jangle

Exercise will improve you, but from my experience it doesn't necessarily last and I believe this is Rama's experience as well.

At my best (mind you I was jogging 5-6 miles + weights + stairmaster + salt water fluids) I would have times when I felt near remission from POTS.

Currently I'm starting to feel better again, but everything fluctuates for me. I had a pretty bad 2 month long relapse.

Rama good points mate. And don't worry we are talking about the something... .

Jangles- pots has so many symptoms that's why it's a syndrome so what ever study says they can induce pots symptom, I don't believe it. What exactly are the symptoms? We all have a mix of tons of symptoms. It's not the same as saying they can induce a heart attack which has very little clinically observed symptoms. I think you are giving that study to much weight. I do however think they probably induced a had full of the same symptoms, but again pheo probably has the same symptoms they induced bet blocking NET. So I think all they proved was NE plays a role, which I think most pots hyper research already alludes to. Maybe this study does go a little further. I just don't think it's a simple matter of the levels we have. It could be a new found sensitivity. I wish there was a way to test to a synaptic chain reaction to neurotransmitters or something like that. For example NE is synthesized by Dopamine yet dopamine levels aren't at higher abnormal level, so that probably means the dysfuction isn't at that stage, but what about the stage after NE is transmitted? NE is most potent acting on a1 receptors? A1 receptors are types of g-protein receptors and Dyfuction of these g-protein receptors have been linked to diabetes, allergies, cardiovascular defects, depression and certain forms of cancer...

One of the best A1 meds I found is Prozosin http://en.wikipedia.org/wiki/Prazosin they use it to treat high BP, anxiety, PTSD, and panic disorder. But here is the problem with a straight of NET/NE issues, NE straight up increase BP by vasoconstriction, some of us have dysfuctioning BP, sometimes it's high sometimes it's low and sometimes it's normal. By decreasing NE by using an antagonist med this causes a lowering a BP, but what happens when my BP is already lowered when I walk. If NE is higher when I stand and walk then my BP should be higher when I do both as well, why does my BP drop when I walk or stand for more than 10 minutes, it can't only be do to NE is my point. We would have a better answer if they did test NE levels at least 6x or so in a tilt and during exercise. The they could say, ahah I can clearly see how everyone's levels are dysfuctioning by going up then dropping and then they can connect the dots..

If infect everyone has different degrees of NET issues or the NET issues are happening in different areas of the body at different levels then wouldn't we need targeted treatments to those areas? More research is needed before I think the docs can target everyone across the spectrum.... That's why I caution you. 1 in 20 btw is not rare, 1 in 100,000 is rare. Would you take Tylenol is 1 in 20 people died form 1 treatment of it? We would have a lot of dead people in just one day... 1 in 2000 is still risky to me, it means if 2 million people took it 100 would die from it.... Maybe some chemo meds have that same risk but what people on chemo are facing is nearly certain death if they don't try it where as I don't think we are in the same boat... I'd have to be 100% sure this was going to cure my pots for life... Then maybe I'd give it shot...

I do think that the base abnormality of POTS is NET deficiency. The subsets are probably explained by additional confounding factors associated with NET deficiency. Some have MCAD, Mito, and/or EDS in addition to other yet to be determined that gives additional factors. Other autoimmune illnesses follow a similar pattern with different people under the same classification experiencing different symptoms yet having relatively the same underlying pathphysiology +/- some other unknown confounding factors. For instance some with lupus have anti phospholipid antibodies which explain the CNS symptoms, whereas others with Lupus have no CNS involvement, but both patients are still said to have Lupus from the underyling common autoantibodies and criteria they share.

I guess it depends on your own individual threshold. For me, 1 in 4 is kinda rare. 1 in 10 virtually never happens, and 1 in 20 is basically like mini lottery odds, but when considering life or death I probably wouldn't do something willingly if I knew there was a 1 in 20 chance of me dying.

1 in 2000 though is two orders of magnitude more rare. That's not something I would even worry about.

I don't know - lol. What I had was a genetic test - are you talking about protein levels?

http://atvb.ahajourn...11.244343.short

What this study found was that although people had normal NET genes, there's something going on acting on the normal gene that is repressing its transcription.

In other words, there's something that's inhibiting your gene from producing enough NET proteins.

I was tested by Vandy for NET deficiency. It was negative. I think they've only found it in one family - if we're talking about the same thing. Isn't this what Linda Smith (the founder of NDRF and she was on Mystery Diagnosis) has?

Naomi are you talking about NET deficiency gene or the actual NET protein levels?

My main concerns with rituximab is that is is being prescribed by doctors who often have an incomplete understanding of the etiologies that they are using it to treat, and ofcourse no one has a clue why it helps the nebulous and ill-defined entity called CFS - an illness based on 'subjective symptoms' rather than objective measurements and a disease that mimics dysautonomias in some ways.

As an example, Vanderbilt found that all the POTS patients they found who also had CFS and those with just POTS were indistinguishable from each other other than increased sympathetic activity in the POTS/CFS group. So its all just speculation - nearly all of the CFS research provides conflicting and confounding results.

I dont think rituximab is an overly scary drug but all biological immuno-supressants have obvious risks. But if the argument is that it would help cytokine regulation then its a long shot since it works on b cells which are actual plasma-based immune cells rather than cytokines.

As Issie has suggested there are many foods that may effect histone regulation of epigenetic gene expression but since our understanding of non methylated regulation of genes is very infantile (from research) its impossible to determine how some dietary substances may effect the gene one way or the other.

Rich - I think your the only one talking about gene therapy and Im not sure what you mean by 'so many levels' and autoimmune issues? Autoimmune v cytokine expression abnormalities - quite different.

Sounds like POTS research. There's articles saying our cerebral autoregulation is preserved, then there are articles that say it isn't. There are articles that say angiotensin ii is elevated, but only in a subset of patients. Then there are articles that say our autonomic nervous system is dysfunctional, and then there are articles that say it is normal and we only have low stroke volume.

The only finding I'm willing to attach myself to anymore is the NET finding, because another study showed that POTS can be induced in normal volunteers by inhibiting their NET.

Certainly I can imagine POTS being dramatic enough to induce PTSD. I don't think I have it as I don't have nightmares, flashbacks, or any of the other typical symptoms.

Although there are different causes of POTS like there are for CFS, I don't think there are many different types of mechanisms. What I mean is, there's many different paths you can take to a building, but in the end there is one building.

Now in the case of POTS, there very much likely are different mechanisms, so it's unlikely to be just one mechanism. But where I'm thinking is that the most prevalent mechanism is NET deficiency. I believe this afflicts most POTS patients as well as CFS patients. In addition to NET deficiency, there can be other things going on in addition to the NET deficiency which explains the additional symptoms people experience. Things like Mito, EDS, MCAD, etc. etc.

It's sort of like Lupus, yes there is a diagnosis of Lupus, but some people with Lupus have CNS involvement. Yes there is a diagnosis of POTS, but some POTS patients have mitochondrial disorders or connective tissue disorders in addition to their baseline POTS.

But I don't think there are many different causes of baseline POTS. If there were, then the NET deficiency study would have observed a large standard deviation in their NET study of POTS patients. The fact that it was small, pretty much says that the overwhelming majority of POTS patients have NET deficiency. Since people with CFS also have orthostatic tachycardia in large numbers, I'm assuming they too have NET deficiency.

Nope, I will not take that.

I did however do isolaz, which I recommend for acne. (But only if you can find someone who does it for max of $150/per)

Interesting to note that only female patients were JHS and POTS.

Jangle I think in the Netherlands they do (that's where I live). I've heard people who were tested for CFS and got a POTS diagnoses as well. We have several CFS clinics here which diagnose both CFS and POTS (or perhaps other forms of Dys like OI). In treating they mostly treat the CFS. I've been wondering what CFS treatment would do for me too but, of course forgot to ask when I saw my Neuro lately.

Oh sorry what I meant was I wish the researchers in that specific study tested their patients for POTS prior to giving them rituximab. This is because it has been shown that a lot of patients with CFS also have POTS, and if the responders (roughly 2/3 of their patient population) had their POTS reduced or taken away, then that would show efficacy for rituximab in POTS and implicate autoimmune etiology for POTS.

It's almost as if one doesn't even need them to have done it. It's a pretty safe assumption a large portion of them did have POTS, in other studies it's well in excess that CFS patients have POTS and there's no way 30 randomly selected CFS patients, not one of them had POTS. But it needs to be "official" we need measurements and objective signs, not just speculation.

Estimates are 25%+ of CFS patients have POTS, and lots more of them have exaggerated tachycardia upon standing suggestive of the same mechanism of POTS.

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0026358

With 2/3 of their CFS patients responding to Rituximab, it seems highly likely that some of those responders had preexisting POTS. If they had POTS, it would have been interesting to see if the POTS also resolved with Rituximab. Interesting to note is that the study population had a very low frequency of detectable autoantibody, most were ANA negative even.

I emailed the authors asking if they tested their patients for POTS, but I doubt they did. It just seems like they should have, they might have been able to help us POTSIES out.

One thing I want to say is that, it is highly possible that these histone modifications are reversible. They have to be, because otherwise we wouldn't observe a significant percentage of people recovering.

If the theory is correct, the remissions from POTS represents a reversion in the histone/epigenetic modification. Unless one argues these people who recover had something else other than NET,

but that seems unlikely given the low standard deviation cited in the study of patients with low NET. (Meaning most of the POTS patients clustered around a lower than normal value for NET.)

Which means that NET pretty much explains the majority of POTS patients' abnormalities.

The most likely explanation for these reversals is a remission of the cytokine/autoimmune attack, but there could be something else to do with the transcription complex.

Rama is correct, Issie. It is unlikely you will find any relevant findings from a serum IL-6 draw. For one thing, CNTF is just one of many IL-6 cytokines, you would need a test specifically for CNTF. However, even this would be flawed, as Rama correctly pointed out, cytokines involved in these types of inflammatory disorders tend to occur locally. For instance in Rheumatoid Arthritis, the increased IL-6 cytokines occur in the synovial fluid.

However, there might be a way to test CNTF concentrations in the sympathetic neural cells, but I do not know of it. Yes Rama I also agree it is worth trying, and I will see if I can get a doctor on board.

Makes me wonder if I have a cyst? I've had two brain MRIs, 5 years apart from each other. Multiple doctors reviewed it and told me it was normal, so I would think someone would have mentioned a cyst - but maybe not?

I'm too afraid to look at the image myself.

Jangle, they do have a genetic team there. I didn't do any testing with them however - 23&me is only $300. That is something you can do on your own and you'd get lots of answers - maybe before you go elsewhere.

Issie

I imagine Mayo could get it approved through my insurance though.

Issie, can Mayo Arizona do genetics testing?

I've called neurologists in my area none have even heard of pots. One neurologist I went to told me to pretend the visit never happened - at least I got my money back. My rheumatologist only tested me for connective tissue disease which I do not have. I don't think I have achr autoantibodies but with the research on cytokines and NET I'd hope Dr. Goodman would be open to the idea.

Ya Arizona girl I got your last PM. I would like to find an immunologist locally, I don't think I have an immunodeficiency, but I do believe POTS is autoimmune. My Rheumatologist is basically ignorning me and I can't seem to find an immunologist who does anything other than allergies.

Even though I don't know the odds of getting Goodman on board some immunotherapy for POTS I figure my only chance is at Mayo, there's literally nothing doing here in Texas.

Well I think I'm going to try Dr. Goodman. I'd like to get my NET gene sequenced to see if it's ok. If it is ok, I'd like to get my IL-6 levels measured and possibly other cytokine levels. Even if those come back normal, assuming my gene test comes back normal I'd like to go ahead and self experiment with a IL-6 blocker to try and increase NET expression.

Hopefully Dr. Goodman is on board the new research.

Do you mean having the experiment done at Mayo?

Yes, but with a drug that's already FDA approved for something else.

Ok, well this doesn't really help me much, I'm 7 years into this. In fact this hurts me because it indirectly affects funding impressions for future research when an illness is thought to go away on its own.

If you want to experiment on yourself and you have the money upfront to do so, will the Mayo Clinic allow you to try assuming of course you have a halfway good idea?

NE reuptake inhibition would cause anxiety/effective NE surges. By losing the ability to remove NE from the synaptic cleft, your sympathetic nervous system stays activated. (It's activated by NE binding the synapse, gets "deactivated" when the NE leaves the synapse i.e. binding sites.)

Really there are two options.

1.) Reduce NE concentration

2.) Increase NE reuptake.

Option 2 would be most preferable as that's being implicated in causing POTS now.

I'm thinking there has to be something in addition to NET deficiency. For instance, one would expect everyone who takes SNRI's to get POTS if NET alone was the causal mechanism. EDIT: Actually this may not be true, reboxetine used in the study is actually a very unique NET in that it binds only NET. The other SNRI's bind other parts of the ANS that might balance out NET inhibition and not cause POTS. Actually reboxetine is having difficulty getting approval in the USA because of its uncertain therapeutic benefit and potential side effects, (which probably includes drug induced POTS).

I believe there is also autoantibodies involved. 15-20% of POTS patients have ACHR antibodies. There's probably other antibodies as well.

Ok thanks! I have been looking at so many different studies I can't keep them straight anymore.

If it only takes a 34% reduction in NET protein, then I think V245I is very close to that. Now what doesn't make sense is how would those with A457P which is >98% reduction in NET protein, not have full blown POTS. Hmmm

It was in the epigenetic POTS study. They posted a picture where they calculated the NET concentration for the control and POTS patients and found POTS patients in their study had about a 34% reduction of NET protein.

It might be possible that even with A457P one could have normal NET expression. What I mean is, maybe the mutation only achieves 98% reduction in NET protein if an environmental cue also triggers it. Now if a person had that mutation and they measured their NET protein to be 98% reduced and they still did not have POTS then that would be confusing.

But really the study where they blocked people's NET protein and it produced POTS pretty much sealed the deal for me already. There's no mistaking that.