibody isnt routine. And youd have to have high numbers for the UK medics to take much notice anyway.

 

[Gingergrrl]

Thanks, sorry my typing is not great. You certainly have a complex picture too. The best tests for any kind of sero negative myasthenia is a tensilon test I am surprised they havent done that with your history, maybe the other issues you have make it inappropriate. I have the heart issues of POTS but not The actual OT thingy.

No worries and I think I understand most of what you are asking! My doctors do not feel that I have any kind of myasthenic syndrome based on the entire panel of tests that I have (vs. muscle weakness from the calcium channel antibody plus severe dysautonomia). I bolded part of your post b/c I was not sure what you meant by the "actual OT thingy." Which issue were you referring to?

Am i to understand in USA there is a panel which tests for all antibodies? here in UK they do one antibody at a time!

No, there is absolutely nothing like that in the US that I am aware of. I was tested for thyroid auto-antibodies by my Endo in 2013 and then was not tested for any other auto-antibodies until very recently when a Neuro ran some tests via the Mayo Clinic (the PAVAL panel, the myasthenic syndromes and MuSK panel, etc) and then a rheumy tested me for the ANA and some other auto-antibodies.

At present I test positive for the two Hashimoto's Abs, Anti GAD65, and N-type Calcium Channel Ab, plus the positive ANA of 1:160 speckled pattern. I am working on getting the tests from Cell Trend in Germany and finally had the chance to reply to their e-mail this morning with all of my questions.

My doctor said to run the test as far apart from my IVIG as possible and Cell Trend said to do it at the beginning of the week so once I hear back from them with further instructions, I need to figure out the best day of the week to run the test and confirm with a specialty lab that they can do it and confirm with Fedex International. So this process may still take me a while but I am very determined to do it!

Am hoping even if the results do not change my treatment, that they will be informative to my doctors and confirm that I am doing the right treatment path now plus maybe make it less of a struggle with my insurance. Either way, I just want to know!

 

[Groggy Doggy]

I am working on getting the tests from Cell Trend in Germany and finally had the chance to reply to their e-mail this morning with all of my questions.

My doctor said to run the test as far apart from my IVIG as possible and Cell Trend said to do it at the beginning of the week so once I hear back from them with further instructions, I need to figure out the best day of the week to run the test and confirm with a specialty lab that they can do it and confirm with Fedex International. So this process may still take me a while but I am very determined to do it!

Am hoping even if the results do not change my treatment, that they will be informative to my doctors and confirm that I am doing the right treatment path now plus maybe make it less of a struggle with my insurance. Either way, I just want to know!

I am utterly amazed hearing about all of the things you have accomplished this year. I hope you can take a break, pat yourself on the back, and reflect on your progress

GD

 

[Gingergrrl]

I am utterly amazed hearing about all of the things you have accomplished this year. I hope you can take a break, pat yourself on the back, and reflect on your progress

GD

Thank you for the kind words but taking a break from pursuing these health issues is extremely hard for me! I still feel like I have to "solve" what is wrong with me before some imaginary hourglass runs out of sand. I feel like if I do, I can improve my QOL but if I take a break, I will keep worsening (especially my breathing and muscle weakness) and will have lost my opportunity. But that is really for another thread!

 

[Hip]

So here is my understanding of:

Which adrenergic and muscarinic receptor antibodies bring about or contribute to POTS in some people and how do they do this?

POTS
Here A1, B1 and B2 are elevated. A1 blocks receptors for vasoconstriction. This is a bad thing because when standing up, you need a lot of vasoconstriction otherwise all blood pools into the legs. This is what happens when you see all in black after standing up. If it takes longer, you faint.

To avoid this, your sympathetic nervous system (SNS) will try to constrict the blood vessels. This won't work if you have A1 receptor antibodies, which block block vasoconstriction. Hence, the SNS activates more and more, and will try stronger and stronger. Essentially, standing up becomes so stressful as when a healthy person stands in front of a lion. This will make the heart beat more.

Here come in the B1 and B2 antibodies, which will make the heart even more prone to tachycardia. The trick is: Receptor antibodies can be agonistic or dysfunctional. So they activate the receptor or switch it off.

in POTS, the A1 antibody is dysfunctional, the B1 and B2 antibodies are agonistic:
http://www.ncbi.nlm.nih.gov/pubmed/24572257
http://press.endocrine.org/doi/abs/10.1210/endo-meetings.2012.CE.2.OR48-1

There is a preliminary report on elevated levels of M1 and M2 antibodies in POTS patients, however no mechanism is presented as to how these antibodies contribute to the disease:
http://forums.phoenixrising.me/inde...-with-pots-potential-disease-biomarker.44890/

Interesting analysis, @Lolinda.

So because of these autoantibodies found in POTS:

α1AR will be over-activated
β1AR and β2AR will be under-activated

Though if you look at the blood vessels that α1AR vasoconstricts, these are the skin, the sphincters of the gastrointestinal system, kidney and brain (ref: 1).

If you look at this study: The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress; the study found that experimental alpha-adrenergic blockade did not reduce vasoconstriction in the legs on standing up. So if I understand correctly, vasoconstriction in the leg blood vessels is not controlled by the alpha adrenergic receptors.

However, this study and this study talk about α1AR and α2AR-induced vasoconstriction in the legs. So I am not clear as to whether α1AR and α2AR can control leg blood vessel vasoconstriction or not.

 

[kangaSue]

That what I thought!
We all carry hundreds of antibodies.
It would be impossible to scan for all. When you get a positive ANA they may look for a specific but in UK testing for any antibody isnt routine. And youd have to have high numbers for the UK medics to take much notice anyway.

Oxford University Hospital's Neuroimmunology service does specialized antibody testing.
http://www.ouh.nhs.uk/immunology/neuroimmunology/default.aspx

 

[Jemima]

Oxford University Hospital's Neuroimmunology service does specialized antibody testing.
http://www.ouh.nhs.uk/immunology/neuroimmunology/default.aspx

yes, I know of Oxford and had my myasthenia antibodies tested there. Unfortunately you can only get antibody tests done through the NHS in UK.

 

[Lolinda]

Interesting analysis, @Lolinda.

So because of these autoantibodies found in POTS:

α1AR will be over-activated
β1AR and β2AR will be under-activated

Though if you look at the blood vessels that α1AR vasoconstricts, these are the skin, the sphincters of the gastrointestinal system, kidney and brain (ref: 1).

So it does not seem that activation of α1AR will help much to prevent blood pooling to the legs when standing up, because α1AR is not found on the leg blood vessels (the sympathetic nervous system does not extend to the legs, I believe).

If you look at this study: The role of the alpha-adrenergic receptor in the leg vasoconstrictor response to orthostatic stress; the study found that experimental alpha-adrenergic blockade did not reduce vasoconstriction in the legs on standing up. So if I understand correctly, vasoconstriction in the leg blood vessels is not controlled by the alpha adrenergic receptors.

However, this study and this study talk about α1AR and α2AR-induced vasoconstriction in the legs. So I am not clear as to whether α1AR and α2AR can control leg blood vessel vasoconstriction or not.

Thanks a lot for posting these studies!! Now, the first study you cite does not say that alpha 1 does not control vasoconstriction in the leg, but that if the centrally controlled alpha 1 mediated vasoconstriction is not available, then leg vasculature still constricts properly because of redundant mechanisms.
The article abstract is not exactly easy to read for this but there is a comment to the article linked at the bottom of the abstract, which says it clearly. For observing copyright, I PM you with the pdf of the comment text (and anyone else too, just PM me!). The comment proposes a mechanism: "It seems most likely that these results can be explained by myogenic vasoconstriction in arterioles in response to the increase in lower limb transmural pressure."

But this is an academic nuance and it does not change but only confirms your message that alpha 1 block does not make blood go into the legs!

I add that in me there are no swollen legs at all when I stand. After a meal, I am able to get out of bed only very short (increase of heart rate >30bpm, its fairly unpleasant) so I cannot test. But before meals, I can stand. It is not pleasant, but I can. And I never ever have any thick legs.

So then where on earth does the blood go in POTS and OH??
a) to the abdomen & pelvis?
b) to the skin?

update:
http://journal.frontiersin.org/article/10.3389/fphys.2014.00220/full
The following are from the paper text:

In addition, “low-flow” POTS patients had increased splanchnic blood flow compared to healthy subjects (P < 0.01) with upright position (Stewart et al., 2006b). “High-flow” POTS patients had increased pooling in the pelvis and legs versus healthy subjects (P < 0.05 and P < 0.025 respectively) (Stewart and Montgomery, 2004).

Stewart and Weldon confirmed increases in orthostatic leg volume and venous blood flow consistent with excessive pooling in the lower extremities in a pediatric POTS population using strain-gauge measurements (Stewart and Weldon, 2000). They further dichotomized POTS patients into two groups based on lower extremity venous pressure (VP) > 20 mmHg (high-VP POTS) or ≤20 mmHg (low-VP POTS) and found defective vasoconstriction in both groups as evidenced by significantly more blood flow in the calves during orthostasis compared to healthy subjects. While supine, high-VP POTS group had normal arterial resistance but lower blood flow in the lower extremities compared to healthy subjects, and the low-VP POTS group had less arterial resistance and higher blood flow in the lower extremities compared to healthy subjects (Stewart and Weldon, 2001). High-VP POTS patients, also referred to as “low-flow” POTS patients (LFP), had inappropriate vasodilation during orthostasis instead of the vasoconstriction that was seen in healthy subjects and “high-flow” POTS (HFP) patients. The excessive blood pooling in the lower extremities and increased orthostatic leg volume is due to a defect in arteriolar vasoconstriction and not an abnormality of venous capacitance (Stewart, 2002;Stewart et al., 2003). These studies indicate there is an abnormal vascular response in the extremities that predisposes POTS patients to venous pooling secondary to arteriolar dysregulation.

http://ajpheart.physiology.org/content/301/3/H704
increased NO bioavailability in skin -> sounds like a more easy cutaneous vasodilation

==> so all in all, blood can go just anywhere: legs, abdomen, pelvis, and probably the skin.

 

[Gingergrrl]

I add that in me there are no swollen legs at all when I stand.

I have never at any point in this illness had swelling in my legs either. When I sit too long with my feet dangling, the blood pools in my feet and they turn purple-ish but they are never swollen. I do often get pain in my calves but am not sure if this is related? I do wonder if the blood pools in my abdomen/pelvis area like you mentioned and is just not making it up to my lungs when I stand (this combined with the muscle weakness aspect-- and I am pretty sure the two relate to each other-- the dysautonomia and the muscle weakness).

I am looking forward to hearing back from Cell Trend labs soon so I will get the additional info needed to do the blood test. I do feel an improvement after IVIG but am not sure exactly how this all relates. My brain is not quite smart enough to tie it all together or to grasp these articles at the level that you guys do as much as I wish it could!

 

[ryan31337]

Just to chime in whilst on the subject of POTS sub-types and peripheral vasoconstriction etc...this study is salient for me right now:

Postural hypocapnic hyperventilation is associated with enhanced peripheral vasoconstriction in postural tachycardia syndrome with normal supine blood flow
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4511478/

In a nutshell, there's normal-flow POTS patients with and without orthostatic hyperventilation. Difference being greater sympathetic activation and peripheral vasoconstriction in the hyperventilating patients.

I think there's a tendency to overlook/dismiss the quite significant effects of chronic hyperventilation in ME/CFS/POTS because of the association with panic disorders etc. that we don't want to apply. What this paper (and a much more recent one by Stewart showing Cerebral Blood Flow disturbance precedes hyperventilation) is saying is there's a physiological trigger for the hyperventilation. The breathing is usually deep and goes unnoticed as its not the rapid shallow panic breathing that people usually associate with hyperventilation.

I'd guess that regular respiratory alkalosis raises blood pH and hits us with more symptoms, not to mention the Bohr effect ruins aerobic metabolism and then we're even worse off...

 

[Gijs]

@ryan31337, very intersting. If we know what is driving chronic hyperventilation in this POTS/ME group we know the cause.

 

[Gingergrrl]

I am open to whatever happens with the thread and am very interested in how these autoantibodies affect everything from POTS to muscle weakness to breathing to overall ME/CFS. I just want to learn more about the Ab's, potential treatments, and eventually test if I have them (or some of them).

 

[Hip]

Thanks a lot for posting these studies!! Now, the first study you cite does not say that alpha 1 does not control vasoconstriction in the leg, but that if the centrally controlled alpha 1 mediated vasoconstriction is not available, then leg vasculature still constricts properly because of redundant mechanisms.

But this is an academic nuance and it does not change but only confirms your message that alpha 1 block does not make blood go into the legs!

I am a bit confused about this, because if there are additional backup (redundant) mechanisms that kick into action to vasoconstrict the leg blood vessels, even when the sympathetic nerve signals that normally do this are blocked by the α1AR autoantibodies, how can the well-known blood pooling in the legs occur in POTS?

Perhaps the backup mechanisms are not as good at vasoconstricting the leg blood vessels, so that is why there is blood pooling.

I am a bit brain fogged in recent days, so cannot think very clearly at the moment.



(We can keep discussing on this thread, but if any interesting ideas come up, then we could post in a new thread).