MomtoGiuliana

calypso I may be incorrect, but what I infer from the researcher's direct response to me was that even people with Mast Cell Activation *symptoms* may do ok with conventional treatment--only b/c you can have the symptoms (flushing spells), yet not actually have the MCA problem. Regardless, it sounds like this urine test (to be done immediately after a spell) might be in order for you. Hope you can talk to your doctor about that and figure out how to do the test. take care, Katherine

This is a complicated and sensitive subject and this has been such an interesting discussion. In my opinion, the bottom line is that if you have POTS it MAY be difficult to separate at times whether the anxiety you are experiencing stems from POTS or from another source of dysfunction. But, regardless, it is good to recognize that you do indeed have this symptom (as avais1 says--let's not make "anxiety" a bad word--I do so agree). If it continues to be a problematic symptom--seeking medical treatment is a prudent step. It may be that POTS meds alone, that aren't per se, for treatment of anxiety, may help relieve the symptom for you (in the long-term, that was the case for me, I believe). There are also drugs that are safe and effective for treatment of anxiety. I used Xanax (and many of us have) when my POTS was very bad, for short-term relief. I also know from my personal experience that certain lifestyle changes and habits--e.g., meditation, exercise/yoga, learning breathing exercises. biofeedback training--can help, at least to some degree, over time. There may be other meds/treatments that will help you, and a doctor should be able to help. This has really already been said, but I'll just add that I know that when I was really sick, and didn't know what was wrong, the last symptom I wanted to describe to any doctor was anxiety. I believed that if I did that, my other symptoms would be discounted. I think a good number of us went through this and became programmed to deny this symptom for the pure reason that we wanted a proper diagnosis and that the medical community seems so quick to diagnose women in particular with anxiety disorder/depression. Thus, one reason it is a sensitive and difficult subject for some of us. It's also sensitive b/c in our culture, although attitudes are changing, we tend to believe that mental conditions are ones we bring upon ourselves--the patient is more likely to feel at fault for their symptoms/condition--which of course is completely unfair. But, importantly, as some others have pointed out, not all POTS patients have anxiety as a symptom. Unfortunately, as POTS patients in particular, we have to learn to accept so many unknowns and things barely understood. This is a hard skill to master. Faced with that, though, it is probably best to take care of ourselves by addressing our current symptoms in whatever ways end up being most helpful, and not to dwell too much on the past or worry about what we might have done differently to avoid developing this condition. Katherine

Christine Would you describe these as muscle cramps? I get bad muscle cramps in my lower legs and feet from time to time--but worse and more frequent when my POTS was bad. What helps me (I think) is to increase magnesium a bit. There are magnesium supplements available. I use a powder form that I stir into juice when I feel I need it. (You might want to seek medical advice on this--you certainly don't want to overdose on magnesium either.) It certainly makes sense that low potassium would cause pain like this as well. I have almost chronically, slightly low potassium, (at least when my POTS was significant this was the case) so I always make sure to eat lots of fresh fruit and veggies each day. I also used to get body twitching like you describe--especially when resting/lying down. That for me corrected itself/went away over time. I think that is a pretty common POTS symptom. Katherine

Wow, I can't understand this either--except that he isn't your treating physician? And with all the testing of subjects he does, I could see that getting involved with disability claims could become time-consuming. Can you see a local electrophysiologist and see if they can help you? My electrophysiologist is an autonomic dysfunction specialist. He definitely understands that POTS is more than fatigue and tachycardia for some people. When I was incapacitated by it, he gladly completed the needed paperwork for me to go on temporary disability. I had no problem getting temporary disability thanks to help from him and his staff. A local neurologist with experience in this should be able to help you too. Katherine

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

Welcome Christine. How exciting it is to be thinking about starting a family. I wish you the very best in that. I am glad you found us, and hopefully we can help provide some of the support and information you are looking for on this topic. Our experiences with pregnancy all vary A LOT, and there have been MANY discussions on this forum in the past on this topic. Here are some links to previous threads to get you started: http://dinet.ipbhost.com/index.php?act=ST&f=1&t=201 http://dinet.ipbhost.com/index.php?act=ST&f=1&t=1094 http://dinet.ipbhost.com/index.php?act=ST&f=1&t=514 http://dinet.ipbhost.com/index.php?act=ST&f=1&t=238 After reading through these, if you still have questions, we can try to answer them! Katherine

I think it is thought that in some cases, yes. In my personal experience, both one of my sisters and I have POTS. I can only think it is more than accidental coincidence that we both have it.

An SSRI (zoloft is one of them) did wonders for me post partum. I was also bedridden at times late pregnancy through post partum. (I think I would have been better without the trauma of the c-section.) My daughter's pediatrician said no to breastfeeding and the SSRI, so I stopped breastfeeding at 4 months when I started the SSRI. In retrospect I wish I had done more research on my own before making that decision, since my electrophysiologist disagreed and said I could continue with low risk to my daughter. Anyway, glad to hear that she is improving with zoloft. That is great news. Katherine

I think it is pretty well established that anxiety does not cause POTS. It's the other way around--anxiety is often a POTS symptom. While in general it is also true that stress can exaccerbate illness, I think there is no evidence out there in research land that shows that stress itself definitely *causes* particular illnesses. Sadly, I think some doctors talk us into thinking that our POTS symptoms are caused by stress. I was told I was stressed out and depressed for months prior to my accurate diagnosis. Anyway, if you are interested, here's a web site (the about.com pages) that I find helpful and accurate for answering basic questions, like this: http://stress.about.com/od/chronicconditions/ I would also add, that working to reduce stress in your life can only be helpful to your health. Meditation, yoga and other practices can really help. If you are still feeling anxious on a regular basis, it would be worth discussing this with your doctor. I saw a psychologist for awhile when I was quite sick for the sole purpose of learning relaxation techniques through biofeedback. It helped me tremendously. Some additional thoughts--Do you think it is possible that, rather than being anxious for no reason, that your anxiety that started as a child was actually caused or greatly exaccerbated by having undiagnosed POTS? Also, POTS patients can have trouble swallowing--as the autonomic nervous system plays a role in that. In any case, please don't feel that you brought POTS upon yourself. Besides the fact that this is not likely, you can't change the past, you can only start to work on changing your approach to life now. Take care, Katherine

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

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

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.

Tearose--good idea. I am particularly interested in what might be happening while I am asleep. The thing is this stuff is SO variable that a 24-hour monitor might not be terribly informative? I mean I have days where my hr seems absolutely normal all day, and others where it is suddenly all over the place again. It is definitely all tied up with my menstrual cycle and fluid intake. Well, something to ask my specialist about when I seen him this summer! Katherine

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

Thanks so much everyone, for your responses. I seem, like many of us, to often have a heightened awareness of my heartbeat. So I notice both excessive tachycardia and the short-lived brady, but usually without other symptoms these days. tearose--like you say, improving fluid and electrolyte intake always seems to even things out at least a bit! Katherine

I hope for the best for you and your son and family. It is so natural to fear the unknown and be anxious about your child's health. I agree with Ernie that understanding about this condition is improving all the time. Treatments WILL be better for his generation than for ours. I worry about my daughter, too, since POTS is in my family, so I do understand your worries and fears. And we do all know that while POTS CAN greatly affect our ability to do some to many things, it is not going to end our lives. Hopefully your son will end up with only a very mild case. Not everyone experiences severe disability with POTS. Good thoughts your way... Katherine

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

ramakentesh I agree with your line of thought b/c I also thought that all POTS is hyperadrenergic (see my last post in this thread). I was hoping someone more knowledgeable, or someone with a non-hyperadrenergic variant, would respond to clarify. Anyway, here is a quote from the recent article on mast cell activation disorder in some POTS patients. This states there are (at least) two variants of POTS--one neuropathic and one hyperadrenergic. This sentence is in the introduction of the article: "In the neuropathic variant, the primary defect is thought to be a partial autonomic denerva-tion that compromises lower limbs with exaggerated ortho-static venous pooling,1 and perhaps the kidneys with low levels of plasma renin activity.2 Patients with the hyperadren-ergic variant are thought to have centrally driven sympathetic activation.3 Here are the references to the above statements from the article: 1. 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. N Engl J Med. 2000;343:1008 ?1014. 2. Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni I. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system. Am J Med. 1997;103:128 ?133. 3. Jordan J, Shannon JR, Diedrich A, Black BK, Robertson D. Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension. 2002;39:173?178. The answers to Radha's questions *might* be available in these articles, if no one else can completely answer them. I think tearose has already explained the conventional testing for the hyperadrenergic variant. If someone can't stand at all though--as Radha states--how do you do this test?! Can it be partially done (just not the standing part?) This is probably a question for a specialist. Katherine

Good for you! My original response/post was either deleted or never made it. Katherine

Sure Ernie--send me a personal message with your e-mail address. Yes tearose--an important symptom that appears associated with MCA disorder, besides significant flushing episodes, is high blood pressure in the upright posture.

BTW, I don't know what I was thinking yesterday when I offered to mail the article to anyone--I can also e-mail it as an attachment to you. It is in PDF format. I converted it to paste in to this thread, but that made it lose all formatting. Just send me a private message with your e-mail address, and I will e-mail the attachments to you. (there is a supplemental that I didn't paste in here, as well). Regarding diagnosis and treatment for someone with mast cell activation disorder, I would only add again what the researcher wrote to me on this yesterday: "The patients we described had episodes of obvious severe flushing in the face and neck. Even in these patients, only half had documented mast cell activation (with elevated urine methylhistamines immediately after a spell). Depending on the patient, we have been successful in treating hyperadrenergic POTS with aldomet alone or in combination with fludrocortisone. Only some patients require more targeted therapy against mast cell activation, which requires medical supervision."

These are great. How about Singer in a choir, wearing a long robe in a warm, packed church, standing on the top steps of the choir stand. I have sung in choirs since a child and ALWAYS hated being put at or towards the top. I always felt a bit unbalanced in that position. Once as a teenager I did nearly pass out during practice!

Here is the text of the article. It is minus the tables of course (except one that I attempted to paste in--but I am afraid it is confusing due to lack of formatting), but perhaps this will be helpful to peruse, regardless! I didn't include the abstract since that is already available at the link above. It is six pages, plus a 5-page supplemental and I would be glad to copy and snail mail it to anyone who needs it for $1.75 for the whole thing (enough to cover postage and copying costs! ). ________________________________________________________ Postural tachycardia syndrome (POTS) is a disabling condition that commonly affects otherwise normal young females. This disorder is characterized by symptoms of fatigue, tachycardia, shortness of breath, and even syncope on standing. The etiology is not clear, but 2 possibilities have been proposed previously. In the neuropathic variant, the primary defect is thought to be a partial autonomic denerva-tion that compromises lower limbs with exaggerated ortho-static venous pooling,1 and perhaps the kidneys with low levels of plasma renin activity.2 Patients with the hyperadren-ergic variant are thought to have centrally driven sympathetic activation.3 A circulating vasodilator could produce reflex sympathetic activation, presenting clinically as ?hyperadrenergic? POTS. In our evaluation of patients with POTS, some described flushing episodes associated with orthostatic intolerance. On the basis of this observation, also reported by others, we hypothesized that activated mast cells may provide a source of circulating vasodilators in a subset of patients with hyperadrenergic POTS. If true, histamine and other mast cell mediators could play an important role in the pathogenesis of this syndrome. There is a wide spectrum of disorders associated with mast cell pathology. Mastocytosis is a common term used to define abnormal proliferation and accumulation of mast cells in 1 or more body tissues. The clinical manifestation is produced by episodic release of mast cell mediators in response to specific stimuli 8 and can follow either an indolent or aggressive course ranging from circumscribed cutaneous involvement to life-threatening mast cell leukemia. In 1991, Roberts and Oates described the clinical syndrome of idiopathic mast cell activation (MCA).9 In this condition, there is no evidence of mast cell proliferation, but patients are disabled by episodic MCA, documented by accumulation of mediators in plasma or urine. Patients with this syndrome typically present epi-sodes or ?attacks? of flushing accompanied by palpitations, lightheadedness, dizziness, shortness of breath, occasional nausea and diarrhea, headache, and syncope. Here we describe patients disabled by persistent orthostatic intolerance and evidence of MCA. These patients often present with a typical hyperadrenergic variant of POTS and biochemical evidence of MCA. _-Blockers should be used with great caution in these patients, if at all, and treatment directed against mast cell mediators may be required. Methods Subjects We evaluated 177 subjects referred to the Vanderbilt Autonomic Dysfunction Clinic for disabling orthostatic intolerance who were studied as inpatients from January 1995 to January 2004. A patient was considered to have an MCA disorder and POTS (also known as orthostatic intolerance) if they met the following criteria. (1) Long-standing (_6 months) disabling orthostatic intolerance; (2) an increase in heart rate of _30 bpm within 5 minutes after assuming a standing position; (3) absence of an underlying cause (debilitating disease, substantial weight loss, prolonged bed rest, previous history of any disease producing peripheral neuropathy, or any medication impairing autonomic reflexes); (4) a history of facial or upper trunk flushing (defined as objective and intense facial redness witnessed by a physician or caregiver); and (5) urine methylhistamine _230 _g/g creatinine associated with a flushing episode.9 Patients were classi-fied into 3 separate groups. Eight young female subjects met the criteria of MCA and POTS (MCA_POTS). An additional 5 patients were identified as having similar characteristics, with the exception that they presented with orthostatic hypotension (OH; identified by a decrease in systolic blood pressure of _20 mm Hg or in diastolic blood pressure of _10 mm Hg; MCA_OH). We thought it impor-tant to include a group of 16 patients with a history of POTS with facial flushing but no evidence of MCA (documented by absence of increased urine methylhistamine, POTS). This provides a compari-son group to determine whether the presence of MCA modifies the clinical presentation of POTS. We also include a fourth control group of 12 normal, healthy, age-matched females. Procedures All subjects were admitted to the Vanderbilt General Clinical Research Center and were fed a low-monoamine, caffeine-free diet containing 150 mEq sodium and 70 mEq potassium per day for at least 3 days before evaluation. Medications affecting the autonomic nervous system were withheld for at least 3 days before admission. Autonomic function tests were used to evaluate the integrity of the different reflex arcs. These included Valsalva maneuver, the cold pressor and handgrip tests to assess cardiovascular autonomic function, and the sinus arrhythmia ratio (change in heart rate in response to controlled breathing) to assess cardiac parasympathetic activity.10 All tests were standardized previously in our laboratory.11 An orthostatic test was performed to evaluate hemodynamic and hormonal changes on standing. An indwelling catheter was placed in an antecubital vein to obtain blood samples while patients remained supine after an overnight rest. Subjects were encouraged to stand as long as possible or up to 30 minutes. During this period, they were allowed to sit at intervals if presyncopal symptoms developed. Blood samples were obtained for catecholamines, aldosterone, and renin measurements. Brachial blood pressure and heart rate were obtained using an automated sphygmoma-nometer (Dinamap; GE Medical Systems Information Technologies) during supine and standing test phases. Plasma catecholamine levels were determined by high-performance liquid chromatography with electrochemical detection.12 Plasma renin enzymatic activity was assessed by the conversion of angiotensinogen to angiotensin I and expressed as nanograms of angiotensin I produced per milliliter of plasma per hour. Plasma aldosterone was measured by radioimmunoassay.13 Urine samples were obtained in patients with a history of flushing in the face or upper trunk. Patients were asked to collect urine for 4 hours immediately after a spontaneous severe flushing episode, defined by a subjective intensity of symptoms of ?7 to 8? on a scale of ?0? (no symptoms) to ?10? (the worst symptoms ever). This was done during the inpatient or outpatient evaluation. Samples were obtained within 4 hours after a spontaneous episode. Methylhistamine levels were measured by gas chromatography negative ion chemical ionization mass spectrometry.14 In no case was there any abnormality in hematologic laboratory results consistent with systemic mastocytosis. To determine the response to treatment, a research nurse contacted the patients 3 months after discharge and obtained information about the medication, the frequency of mast cell episodes with flushing, and the intensity of orthostatic tachycardia. We were able to obtain infor- mation on 6 patients with MCA_POTS and in 3 patients with MCA_OH. Statistical Analysis Data were analyzed using SPSS version 11 (SPSS). Frequency tables were generated for categorical variables. Continuous variables are expressed as mean_SEM. Group comparisons were made using the nonparametric Kruskal?Wallis test. Post hoc analysis between 2 groups was made using the nonparametric Mann?Whitney test. Criterion for significance was P_0.05. Results Clinical Characteristics and Autonomic Response to Posture Clinical characteristics of patients and controls are presented in Tables 1 and 2. All patients except 1 were female, and all were white, non-Hispanic, with an age range between 18 and 50 years. There was no significant difference in age, weight, and body mass index between groups. Symptoms during episodes included flushing, palpitations, lightheadedness with severe orthostatic intolerance, nausea, diarrhea, abdominal cramping, and polyuria. Blood pressure increased acutely in some cases. Patients often exhibited hypersomnia, sleeping for hours after these episodes. Hemodynamic and humoral responses to posture are shown in Figures 1 and 2. As expected by the selection of subjects, standing heart rate was significantly higher in the MCA_POTS, POTS, and MCA_OH groups compared with normal subjects (P_0.001). Mean supine diastolic blood pressure was signifi-cantly different between groups (P_0.005); MCA_OH patients had higher values compared with MCA_POTS, POTS, and normal subjects. Upright systolic blood pressure was signifi-cantly increased in the MCA_POTS group compared with normal subjects (Table 1; Figure 2; P_0.013). We identified 5 patients who presented with orthostatic hypertension, defined by an increase in systolic blood pressure on standing of _20 mm Hg. Furthermore, 4 patients presented with episodes of sudden onset of hypertension and palpitations. There were no obvious triggering events, and these episodes resolved sponta-neously. The supine and upright blood pressure obtained from these patients as well as the blood pressure values during the hypertensive crisis are presented in supplemental Table I and supplemental Figure Ia and Ib (available online at http://www.hypertensionaha.org). Mean supine plasma norepinephrine levels were significantly different between groups: MCA_OH was higher than MCA_POTS, POTS, and normal subjects (Table 1; Figure 2; P_0.004). Supine plasma norepinephrine was also significantly higher in MCA_POTS patients compared with controls (269_41 and 129_22 pg/mL, respectively; P_0.05; Figure 2) but not compared with POTS patients. No differences were observed in supine and upright epinephrine, renin activity, or aldosterone. As expected, the methylhistamine levels were different be-tween patients with MCA_POTS and MCA_OH compared with POTS controls (P_0.001). Although not statistically sig-nificant, patients with MCA_OH tended to have higher levels of urinary methylhistamine compared with MCA_POTS pa-tients (Table 1). Characterization of Autonomic Function Autonomic function tests are presented in Table 3 and Figure 3. No significant differences in systolic blood pressure were observed between groups at baseline for Valsalva maneuver, the hyperventilation test, the cold pressor test, and the handgrip test. There was a difference in systolic blood pressure during phase IILate of the Valsalva maneuver (P_0.048; Table 3; Figure 3). The MCA_POTS group had a significantly higher systolic blood pressure compared with POTS and normal controls (P_0.023 and P_0.027, respec-tively). During phase IV of the Valsalva maneuver, we observed that groups with MCA_POTS and POTS presented an excessive increase in systolic blood pressure (hypertensive overshoot) compared with normal controls (Figure 3). The change in systolic blood pressure between baseline and phase IV of the Valsalva maneuver was significantly higher in the MCA_POTS group (50_10 mm Hg) compared with the POTS group (31_5 mm Hg) and controls (17_3 mm Hg). In a post hoc analysis, no differences were found between patients with MCA_POTS and POTS (P_0.168). The sys- tolic blood pressure and diastolic blood pressure after 1 minute of the cold pressor test and after 3 minutes of the handgrip test were different between groups. In MCA_POTS patients, systolic blood pressure increased 35_12 mm Hg during the cold pressor test, whereas the response in normal controls averaged 20_5 mm Hg. Triggering of MCA With Exercise Because patients often referred to episodes of flushing trig-gered by exercise, we performed treadmill exercise on 3 subjects. Flushing was triggered in these patients, and this was associated with an increased in urinary methylhistamine (supplemental Figure II). In 1 patient, we documented an increase in plasma histamine, indicative of mast cell degran-ulation but not of plasma prostaglandin D2 (PGD2), a marker of newly formed mast cell mediator release (supplemental Figure II). Response to Treatment The response to treatment in patients in whom follow-up was available is shown in supplemental Table II. Because of the number of patients, we did not attempt to perform a controlled study, and these observations remain anecdotal. However, it is noteworthy that patients improved clinically when treated with H1 and H2 histamine receptor blockers with the sympatholytic _-methyldopa, or with a combination of both. Of note, _-blockers triggered episodes consistent with acute MCA in 2 patients, and 4 patients had allergic reactions to aspirin, ranging from bronchoconstriction to anaphylaxis. Discussion We describe here a novel syndrome characterized by chronic disabling orthostatic tachycardia associated with episodes of sys-temic MCA. It affects otherwise normal young subjects, typically women, and causes substantial disability. We found no evidence of a primary diffuse autonomic neuropathy as the cause of this syndrome; autonomic reflexes appeared to be intact or overactive. On the contrary, exaggerated sympathetic activation was suggested by high plasma norepinephrine levels and increased systolic blood pressure in the upright posture. We and others have described patients with orthostatic intolerance, in many ways indistinguishable from patients presented here, who seem to have partial sympathetic denervation, preferentially involving lower limbs, the ?neuropathic? POTS.1 The clinical criteria that differentiate between the neuro-pathic and hyperadrenergic forms of this disease are not defined. We believe that the patients described in this report correspond to the hyperadrenergic form of POTS because of the exaggerated sympathetic pressor response during phase IILate and phase IV of the Valsalva maneuver and the exaggerated increase in blood pressure on standing. Episodes of MCA were documented in these patients by elevated levels of urinary methylhistamine taken immediately after a spontaneous event. It should be noted that urinary methylhistamine is usually normal in between episodes in patients with MCA disorders,9 and patients should be instructed to collect urine for a 4-hour period immediately after a severe spontaneous flushing episode. Urinary histamine is often mea-sured in the evaluation of flushing, but it is less specific than methylhistamine and not useful in the diagnosis of MCA. The symptoms described during these spells are probably induced by acute release of mast cell mediators such as histamine and PGD2.15,16 Patients with isolated MCA are symptomatic only during episodes, whereas our group of patients also experienced chronic fatigue and orthostatic intolerance in between episodes, eventually leading to a disabling condition. Hypertension can be a prominent feature in some patients with MCA and POTS. We observed 2 different clinical presen-tations of this association. Patients may present with a consistent hypertensive response to upright posture or with acute hyperten-sive crisis. During these hypertensive episodes, blood pressure can increase to as high as 240/140 mm Hg, and the episodes are similar to the hypertensive variant of MCA disorders described previously.9 These events resemble pheochromocytoma inas-much as they are accompanied by tachycardia, nervousness, shortness of breath, and hypertension. A similar clinical presen-tation, known as pseudopheochromocytoma or diencephalic hypertension, has been described by Page.17 Flushing is promi-nent in MCA disorders and in pseudopheochromocytoma and is a useful clinical distinction with pheochromocytoma, which is accompanied by pallor. Plasma norepinephrine is increased in both conditions, but levels are much higher in pheochromocy-toma because catecholamines are released directly into the circulation, whereas in pseudopheochromocytoma, catechol-amines are released into the synapse, and only a relatively small proportion spills over into the circulation. We also report a group of patients with flushing and orthostatic intolerance but no evidence of MCA. The cause of flushing in those patients is not clear. Other entities associated with flushing and similar clinical characteristics are associated with dopamine release, as described by Kuchel.18 Panic attacks can also be associated with flushing and regional sympathetic activation,19 but patients usually do not experience orthostatic intolerance between attacks. Mast cells are localized in close proximity to blood vessels and peripheral nerves and are therefore strategically positioned to modulate sympathetic activity, vascular tone, and angiogenesis.20 Histamine is a powerful vasodilator that could explain the cutaneous vasodilatation responsible for flushing. With regard to the patho-physiology underlying the association between POTS and MCA, we propose a positive feedback loop by which MCA, with the subsequent release of vasoactive mediators, may contribute to vasodilation, reflex sympathetic activation, central volume contrac-tion, norepinephrine release, and orthostatic intolerance (Figure 4). Conversely, our results indicate that exercise can lead to MCA, presumably through sympathetic activation. In this regard, neu-ropeptide Y (NPY), a 36-aa neuropeptide that is coreleased with norepinephrine from noradrenergic neurons, has been shown to induce mast cell degranulation with the release of preformed mediators in purified rat peritoneal 21,22 and human jejunal mast cells 23 and to induce hypotension in animals secondary to MCA in vivo.24 This appears to be a nonreceptor-mediated effect related to the presence of positively charged amino acid residues of the C terminus of NPY. Therefore, the physiological significance of NPY-mediated MCA remains speculative. Our findings have potential implications for the treatment of these patients. Because of the prominent orthostatic tachycardia, _-blockers are commonly used in the treatment of POTS patients. However, these drugs should be used with great caution in these patients, if at all, because of possible worsening of MCA. In our experience, a therapeutic trial with _-methyldopa should be consid-ered, given the evidence of a hyperadrenergic state. Some patients may require treatment directed at controlling mast cell mediators, including H1 and H2 receptor antagonists. Perspectives We report a novel syndrome of chronic hyperadrenergic orthostatic intolerance associated with episodes of MCA. This syndrome should be considered in POTS patients with a history of flushing. This symptom is often not volunteered by patients and may require careful questioning by the physician. Diagnosis requires biochemical documentation of MCA be-cause other causes of flushing can be associated with POTS. A correct diagnosis is important because the presence of MCA mandates a different approach in the treatment of these patients. _-Blockers, a commonly used therapeutic option in POTS patients, should be used with caution, if at all, because of the risk of triggering MCA. These patients can be treated with H1/H2 histamine antagonist and central sympatholytics. Acknowledgments This research was supported in part by a general clinical research center grant from National Center for Research Resources and by grants HL56693 and HL67232 from the National Institutes of Health. S.R.R. is supported by a K12 grant from the National Institutes of Health. C.S. is recipient of the international fellowship in clinical pharmacology supported by Merck Foundation. References 1. 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. N Engl J Med. 2000;343:1008 ?1014. 2. Jacob G, Robertson D, Mosqueda-Garcia R, Ertl AC, Robertson RM, Biaggioni I. Hypovolemia in syncope and orthostatic intolerance role of the renin-angiotensin system. Am J Med. 1997;103:128 ?133. 3. Jordan J, Shannon JR, Diedrich A, Black BK, Robertson D. Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension. 2002;39:173?178. 4. Kuchel O, Leveille J. Idiopathic hypovolemia: a self-perpetuating autonomic dysfunction? Clin Auton Res. 1998;8:341?346. 5. Biaggioni I. Orthostatic intolerance syndrome, vasoregulatory asthenia and other hyperadrenergic states. In: Robertson D, Biaggioni I, eds. Disorders of the Autonomic Nervous System. London, UK: Harwood Academic Pub-lishers; 1995. 6. Streeten DH, Kerr CB, Kerr LP, Prior JC, Dalakos TG. Hyperbradykininism: a new orthostatic syndrome. Lancet. 1972;2:1048 ?1053. 7. Valent P, Akin C, Sperr WR, Horny HP, Metcalfe DD. Mast cell proliferative disorders: current view on variants recognized by the World Health Organi-zation. Hematol Oncol Clin North Am. 2003;17:1227?1241. 8. Castells M, Austen KF. Mastocytosis: mediator-related signs and symptoms. Int Arch Allergy Immunol. 2002;127:147?152. 9. Roberts LJ, Oates JA. Biochemical diagnosis of systemic mast cell disorders. J Invest Dermatol. 1991;96:19S?24S. 10. Mosqueda-Garcia R. Evaluation of the autonomic nervous system. In: Robertson D, Biaggioni I, eds. Disorders of the Autonomic Nervous System. London, UK: Harwood Academic Publishers; 1995. 11. Robertson D. Clinical pharmacology: assessment of autonomic function. In: Clinical Diagnostic Manual for the House Officer. Baltimore, Md: William and Wilkins; 1981. 12. Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ. Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest. 1988;81:213?220. 13. Workman RJ, Sussman CR, Burkitt DW, Liddle GW. Circulating levels of angiotensin I measured by radioimmunoassay in hypertensive subjects. J Lab Clin Med. 1979;93:847? 856. 14. Roberts LJ, Oates JA. Accurate and efficient method for quantification of urinary histamine by gas chromatography negative ion chemical ionization mass spectrometry. Anal Biochem. 1984;136:258 ?263. 15. Morrow JD, Guzzo C, Lazarus G, Oates JA, Roberts LJ. Improved diagnosis of mastocytosis by measurement of the major urinary metabolite of prosta-glandin D2. J Invest Dermatol. 1995;104:937?940. 16. Roberts LJ, Sweetman BJ, Lewis RA, Austen KF, Oates JA. Increased production of prostaglandin D2 in patients with systemic mastocytosis. N Engl J Med. 1980;303:1400 ?1404. 17. Page IH. A syndrome simulating diencephalic stimulation occurring in patients with essential hypertension. Am J Med Sci. 1935;190:9 ?14. 18. Kuchel O, Buu NT, Hamet P, Larochelle P, Gutkowska J, Schiffrin EL, Bourque M, Genest J. Orthostatic hypotension: a posture-induced hyperdo-paminergic state. Am J Med Sci. 1985;289:3?11. 19. Wilkinson DJ, Thompson JM, Lambert GW, Jennings GL, Schwarz RG, Jefferys D, Turner AG, Esler MD. Sympathetic activity in patients with panic disorder at rest, under laboratory mental stress, and during panic attacks. Arch Gen Psychiatry. 1998;55:511?520. 20. Feoktistov I, Ryzhov S, Goldstein AE, Biaggioni I. Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res. 2003;92:485? 492. 21. Arzubiaga C, Morrow J, Roberts LJ, Biaggioni I. Neuropeptide Y, a putative cotransmitter in noradrenergic neurons, induces mast cell degranulation but not prostaglandin D2 release. J Allergy Clin Immunol. 1991;87:88 ?93. 22. Grundemar L, Hakanson R. Neuropeptide Y, peptide YY and C-terminal fragments release histamine from rat peritoneal mast cells. Br J Pharmacol. 1991;104:776 ?778. 23. Santos J, Saperas E, Nogueiras C, Mourelle M, Antolin M, Cadahia A, Malagelada JR. Release of mast cell mediators into the jejunum by cold pain stress in humans. Gastroenterology. 1998;114:640 ?648. 24. Shen GH, Grundemar L, Zukowska-Grojec Z, Hakanson R, Wahlestedt C. C-terminal neuropeptide Y fragments are mast cell-dependent vasodepressor agents. Eur J Pharmacol. 1991;204:249 ?256. _______________________________________ If you can interpret this table with its lack of formatting, I thought this might be useful to include. KM ________________________________________ TABLE 2. Clinical Manifestation of Patients With POTS and MCA Disorder Orthostatic Symptoms?n (%) MCA_POTS MCA_OH n %n% Flushing 8 100 5 100 Palpitations 8 100 5 100 Lightheadedness 8 100 3 60 Chronic fatigue 7 88 3 60 Headache 5 63 2 40 Dizziness 5 63 4 80 Presyncope/syncope episodes 3 38 1 20 Shortness of breath 3 38 2 40 Confusion 3 38 Increase in blood pressure 3 38 Paresthesias 3 38 Gastrointestinal symptoms (nausea and vomiting) 3 38 4 80 Abdominal cramps and diarrhea 3 38 3 60 Blurred vision 2 25 Anxiety 2 25 1 20 Excessive diuresis 5 100 Orthostatic intolerance exacerbated by?n (%) After exercise 5 63 5 100 Prolonged standing 3 38 1 20 After meals 3 38 1 20 Premenstrual 2 25 1 20 Heat intolerance 2 25 5 100 Emotional stress 1 13 1 20 Sexual intercourse 1 13

I got a very prompt response to my e-mail to Dr. Biaggioni. What a kind soul. Here is his response. He also sent me the entire article that I will also post next(hopefully that is ok for copyright reasons.) This is his reply to me: Many patients do not respond well to a regular dose of beta blockers and do better with a low dose. Lack of response to beta blockers, therefore, is not an indicator of mast cell activation. The patients we described had episodes of obvious severe flushing in the face and neck. Even in these patients, only half had documented mast cell activation (with elevated urine methylhistamines immediately after a spell). Depending on the patient, we have bee successful in treating hyperadrenergic POTS with aldomet alone or in combination with fludrocortisone. Only some patients require more targeted therapy against mast cell activation, which requires medical supervision. I hope you understand that these are only general comments. I cannot make more specific recommendations over the internet. Hope this helps. Italo Biaggioni

I found this definition. Tearose you are of course correct that you can have hyperadrenergic POTS and still have low blood pressure on standing. "...patients with incapacitating orthostatic hypotension can have either a "hyperadrenergic" or "hypoadrenergic" presentation. Although the latter is related to overt autonomic neuropathy, the former is proposed to be explained by appropriate autonomic responses. We hypothesize, however, that both conditions are part of a spectrum of autonomic dysfunction. " "Two distinct clinical presentations of orthostatic hypotension have been described ... The distinction was based on their plasma norepinephrine response to standing. Patients with a blunted norepinephrine response, "hypoadrenergic" orthostatic hypotension, were considered to have true autonomic neuropathy. Other patients appeared to have an exaggerated norepinephrine response to standing, a condition termed "hyperadrenergic" orthostatic hypotension (8), for which the pathophysiology has not been completely elucidated..." It appears that in a hypoadrenergic response, hr on standing does not increase as significantly. That's where I was getting confused, I guess. Here's where I found the quote above. This is an article about POTS in diabetic patients, but I assume the definitions are universal. http://care.diabetesjournals.org/cgi/content/full/26/7/2174 Hope this is more helpful than my first response!! Katherine The question I have after reviewing this is--isn't POTS by definition hyperadrenergic? Can you have POTS that isn't--and what would the definining symptoms be in a non-hyperadrenergic POTS patient? Certainly you can have orthostatic intolerance that is not hyperadrenergic, but POTS? Great question, Rahda. These definitions of autonomic dysfuction conditions ARE confusing. It certainly helps to have our terminology straight when researching for ourselves and talking to our doctors!