A 46-year-old white female presented to a neurology practice with symptoms of heaviness in her legs and arms, dizziness, and “head pressure.” Paresthesias in both feet had been progressing for several weeks. Her past medical history and findings on physical examination were unremarkable. The neurologist ordered a CBC with differential; complete metabolic panel (CMP); ESR; vitamin B12, vitamin B6, folate, iron, free thyroxine (T4), thyroid-stimulating hormone (TSH), and C-reactive protein (CRP) determinations; urinalysis; and CSF analysis for antibodies to Borrelia burgdorferi (the causative agent of Lyme disease), cytomegalovirus, and varicella-zoster virus. MRI of the brain and thoracic spine were also ordered. No diagnosis was reached based on laboratory results. A tilttable test revealed tachycardia and an increase in BP with several orthostatic positions. Based on the results of the tilt-table test, the patient was started on metoprolol 25 mg daily. She was also prescribed lamotrigine 25 mg for the headaches and instructed to double the dose in 2 weeks.
Approximately 3 weeks later, the patient presented to cardiology for evaluation of the tilt-table results. The cardiologist ordered an ECG and 30-day cardiac event monitoring. All the tests returned negative results. The diagnosis given was postural orthostatic tachycardia syndrome (POTS). The cardiologist instructed the patient to increase her sodium and water intake as well as her exercise activity and to double her metoprolol dose to 25 mg twice a day. She was also started on escitalopram 10 mg daily.
The patient was given a referral to see a neurologist at the Cleveland Clinic for follow-up of POTS. The neurologist ordered an electromyogram (EMG), a quantitative sudomotor axon reflex test (QSART), an autonomic reflex test, and a second tilt-table test. The EMG revealed small- and large-fiber sensory motor polyneuropathy, absent plantar sensory response, and intact sural response. Results of the QSART and autonomic reflex test were negative. The tilt-table test again revealed tachycardia and an increase in BP with several orthostatic positions.
Given these results, the neurologist ordered methylmalonic acid, paraneoplastic autoantibody, metanephrine, monoclonal antibody, catecholamine, and TSH determinations and a 24-hour urinalysis. The tests returned normal results except for the catecholamine levels, which were as follows: normetanephrine, 1.3 nmol/L (normal, <0.9 nmol/L); norepinephrine, 833 pg/mL (normal, 80-520 pg/mL), and epinephrine, less than 10 pg/mL (normal, 10-200 pg/mL), all of which supported a diagnosis of hyperadrenergic POTS.
Epidemiology Postural orthostatic tachycardia syndrome has a multifaceted pathophysiology and etiology. POTS typically affects women between the ages of 20 and 40 years who are experiencing anxiety or underlying stress. The prevalence of POTS in the United States is 170/100,000.1 The disorder is commonly seen in women after pregnancy, sepsis, viral infection, fever, trauma, or surgery2 or secondary to other disorders, such as diabetes mellitus, mitral valve prolapse, irritable bowel syndrome, sarcoidosis, alcoholism, and Sjögren syndrome.3
Clinical presentation The clinical criterion for a POTS diagnosis is a heart rate greater than 120 beats per minute or an increase in heart rate of 30 beats per minute with standing for 10 minutes or walking for 30 minutes.1 These clinical signs can be elicited by a head-up tilt test (HUT) in which the patient's head is raised to 70° from a supine position. The tachycardia of POTS is not associated with orthostatic hypotension; instead, it is more directly linked to sympathetic nervous system dysfunction and brain hypoperfusion.1
Depending on the underlying etiology, POTS may present in a number of ways, but the most common “orthostatic” symptoms include tachycardia, light-headedness/ dizziness, palpitations, tremulousness, shortness of breath, chest pain, and loss or increase of sweating.4 Symptom resolution can be achieved by maintaining a recumbent position.4 Other symptoms of POTS include bloating, nausea, vomiting, abdominal pain, constipation, diarrhea, bladder dysfunction, and pupillary dysfunction. Many individuals also experience generalized symptoms, such as fatigue, sleep disturbance, anxiety, migraine headaches, and myofascial and neuropathic pain.4
Pathophysiology Over time, four pathophysiologic mechanisms have been identified in patients with POTS. Each may act independently, or two or more may overlap. The first mechanism is a neuropathic pathogenesis that involves adrenergic denervation with partial dysautonomia and autoimmune cause. A study conducted by researchers at the Mayo Clinic revealed that 10% of POTS patients had a ganglionic alpha3 acetylcholine receptor antibody, suggesting an autoimmune cause.1 The antibody is thought to destroy the postganglionic receptor in the peripheral autonomic system, resulting in peripheral denervation that reduces the ability of vessels to constrict and leads to pooling of peripheral blood in the extremities. The destruction of the postganglionic acetylcholine muscarinic receptor can also result in increased or decreased anhidrosis.5 A diagnosis of neuropathic POTS is supported by positive results on a QSART, an axon reflex test, and/or a thermoregulatory sweat test, all of which monitor the postganglionic sympathetic sudomotor fibers and measure sweat output.
The hyperadrenergic pathogenesis of POTS is characterized by increased blood levels of the sympathetic neurotransmitter norepinephrine. These levels are the result of increased production from the adrenal glands or decreased destruction in the postganglionic receptor. Genetic research has identified a single point mutation on the gene SLC6A2 that controls the noradrenaline transporter protein in this pathogenic process.6 Normally, this protein destroys the norepinephrine from the postganglionic receptor, but a faulty protein allows increased amounts of norepinephrine and increased sympathetic activity. Patients with POTS have standing norepinephrine levels of greater than or equal to 600 pg/mL (reference range, 80-520 pg/mL) as well as an increase of 10 or more mm Hg in BP during 10 minutes of HUT. Levels of other plasma catecholamines, such as epinephrine, dopamine, and their metabolites, are analyzed in supine and standing positions to determine whether the etiology is hyperadrenergic. A 24-hour urinary sodium excretion is also helpful in making the diagnosis, acting as a “surrogate index of plasma volume.”4
“The first step in treatment is to increase water and sodium intake for volume expansion and to begin regular exercise.”
The hypothesis involved in hypovolemic POTS describes a dehydrated state and may involve an abnormal renin-angiotensin-aldosterone system (RAAS). In a patient with a normal RAAS, hypovolemia stimulates production of renin, which activates angiotensin II and aldosterone to constrict the blood vessels and allow retention of water and sodium in the kidneys. Patients with POTS involving this pathogenesis have decreased renin and aldosterone levels, resulting in less water and sodium retention and therefore hypovolemia.3 In a study led by researchers at the Mayo Clinic, 28.9% of hypovolemic POTS patients had a 24-hour urinary sodium excretion of less than 100 mEq/24 hours.
- Postural orthostatic tachycardia syndrome typically affects women between the ages of 20 and 40 years who are experiencing anxiety or underlying stress.
- The disorder is commonly seen in women after pregnancy, sepsis, viral infection, fever, trauma, or surgery or secondary to other disorders, such as diabetes mellitus, mitral valve prolapse, irritable bowel syndrome, sarcoidosis, alcoholism, and Sjögren syndrome.
- The clinical criterion is a heart rate greater than 120 beats per minute or an increase in heart rate of 30 beats per minute with standing for 10 minutes or walking for 30 minutes.
- The most common “orthostatic” symptoms include tachycardia, light-headedness/dizziness, palpitations, tremulousness, shortness of breath, chest pain, and loss or increase of sweating. Symptom resolution can be achieved by maintaining a recumbent position.
- Studies have shown that 50% of POTS cases secondary to a virus may remit within 2 to 5 years and that with a combination of pharmacologic and nonpharmacologic treatment, more than 90% of patients experience symptomatic improvement over time.
POTS that occurs as a result of deconditioning is a process in which physiologic response is degraded due to decreased activity from a variety of factors, such as bed rest, casting, and paralysis. The diagnosis is closely related to such disorders as fibromyalgia and chronic fatigue syndrome and affects patients with decreased exercise tolerance.7 A psychogenic feature has also been suggested for the condition. Researchers at the Mayo Clinic attempting to differentiate a psychological etiology as opposed to a physiologic etiology for deconditioning POTS conducted a study involving 14 POTS patients. In order to replicate the physiologic symptoms of POTS, lower-body negative pressure (LBNP) was applied to participants in one group to cause peripheral pooling of blood in the legs and decrease central blood volume. The other group of patients was administered a placebo-type LBNP and exposed to mental stressors. Patients stimulated with LBNP developed tachycardia whereas those who received placebo LBNP and mental stressors did not.7 Although this study helps to substantiate deconditioning POTS as a physiologic process, exaggerated somatic hypervigilance was confirmed with psychological testing in these patients,7 thereby reinforcing a commonly seen symptom in the literature.
Treatment Once the complex etiology of POTS is understood and identified in a specific patient, treatment can be initiated on an individual basis with pharmacologic and nonpharmacologic management. The first step is to instruct the patient to increase water and sodium intake for volume expansion and to begin regular exercise. For patients determined to have hypovolemic POTS, an intake of 10 to 20 g of salt and 2 to 2.5 L of water per day is recommended.1 Fludrocortisone 0.4 mg/day has also been effective for increasing sodium and fluid retention.1,2 In patients with hyperadrenergic POTS, beta blockers, such as propranolol 10 mg/day, help to decrease tachycardia.3 Patients with greatly increased BP (250/150 mm Hg with standing) may respond well to phenobarbital or clonidine.1 Because clonidine is an alpha2-agonist, it acts as a sympatholytic agent and may also help with symptomatic improvement.3
For the neuropathic patient, a combination of fludrocortisone and midodrine has been most effective.1 Midodrine is an alpha1-adrenoreceptor agonist that causes peripheral arterial and venous constriction.3 Patients may also benefit from a combination of midodrine and pyridostigmine, an acetylcholinesterase inhibitor that increases the activity of the parasympathetic systems and combats peripheral sympathetic denervation.3 Another approach uses compression stockings to prevent venous pooling in the extremities.6
Both selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are effective for alleviating the psychological aspect of all POTS subgroups. The SSRIs may additionally stabilize BP by improving peripheral vasoconstriction.3 Venlafaxine has been shown to be helpful for treatment of POTS because of the medication's activity on noradrenaline and serotonin.6
POTS treatment often comes down to a trial-and-error process, with relief of symptoms as the primary goal. Although many patients may require lifestyle changes and/ or pharmacologic therapy, studies have shown that 50% of POTS cases secondary to a virus may remit within 2 to 5 years.2 Patients whose POTS is diagnosed during the adolescent years have the best prognosis, with 75% demonstrating great improvement by the time they reach their mid-30s. Studies have shown that with a combination of pharmacologic and nonpharmacologic treatment, more than 90% of patients experience symptomatic improvement over time.2
The patient whose case is presented here currently manages her POTS with medication (atenolol 25 mg daily), regular exercise, and increased fluid intake. Despite adhering to this regimen, she continues to experience tachycardia and chest pressure seven to 10 times per day with positional changes. She also reports continuing neuropathy of the feet that is exacerbated by standing. Regardless of these lingering symptoms, the patient states that her condition is much improved with treatment. She is able to perform normal activities of daily living and maintain a full-time job.