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Research on how adrenergic & muscarinic receptor antibodies cause symptoms in POTS, OH and CFS

kangaSue

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@kms1990 I am so glad that @kangaSue replied b/c I was not sure of the answer and didn't want to guess and tell you something incorrect! It does not appear that autoantibodies are the issue for you but my understanding, like KangaSue's is that you can be seronegative on some of them.

@kangaSue I asked this in another thread (now am not certain which one?!) but are "anti-neuronal" and "paraneoplastic" antibodies just two terms for the same thing or do they actually mean two totally different things? Have been trying to understand this from posts on PR and Google search but still unclear! I think different countries may also use the terms differently adding to my confusion?
Having a paraneoplastic syndrome involves having anti-neuronal antibodies so they can get referred to as paraneoplastic antibodies but you can have anti-neuronal antibodies without having a paraneoplastic syndrome.
 

Gingergrrl

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Having a paraneoplastic syndrome involves having anti-neuronal antibodies so they can get referred to as paraneoplastic antibodies but you can have anti-neuronal antibodies without having a paraneoplastic syndrome.
Thank you so much for explaining this @kangaSue! So if I have those two auto-antibodies, would you say it is most accurate to say that I have anti-neuronal antibodies (vs. paraneoplastic) since so far, there is no cancer found to indicate that I have a Paraneoplastic syndrome?

I've heard of cases where there were just a few cancer cells and the body destroyed them before any tumor/cancer could be detected but the antibodies still got produced. I have absolutely no idea if this occurred in my case but would that be a more accurate scenario to also say "paraneoplastic abs" vs. "anti-neuronal abs"?

Thanks again!
 

kangaSue

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Personally, I think it's something of a misnomer to refer to it as paraneoplastic antibodies and I would just call it as anti-neuronal antibodies. According to the literature, if you have had the anti-neuronal antibodies for more that 4 years, chances are very high that it is not a paraneoplastic syndrome so then the paraneoplastic abs term no longer applies
 

Gingergrrl

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Personally, I think it's something of a misnomer to refer to it as paraneoplastic antibodies and I would just call it as anti-neuronal antibodies. According to the literature, if you have had the anti-neuronal antibodies for more that 4 years, chances are very high that it is not a paraneoplastic syndrome so then the paraneoplastic abs term no longer applies
Thanks, KS, and that is incredibly helpful. I have been referring to my auto-antibodies as "paraneoplastic" b/c this is the term that the doctor used who ran the tests (who is not my regular doctor and not someone I will ever be seeing again). I think I am going to use "anti-neuronal" from now on unless I forget b/c I am so used to the other term.

In my case, I had the auto-antibodies on the test in Feb 2016 (so 100% I have had them for one year) but I was never tested prior to this so I do not actually know how long I have had them. I have heard that you should have the cancer checks for up to five years before you can rule this out but this seems like a very long time to me to keep exposing yourself to high doses of radiation.

My main doc (and some very smart friends!) all feel that since I have 11 auto-antibodies total (and not all of them are anti-neuronal like the two Hashimoto's Abs), that it is more autoimmune chaos vs. a cancer/paraneoplastic syndrome (where you are more likely to just have one or maybe two auto-abs total). This makes sense to me so I am not obsessing about the cancer but at the same time, it is often in the back of my mind on some level and I will continue the lung cancer check at least for 2017.
 
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Thank you both for your replys.

@Gingergrrl - I believe paraneoplastic refers to a syndrome caused by cancer. The cancer causes autoantibodies itself and produces them. From some of the recent medical reviews I have read, the paraneoplastic antibodies are much more "insidious" and damaging and can cause long term irreversible damage very quick. IE/ weeks.

It seems like the autoantibodies that are anti-neuronal but NOT caused by cancer are then not paraneoplastic. Instead they may be very similar but produced at lower levels, or the same but caused by the immune system instead of tumors. In these cases it seems treatment helps and sometimes even reverses the disease, whereas with the paraneoplastic syndrome things go down hill very quickly and sometimes even treatment does not help.
 

Gingergrrl

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From some of the recent medical reviews I have read, the paraneoplastic antibodies are much more "insidious" and damaging and can cause long term irreversible damage very quick. IE/ weeks.
I had not heard that and read some stuff (back when I was first diagnosed w/these Auto Abs), that someone could have a paraneoplastic syndrome for up to five years before any cancer is detected. This never quite made sense to me and I still find it confusing!

It seems like the autoantibodies that are anti-neuronal but NOT caused by cancer are then not paraneoplastic.
That makes more sense to me and I am hoping mine are the non-cancerous, anti-neuronal ones!

In these cases it seems treatment helps and sometimes even reverses the disease, whereas with the paraneoplastic syndrome things go down hill very quickly and sometimes even treatment does not help.
Maybe this is why I have had improvements from high dose IVIG? No doctor has said that I have a paraneoplastic syndrome (PNS) but they have said that I have paraneoplastic auto-antibodies. I think different docs just use different terms and this entire concept is still relatively new.
 

pibee

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My main doc (and some very smart friends!) all feel that since I have 11 auto-antibodies total (and not all of them are anti-neuronal like the two Hashimoto's Abs), that it is more autoimmune chaos vs. a cancer/paraneoplastic syndrome (where you are more likely to just have one or maybe two auto-abs total). This makes sense to me so I am not obsessing about the cancer but at the same time, it is often in the back of my mind on some level and I will continue the lung cancer check at least for 2017.
I didnt test much except CellTrend, Hashimoto ab, and ENA/ANA. I'm positive for 10 of those (8 CellTrend, Anti-TPO and SS-A).
I am very convinced my dad had paraneoplastic syndrome, and even my uncle who died recently. My dad developed psychotic symptoms at age 45 first time (which is a red flag when accepted in mental institution to screen for cancers, which they didnt), and he was there on and off for 2 years. Since he was war veteran they were going in a direction of PTSD, but it was long since war and it didnt fit clinical picture so the conclusion was it's more than PTSD. He died from lung cancer within 2 years, and lung cancer is especially known to cause paraneoplastic syndrome.
Very similar thing happened to my uncle, mom's brother, at age 60, first psychiatry, within 1-2 years death from lung cancer.


So it doesnt surprise me I have so high anti-neuronal scores, especially because I have big psychiatric and cognitive (more than CFS brain fog) component.

I'd even say after a bit of reading my very high M1, M4 numbers could be more linked to mental symptoms than to CFS. Even though I have also CFS, it is not extreme, more moderate.

Many studies on significance of M1 and M4 in psychoticand cognitive functions disorders

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3913542/

The efficacy of AChEIs observed in patients with AD highlights the potential of cholinergic modulation in treating both cognitive- and psychosis-related behavioral disturbances. Furthermore, administration of nonselective muscarinic antagonists can induce cognitive deficits and psychosis in humans,16,37 indicating that mAChR activation may provide pro-cognitive and antipsychotic efficacy. Accordingly, several mAChR agonists have been developed and have entered clinical testing with the goal of ameliorating the behavioral and cognitive deficits observed in numerous psychiatric diseases. Of these, the M1/M4-preferring agonist xanomeline was the only one to progress to a phase III clinical trial, where it was assessed for efficacy in ameliorating cognitive deficits observed in AD patients. While xanomeline showed a trend toward improving cognitive function in these patients, this effect did not reach statistical significance.
 
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kangaSue

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I didnt test much except CellTrend, Hashimoto ab, and ENA/ANA. I'm positive for 10 of those (8 CellTrend, Anti-TPO and SS-A).
I am very convinced my dad had paraneoplastic syndrome, and even my uncle who died recently. My dad developed psychotic symptoms at age 45 first time (which is a red flag when accepted in mental institution to screen for cancers, which they didnt), and he was there on and off for 2 years. Since he was war veteran they were going in a direction of PTSD, but it was long since war and it didnt fit clinical picture so the conclusion was it's more than PTSD. He died from lung cancer within 2 years, and lung cancer is especially known to cause paraneoplastic syndrome.
Very similar thing happened to my uncle, mom's brother, at age 60, first psychiatry, within 1-2 years death from lung cancer.


So it doesnt surprise me I have so high anti-neuronal scores, especially because I have big psychiatric and cognitive (more than CFS brain fog) component.
You might want to consider getting the equivalent of the Mayo ENS1 panel run. It covers all the main antibodies known to be related to a paraneoplastic syndrome but also checks for NMDA receptor antibodies which can cause cognitive and psychiatric issues too.
https://www.mayomedicallaboratories.com/test-catalog/Overview/48401
 

pattismith

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interesting that M1 and M3 are important for REM sleep (and for dreams)...And:

"Identification of Candidate Allosteric Modulators of the M1 Muscarinic Acetylcholine Receptor Which May Improve Vagus Nerve Stimulation in Chronic Tinnitus"

Discussion

We hypothesized that allosteric activation of M1 receptors in the circumstances of increased cholinergic neurotransmission to the auditory cortex by targeted VNS, will provoke an increase of M1 mediated effects:

(1) Neuromodulatory action of BDGF and NGF (Da Penha Berzaghi et al., 1993) in neuronal zones adjacent to the tinnitus;

(2) Neuromodulatory action on frequency specific neuronal zones enabling the recruitment of pathologically active neurons back to the physiological pattern of activity;

(3) Regaining the physiological tonotopy (Zhang et al., 2006) of the auditory cortex;

(4) Recruitment of novel neurons from undifferentiated neuronal pools in the hippocampus (VanDeMark et al., 2009) and

(5) The dendritic and axonal “rewiring” of the tinnitus “subnetwork” (De Ridder et al., 2014b).

The AQVN/EIIP approach was applied previously for the selection of new candidates in pharmacotherapy of the vasovagal syncope (VVS) revealing that the majority of antimuscarinic drugs might have a therapeutical potential for VVS. In this study sequential virtual screening criteria were applied, first the AQVN/EIIP based filter for the selection of candidate allosteric agonists of the M1 receptor selecting 50 drugs out of 1463 approved drugs from the DrugBank (http://www.drugbank.ca; Wishart et al., 2006). This step was followed by 3DQSAR analysis and finally docking.

The screening identified bromazepam, estazolam, and flumazenil as the most promising drugs which could be repurposed as allosteric agonists of the M1 receptor.

Bromazepam and estazolam are known anti-anxiety agents with a hypnotic effect. Flumazenil has specific antibenzodiazepine action and is used as an antihypnotic agent in circumstances where the benzodiazepine and nonbenzodizepine hypnotic effect has to be reduced.

If we expand the concept to other methods of treatment of tinnitus (invasive or noninvasive; Vanneste and De Ridder, 2012), it is reasonable to propose that pharmacological facilitation of neuromodulatory changes by the in silico identified drugs in our investigation in tinnitus network structures would be beneficial even in these treatments. Future clinical studies of the combined M1 allosteric agonist therapy with VNS and potentially other invasive and noninvasive methods of chronic tinnitus treatment will reveal the final answer regarding their synergistic action.
 

Gingergrrl

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@Gingergrrl I've had a positive VGCC P/Q-type antibody test, and am just looking into all the calcium ion signalling stuff. Would you mind sharing where the CA+ group you mentioned is hosted and how I can join it, if it still exists? Thank you!
Hi @ChloeC, it is a private group on FB and I will send you the info shortly via PM. Did you test positive for the P/Q type calcium channel autoantibody on one of the Mayo Panels? Were you also positive for the N-type? What symptoms and diagnoses do you have (only if you are comfortable saying of course)!
 
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Did you test positive for the P/Q type calcium channel autoantibody on one of the Mayo Panels? Were you also positive for the N-type? What symptoms and diagnoses do you have (only if you are comfortable saying of course)!
Yes, I tested positive for it (but not for the N-type) on the Mayo Paraneoplastic (PAVAL) panel, which Dr. Systrom ordered for me back in February as a screen for neurological autoimmunity. The P/Q-type CC autoantibody was the only positive one (at .04, normal is <.02) from the panel.

Dr. Systrom referred me to Dr. Khosro Farhad because of it, but I didnt get in to see him until 2 weeks ago-- which is super frustrating, cause it sounds like there is a specific LEMS drug I can likely benefit from, which would have been nice to be on the last 8 months!

I tried to get Dr. Farhad to order the CellTrend tests or any other neuromuscular/dysautonomia autoantibodies there might be out there that weren't on the PAVAL panel, but he gave me a line I hate hearing from doctors: "What's the point of doing more testing if it won't affect your treatment?" His point being that the positive CC antibody is enough of a rationale for insurance and of a medical indication for starting IVIG (or really SCIG i think?), which would also treat any other autoantibodies I may or may not have.

But, um, Id like to know what is going on with my body! Especially since the IVIG is a second-line treatment to start if the LEMS drug (3,4-dap) doesnt help enough, whereas if I knew I had other autoantibodies that have no drug treatment available, Id push to start the IVIG right away. Not to mention baseline numbers are helpful to evaluste the success of treatment, knowing a certain symptom is due to a certain cause means you can stop going down all the other rabbit holes, etc.

My main diagnosis is ME/CFS, along with a diagnosis of dysautonomia based on the iCPET results showing heart preload failure (unmeasurable right atrial pressure!). In the dysautonomia area I also have POTS sx (tho my TTT was officially "negative"), and stuff like hypohidrosis, constipation, and dry mouth/nose. I also have muscle weakness and coordination issues that started out mild but have progressed significantly over the past year or so. You can read about the rest of my symptoms in my intro post: https://forums.phoenixrising.me/threads/still-processing-in-boston-and-nyc-former-lurker.75698/

I have more to say, but not the energy to say it, sigh. So glad to have these awesome threads to learn from!
 

pattismith

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@ChloeC that's a shame you had to wait so long, but you are now in good hands!

Does Dr Farhad want to start IVIG right away, or does he want to try the firstline treatment before?
or maybe you are waiting for the insurance answer for IVIG?
 
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My understanding from the appointment was that he wants to start the LEMS drug 3,4-dap first and see how that goes. Im eager to start it, but need to do a repetitive nerve stimulation test and brain MRI first to establish a pre-treatment baseline, and its proving absurdly difficult to just figure out how to schedule those. (I recently saw him in NH, but live in MA, so he said to do the tests at MGH, but its unclear whether he alresdy ordered them or just planned to later, and now both the NH and MGH offices are telling me only the other one can help me, sigh.)
 

Gingergrrl

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Yes, I tested positive for it (but not for the N-type) on the Mayo Paraneoplastic (PAVAL) panel, which Dr. Systrom ordered for me back in February as a screen for neurological autoimmunity. The P/Q-type CC autoantibody was the only positive one (at .04, normal is <.02) from the panel.
Thank you so much for your detailed reply @ChloeC and your PM. I initially learned that I was positive for the N-type Calcium Channel Autoantibody on the PAVAL Panel from Mayo in 2016. I was positive at .05 and later when re-tested on the DYS1 Panel (also Mayo), I was positive at .06. I was negative both times for the P/Q calcium autoantibody. I am so thrilled to learn that more doctors are now testing for autoimmune causes of neuromuscular issues and of dysautonomia.

Dr. Systrom referred me to Dr. Khosro Farhad because of it, but I didnt get in to see him until 2 weeks ago-- which is super frustrating, cause it sounds like there is a specific LEMS drug I can likely benefit from, which would have been nice to be on the last 8 months!
I am not familiar with Dr. Farhad and will definitely Google him. I am sorry that it took eight months to get an appt. I had tried to get a consult with a different doctor who worked with these autoantibodies but she was closed with a 2.5 year waiting list at the time! But she was very kind to reply to my e-mails and was very helpful.

I tried to get Dr. Farhad to order the CellTrend tests or any other neuromuscular/dysautonomia autoantibodies there might be out there that weren't on the PAVAL panel, but he gave me a line I hate hearing from doctors: "What's the point of doing more testing if it won't affect your treatment?"
You can order the Cell Trend tests on your own as long as any doctor just signs the form approving the blood draw (although this may vary from state to state). My main doctor found the Cell Trend results to be helpful in my case b/c I tested positive for 7 out of 9 autoantibodies and we ran the test twice (prior to starting treatment). I also tested positive (on Mayo Panel) for anti GAD65.

My doctor ultimately felt the same as yours though and we stopped testing for autoantibodies once I had eleven of them! He said that even if I had more (which he assumed that I did), it would not have changed the course of my treatment plan which was high dose IVIG and then Rituximab.

His point being that the positive CC antibody is enough of a rationale for insurance and of a medical indication for starting IVIG (or really SCIG i think?), which would also treat any other autoantibodies I may or may not have.
I agree that for insurance purposes, if you are trying to get IVIG, they will accept the LEMS diagnosis (although they may still try everything in their power to deny you b/c IVIG is such an expensive treatment). IVIG will work on autoantibodies even if they are not specifically labeled yet (so even if you are positive for the Cell Trend Abs, the treatment will still help prior to you knowing). I hope that makes sense!

But, um, Id like to know what is going on with my body! Especially since the IVIG is a second-line treatment to start if the LEMS drug (3,4-dap) doesnt help enough, whereas if I knew I had other autoantibodies that have no drug treatment available, Id push to start the IVIG right away.
That is interesting that he was going to start you on 3,4-dap and I assume this means that he feels that you have a definitive LEMS diagnosis? Is he basing it solely on the P/Q autoantibody, or on an EMG & nerve conduction study, or on clinical symptoms/criteria? The gold standard is the "single fiber EMG" (which I did not have and wish that I did back in 2016).

When I sent you the info via PM re: the N-type Calcium Channel Ab group, I should have also sent you the info on a LEMS group that I also participate in. Many of the members of that group are on 3,4-dap or Firdapse. But others are on Mestinon, IVIG, Rituximab, etc. There is a lot of variation and they would be able to give you a lot of good feedback.

Not to mention baseline numbers are helpful to evaluste the success of treatment, knowing a certain symptom is due to a certain cause means you can stop going down all the other rabbit holes, etc.
Does this mean that you feel your diagnosis is LEMS vs. ME/CFS? I had been given a diagnosis of "CFS" by 5-6 doctors in 2013 and 2014 and it was not until I tested positive for the calcium autoantibody in 2016 that my doctor started to really re-think if I had the correct diagnosis. Some neuros feel that you must have the P/Q Ab in order to be given a LEMS diagnosis but others feel that the N-type Ab is equally sufficient. There is also sero-negative LEMS.

I also have muscle weakness and coordination issues that started out mild but have progressed significantly over the past year or so. You can read about the rest of my symptoms in my intro post: https://forums.phoenixrising.me/threads/still-processing-in-boston-and-nyc-former-lurker.75698/
Thank you for linking to that and I missed your intro post when you originally wrote it. I skimmed through it last night but am planning to read it in more detail. What is your muscle weakness like? Does it affect your breathing (lungs and diaphragm strength)?

My understanding from the appointment was that he wants to start the LEMS drug 3,4-dap first and see how that goes.
That is interesting and he must feel fairly certain that LEMS is your diagnosis.

Im eager to start it, but need to do a repetitive nerve stimulation test and brain MRI first to establish a pre-treatment baseline, and its proving absurdly difficult to just figure out how to schedule those.
Will you be having a high resolution lung cat scan to rule out small cell lung cancer (SCLC) in case you have the P/Q Ab as part of a paraneoplastic syndrome or cancer? These calcium Abs often link to lung cancer or LEMS but I don't want to sound alarmist and they are also often due to random autoimmunity and no cancer is ever found (like in my case). I have done three lung cat scans and no cancer was ever found.

In Feb, it will be four years since we discovered I had the Calcium Ab (and I may have had it longer but just did not know b/c I hadn't been tested for it prior to 2016). Some studies say to have the lung cat scans for five years but my main doctor did not think it was necessary in my case and that three years was adequate (and it is a lot of radiation). I also do regular mammograms and pap smears and recently did a colonoscopy (but the link is to lung cancer).

Also, if you can and it is not too late, I would request the single fiber EMG which is the gold standard test.

and now both the NH and MGH offices are telling me only the other one can help me, sigh.
That is so frustrating and I hope you can get this straightened out :bang-head: