neuropathic vs. hyperadrenergic POTS

[MomtoGiuliana]

Radha started a thread asking how a doctor determines whether or not your POTS is hyperadrenergic. I discovered how little I know as I tried to help answer the question.

What I did find on some reading -- and I still may be off on this-- is that there are at least two variants of POTS: hyperadrenergic and neuropathic.

Here is a basic article on neuropathic POTS:

Jacob G, Costa F, Shannon JR, Robertson RM, Wathen M, Stein M, Biaggioni I, Ertl A, Black B, Robertson D,The neuropathic postural tachycardia syndrome. New England Journal of Medicine. 343(14):1008-14. October 2000

Here is the Abstract:

BACKGROUND: The postural tachycardia syndrome is a common disorder that is characterized by chronic orthostatic symptoms and a dramatic increase in heart rate on standing, but that does not involve orthostatic hypotension. Several lines of evidence indicate that this disorder may result from sympathetic denervation of the legs.

METHODS: We measured norepinephrine spillover (the rate of entry of norepinephrine into the venous circulation) in the arms and legs both before and in response to exposure to three stimuli (the cold pressor test, sodium nitroprusside infusion, and tyramine infusion) in 10 patients with the postural tachycardia syndrome and in 8 age- and sex-matched normal subjects.

RESULTS: At base line, the mean (+/-SD) plasma norepinephrine concentration in the femoral vein was lower in the patients with the postural tachycardia syndrome than in the normal subjects (135+/-30 vs. 215+/-55 pg per milliliter [0.80+/-0.18 vs. 1.27+/-0.32 nmol per liter], P=0.001). Norepinephrine spillover in the arms increased to a similar extent in the two groups in response to each of the three stimuli, but the increases in the legs were smaller in the patients with the postural tachycardia syndrome than in the normal subjects (0.001+/-0.09 vs. 0.12+/-0.12 ng per minute per deciliter of tissue [0.006+/-0.53 vs. 0.71+/-0.71 nmol per minute per deciliter] with the cold pressor test, P=0.02; 0.02+/-0.07 vs. 0.23+/-0.17 ng per minute per deciliter [0.12+/-0.41 vs. 1.36+/-1.00 nmol per minute per deciliter] with nitroprusside infusion, P=0.01; and 0.008+/-0.09 vs. 0.19+/-0.25 ng per minute per deciliter [0.05+/-0.53 vs. 1.12+/-1.47 nmol per minute per deciliter] with tyramine infusion, P=0.04).

CONCLUSIONS: The neuropathic postural tachycardia syndrome results from partial sympathetic denervation, especially in the legs.

__________________________________________________

If anyone has the neuropathic variant of POTS, perhaps they can respond and describe how it was diagnosed and what treatments have helped --especially if the treatment is any different for this variant than for hyperadrenergic variant.

I think some to many of us may not know which variant we have? That is my guess. I was never diagnosed with one or the other. The other thing I wonder is whether some of us have a combination of the two.

I also don't know if or how the symptoms differ. Perhaps someone can answer that as well.

Hope this helps Radha!

Katherine

[Guest tearose]

Oh my goodness, oh dear! Now what do we do? Katherine, Radha, but I have both the denervation and the norepinepherine spillover! Please don't tell me that this is an exception.

Here is what I am thinking...This abstract is from 2000. That means the research is probably five years old. Maybe they have learned a lot more and have different ways of naming the kinds of pots/dysautonomias that are now idendified?

I was taught that first they try to figure out the following: "a normal reaction to an abnormal condition" OR "an abnormal response to a normal condition" and then they figure out which chemical or nerves are involved.

To make this clearer: I have an excessive release of norepinepherine which is my body's Normal response to denervation which is my abnormal condition. In someone who has a an excessive release of norepinepherine and NO denervation this would be considered an abnormal response to a normal condition.

I do not know how they intrepret those people who have "receptors" who misintrepret the seratonin and this can also cause pots.

I also thought the " hyper " response could be from other chemical imbalance OTHER than just norepinepherine...seratonin epinepherine....

Maybe Michelle has someone on the DINET advisory board who could share the latest in information with us?

still seeking answers...tearose

[MomtoGiuliana]

Tearose

I am equally, no, probably even more, confused.

The reason I selected this article is that it is referenced by the article on mast cell activation disorder that was just published. I assumed they wouldn't refer to an out-of-date article?

Tearose--your statement below...

"someone who has a an excessive release of norepinepherine and NO denervation this would be considered an abnormal response to a normal condition. "

I am not sure this is completely correct, b/c this excessive release may be a normal response to something other than denervation. I am thinking--hypovolemia would cause this response, but is hypovolemia only caused by denervation?

OK, now I am really getting confused!

Katherine

[Guest tearose]

Well Katherine, let's think about this....not everyone has hypovolemia and denervation. You can have hypovolemia without denervation too.

It would still hold true though, if the "abnormal condition" a defect in the body's ability to hold blood pressure (hypovolemia) brought the "normal response" for chemical release to get heart to pump oxygen to the brain.

I would call this case the "normal response" to an "abnormal condition".

In my previous post I was trying to demonstrate an example of the opposite: An "abnormal response" to a "normal condition"...let me try again....

A person who has normal blood pressure and no denervation and no physiological comprimises is having an "abnormal release/response" of an adrenal chemical in a "normal body/condition"

...from what I learned ...

tearose

[MomtoGiuliana]

OK, I think I have some better answers here now to clarify the definitions! Merrill sent me (again PDF form) the article referenced below. Thanks Merrill!! 2003--which is more current!! I pulled out the relevant material and pasted it below. What surprised me here the most is the statement that only about 10% of primary POTS patients are hyperadrenergic.

This divides POTS patients into two classes--primary and secondary. Within primary the further classification is partial dysautonomic or hyperadrenergic, with partial dysautonomic reported to be far more common. However, the article also states that some primary POTS patients do not fit into either category-- and therefore there are probably other categories of primary POTS as yet undefined.

Even the authors of this paper concede that these classifications are confusing and that there is still much more to be understood. What I pasted in below doesn't get into secondary POTS (caused by EDS, diabetes or other conditions). But the article does describe them.

This looks like a great, basic article that would help begin to answer many POTS questions.

__________________________________________

The Postural Orthostatic Tachycardia Syndrome:

Definitions, Diagnosis, and Management

YOUSUF KANJWAL, DAN KOSINSKI, and BLAIR P. GRUBB

From the Electrophysiology Section, Division of Cardiology, Department of Medicine, The Medical College of Ohio,

Toledo, Ohio

August 2003

Definitions

The wide range of terms that have been used

to describe these disorders have made the literature

confusing... [yeah--no kidding! )

...

Classification and Clinical Features

Not long after POTS was recognized, it became

increasingly evident that the condition was probably

composed of a heterogenous group of different

disorders associated with similar clinical manifestations.

While a number of different classifications

have been proposed, the one presented here seems

to be clinically useful and consistent with scientific

evidence. It should be kept in mind that any

system that attempts to classify natural phenom-ena

is, by its very nature, arbitrary and open to

discussion, debate, and revision over time.

The present authors divide POTS into primary

and secondary forms. The primary forms tend to

be idiopathic and are not associated with other diseases.

The secondary forms are usually seen in association

with a particular disease or are known to

arise secondary to a known biochemical or struc-tural

abnormality.

The primary forms are presently divided into

two major subtypes. The first and largest sub-type

is referred to as the partial dysautonomic

form. These patients appear to be suffering from

a mild form of peripheral autonomic neuropathy

manifested by an inability of the peripheral vasculature

to constrict adequately in response to orthostatic

stress. They demonstrate an increase in

heart rate and contractility while upright that rep-resents

a compensatory mechanism that attempts

to maintain systemic blood pressure and cerebral

perfusion at adequate levels. While in the early

stages of this form of POTS, the increase in heart

rate and contractibility may be fully compensatory,

as the disorder progresses greater and greater de-grees

of peripheral venous pooling occur, and pa-tients

become increasingly dependent on their

skeletal muscle pumps to maintain adequate ve-nous

return. As upright venous pooling increases

there is a progressive fall in ventricular preload

with more baroreceptor unloading resulting in an

increase in sympathetic outflow. Some researchers

have used microneurography and heart rate vari-ability

analysis to measure sympathetic nerve ac-tivity

in this form of POTS, finding that they

demonstrate an overall increase in adrenergic tone

at rest and an enhanced postganglionic sympa-thetic

response to upright posture.22 However,

serum catecholamine levels are usually normal or

are only slightly elevated with upright posture.

Transcranial Doppler studies have suggested that

some symptoms in POTS may be due to an impair-ment

of cerebrovascular regulation.30 One striking

clinical manifestation of the partial dysautonomic

form of POTS will be the development of a deep

mottled (almost bluish) discoloration of the lower

extremities after prolonged standing.28

The majority of patients report that symptoms

began suddenly after an acute febrile illness (pre-sumed

to be viral).2 Other reported precipitating

events have been pregnancy, immunization, sep-sis,

surgery, and trauma.28 Presenting complaints

include palpitations, lightheadedness, extreme fa-tigue,

exercise intolerance, cognitive impairment,

visual blurring or tunneling, and weakness (partic-ularly

of the legs). Less frequent symptoms are anx-iety,

nausea, chest wall pain, coldness, pain in the

peripheral extremities, and abnormal sweating.31

Patients often complain of headaches beginning in

the occipital region of the skull and radiation to

the shoulders. A feature of this form of POTS is

the cyclic nature of symptoms.29 Symptoms often

worsen 4?5 days prior to menstruation. Some pa-tients

may report occasional symptoms at rest as-sociated

with changes in blood pressure and heart

rate unrelated to arrhythmias. Holter monitoring

typically shows a sinus tachycardia, however si-nus

bradycardia has also been seen.

....

A second (and less frequent) subtype of POTS

has been identified where patients seem to man-ifest

a form of ? -adrenergic receptor hypersensi-tivity,

a disorder referred to as hyperadrenergic

POTS.26 While these patients share many char-acteristics

with those suffering from the partial

dysautonomic form of POTS, they have several

unique features. Patients more commonly report

a long, slow onset of symptoms rather than a dra-matic

abrupt one.

Hyperadrenergic POTS patients often com-plain

of extreme tremulousness, anxiety when up-right,

and cold sweaty extremities.22 Some patients

may experience a significant increase in urinary

output after a short time upright. Over half of these

patients will suffer from true migraine headaches

that include a definite prodrome and unilateral (of-ten

frontal) onset with photophobia and nausea.32

Many of these patients will display orthostatic hy-pertension

during standing or tilt and an exagger-ated

response to low dose isoproterenol infusions

while supine (an increase of >30 beats/min after

receiving 1 ?g/min of isoproterenol).33 It is unclear

whether this hypersensitivity is primary in nature

or a manifestation of deinnervation sensitivity.34

Many of these patients appear to have experienced

excessive sympathetic activation in some neuronal

distribution nearly all the time, which is not appro-priately

modulated by baroreflex activity.26 As op-posed

to the partial dysautonomic POTS patients,

the serum catecholamine levels of the hyperadren-ergic

patients are often significantly elevated dur-ing

upright posture (serum norepinephrine levels

are often >600 ng/mL).

It is likely that other

primary forms of POTS will be elaborated over

time, as some patients do not fit well into the

aforementioned groups. About 90% of the pri-mary

POTS patients appear to suffer from the par-tial

dysautonomic form while only about ≤10%

have the hyperadrenergic form (a small num-ber

of patients do not seem to fit into ei-ther

grouping). Robertson et al.35 have reported

that approximately 500,000 Americans may suf-fer

from some form of POTS and orthostatic

intolerance.

[avais1]

Hi all,

Here is information from Dr. Grubb's review in 2002. There appear to many POTS variants, some named, some not. Forgive, the typos, I didn't have the link anymore, so I had to hand type.

1) "The largest group of POTS patients appear to have a mild form of Idiopathic Peripheral Autonomic Neuropathy (a partial dysautonomia) - in which an inability to increase peripheral vascular resistance during upright posture results in excessive compensatory postural tachycardia. Venous pooling appears to be present."

2) "A second group of patients may have a component of Beta-Receptor Supersensitivity. Many investigators have called this HYPERADRENERGIC Orthostatic Intolerance to describe this subset. Many of these patients complain of extreme tremulousness, and anxiety in addition to palpitations and tachycardia while standing. Serum catecholamine levels are quite high (norepinepherine levels are often >600 ng/ml). It is unclear whether this supersensitivity is primary in nature, or due to some secondary denervation supersensitivity. This excessive sympathetic activation is not appropriately attenuated by baroreflex mechanisms. While these patients SHARE a number of characteristics WITH those who suffer from the Partial Dysautonomia Form of POTS, THE HYPERADRENERGICS MORE OFTEN COMPLAIN OF TREMOR, MIGRAINE HEADACHE, AND COLD AND SWEATY EXTREMITIES. "

3) "Recent data have suggested a third type exists - those with Ehlers-Danlos III Syndrome. These patients demontrate reduced vascular reactivity and failure to constrict during upright posture."

4) "The term SECONDARY POTS is applied to those patients with a known autonomic disorder with preserved cardiac innervation depite peripheral outonomic denervation. This can be due to diseases such as diabetes, amyloidosis, Sjogren's syndrome, or Lupus. "

Does this help you guys and gals?

[MomtoGiuliana]

Thanks avais1

this corresponds to everything stated above, except that your material classifies EDS patients differently (as separate from secondary POTS instead of a subset of secondary POTS). It's great to see it all stated again, and very clearly too.

Thanks.

Radha--is this what you were looking for?!

Katherine

[avais1]

Oh too funny! I looked at the time badges on the replies - we must have been typing at about the same time . I think we both were even looking at the same (definitely similar) article . Oh well, better too much than too little info!

[DawnA]

Thanks guys for sharing this valuable information. I guess I fit into the secondary POTS category. I definitely have neuropathy but also have symptoms of hyperadernergic POTS. I have not had any of the blood test. Interesting stuff.

Dawn A

[MomtoGiuliana]

avais--oh yes, I see that now. Well, and I agree, more info is better than less on this confusing topic.

DawnA--I think the two types of POTS do have overlapping symptoms, so it wouldn't be unusual to have symptoms of both. Without the testing, it may not be possible to determine what you have based on symptoms alone (except to guess).

Anyway, like I said before, I am not sure that knowing what type you have generally informs the treatment regime at this point.

Katherine

[calypso]

This is all very interesting. I don't think I fit into any of these categories completely -- since I have hot, dry extremities much of the time (except when my hands are exposed to the cold, which is when they ache and immediately freeze up); I don't have headaches; I am always, always having a high heart rate and only have a mild drop in BP on standing; I do have twitching/tremors; I do have feelings of too much adrenaline; but my EMG shows my nerves are intact and don't have denervation (despite not being able to feel my fingers lately).

I think the bottom line is that POTS attacks our bodies differently because we are all different to begin with. I don't think any of us have the same exact symptoms -- we share certain ones, but have things that are unique or some that are shared with others who seem nothing like us. For instance, I don't have malignant hypertension, but Morgan and I share some symptoms. But then I also share some with Tearose, who has low blood pressure. I have mostly normal BP.

Nevertheless, it's interesting to hear all of this research and debate. At the least, it may give us some ideas on what meds might help us best.

Amy

[morgan617]

I think my overriding is neuropathic, but that I have overlapping symptoms also. I think is quite common just due to the compexities of this disease. My bp never really dropped, it was always a tachycardic problem. Since the ablation, the more my heart tries to increase and can't, the more arrythmias I get. My feet have started turning a mottly color since the sudden drop in my bp, and my knees, I know, that's a weird one. But all this is very interesting. I guess when it comes down to it pots is pots, but it is sort of nice to have some idea of what is going on. My doctor will find this interesting I'm sure. The thing is, all I've had are the most basic tests, which come out normal and so no doctors believe me, but this verifies that. My nephrologist says my body always thinks it's dry even if it's not. Interesting..... morgan

[Radha]

thanks to all of you for your valuable input, its very confusing! i have symptoms of both, have sweaty extremities, terrible headaches, anxiety, but low bp, so i dont know either, and i cant have that blood test done since i cant stand at all, so i guess i will just have to live with unanswered questions, thanks again to all of you for taking the time to explain things,

radha

[StaceyYount]

Thanks I understand a bit more but one question. One doctor said that I had the hyperadregenric form of POTS but I don't think I have ever had my serum catecholamine levels/norepinepherine levels ever taken while I was standing, I did have a 24 urine catecholimine test but I think that is different yes?. I think I have a crossover of both but I guess my question is should I have those tested to see if I do have that form becuase maybe it would be a way for me to be treated wiht something as of right now I am on no meds to treat this due to intolerence.

Hope this makes since my brain is not working!

Stacey

[RunnerGirl]

This is a really fascinating discussion and I appreciate what everyone has contributed. I think Tearose posted something similar on another thread, but here is my understanding of hyperadrenergic autonomic dysfunction, per discussions with various doctors. One of two things is happening in our bodies:

1) We have a NORMAL response to ABNORMAL levels of adrenaline (ie, our bodies produce too much adrenaline either continuously or upon postural changes, etc. and our bodies are simply responding 'appropriately' to that excess adrenaline with HR and BP increases, sweating, feeling anxious, tremors, etc.) The issue here is WHAT IS CAUSING the excess adrenaline. Sometimes a cause can be pinpointed and treated: an adrenal gland tumor (pheo), panic or anxiety disorders, hypoglycemia, etc. can all cause an excess outpouring of adrenaline. Fix the underlying problem and the excess adrenaline goes away. But for many of us, these conditions have been ruled out, and the cause of our excess adrenaline is idiopathic. Maybe it's a chemical imbalance in the brain, but we just don't know. So, we're left with treating the symptoms, not the cause, since we don't know what it is. We take beta blockers to reduce HR and/or BP, we take anti-anxiety meds to curb those horrible excess adrenaline feelings, we take SSRIs because they may help rewire our brains and mitigate symptoms.

OR....

2) We have an ABNORMAL (hyper-sensitive or over-reactive) response to NORMAL levels of adrenaline. I have had my catecholomines measured on numerous occasions and every time they have fallen into the normal range - even when I've been symptomatic (my BP was 160/90 before one blood draw and I was very tachy). So I clearly fall into this second category. But the issue again is WHY is my body so reactive to adrenaline? Are the receptors in my heart's sinus node and along my sympathetic nervous system more numerous, more sensitive, etc. Do I have an imbalance in my brain chemistry that is telling my nervous system to react this way? There are lots of theories, but the fact remains that we are still left with treating the symptoms of excess adrenaline - even though, technically speaking, we don't have "excess adrenaline" - in these cases, too. Beta blockers, SSRIs, benzos, etc. - things to 'tone down' the reactivity of the autonomic nervous system.

All of this is a round about way of saying that it's interesting to know what form of dysautonomia we have, but treatment is still dictated by symptom management. The condition is so poorly understood, in part because, as others have stated, it manifests itself so differently in its sufferers. I look forward to the day when we will be able to pinpoint the cause of our disease (not just the form of it), and ultimately cure it (not just manage it).

RG

[geneva]

Katherine/Merrill, can you post a link to where we can access the full document?

This is a very interesting topic! I am going to try to process the new information and maybe take to my next doctor visit.

[MomtoGiuliana]

RG

Thanks for your excellent summary. You explain very clearly why, regardless of which type of primary POTS you have, treatments at this point are the same, as the goal is symptom control--not fixing what has gone wrong.

This discussion has clarified a lot for me and it is frankly very interesting! Thank you Radha for bringing this question up!

Katherine

[ramakentesh]

If i were to look at those two types of POTS i would say that i probalby fall More into the second catagory, rather than the first - that is i dont have pooling in my legs, i do have hypovolumia and i do have constant hand tremors that are worsened by standing and i get migraine-type phenonema.

My doctor sort of put POTS to me a different way. He said that basically, there are a variety of possible causes - some patients have low blood volume, others have blood pooling, others just have such an overactive response to orthostatic stress that the adrenaline actually further constricts the arteries to the brain resulting in even greater dizziness, and as a result even more tachycardia and tremors.

He feels that the distinctions are just really speculative at present, but that there are three or so different manifestations that he sees. At the end of the day, despite what is causing it, the autonomic nervous system will go into overactivity to compensate - resulting in very similar symptoms.

The thing about the migraines is that POTS causes a type of 'false' migraine. He explained to me in detail how a classic migraine will constrict arteries before it actually dilates them - and in POTS patients there seems to be a mechanism where the arteries go into constriction causing a varierty of odd migraine-like symptoms, but enver result in a true migraine.

He said that most patients find that once POTS is on the scene, a patients migraines will be more frequent, but different.

[leah1321]

So weird thing for me is that I definitely have hyperadrenergic POTS that developed slowly starting from infancy. However, I got mono in high school and developed NCS that was severe for a while and has improved somewhat with therapy. I have recently been diagnosed with Lupus. I think that I do have two very different responses depending on how I am feeling and what I am doing. Sometimes my bp shoots up at first when I stand. Sometimes it stays the same or falls. My heartrate always increases. I have NEVER had anxiety, but I have tremulousness, cold, sweaty extremities, true migraines with a terrible prodrome (and starting in infancy) and high bp at times. I think I may be the person with primary hyperadrenergic POTS who then developed a secondary type autonomic disorder following a virus. Why wouldn't it attack a place that was already affected? I wonder if that makes sense? My docs have always said I was different. I wonder if all of us can be categorized? I feel like everyone is different and it is hard to delineate since I think some of us get adrenaline responses with secondary POTS. hmm.

Leah