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Clinical challenges in the diagnosis and management of postural tachycardia syndrome
  1. Pearl K Jones1,
  2. Brett H Shaw2,
  3. Satish R Raj3
  1. 1Department of Neurology, UT Health Science Center San Antonio, San Antonio, Texas, USA
  2. 2Cumming School of Medicine, University of Calgary, Calgary, Canada
  3. 3Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, Cumming School of Medicine, University of Calgary
  1. Correspondence to Dr Pearl K Jones, University of Texas Health Science Center, 8300 Floyd Curl Drive, San Antonio, TX 78229-3900, USA; Jonesp3{at}uthscsa.edu

Abstract

Postural tachycardia syndrome (POTS) is a multifactorial clinical syndrome defined by an increase in heart rate of ≥30 bpm on standing from supine position (or ≥40 bpm in children). It is associated with symptoms of cerebral hypoperfusion that are worse when upright and improve when in supine position. Patients often have additional symptoms including severe fatigue and difficulty concentrating. There are several possible pathophysiologic mechanisms including hypovolaemia, small-fibre peripheral neuropathy and hyperadrenergic states. POTS can also be associated with several disorders including mastocytosis, Ehlers-Danlos syndrome (hypermobility type) and autoimmune disorders. The treatment is focused on symptom relief and not solely on reducing tachycardia. Given its varying presentations, it is important to employ a practical, mechanism-focused approach to the diagnosis and management of POTS.

  • postural tachycardia syndrome
  • POTS
  • tachycardia
  • orthostatic intolerance
  • AUTONOMIC
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Introduction

Postural tachycardia syndrome (POTS) is a chronic, multifactorial syndrome with symptoms of orthostatic intolerance. It is defined as an increase in heart rate by ≥30 bpm in adults (or by ≥40 bpm in children), within 10 min of standing, with no orthostatic fall in blood pressure. It is associated with a constellation of symptoms that are worse when upright and improve with recumbence1 ,2 (box 1). POTS is more common in women (5:1), especially in those of childbearing age (15–50 years).3 While there are no reported deaths as a direct result of POTS, the symptoms are quite debilitating and patients report a poor quality of life.4 One study found the functional impairment in patients with POTS to be similar with those having congestive heart failure and chronic obstructive pulmonary disease.5 Common daily activities such as mild exercise, heat and food ingestion can lead to dramatic exacerbations of symptoms. Severe fatigue6 and attentional problems4 are often disabling and may limit a patient's ability to work, attend school and to exercise.

Box 1

Diagnostic criteria for postural tachycardia syndrome (POTS)

  • An increase in heart rate by ≥30 bpm on standing in adults (or ≥40 bpm in children) with no orthostatic hypotension (fall in systolic blood pressure by ≥20 mm Hg or diastolic blood pressure by ≥10 mm Hg)

  • Associated symptoms that are worse with standing (light-headedness, fatigue, palpitations, syncope) and better with recumbence

  • Additional causes of tachycardia excluded, including prolonged bed rest, hyperthyroidism, medications, acute blood loss

  • Chronicity implies symptoms for longer than 6 months

Neurologists frequently encounter patients with light-headedness or syncope and they should consider POTS among the differential diagnosis in younger patients. In addition to postural light-headedness, these patients may report chronic fatigue, migraine, cognitive slowing and tingling in their extremities. The multiple symptoms can make POTS difficult to manage and no single treatment plan is consistently effective. Thus, neurologists must understand the putative mechanisms underlying POTS, in order to deploy appropriate, targeted interventions.

Proposed pathophysiology

In response to standing, there is normally a fall in venous return and of stroke volume due to a downward shift in blood volume. This triggers a baroreflex-mediated increase in sympathetic activity and a decrease in parasympathetic activity, which in turn leads to an increase in heart rate (by 10–20 bpm) and systemic vascular resistance. In patients with POTS, a more marked fall in stroke volume triggers an excessive increase in sympathetic activity, resulting in the characteristic exaggerated tachycardia (of at least 30 bpm). A variety of pathophysiological mechanisms may underlie and lead to this presentation; however, the rise in heart rate is the final common pathway. POTS is not a disease but rather a clinical syndrome that can result from one of several underlying disorders. While we do not know its exact mechanisms, POTS has several putative pathophysiological subtypes (see below). The subtypes often overlap and so it may be difficult to make the clinical distinction between them in a particular person.

Neuropathic POTS may be associated with a small-fibre neuropathy leading to sympathetic denervation (particularly in the lower limbs), resulting in diminished capacity for venoconstriction.7 This promotes increased venous pooling when standing and perpetuates a greater reduction in stroke volume. Up to 50% of patients with POTS show signs of peripheral autonomic denervation.2 ,8 One study found evidence of a small-fibre neuropathy on skin biopsy in 9 out of 24 patients with POTS. While these patients may not present with typical symptoms of a painful, length-dependent, small-fibre neuropathy, the abnormal biopsy results may suggest the need for further serological testing for underlying causes.9–11

Hypovolaemia is fairly common in POTS, occurring in up to 70% of patients.2 ,12 These patients have low serum levels of aldosterone, with inappropriately low renin activity—a key contributing mechanism for their hypovolaemia.12

Hyperadrenergic POTS describes patients with a hyperactive sympathetic response to standing. This is more common as a secondary mechanism in patients with POTS who have hypovolaemia or peripheral sympathetic denervation, but in some cases it is the primary cause.13 They often have increased sympathetic activity at rest, which becomes markedly exaggerated when upright.14

Autoimmune POTS describes a subset of patients with an immune-mediated pathophysiology. Many of these patients report symptoms consistent with POTS ranging from a few weeks to a few months after a viral illness, suggesting that it is triggered by an autoimmune response. Patients with POTS have a high reported rate of autoimmune antibodies,15 including elevated autoantibodies to α1-adrenergic receptors.16 Activation of these receptors could lead to increased central sympathetic nervous system activity, increased circulating norepinephrine and subsequent exaggerated tachycardia.16 These mechanisms are intriguing, but remain to be proven.

Norepinephrine transporter deficiency was the cause of POTS in one family, caused by a loss-of-function mutation in the SLC6A2 gene, which encodes the norepinephrine transport receptor.17 A deficiency of this transporter increases synaptic norepinephrine by decreasing norepinephrine clearance and thus overall increases sympathetic activity. Pharmacological blockade of the norepinephrine transporter with atomoxetine further exacerbates the heart rate increases and its symptoms in patients with POTS when upright.18 Some patients with POTS (without a mutation) have a lower19 norepinephrine transporter protein concentration in their peripheral sympathetic nerves.20

Mast cell activation disorder describes a subset of patients who have episodes of symptomatic postural tachycardia with elevated urine methylhistamine concentrations, without autonomic impairment.21 These patients commonly have severe generalised flushing around the time of tachycardia and hyperadrenergic features accompanying orthostatic hypertension.

Diagnosis

History and physical examination

The initial evaluation of patients with POTS requires a detailed history and physical examination. Up to half of people with POTS report a preceding viral infection and a quarter of patients report a family history of similar symptoms.22 Patients may have multiple symptoms with standing, including nausea, light-headedness, chest pain, palpitations, tunnel vision and tremulousness. It is important to differentiate POTS from other forms of orthostatic intolerance, including reflex (vasovagal) syncope, cardiac syncope and orthostatic hypotension; the physical examination and laboratory testing can help with this. While obtaining a history, it is important to explore exacerbating factors for symptoms of orthostatic intolerance, including exercise, heat, menses and symptoms following meals.8 Interestingly, 20%–30% patients with POTS have a tendency towards syncope,3 often through a vasovagal mechanism.

These patients may also report a myriad of non-orthostatic symptoms, including headaches and poor sleep, which are often not directly related to POTS. Severe fatigue is almost universal in POTS (93%) and many patients (64%) also fulfil the criteria for chronic fatigue syndrome.23 Patients may also have chronic joint pain or Ehlers-Danlos syndrome (hypermobility type), as these disorders may also be associated with POTS.24 Many formerly active patients report being unable to exercise or perform activities of daily living due to symptoms related to excessive tachycardia. Symptoms of gastroparesis (early fullness or nausea with meals) and irritable bowel symptoms are also common. Patients may also report anxiety and depression, but the prevalence of these is no higher in patients with POTS compared with the general population.4

Many patients report cognitive problems (‘brain fog’), though the mechanisms for this are poorly understood. One study found that patients with POTS scored significantly higher on an inattention scale compared with control subjects.4 A follow-up study of cognitive function in patients with POTS identified decreased selective attention, reduced cognitive processing speed and problems with executive function.25 These studies were done with the patients seated in a reclined position. Ocon et al26 found that executive function in patients with POTS worsened with increased orthostatic stress. Given the unclear mechanisms behind these cognitive complaints, further research is needed, both to understand what “brain fog” is and also to determine effective treatments.

Most presenting patients have undergone a cardiac evaluation before neurology referral. It is helpful to review previous records to ensure that an ECG has been performed to exclude any cardiac conduction abnormalities. A key element of the physical examination is orthostatic vital signs. Patients are instructed to lie flat for several minutes, while the baseline blood pressure and heart rate measurements are recorded. They should then stand, with recording of both blood pressure and heart rate after 1, 3, 5 and 10 min of standing. Patients need a complete neurological examination, including a sensory examination for evidence of a small-fibre neuropathy and evaluation for dependent acrocyanosis (figure 1). Patients may also be evaluated for joint hypermobility syndromes, using the Beighton criteria (skin and joint flexibility examination).27

Figure 1

Images showing the physical findings in postural tachycardia syndrome (POTS)—dependent acrocyanosis. Patients with POTS may develop skin colour changes with standing. This figure shows the lower limbs of a patient with POTS (right panel) and of a healthy control (left panel) after 5 min of standing. The patient with POTS (right panel) has significant lower limb erythema during standing, while the control subject has no discolouration. Figure reprinted with permission from Raj et al.31

Pertinent negatives are also valuable for excluding POTS from other causes. It is worth noting that a patient with POTS must have orthostatic tachycardia in the absence of orthostatic hypotension. If the only times that a patient develops tachycardia is with orthostatic hypotension, then consider a diagnosis of mild autonomic failure. In addition to the documented haemodynamic changes, patients must have a clinical presentation that is consistent with POTS (orthostatic symptoms that improve with recumbence and typical non-orthostatic symptoms; table 1). It is also worth considering other causes of tachycardia, including endocrine causes and cardiovascular deconditioning.

Table 1

Common symptoms reported by patients with POTS.

Patients should also be assessed for the contribution of behavioural and/or emotional elements. Many patients with POTS experience symptoms of anxiety and depression, mainly from dealing with a chronic illness, and not usually secondary to a primary psychiatric disorder. Some of the apparent anxiety may be because POTS and anxiety share similar somatic symptoms, including palpitations and tremulousness. Patients also often report frustration from delayed diagnosis. While some individual patients may experience mood and anxiety disorders, patients with POTS as a group do not have a higher prevalence of these disorders as compared with the general population.4

Laboratory evaluation

The laboratory workup includes a full blood count and a basic blood chemistry to look for severe anaemia or electrolyte abnormalities. Supine and upright plasma norepinephrine concentrations are often obtained. In patients with POTS, supine plasma norepinephrine concentrations may be normal or slightly elevated but can increase excessively with standing (>600 pg/mL).28 Additional testing depends on individual symptoms. For instance, if the physical examination suggests a small-fibre neuropathy, additional testing should include haemoglobin A1c, serum vitamin B12, antinuclear antibody survey (screening for autoimmune disorders) and a screen for coeliac disease.10 Patients reporting flushing episodes may have a mast cell activation disorder—an indication to measure urinary methylhistamine after a flushing episode. Patients can take a urine collection container home, collect a 4-hour urine sample following an episode and later return it to the laboratory.

Autonomic testing

It is sometimes difficult to obtain heart rate and blood pressure recordings for 10 min in clinic or patients may be unable to stand for the required time to make a diagnosis. In these cases, further autonomic function testing can help to solidify the diagnosis and to characterise the postural tachycardia. Autonomic function testing typically includes evaluation of parasympathetic function (heart rate response to deep breathing and to a Valsalva manoeuvre) and sympathetic noradrenergic vasoconstrictor function (blood pressure changes during Valsalva manoeuvre and head-up tilt-table testing).29 Measures of parasympathetic or vagus nerve function are typically normal in POTS. A 10 min head-up tilt-table test can obtain the necessary orthostatic vital signs in a safe, controlled environment and can also help to characterise the symptoms experienced while upright (figure 2). While not absolutely necessary to make the diagnosis, autonomic testing often helps in practice, particularly in characterising the autonomic response: to see if there is blunted vasoconstriction on the Valsalva manoeuvre or a very vigorous (hypertensive) blood pressure response. Autonomic testing particularly helps in patients with intermittent hypotension, to exclude mild autonomic failure.

Figure 2

Graph showing the head-up tilt-table testing in a patient with postural tachycardia syndrome (POTS). The tilt-table results of a patient with POTS (left panel) and a healthy control (right panel) are shown. On head-up tilt, the heart rate increases by 30 bpm within 10 min and remains elevated. This contrasts with that of the healthy control subject. Of note, in the patient with POTS, there is no orthostatic fall in blood pressure during the test. Figure reprinted with permission from Raj et al.31

Treatments

Non-pharmaceutical measures

Given the multifactorial nature of this syndrome, there is no one uniformly recommended treatment for all people with POTS. The first priority is to manage patient expectations. POTS is a chronic syndrome that requires symptom management and while some interventions may help to relieve symptoms and to improve functioning and quality of life, there is no single ‘magic bullet’ or cure. It is also important to inform patients that while POTS may cause significant symptoms, there have been no reported deaths. Furthermore, POTS typically does not occur in older people. It is also important to educate patients that symptoms associated with a postural tachycardia are typically present when upright (such as light-headedness or palpitations with standing). While there may be other systemic problems (including migraine, gastrointestinal symptoms, cognitive and sleep disturbance), these should not be dismissed as being due to POTS; they require investigation for underlying causes and for appropriate treatments.

Non-pharmacological measures should precede any medications. Patients are advised to increase their fluid intake (up to 3 L/day) and dietary salt intake (8–10 g/day); they should be cautioned to avoid hot environments (such as hot showers or Arizona summer days), which may exacerbate their orthostatic intolerance symptoms. Waist-high compression stockings can improve symptoms by minimising venous pooling in the abdomen, pelvis and legs. The stockings should be fitted to provide 30–40 mm Hg of compression; although this may be uncomfortable initially, if there is symptom improvement, most people can manage to be compliant.

Exercise training has been repeatedly shown to improve symptoms in POTS.19 ,30 One study found that 3 months of exercise training decreased orthostatic tachycardia, reduced symptom burden and increased quality of life.30 In order to dissociate the tachycardia that accompanies exercise from the heart rate increase that accompanies standing, we recommend a slow, graded exercise programme. This should start with recumbent exercise, with primarily aerobic activity, and some leg resistance. Rowing machines are preferred, although swimming or a recumbent bicycle can also be used. The choice of activity may need to be modified for individual patients. For example, rowing may not be tolerated in patients with Ehlers-Danlos syndrome due to risk of joint dislocation and swimming may be safer. It is important that patients exercise regularly (every other day) for 30 min in each session. The goal is to gradually make the transition to upright exercise over several months. Patients should be counselled that they may feel worse initially (for up to 6 weeks) and must continue in order to see improvements. It is also important to recognise and prevent deconditioning, which can occur when patients decrease activity due to tachycardia. An ongoing exercise plan can help to prevent deconditioning.

Pharmacological treatments

Patients also often require selected medications (table 2), in addition to non-pharmaceutical measures. There are no Food and Drug Administration (FDA)-approved treatments for POTS, thus all treatments are ‘off label’. They can be started individually but can also be used in combination.

Table 2

Medications for the Management of POTS

Midodrine is a prodrug that is converted to a selective α1-adrenergic agonist. It acts as a vasoconstrictor and venoconstrictor. It is typically used as a first-line or second-line medication in POTS. It may particularly helpful patients with small-fibre neuropathy, in which there may be a decrease in peripheral venoconstriction or vasoconstriction. It has a short half-life and duration of action of about 3–4 hours. Patients can take 5–10 mg every 4 hours, or three times a day, as needed. They are advised not to take the medication for 4 hours prior to bedtime to prevent the side effect of supine hypertension. Caution should be exercised while prescribing this medication in patients who are hypertensive. Additional side effects include piloerection, scalp tingling, urinary retention and headache.

Propranolol is another useful first-line medication in many patients who report symptoms from the tachycardia that occurs with standing. It has a short half-life, requiring frequent dosing. We recommend a low dose of 10–20 mg up to four times a day. Higher doses are typically not tolerated due to excessive fatigue. One study reported that low doses of propranolol—but not higher doses—significantly improved POTS symptoms.31 The overall goal should be to ‘take the edge off’ of the orthostatic tachycardia and not to normalise the heart rate.

Fludrocortisone is a volume expander that may help people with hypovolaemic POTS. It is a synthetic mineralocorticoid that enhances renal sodium reabsorption and increases plasma volume, but at the expense of losing potassium. When prescribing fludrocortisone, the serum potassium should be monitored to evaluate for hypokalaemia. It can be started at 0.05 mg/day and can be increased up to 0.2 mg/day. Side effects include hypokalaemia, oedema and hirsutism (although this is uncommon).

Pyridostigmine is typically used to treat myasthenia gravis, but it may also be useful in POTS. It is an acetylcholinesterase inhibitor, which increases the concentration of acetylcholine at post-ganglionic muscarinic and nicotinic receptors, leading to a net increase in parasympathetic tone. It decreases the heart rate in response to standing and reduces the symptom burden in patients with POTS.32 When used longitudinally in outpatients with POTS, most patients report improvement, although 20% of patients had to stop medication due to diarrhoea.33 Doses of 30–60 mg three times a day may be effective, without decreasing the blood pressure.

Desmopressin is typically used to treat nocturnal enuresis. It works by increasing renal-free water retention. Desmopressin lowers standing heart rates in patients with POTS, while improving symptoms.34 The dose is typically 0.2 mg/day orally and may be reserved for special occasions. Its use must be carefully monitored, with serum sodium monitoring every 1–2 weeks, due to the side effect of hyponatraemia.

Acute blood volume expansion through intravenous saline can give symptom relief and can control heart rate.35 While this can be used in an emergency setting, it is not a practical plan for long-term management. The primary concern is long-term intravenous access and the complications of central catheters.

Centrally acting sympathetic agents such as clonidine and methyldopa may help patients with hyperadrenergic POTS. Both these medications reduce sympathetic outflow and may help to stabilise heart rate and blood pressure in some patients with POTS. Methyldopa may be better tolerated due to its longer half-life; however, both medications have the side effects of sedation and worsening fatigue.28

Ivabradine was recently approved by the FDA for treating heart failure. It is a funny channel blocker that lowers the heart rate, with little effect on blood pressure. There are no randomised studies on its use in POTS. In one non-randomised case series, 60% of patients with POTS reported relief on this medication.36

While the above medications may help the orthostatic symptoms of tachycardia and light-headedness, treating cognitive deficits or the so-called brain fog can be challenging. Modafinil has been occasionally used to increase concentration and alertness in patients with POTS. Given that it is a stimulant, this medication may potentially worsen tachycardia, although in a recent study the pro-tachycardia effects were minimal.37

Thus, no one treatment is uniformly effective. We recommend that all patients with POTS are provided with education about situations that may exacerbate symptoms, are advised to increase salt and fluid intake, and are provided with an exercise plan. If there is no improvement, then medications can be added. While there is no set protocol for first-line medications, we often start with low dose of propranolol.

Conclusion

The heterogeneous presentation and multiple symptoms of POTS can make it challenging to diagnose and manage. For the consulting neurologist, POTS should be considered in younger people presenting with postural light-headedness and/or syncope. After the initial diagnosis and evaluation, we recommend focussing on symptom improvement, emphasising patient education and a graded-exercise programme. Medications can be selectively added as needed. Although patients with POTS may have numerous symptoms, a good understanding of the underlying pathophysiology and appropriate diagnostic testing allow clinicians to select effective treatments.

Key points

  • Postural tachycardia syndrome (POTS) is a multifactorial clinical syndrome defined by an increase in heart rate of ≥30 bpm on standing from a supine position (or ≥40 bpm in children), with symptoms of cerebral hypoperfusion that are worse when upright and improve when supine.

  • Patients with POTS commonly attend neurology clinics for a myriad of symptoms, including light-headedness, syncope, headaches, cognitive slowing and tingling in their extremities.

  • Once the diagnosis is established through history, examination and heart rate evaluation, the next step is to try and identify putative mechanisms.

  • In managing POTS, education and management of expectations is the key; clinicians need to help patients to develop an exercise plan and to select medications for symptom improvement.

References

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Footnotes

  • Contributors PKJ and BHS: drafting of manuscript and tables; revision of manuscript. SRR: drafting and critical revision of manuscript and tables for intellectual content.

  • Competing interests SRR: He serves on scientific advisory board—Lundbeck Pharmaceuticals, GE Healthcare; serves on the Medical Advisory Board for multiple non-profit POTS Patient Groups (no financial compensation); Funding for travel—POTS UK International Speakers' Fund; serves on editorial boards for Autonomic Neuroscience: Basic and Clinical (Elsevier) Clinical Autonomic Research (Springer), Frontiers in Autonomic Neurosciences; none are compensated financially; honoraria—Lundbeck Pharmaceutical; government research support: NIH R01 102387 and Canadian Institutes of Health Research MOP 142426; Foundation Research Support—Dysautonomia International; Commercial Research Support—Medtronic Canada; witness or consultant for a legal proceeding dealing with POTS causality.

  • Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Gordon Ingle, London, UK, Wojtek Rakowicz, Hampshire, UK, and Paul Cooper, Manchester, UK.

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