Italo Biaggioni, a respected Vanderbilt researcher in the field, has co-authored 100’s of studies on dysautonomia. He was an impressive speaker, at ease and relaxed in front of the room. I felt like I was sitting in his living room.
He noted that the sympathetic nervous system (SNS; flight or fight) is great for action and getting us out of danger but not so good when chronically turned on – which is what’s happening to the most wired and hard to treat postural orthostatic tachycardia syndrome ( POTS) patients of all – the hyperadrenergic POTS subset.
In hyperadrenergic POTS, the sympathetic nervous system is engaged even during rest and sleep.
The parasympathetic nervous system (rest and digest) system should keep the hard-charging SNS under control. After getting all riled up, our systems need time to kick back, relax and heal, but healing time is in short supply in hyperadrenergic POTS. Their systems go pretty much all the time and that includes rest periods and sleep.
In most hyperadrenegic POTS patients, the high SNS activity is a compensatory response to low blood volume and/or to nerve problems that are causing the blood to pool in their lower bodies when they stand. Raj posits that for about 10% of hyperadrenergic POTS patients, though, the brain is producing the SNS hyperactivity.
That high sympathetic (norepinephrine) outflows from the brain are present even during rest suggests these patients are dealing with a primary disorder – not one that is compensating for problems elsewhere. Their blood pressure also tends to be higher than normal when they’re resting (or what passes for rest in this group).
About half of the group also shows evidence of mast cell activation (increased tryptase, methylhistamine). One group of hyperadrenergic POTS patients also carries a genetic defect in a norepinephrine transporter which results in increased NE levels.
Biaggioni thinks maybe 30–40% of people do. Grubb’s 2011 study, on the other hand, found that 10% of 300 POTS patients met the criteria for hyperadrenergic POTS. Zhang’s smaller 2014 study found 50% of children with POTS were hyperadrenergic.
Diagnosis
Grubb’s 2011 study described hyperadrenergic POTS as having an increase in systolic blood pressure of ≥ 10 mm Hg during a tilt table test with rapid heart beat (tachycardia) or serum norepinephnrine levels that were greater than 600 pg/mL upon standing. (The mean standing norepinephrine levels in Grubb’s hyperadrenergic study were 828 ± 200 pg/mL; normal range: 520 pg/mL.)
More recent studies suggest that hyperadrenergic POTS patients have a more rapid heart beat at rest and are more prone to fainting than are non-hyperadrenergic POTS patients.
Home Test
Biaggioni reported that the valsalva maneuver – which researchers do to stress the autonomic nervous system – can be helpful in diagnosing hyperadrenergic POTS. In the hyperadrenergic group, the maneuver – which can be done at home – often causes what Biaggioni called an “adrenergic crisis” consisting of episodic flushing, severe high blood pressure, and tachycardia (rapid heart beat).
- How to do the Valsalva Maneuver – Variations of the Valsalva maneuver exist, but the typical maneuver simply consists of closing your mouth, pinching your nose, and blowing out as if you were clearing your ears coming back down from higher altitudes.
Dizziness, tremulousness, and feelings of fainting more are common in hyperadrenergic POTS.
Signs and Symptoms
High blood pressure (hypertension; 33.3%), migraine (29.6%) and joint hypermobility syndrome (18.5%) appear to be common.
- Do you have joint hypermobility syndrome? Take the Beighton Test
The symptoms in hyperadrenergic POTS are similar to ME/CFS and FM but also different. Fatigue is common (51%) – but not nearly as common as in ME/CFS – and pain is present – but not nearly as prominent as in fibromyalgia.
Zhang found the key symptomatic differences in hyperadrenergic vs non-hyperadrenergic POTS were increased dizziness, headache, and tremulousness in hyperadrenergic patients. (Tremulousness refers to trembling, quivering, or shaking hands, voice, etc.)
The Gist
From 10-40% of POTS patients are believed to have the hyperadrenergic form of POTS. In primary hyperadrenergic POTS the brain produces higher than normal levels of norepinephrine (adrenaline) even when at rest
The high levels of norepinephrine stimulate the fight or flight (sympathetic nervous system) and contribute to the high hearts that occur during standing
Increased levels of dizziness, headache, and tremulousness distinguished hyperadrenergic POTS patients from other POTS patients in one study
If doing the Valsalva maneuver results in a “adrenergic crisis” consisting of flushing, severe high blood pressure, and tachycardia (rapid heart beat).
Hyperadrenergic is a more difficult kind of POTS to treat but drugs such as Ivabradine, Methyldopa, Propanolol and Clonidine which can reduce sympathetic nervous system activity can help.
POTS may not be getting as much funding as chronic fatigue syndrome but it has far more robust treatment activity; compare the approximately 20 drugs in clinical trials now in POTS to the one drug under trial for ME/CFS now.
Note that all of these problems can be caused by autonomic nervous system problems, and probably reflect the more severe ANS problems in this group than ME/CFS/FM patients at large.
- For more on “anxiety” and the ANS check out – When Panic Isn’t: Maggie’s Story
Treatment
Treatment isn’t easy in any POTS subset, but this is the hardest group to treat.
Biaggioni reported that hyperadrenergic patients with and without mast cell activation syndrome (MCAS), can respond to drugs called central sympatholytics which tone down the SNS, such as methyldopa (an old drug) and guanfacine. Trying methyldopa constitutes another fun kind of diagnostic test: hyperadrenergic POTS patients usually do fine on the drug, but other POTS patients get worse.
Because these drugs can be sedating, Biaggioni starts with them at low doses and gives them at a good time to get sedated – at bedtime. Biaggioni said he was trying to get other drugs into clinical trials.
Biaggioni reported that Clonidine not a good choice in this group. It works very fast and very well but when it wears off it can have a rebound effect, causing the SNS activity to snap back – not a good thing in a hyperactive SNS disease. Grubb’s 2011 study, however, found Clonidine to be one of the more effective drugs in a subset of hyperadrenegic POTS patients.
Propanolol – a beta blocker – is commonly used to knock down the sympathetic nervous system. (Beta blockers were the most commonly used drug in Grubb’s 2011 study. SSRI/NERI’s were next (63%).)
If you do well on propranolol, Biaggioni stated that you probably do not have mast cell activation because theoretically it should make MCAS worse. Biaggioni reminded everyone, though, that treatment is an art and the body doesn’t always follow the rules: sometimes propanolol does work in people with MCAS.
Biaggioni reported that everybody’s favorite newish drug in POTS, Ivrabadine, can be very helpful in hyperadrenergic POTS – particularly if a patient’s resting heart rate is high. One mother spoke of the complete turnaround her daughter had in just three days on the drug. The U.S. company making Ivrabadine jacked up the price enormously but it can be gotten cheaply from Canada. The pharmacies up north, Biaggioni said, are every bit as good as those in the U.S.
Check out an Ivabradine Success Story
- Next up – Hyperadrenergic POTS Meet Chronic Fatigue Syndrome Plus the Great POTS / ME/CFS Drug Divide
Articles From the 2018 Dysautonomia International Conference
- 2018 Dysautonomia International Conference I: Small Fiber Neuropathy, POTS, MCAS and Vagus Nerve Stimulation
- The 2018 Dysautonomia Conference Pt. II: Could You Have a Spinal Fluid Leak? An ME/CFS, POTS, FM Perspective
- Dysautonomia International Conference Pt III: The Autoimmunity Revolution in POTS
- “Sticky Blood” – Antiphospholipid Syndrome, POTS, Chronic Fatigue Syndrome and Fibromyalgia – The Dysautonomia Conference #4
Well, you just wrote about my subset type. It is soooooo very hard to deal with. Best way to describe the feeling that too high NE brings with upright posture is “being locked in a room with a hungry lion”. (I borrowed that description from a fellow POTSie. And it conveys the feeling the best of any that I’ve heard.) I didn’t find any of the mentioned medicines to be a long term help for me. I had rebound with several of them. The short term effects weren’t worth the rebound.
Some of us have not only the high blood pressure, but we also have the drops that may put us into a more normal range but with the same response of near faints or complete faints. We can’t treat the high pressures because of the lows – and vica-versa. I was told it is the hardest subset type to treat.
Thanks for bringing POTS more into awareness with your blogs Cort. The more awareness we have, the better chance of research and answers. There are probably more people with these issues and don’t know what’s wrong with them. When someone gets an answer as to What – it’s such a huge sense of relief. Now we just need the answers to WHY.
Issie
Several articles mentioned that this is the most difficult type of POTS to treat. With the possible exception of Ivabradine, I don’t think doctors are too excited about the other drugs. (An Ivabradine trial is under way).
I imagine alot more people have POTS and orthostatic intolerance than we think. In fact, my guess is that OI is present in virtually everyone with ME/cFS but not everyone meets the criteria for the different types. I think its a core problem in ME/cFS,FM and allied diseases.
We need a lot more study on hyperadrenergic POTS and as Lauren Stiles has pointed out, a lot more studies incorporating ME/CFS/POTS and other diseases.
Is anyone looking at a correlation between the autoimmunity directed at adrenergic receptors that’s showing up in recent POTS studies, and the symptoms in this sub-group of high adrenaline/nor-epinephrine POTS patients?
It seems to me that if receptors to adrenaline/nor-epinephrine are damaged, that would account for high circulating levels of nor-epinephrine, and even at rest, as the correlating receptors are responsible for a number of actions in the body (not just smooth muscle contraction of blood vessels to allow for standing). Maybe the brain is making larger than normal amounts of nor-epinephrine in order to get the signal through to stimulate those other functions. That may even include really fundamental things that need to occur at rest and all night, like raising blood sugar.
Furthermore, if just one or two types (categories) of adrenergenic receptors were damaged, and the body had to raise overall serum levels to stimulate those damaged sites, it seems to me that the other receptors in the body that also respond to nor-adrenaline would end up perpetually hyper-stimulated, as a side consequence. So, some adrenaline/nor-epinephrine functions struggling along, while others are being stimulated way too much.
https://en.m.wikipedia.org/wiki/Adrenergic_receptor
This would fit my experiences very well, so I’ve been thinking of having my blood sent to CellTrend fit their POTS autoimmune panel, just to have that information (which includes adrenergic auto-antibodies). But I’ve also just found out that I have markers for APS, and neurological autoimmunity associated with dysautonomia (tested for through the Mayo Clinic’s panel)…so now I’m not sure what to think.
Many interesting new avenues to explore though. Thanks for all of your hard work Cort!
Thanks! You’re on the right track! A group of POTS patients – hyperadrenergic POTS patients – do have problems clearing NE because of a genetic defect with an NE transporter. There are lots of ways to skin a cat. (I just realized what a horrible saying that is!)
https://www.sciencedirect.com/topics/neuroscience/norepinephrine-transporter
Mechanisms of Postural Tachycardia Syndrome – Satish R. Raj, in Primer on the Autonomic Nervous System (Third Edition), 2012
Norepinephrine Transporter Deficiency
The norepinephrine transporter (NET) is a presynaptic transporter in sympathetic neurons that is important for the clearance of synaptic norepinephrine. A specific genetic abnormality has been identified in a kindred with hyperadrenergic POTS [4]. These individuals have a single point mutation that causes a loss of function in the norepinephrine transporter, and the resultant inability to adequately clear norepinephrine produces a state of excess sympathetic activation.
Although this functional NET mutation is infrequent, pharmacological NET inhibition is very common. Many psychotropic and fibromyalgia medications inhibit NET. This includes traditional drugs such as tricyclic antidepressants (e.g., desipramine), and newer medications which are pure NET inhibitors (e.g., atomoxetine or reboxetine). Pharmacological NET inhibition can recreate an orthostatic tachycardia phenotype in otherwise healthy volunteer subjects [5,6].
And
One loss of function NET mutation is associated with altered NE in plasma and intracellular stores, and orthostatic tachycardia. More research is needed to further understand how such genetic variation in NET contributes to cardiovascular disorders in which NET activity is disturbed, such as heart failure. Finally, the observed comorbidity of cardiovascular disease with psychiatric conditions may involve common underlying genetic determinants that include NET.
I can follow MarthaLauren’s idea’s, but starting from a poor blood flow angle.
If blood flow is poor in the capillaries, the endothelial cells and nearby tissue will see low volume of blood passing by per second. If the amount of (nor)adrenaline and other signal molecules would be normal (per volume), these tissues would see very few amounts of (nor)adrenaline and other signal molecules.
As many of them are “consumed” per action they perform, that would lead to very few “action”. In the case of noradrenaline it would present itself almost as really low levels of noradrenaline.
Two common things can be done:
A) increase amount of noradrenaline a lot per volume of blood
B) increase number of receptors in the endothelial cells in order to “capture” a higher portion of the noradrenaline out of the blood
Both option would make it appear to the tissue as having closer to normal values for noradrenaline. Problem is: reduced blood flow is not constant over time and over the body.
Option A) can only set body-wide settings. This makes for poor control as for example the ratio of blood flow in big veins to the blood flow in capillaries is a lot higher in POTS/ME patients then in healthy people.
Option B) can better adjust settings to local needs: more or less receptors grown/created locally.
B) does not deal well with time variance like standing up, exercising or day to night changes. Therefore we need both options combined and still have poor control.
This would lead to increased average noradrenaline levels. In the big veins with decent flow this would resemble high noradrenaline levels. In order to compensate for it the body could trim/remove receptors up there so as the tissue near the big vessels sees “somewhat normal” noradrenaline levels. This trimming, if it happened, might be initiated by auto-antibodies and the immune system.
In the cappilaries, both increased amounts of noradrenaline per volume of blood and an increased number of noradrenaline receptors would be desirable.
It is clear that *if* the body made adaptations like this, it’s no more then a makeshift solution to function somewhat. Stability and ability to regulate processes would be poor at best.
This would result in poor life quality. In the muscles it would also result in a lot of variation of how the micro-fibers react to commands as it would be totally dependent on hard to control parameters such as local blood flow and amount of receptors per tissue. Movement would be clumsy, painful and energy inefficient. The local variations could easily cause local cramping and the inability to “relax” the muscles.
In the brain, varying blood flow plus varying amount of receptors would make the individual neurons response to a given signal noisy/unpredictable. That would decrease brain functioning drastically. It would also result in unpredictable response to stimuli, leading to easy overstimulation of the brain by pain, sight, hearing…
When a certain brain region is activated, higher local blood flow in combination with more signal molecules (increased body wide to compensate for poor blood flow) and higher number of receptors could create a “stimulatory bombing”.
In exercised muscle something likewise could happen to pain: increased local blood flow, increased number of “local sensors” to detect chemicals indicating damage and easy to damage/overstrain tissue could create very strong pain spikes.
All of the above would be an undesirable situation that needs healing. A normal healing reaction, like one that happens when there is only local or short lasting damage, could be to restore blood flow and simultaneously already start reducing the number of receptors (for example by use of auto-antibodies). On plus it could trow in a small amount of chemicals stimulating receptor growth, for when the healing is slower then expected and receptors were trimmed too fast.
That may sound an odd way of reasoning, but the body uses this “dual approach” very often. Think about having always both activating and sleep generating hormones or always having pro- and anti-inflammatory chemicals in the blood. The net effect is determined by ratio’s. This method of control is a more robust one leading often to better results then the “only one action/chemical at a time” approach.
This approach could work well to heal most problems as long as they are not body wide and long lasting…
In POTS/ME/FM patients this resembles a vicious circle of poor blood flow, high amounts of damage, a strong immune response to clean up the damage, even worse blood flow and damage as a collateral effect…
I see your point dejurgen. It’s easy for me to forget how something so fundamental, like a lack of sufficient blood flow, might account for so much by itself, including (but not limited to), as you point out, muted chemical signals, excessive damage, and insufficient opportunity for healing. That is a big deal.
I think the fact that we know these things about ourselves for years (that we have POTS, blue feet, etc.) but the wider research/treatment communities don’t sit up and take notice and take them seriously…I always end up feeling like there must be something else more important that isn’t understood yet. But maybe, in some cases anyway, the very things that so obviously appear to be interrupting our lives (and our basic ability to function)…really are. Thanks for that reminder!
Thanks again for an other informative article Cort. I have a question which is slightly off piste, but is PEM a feature of any other illness apart from ME/CFS? Sometimes when I read a list of symptoms, I might struggle to fit the criteria eg sore throat – well yes over the years, but not right now. For me, the whole nub of my problems is PEM, and it seems to me that that is what this illness is all about. Thanks heaps 🙂
I get PEM, but have FMS And EDS. So I think that’s where the PEM comes in.
Issie
I think we’re in the same boat Michelle. For me the most prominent symptoms are PEM, fatigue and pain. Every since I became ill I’ve thought that in order to understand ME/CFS what we need to do is to have a massive study, get the participants exercise and then measure every darn thing they can think of over the next couple of days – that’s how central PEM is for me. I do think PEM is present in other disorders like FM and POTS but not to the same degree.
One study which assessed symptoms before and after exercise found more fatigue in multiple sclerosis and not nearly as much PEM and more PEM in ME/CFS and not as much fatigue.
PEM has so far been found to be a unique feature of ME/CFS as demonstrated by 2 day CPET. Other illnesses can have symptom flares but PEM is kind of different in the sense that it is delayed (so hard to pinpoint what the cause might be), completely disproportionate to whatever caused it, can permanently lower baseline, and usually comes with a slew of new symptoms — not just a flare of current symptoms.
Eg. I have had chronic illness like Fibro, EDS and dysautonomia since childhood and can confidently say that all the flares from that felt completely different to what I experience now that I have ME/CFS and PEM.
For me, blocking the effects of NE are way worse. I do feel it is a compensatory response and necessary. I tame my response down some with 2 medicines not normally even considered for POTS. But it works for me. I haven’t found any other meds or supplements to work as well. I use a combo of very, very low dose Tramadol and Bentyl. When the low dose stops working, I cycle off it and then back on to maintain its affect. I have hyper coagulation issues and find that vasodilation is better for me (to a degree) and keeping my blood thinner. I’ve also found abdominal binders to be better than leg compression. Though I wear both when I travel.
Issie
That’s interesting, to think the excessive vasodilation may be an intentional compensation for the passage of thicker blood. How complicated. The more I know, the more I know I don’t know.
I agree with you. My daughter was diagnosed over a year ago with POTS. I am familiar with Dysautonomia. My friend has it.
Now there is a new Pots called hyperagenic Pots. This is very confusing for me. I work in Special Education. I have seen many chronic diseases and conditions.
But this o e baffles me.
Does the Tramadol do anything other than block pain?
Since i have said “more than one way to skin a cat” for many years, it made me feel a bit better to learn that the phrase actually refers to skinning a catfish 🙂
🙂 Good!
Yes, Tramadol does more than help pain. I have pain, but I don’t take enough of it to help with pain. I take it to calm my autonomic nervous system. It tweaks all the neurotransmitters. Before it was put into an opiate catagory (catagory 4) – they weren’t sure exactly how it worked. It was given off label to some who SSRI and SNRI didn’t help. (Some POTS people find help with those.) I personally couldn’t take them. Throwing one or two transmitters out of balance messed me up even more. I haven’t been able to figure out exactly why it helps me. But I’m guessing that some of the sympathetic response is due to imbalance in glutamate/GABA (NMDA receptor). Along with this it can affect calcium channels. I have found that I have some mutations in TRMP3 calcium channels. Also, GastroCrom is a mild calcium channel blocker and is a mast cell stabilizer. The addition of GastroCrom was a turning point in how I felt.
Tramadol can also work on seratonin, dopamine and norepinephrine. It covers/affects all the neurotransmitters. It along with Bentyl – which is a mild muscle relaxer has been my best help. (I’m careful with Bentyl as it can be a depressant. It is given to people with IBS usually. And affects cholinergic balance. Tramadol can also affect this function.)
Tramadol can be addictive. I use a very low dose and when I notice it isn’t working, I come off it for several weeks to a month and then go back on 1/2 of a 50mg pill and go up to max of 1 to 2 pills a day. Usually only 1. These were prescribed to me 4 times a day. They could have been raised in strength from 50 mg. To 100mg. But, as I said – I don’t use them for pain…..I use them to tweak my autonomic nervous system. It works for me.
I do have NE levels above 800. Above 600 is where they put you into a hyperadregenic subset catagory.
I haven’t kept up with latest research on NET genetic dysfunction. But several years ago there was only one known family with it. We all thought there must be more with issues there. But at that time, none of us could confirm if it was an issue with us genetically. We just knew we had too much of it. We also were looking at all our symptoms as being a bad thing and something that needed to change/end. But as science has advanced some of us realized that our “symptoms” are “compensations” and the lessor of the two evils. Sometimes what feels bad may actually be saving us. For example; Tachycardia, as uncomfortable as it is – helps our heart pump blood to our heart and head. It pulls it away from lessor needed areas to get it to the most vital places for life. If we can aid our heart with its pump, by pumping with our legs, it assist and there is less need of the hard pumping of the heart. But, some people are so bad they can’t stand up and thinking of using their legs is beyond even a thought. If you can get an in-place pedal bike, and sit on your couch, and get your legs to pump some – it will help. It is a slow process – but it does make a difference. Few of us get diagnosed with having a heart “problem” – but all of us have tachycardia as a symptom of POTS. It’s not based on your blood pressure (though that helps determine your subset) it’s based on how high does your heart rate go.
Issie
That is so interesting Issie. Thanks for all the info. I had no idea.
I took Tramadol for the first time last week. It did help with my pain but what was really fascinating was how much my cognition and energy improved (!)….
Who knew? These drugs effect so many systems that labeling them as being pain relievers or antidepressants or whatever just doesn’t do them justice.
Tramadol and Bentyl both have a vasodilator effect.
Issie
I think the problem here is that ‘hyperadrenergic’ POTS is defined differently by different researchers, hyper pots patients have as many QSART abnormalities as supposedly non hyper POTS patients and POTS by definition is itself a hyperadrenergic state.
This delineation doesnt really tell you that much about why the condition is present unless the patient fits the ‘Low Flow’ subset with a mechanism that has at least some evidence. All the other supposed mechanisms are conjectural and far from demonstrated with objective evidence.
In normal people NET inhibition results in reduced sympathetically mediated vasoconstriction in response to tilt, not hyperadrenergic features.
Anecdotally many ‘hyperadrenergic’ patients respond to medications that increase volume status and or venous return.
I tend to agree with Mayo’s assessment that hyperadrenergic POTS is probably a phenotype of compensatory or exaccerbating sympathetic excess with still an underlying abnormality in venous return, stroke volume or alpha 1 receptor sensitivity.
Too many assumptions, too little evidence in my opinion and I know some researchers feel the same way.
If true central hyperadrenergic POTS had a central origin then why would it be postural? Wouldn it just look like a hyperadrenergic form of essential hypertension or baroreflex failure?
If a subset of patients were purely suffering from the effects of low blood volume then why arent these patients back up running marathons on Florinef or saline infusions?
I think the work on Alpha adrenergic and angiotensin ii receptor antibodies in POTS probably provides the most rational explanation of POTS and its phenotypes which might be dependent on aab titer variations.
Time will tell but most patients who think they are ‘hyper’ probably arent actually helped by clonidine or methyldopa – most respond better to volume explansion and/or venoconstriction.
You’re further along with this than me but I was struck by how messy it all is. It’s hard from the literature to differentiate primary hyperadrenergic from secondary hyperadrenergic from autoimmune from non-hyperadrenergic from NET transporter issue POTS from low blood volume POTS patients. My guess is that there’s a tremendous amount of overlap between these groups. We really need large studies which examine all these factors and identify the subsets that are present.
Neither hypovolemia or high NE levels are found in all POTS though – just 29% fulfilled those criteria in a Mayo clinic study – https://www.ncbi.nlm.nih.gov/pubmed/21906029
As for the comments on blood pressure; arterial blood pressure readings do not tell you a whole lot about venous return, cardiac refill and stroke volume which are the problems in POTS.
Inadequate venous return.
Agreed! If I have it right that seems to be what Systrom is finding – it’s problems with the veins – but the POTS field hasn’t yet gloomed onto the effectiveness of exercise studies.
This fascinating field needs a lot more money. The thing I really like about POTS in contrast to ME/CFS is that POTS researchers have found the main issue – problems with the autonomic nervous and cardiovascular systems. If they can get more money my bet is they could really make a lot of progress.
@Rama -“Too many assumptions, too little evidence in my opinion”. I so agree! I don’t think they have gotten to the WHY yet. And base most treatments on symptoms. I’m a bit of a rebel when it comes to what they generally use. I disagree with many treatments. Most of them I have tried extensively, some more than once – they didn’t “fix” anything.
“arterial blood pressure readings do not tell you a whole lot about venous return, cardiac refill and stroke volume” – this is true! Mayo does have a test that checks this and is done by a doctor who specializes in the veins and their functions.
@Rama, glad you are still around. Hope you’re doing better.
Issie
Cort, anybody,
I read with special interest about the single point mutation on SLC6A2 being linked to hyper-POTS. I have the attributes of hyper-POTS although I have not been formally diagnosed.
What I want to know is what is the proper genetic address of this mutation and the DNA to RNA (C>T etc.)translation and also its effect (missense,splice region etc.), so I can look up my SLC6A2 variants to see if I possess it?
From my exome, I have printed out my 88 variants related to this gene and looked around the Internet but have found this particular piece of information either paywalled, or if I look in ClinVar, there are too many variants (which are involved in controlling autonomic function) on SLC6A2 which are either ‘of unknown significance’ or even ‘pathogenic,’ to know which one specifically the researchers are referring to.
Can anyone help?
Thank you for this article and for the very informative and well articulated comments.
My daughter, wife, sister-in-law and father-in-law all have sever Orthostatic Intolerance but, so far, only my Son has POTS. My Daughter’s OI is very sever and I wonder about how taxing that must be on her system, the constant flush of norepinephrine needed to pump blood throughout her body and into her brain. She is almost 15 and healthy.
Cort has chronicled the success my son had with sucrose Iron infusions (he no longer needs them) and below is a blog that my wife and son put together about his journey. He is 17 now and doing well – I feel so horrible for all those not progressing in the same fashion and wish you all the very best.
I remember searching the web for hours and hours and hours when my son first became ill with “virurally induced fatigue” and told to go home. I could not find one success story on the web. There are some now. Fingers crossed, my son is a success story and we put the blog out into the public not to show off, but to provide hope for those who find their way to this site and to this article.
https://saltwaterrunrepeat.com
Thanks Eric
Here’s a link to an article I wrote on Eric’s son’s success.
https://www.healthrising.org/blog/2016/08/23/iron-man-young-persons-pots-mecfs-recovery-story-pt/
I recently saw with dismay that Mayo’s iron sucrose trial was terminated. Why? They stated that it was because they couldn’t find participants. Over four years just three people participated in the trial. I just cannot understand this.
https://clinicaltrials.gov/ct2/show/results/NCT01978535?recrs=h&cond=Postural+Orthostatic+Tachycardia+Syndrome&rank=1
Recruitment Status : Terminated (Difficulty in recruiting subjects.)
First Posted : November 7, 2013
Results First Posted : November 17, 2017
Last Update Posted : November 17, 2017
How disappointing and how interesting that other members of your family can have OI issues and remain healthy.
Hi. First, thanks much for writing and posting summary of the 2018 conference; refreshing to read an excellent reporting of science.
For now, just a clarfication of something. You mention that “Raj” says that about 10 percent of hyperandrenergic pots have the presumed primary type where brain just produces too much including during the night and not in compensation for anything. Question is who is Raj? (earlier in the article, you mention the Vanderbilt researcher). I assume Raj is not his nickname. so someone else? or maybe a typo? Thanks much. (that’s the type I think I have btw)
🙂
Satish Raj -now leads the Dysautonomia dept in Calgary.
https://www.dinet.org/physicians/raj-r62/
Awesome. Thanks much for his name and link. Too far away to get to, but will look up some of his papers.
Very nice article, Cort. Thank you. I came across it doing some research and glad I did.
Re the genetic link to H. POTS: I believe it was Issie who mentioned the mutation in the SLC6a2 (Norepinephrine Transporter, NET) gene above. As she said, many were tested for the same mutation that was found in that one family, but researchers were not able to find it in others. They stayed with that gene, however, because it just made sense, and they were recently rewarded. Researchers in Australia found that a portion of the gene had been silenced, rather than having a mutation, an inheritable epigenetic issue. They also found a medication which could reactivate the silenced portion of the gene. Their research is sited in the article at the link.
https://neurosciencenews.com/fainting-disorder-neurology-6293/
Thanks Gail!
I’m so happy to see this is finally a recognized disorder. After becoming ill and after the 12 specialists I saw were unable to dx me, I did some hardcore research and pretty much figured it out out of desperation (hyper-POTS and MCAS). I then asked my GP to do orthostatic testing. She said she wouldn’t have believed it if she hadn’t seen it herself.
I used those results to get an appt. at the dysautonomia clinic at Stanford, but the doctor I saw put me on the tilt table test and after 5 minutes said he’d seen enough, said it wasn’t POTS because presumably POTS only makes your blood pressure drop, didn’t know what it was, had no idea why my feet were purple, and tried to put me on blood pressure meds. He was very into POTS, but only standard POTS.
Sigh. He was my 12th doctor and best hope. I was also dx with antiphospholipid syndrome in 2004 when trying to conceive (which I finally did with the assistance of Lovenox, and after giving birth was told to just take a daily baby aspirin).
What kind of doctor should I look for to help me manage this?
I would guess another dysautonomia specialist. Dysautonomia International has a list of them. Maybe you’ll finally find a good one! Good luck!
Hi Ann Carol,
I recently went to UT Southwestern in Dallas and saw Dr. Vernino. I went through the whole autonomic testing (which I failed for HR but not BP) and then had tons of bloods tests, most notably one where my norepinephrine levels were checked lying down and standing. This got me the diagnosis of hyperadrenergic POTS that my autonomic testing suggested. Getting the diagnosis was definitely a huge step, but finding out that we have no idea what’s causing it and we have no serious plan of action yet is frustrating. I have Crohn’s disease as well, and had high ANA but no other autoimmune markers. I’m on guanfacine and while it had major effects at first, it’s back to where I’m almost on a placebo as my body has seemingly overridden the results. He was wonderful in the amount of time he spent with me as he was incredibly thorough, but unfortunately no answers or path to figure out the issue at this time for me either.
Hi Mike – did you try Ivabradine by any chance? No studies yet but word of mouth is good.
Hi i have also hyperadrenergic what i should the best treatment.thanks rolan
Hi Carol
I understand where you are coming from. I did not give up and got my HUTT results knowing they did show the massive rise even though the letter to my GP and self said neg for POTs. I am now seeing a specialist in Hypertension who has effectively diagnosed what I know already, but won’t say the words until he has checked all medical details. He redid the basic standing test, massive rise and just said I know what you have, I will get the test results from your cardiologist and get some treatment started in less than two weeks. That was nearly 3 weeks ago. My cardiologists, 7 looked at my results apparently, did not take into account the drug/food sensitivities, beta blockers included, chronic arthritic and other inflammatory conditions (20 years and still can’t decide on a diagnosis), hypermobility, peripheral neuropathy and goodness knows what else. they only told him I was an interesting and unique case that they had never seen before. So I have had to get information from my neurologist, rheumatologist and everyone else and get it through to my cardiologist, info he should have collected in the first place, before trying to dump me 😉
Keep trying, get a referral, there are a list of centres and as Cort says a list of specialists with an interest in dysautonomia. You can also look for the european centres of excellence in hypertension (ESH), they may have a faster referral and carry out research so they like interesting cases. It was only 5 weeks, referral letter date to appointment, to see the Professor at Manchester for me.
https://www.eshonline.org/communities/excellence-centres/directory-of-excellence-centres/?country=United%20Kingdom
Good luck
My BP stays the same, my HR increases, i have episodes of fainting/near fainting, constantly lightheaded, breathless, fatigued,in pain, palpitations, shaky 24/7. Today i fell but i didnt quite faint, i was dizzy and my legs just went haywire so i stumbled backwards onto my butt.. after i fell my BP went UP. I was told it shouldve went down… laying down my hr was 90, standing was 125- i fell and then it was 101. Bp laying and standing was around the average 120/60 but after falling it was 131/94.
Thats what I feel like, such a crazy feeling.
Hey Cort, Is guanfacine still the best treatment for this or has ivrabadine proven to be more successful? Has treating mast cell activation with cromolyn sodium ever corrected a hyperactive sns for those who have mcas?
I wish I knew. I don’t know about guanfacine – I just don’t know it. I would certainly give Ivabradine a try and Cromolyn…Good luck!
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I hope that you are still reading your comments in September 2020. Besides the extreme physical issues Pots create, do you also experience extreme anxiety that lasts. It wakes me up. It stays in my body and this all started 6 years ago when the Pots symptoms had increased to a huge level.
I wouldn’t be surprised if that is not uncommon (unfortunately). Your sympathetic nervous system (fight or flight) is apparently wired, wired, wired.
I was diagnosed with Hyperadrenergic POTS and also have fibromyalgia. When dealing with anxiety, is it better to go with an SSRI and stay away from SNRIs due to the already high levels of norepinephrine? Does anxiety cause the hyperadrenergic diagnosis (does anxiety cause it, or does it cause anxiety)?
I don’t know about the drugs but I would very much thing that a biologically caused increase in the fight/flight system would produce anxiety.
Hello,
I have hyperpots syndrome. And now I am giving DNRS a try to fully recover from it. Has anyone else here try DNRS for their hyper pots syndrome?
Thanks! –Dori
Have you experienced any success or relief?
I had Covid in November 2020. Developed tachycardia a month and a half after acute symptoms. Lightheaded, dizzy, never passed out. I’ve slowly felt better so I don’t get dizzy anymore and I am able to walk and do light exercise. Still have tachycardia and toes turn blue sometimes. Nerve pain and now within the last week I have developed adrenaline surges. They happen during the day and at night. I haven’t been able to sleep. It’s very concerning. I’ve lost my appetite. I’ve seen a cardiologist but he just doesn’t have an answer. Just started taking propranolol which helps the heart rate but hasn’t stopped the adrenaline surges. My doctor will probably say it’s from anxiety. I’m just starting this journey and not sure where to go from here. I can live with all the other symptoms but the lack of sleep it quite concerning.
Good luck Carol! Have you tried Ivabradine?
I appreciate the willingness of this author (and study author) to attempt to describe subtypes at all. It’s a politically charged, under-studied area because the autonomic nervous system can’t be visualized with the naked eye (allowing insurers and special interest groups to dismiss it). What’s more, what’s demyelination small nerve fibers (and sometimes large nerve fibers) is politically charged. The current power-structure has chosen the one-symptom, one-pill model (assuming they choose to even engage with a patient, which many hospitals will not if they don’t want to). That’s code for “at-risk population.” Autonomic nervous system dysfunction is anything but rare.
Tests to better characterization and visualize small nerve fiber damage are not routinely covered by Medicare, Medicaid, and many other “Obamacare” / “RomneyCare” plans. That’s because we decided to let the insurance industry and big business decide the health of America instead of providing basic, direct medical coverage (to include diagnostics that capture root-causes).
Trying to identify subsets of patients in this umbrella disease of dysautonomia (and associated autonomic dysfunction) is challenging. Patients often present with multiple causes and will not fit nicely into one category. The state of science in this field is a bit of a joke…what is the state of science in human experiment on the patients chosen to be experimented on versus the ones completely dismissed versus ones chosen to be stabilized?
Neurology reform is desperately needed. Insurance reform is desperately needed. Some skinny, nerdy dweeb with virtually no human skills and a luxury vehicle (the teaching hospital neurologist) shouldn’t dangle the statistics on this growing population (or decide who lives or dies). One such neurologist purposefully lowered one of my client’s heart rate variability tests by over 30 points. It’s easy-to-manipulate data. These nerds must go (and their backers and dorky residents who are their gofers).
A database of compounds (including supplements) that stabilize fluid dynamics needs to be available to the public…basic nutrients like acetyl-l-carnitine (active in the brain) that supports healthy neurometabolism needs to be provided or reimbursed (like flex spending accounts for Medicaid and Medicare).
I have this too. I’d love to know if you had success with this, thank you!!
This article has made me question my hyperpots diagnosis. I DO NOT EVER get dizzy or faint. I feel perfectly fine 80-100% of the time laying in bed. When i stand (tilt table met hyperpots diagnostic) though, ANY activity causes racing heart, high blood pressure, sweating (especially in the face and neck/chest back is a close second), shortness of breath, widespread pain, fatigue, exhaustion, and severe dehydration. Im sure im missing some symptoms, but again, i have never once ever fainted or felt dizzy, not even close. Its like i fit everywhere and nowhere simultaneously. I know its Dysautonomia, but i swear, its like i have my own personal version no one has named yet. Also…my voice. Its deeper and “gravely” than it used to be. My hair is in a perpetual state of overall thinning and brittleness (ponytail is 60-80% thinner than pre-illness) and ive gained weight, but that could be attributed to the ovarian cancer i had during my illness (and the exercise intolerance that prevented me from exercising the weight off).
All i Do know is (if this helps) before i got sick:
1. I was severely abused by ex who loved trying strangle me to death
2. I had a blocked lymph node (looked like a silly putty egg under my skin in my neck) that required multiple antibiotics and eventual drainage with a needle to cure
3. My first symptom was unexplained, profuse sweating around my neck at the chest and my face.
I went years with just the sweating symptom before the fatigue started to set in. Then the cancer and surgery to cure it, fully disabled me. Full on dysautonomia from that point. I walked into the hospital, i left needing a cane to this day (8 yrs ago now). I live in bed in between any activity at all. And i am only treated with pain meds which ACTUALLY CALM SYMPTOMS in addition to treating the pain (i also have a ton of nerve and spine problems from 2 falls and the decade of beatings).
So…anyone have any clue? What can my doc test for next? No i cannot go to cleveland or mayo clinics, im poor, on medicaid in philly.
Please please please help
I can be reached on gee-mail (writing weird so it remains in post) SanFran 876 without the spaces. So i know you arent spam, make subject dysautonomia help please & thanks!
My Dr just replaced my Codeine with Tramadol as a PRN pain med (I also deal with breakthrough pain that responds well to codeine). But as a person with HPOTS, wouldn’t Tramadol be the worst thing because it increases norepinephrine levels? I just discovered this on YouTube before trying it, which is not a good look for my Dr. Thanks YouTube! Any ideas on this from y’all?
Thanks!
Cort,
I read the above comment about psychiatric disorders and hyper POTS correlation. What exactly is the correlation? I have (mild) borderline personality disorder. I’ve always been impulsive and reckless, though I am very high functioning. I’ve had a horrific time with not just the POTS related disorders but vasculitis and more AI, now extensive AVN, and I recently became very depressed. I had given up my career for my family then became very ill from grief and trauma. I took a drug overdose last spring and couldn’t believe what a low point I’d reached. I was furious at my mother whom I care for, adrenaline rushing through my veins. I was so blinded by the anger I swallowed a whole bottle of pills. When I came to my senses I could not understand why I’d done such a thing… but I was not in control of my actions at all at that moment. I’m having horrific cardiac after effects and I’m not going to make it. I need some sort of physical explanation for my terrible actions to heal my family. I worry about my hyper POTS and ADD son and HIS impulsivity. I’m going to forward this and whatever other info I can find to his psychiatrist; perhaps he should be on one of these other medications for his POTS and anxiety other than Zoloft. THANK YOU.