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POSTURAL TACHYCARDIA SYNDROME
The postural tachycardia
syndrome: When to consider
it in adolescents
Blair P. Grubb, MD
The postural tachycardia
ABSTRACT
syndrome (POTS) is
Since the mid-1980s, there has been a substantial increase in our understanding of illnesses that characterized by symptoms of orthostatic
result from disturbances in the autonomic nerv- intolerance and an exceedingly high heart
ous system.1 Attention was initially focused on con- rate—but often not orthostatic
ditions such as neurocardiogenic (vasovagal) syn-cope. During the course of these investigations, it hypotension—on first standing up.
became evident that a subgroup of patients suffered Symptoms can include palpitations,
from a related (yet distinct) condition characterized fatigue, nausea, headache, near syncope,
by postural tachycardia, fatigue, and exercise intol- and syncope and be severe enough to
erance.2,3 This disorder has now come to be known limit daily functioning. The developmental
as the postural tachycardia syndrome (POTS) and is form of this syndrome affects adolescents,
composed of a group of diverse conditions that often beginning around 14 years of age
share similar clinical characteristics. This review out- after a rapid growth spurt and peaking at
lines the presentation, diagnosis, and management about age 16. In general, the younger the
patient with POTS, the better the
The defining characteristics of POTS
prognosis, and most of those with the
The principal feature of these conditions is ortho- developmental form respond to combined
static intolerance, defined as the provocation of symp- physical therapy and pharmacotherapy
toms after assuming upright posture that are relieved by their mid-20s.
by recumbence.1,2 Patients complain of palpitations,fatigue, lightheadedness, exercise intolerance, nausea,headache, near syncope, and syncope. Symptoms maybe severe enough to limit the performance of daily ac-tivities such as bathing, housework, and even eating.4POTS patients have been reported to suffer from a de-gree of functional impairment similar to that seen inconditions such as congestive heart failure or chronicobstructive pulmonary disease.5 All too often thesepatients are misdiagnosed as having severe anxiety orpanic disorder. A system for grading the degree offunctional impairment in POTS has been developed6(Table 1, page 20).
POTS is currently defined as symptoms of ortho- Dr. Grubb is professor of medicine and pediatrics, Medical University static intolerance associated with documented heart of Ohio, and director of the cardiac electrophysiology service and au- rate increases of 30 or more beats per minute (or a tonomic disorders center, University Hospital, Toledo.
rate that exceeds 120 beats per minute) that occurs VOL. 28, NO. 3, MARCH 2006 • 19
POSTURAL TACHYCARDIA SYNDROME
cusing on heart rate ignores many of the additional Grades of orthostatic intolerance
autonomic symptoms that affect POTS patients, such as disturbances in sweating, temperature regulation, Classifying POTS: A many-faceted syndrome
Orthostatic symptoms are infrequent or occur only under conditions of increased orthostatic As noted, POTS appears to be a diverse group of disorders with similar clinical characteristics. Most Subject is able to stand > 15 minutes on most investigators classify the syndrome as primary or sec- ondary.9 The primary forms are not associated with Subject typically has unrestricted activities of other disease states, while the secondary forms occur in conjunction with a known disease or disorder.
Proper management depends on the adequate recog- Orthostatic symptoms are frequent, developing nition of the subtype affecting the patient. at least once a week. Orthostatic symptoms The most frequently encountered form of POTS is commonly develop with orthostatic stress.
referred to as the partial dysautonomic (PD) form.2,9 Subject is able to stand > 5 minutes on most occasions.
These patients appear to have a mild form of periph- Some limitation in activities of daily living is eral autonomic neuropathy in which the peripheral vasculature (especially the venous system) cannot ini- tiate or maintain vascular resistance in the face of gravitational stress. This results in a much greater than normal amount of blood pooling in the more de- pendent areas of the body (legs, lower arms, and Subject is able to stand > 1 minute on most This tremendous sequestration of blood away from Patient is seriously incapacitated, being bed- the central vasculature produces a compensatory in- or wheelchair-bound because of orthostatic intolerance.
crease in heart rate and myocardial contractility that tries to maintain a constant degree of cerebral perfu- attempts to stand. Symptoms may vary with sion. This increased heart rate and contractility may at time and state of hydration and circumstances.
first compensate fully for a given degree of peripheral Orthostatic stresses include prolonged standing, venous pooling, but over time the amount of pooling may increase and exceed the compensatory effect.2,3 Source: Low PA, Novak V, Novak P, et al. Postural tachycardia syndrome. In: Low
Affected individuals then depend increasingly on their PA, ed. Clinical Autonomic Disorders: Evaluation and Management. 2nd ed. Phila- skeletal muscle pump to maintain adequate blood delphia, Pa: Lippincott-Raven; 1997:681-698.
pressure until the peripheral pooling exceeds its com-pensatory effects as well, producing an even greater within the first 10 minutes of standing or upright tilt; it is not associated with other chronic debilitating Interestingly, there is a roughly 5:1 female-to-male conditions such as protracted periods of bed rest or ratio in this form of POTS. A number of patients re- the use of medications known to affect vascular or au- port that symptom onset occurred after an acute fe- tonomic function.7 The estimated prevalence of those brile illness (presumed to be viral) or after immuniza- who are affected by POTS in the United States is at tion, pregnancy, sepsis, surgery, or trauma. Current least 500,000.8 A number of patients with orthostat- thinking is that a number of patients with the PD form ic intolerance due to POTS will not manifest orthosta- of POTS have an autoimmune disorder. A series of tic hypotension (defined as a fall of more than 20/10 studies have found serum autoantibodies to α3 acetyl- mm Hg). Instead, they may have no change, a small choline receptors in the peripheral autonomic ganglia decline, or even a modest increase in blood pressure on standing.1 Some investigators have noted that fo- A second type of primary PD POTS, labeled devel- 20 • FAMILY PRACTICE RECERTIFICATION
POSTURAL TACHYCARDIA SYNDROME
opmental, has recently been elaborated. This form af- mobility syndrome (JHS).14 This genetic syndrome is fects adolescents and often begins around 14 years of due to replacement of certain types of collagen with a age (frequently after a period of very rapid growth and more elastic form, resulting in connective tissue development). Symptoms steadily worsen and usually fragility, joint hypermobility, and skin with a soft (al- reach their peak around age 16. Orthostatic intoler- most velvety) feel. Patients may experience early vari- ance and other symptoms (such as headache and nau- cose veins, easy bruisability, postural acral cyanosis, sea) may be of such severity that the patient is func- and diffuse muscle and joint pain. The condition may tionally disabled. Once this peak is reached, symptoms also cause POTS because the abnormal degree of elas- will slowly fade so that by young adulthood (19-24 ticity of the vasculature (in particular the venous sys- years) about 80% are asymptomatic. The cause re- tem) does not maintain an adequate degree of vaso- mains unclear but is currently felt to represent a tem- constriction in the face of orthostatic stress, allowing porary period of autonomic imbalance that may occur excessive peripheral vascular pooling of blood with subsequent compensatory tachycardia. Recent inves- Another distant form of primary POTS, termed hy- tigations have reported that as many as 70% of indi- peradrenergic,9 is far less common than the others.
Patients often report a slower, more progressive onsetof symptoms over long periods of time. These patients are more likely to report symptoms such as anxiety,tremor, and cold sweaty extremities. More than halfexperience migraine headaches and a significant in- adolescents, often beginning around crease in urinary output after being upright for even ashort time. The major differentiating feature is that many of these patients manifest orthostatic hyperten-sion in addition to orthostatic tachycardia. Many will also have an exaggerated response to intravenous iso-proterenol and will have significantly elevated serumnorepinephrine levels (above 600 ng/mL). Early obser-vations of a strong familial tendency in hyperadrener- viduals with JHS may be predisposed to orthostatic gic POTS led to identifying a genetic basis of the dis- intolerance.14 Some think there may be a connection order. A landmark study by researchers at Vanderbilt between JHS and the developmental form of POTS, identified a single point mutation resulting in a poorly and this potential relationship is under investigation.
functioning reuptake transporter protein that clears On occasion, POTS may be the presenting form of and recycles norepinephrine from the intrasynaptic the more severe autonomic nervous system disorders cleft.12 This leads to an excessive norepinephrine spill- such as pure autonomic failure and multiple systems over in response to a number of sympathetic stimuli, atrophy. POTS can also be a paraneoplastic syndrome thus producing a relative hyperadrenergic state, (not and occur in association with adenocarcinoma of the breast, lung, pancreas, and ovary. Mayo Clinic stud- The term secondary POTS designates a wide vari- ies have demonstrated that the tumors make antibod- ety of conditions that result in peripheral autonomic ies against acetylcholine receptors in the autonomic deinnervation or vascular unresponsiveness with rela- ganglia,10 much like those seen in postviral syn- tive sparing of cardiac innervation. The most fre- dromes.15 Current trials are under way to better iden- quently encountered form is associated with chronic diabetes mellitus, but it may also accompany disor-ders such as sarcoidosis, amyloidosis, systemic lupus POTS evaluation and management
erythematosus (SLE), Sjögren’s syndrome, alcohol- A careful history is the single most important part ism, chemotherapy, and heavy metal intoxication.
of the evaluation. When did symptoms begin? Was the A recently identified cause of secondary POTS is onset abrupt or gradual? Were there any associated the connective tissue disorder known as joint hyper- events such as infection? What symptoms bother the VOL. 28, NO. 3, MARCH 2006 • 23
POSTURAL TACHYCARDIA SYNDROME
with a goal of at least 20-30 minutes of aerobic activ- Drugs that can cause or worsen orthostatic
ity three or more times a week. We also recommend intolerance
resistance training of the lower extremities in order toenhance the effectiveness of the peripheral skeletal α-Receptor blockers Angiotensin-converting-enzyme inhibitors muscle pump. Patients are also told to drink about 2 L of fluid a day and ingest 2-4 g of salt (except pa- tients with the hyperadrenergic form of POTS).
Compression stockings can sometimes be helpful in the PD form of POTS, but to be effective must be waist high and provide at least 30 mm Hg of ankle While conservative measures alone are effective in treating some patients, others will be so ill that some form of pharmocotherapy will be required. Pharma- cotherapy is used to stabilize patients enough for them to pursue reconditioning. It should be noted that the Food and Drug Administration has not ap-proved any drug for treating POTS, and any treat-ment mentioned in this article is thus off-label.
patient most? Are symptoms other than cardiovascu- Correctly identifying the subtype is valuable in select- lar involved, such as gastrointestinal, thermoregulato- ing appropriate pharmacotherapy (Table 3).
• Therapy for the PD form of POTS is frequently Equally important is the physical examination, aimed at increasing peripheral vascular resistance and which should also include a careful neurologic exam- fluid volume, for which we often use fludrocortisone ination. Heart rate and blood pressure should be acetate, 0.1-0.2 mg qd. The drug promotes sodium and measured supine, sitting, upon initial standing, and at fluid retention and also seems to promote vascular con- intervals of 2, 5, and 10 minutes. Examination of the striction. An alternative agent is desmopressin acetate extremities while upright may reveal a bluish, mottled (DDAVP), 0.1-0.2 mg at bedtime. If necessary, we next discoloration (acral cyanosis) that may indicate pe- add a vasoconstrictor such as midodrine HCl (Pro- ripheral venous pooling. As heart rate and blood pres- Amatine), beginning at 5 mg tid. The dose may be pro- sure responses are variable during upright posture, we gressively increased to 10-15 mg qid if needed. It is often perform tilt table testing, as it is a more con- often useful to give the first dose of midodrine around trolled setting with fewer variables. In select patients, 15-20 minutes before getting out of bed in the morn- other tests of autonomic function such as thermoreg- ing, since symptoms may be worse then. The most ulatory sweat testing, sudomotor axon testing, and common side effects of midodrine are “goose bumps,” cold pressor tests may be useful for evaluating certain scalp tingling, and nausea. In patients who cannot tol- symptoms. Specimens for serum levels of dopamine, erate midodrine, an effective substitute can be methyl- epinephrine, and norepinephrine should be obtained phenidate HCl (Ritalin, Methylin, Concerta, etc.).
in the supine and upright positions in patients in Some authors have also used yohimbine as successful whom the hyperadrenergic form of POTS is suggest- therapy, again because of its vasoconstrictive effects.
ed. More detailed information regarding these disor- If the combination of a volume expander and vaso- constrictor is not effective, we add either a serotonin Adequate treatment depends on adequate diagno- reuptake inhibitor (SSRI) or a norepinephrine inhibi- sis. Any pharmacotherapy that may be exacerbating tor, although SSRIs appear to be more effective in the patient’s condition should be stopped (Table 2), treating neurocardiogenic syncope than POTS. The and any condition that may be contributing to POTS norepinephrine reuptake inhibitor that we usually use should be diagnosed and adequately treated.16 We en- is the extended formulation of bupropion (Wellbutrin courage all patients to start a reconditioning program XL) starting at 150 mg qd and increasing to 300 mg 24 • FAMILY PRACTICE RECERTIFICATION
POSTURAL TACHYCARDIA SYNDROME
Therapeutic options in POTS
Treatment
Application
Effective in
Problems
Key: H = hyperadrenergic; PD = partial dysautonomic; POTS = postural tachycardia syndrome; SC = subcutaneous.
Note: The Food and Drug Administration has not approved any drug for treating POTS.
qd if needed. If an SSRI is used, those with combined POTS secondary to an autoimmune process such as serotonin and norepinephrine reuptake inhibition SLE. Current protocols use a starting dose of 30 mg (duloxetine HCl [Cymbalta] and venlafaxine HCl bid and titrate to 50-90 mg tid if needed. [Effexor]) appear to be most useful.
In quite debilitated patients in whom other thera- A promising new therapy is pyridostigmine bro- pies have either been ineffective or poorly tolerated, mide (Mestinon). This acetylcholinesterase inhibitor we use erythropoietin (Epogen, Procrit). Although appears to enhance neural transmission at the gan- originally developed to treat anemia, it was found to glionic junction of sympathetic and parasympathetic be a potent vasoconstrictor, a property useful in treat- nerves. Pyridostigmine has thus far proven useful in ing orthostatic disorders. Erythropoietin is given sub- patients with postviral POTS and those who develop cutaneously, usually starting at a dosage of 10,000 VOL. 28, NO. 3, MARCH 2006 • 25
POSTURAL TACHYCARDIA SYNDROME
units a week. Complete blood cell counts must be mon- The relatively uncertain prognosis of POTS
itored monthly to assure that the hematocrit does not At the present time, only limited information is available on the prognosis of patients with POTS.
Because of its potent vasoconstrictive effects, the Studies are under way analyzing the outcome of pa- somatostatic analog actreotide acetate (Sandostatin) tients and of specific subgroups. About half the can be used to treat the PD form of POTS. It is also patients with postviral POTS make a reasonable re- given subcutaneously, usually starting at 50 µg bid- covery after 2-5 years, with recovery defined as the tid, (dosages as high as 100-200 µg per day may relative absence of orthostatic symptoms along with sometimes be needed). A recent report found that the ability to perform activities of daily living with plasma exchange produced dramatic clinical success little or no restriction. Nonetheless, some patients do in a patient with severe autonomic failure and high not recover, and others worsen over time.
circulating acetylcholine receptor antibody levels.17 For the most part, the younger the patient, the bet- Further studies will be necessary to better evaluate ter the prognosis. Roughly three fourths of adoles- cents with the developmental form of POTS will dis- • The hyperadrenergic form of POTS responds best to play a significant recovery by their mid-20s. In agents that block norepinephrine release or its effects.
general, about 90% of patients will respond to a com- The most frequently used agent is clonidine HCl bination of physical therapy and pharmacotherapy.
(Catapres), in pill or patch form. The oral dose is 0.1 Most patients with the hyperadrenergic form of mg qd or bid, titrated upward. The patch form is use- POTS require therapy indefinitely. The outcome of ful in that it provides a continuous and constant level those with the secondary form of POTS usually de- of the drug for up to 1 week at a time. The combined pends on the prognosis of the causative disorder.
α /β-blocker labetalol HCl (Trandate, Normodyne) is useful in some patients, as β-blockade alone may Conclusion
worsen symptoms (due to unopposed α-receptor stim- The postural tachycardia syndrome represents a ulation). Starting dosages of 100-200 mg bid are used, heterogenous group of various disorders with similar with a maximum dosage of 400 mg bid. Methyldopa clinical characteristics that occur as a result of a dis- may also be useful in occasional patients. In addition, turbance in normal autonomic control. Adequate the SSRIs and norepinephrine reuptake inhibitors are treatment often depends on determining the subtype helpful in select patients. The interested reader is di- and instituting a complete treatment program. ■ rected to more in-depth discussions of the topic.
• Treatment in patients with secondary POTS is first Disclosure The author has no relationship with any
aimed at correcting or stabilizing the underlying dis- commercial entity that might represent a conflict of order as much as possible. Patients such as those with interest with the content of this article. diabetes or JHS tend to behave and respond to treat-ment as do those with the PD form of POTS. Those S E L F - E X A M I N A T I O N
with paraneoplastic POTS may respond well to ther-apy with pyridostigmine, and symptoms often abatewith treatment of the malignancy.
1. All of the following except ___________ are com- Some patients suffering from POTS may be ex- mon symptoms in the postural tachycardia syn- tremely debilitated by the disorder, to such an extent that they are unable to continue normal employment or educational activities, and many will become un- derstandably depressed. They often need the help ofsocial workers, psychologists, and legal aid to address the scope of problems brought on by their illness. As with many chronic illnesses, the attitude of the treat- ing physician is critical. Hope is a powerful medicinethat should be encouraged.
2. Which of these drug classes is not likely to cause or 26 • FAMILY PRACTICE RECERTIFICATION
POSTURAL TACHYCARDIA SYNDROME
worsen orthostatic intolerance in patients with 2. Grubb BP, Kosinski DJ, Boehm K, et al. The postural ortho- static tachycardia syndrome: A neurocardiogenic variant iden- tified during head-up tilt table testing. Pacing ClinElectrophysiol 1997;20:2205-2212.
3. Karas B, Grubb BP, Boehm K, et al. The postural orthostatic tachycardia syndrome: A potentially treatable cause of chron- d) combined serotonin and norepinephrine reup- ic fatigue, exercise intolerance, and cognitive impairment inadolescents. Pacing Clin Electrophysiol 2000;23:344-351.
4. Benrud-Larson LM, Dewar MS, Sandroni P, et al. Quality of life in patients with postural tachycardia syndrome. MayoClinic Proc 2002;77:531-537.
3. POTS may be secondary to any of the following ex- 5. Benrud-Larson LM, Sandroni P, Haythornthwaite JA, et al.
Correlates of functional disability in patients with posturaltachycardia syndrome: Preliminary cross-sectional findings.
6. Low PA, Novak V, Novak P, et al. Postural tachycardia syn- drome. In: Low PA, ed. Clinical Autonomic Disorders: Evalu- ation and Management. 2nd ed. Philadelphia, Pa: Lippincott-Raven; 1997:681-698.
7. Kanjwal Y, Kosinski D, Grubb BP. The postural orthostatic tachycardia syndrome: Definition, diagnosis, and manage-ment. Pacing Clin Electrophysiol 2003;26:1747-1757.
4. Which of these statements about POTS is false? 8. Schroeder C, Tank J, Boschmann M, et al. Selective norepi- nephrine reuptake inhibition as a human model of orthostat- a) A defining characteristic of POTS is symptoms ic intolerance. Circulation 2002;105:347-353.
of orthostatic intolerance associated with heart 9. Grubb BP, Rowe P, Calkins H. Postural tachycardia, orthosta- rate increases of 30 or more beats per minute.
tic intolerance, and the chronic fatigue syndrome. In: GrubbBP, Olshansky B, eds. Syncope: Mechanisms and Manage- b) Not all POTS patients have orthostatic hypo- ment. 2nd ed. Malden, Mass: Blackwell Publishing; 2005: c) Other autonomic symptoms in patients with 10. Vernino S, Low PA, Fealey RD, et al. Autoantibodies to gan- glionic acetylcholine receptors in autoimmune autonomic POTS include disturbances in sweating, temper- neuropathies. N Engl J Med 2000;343:847-855.
ature regulation, and bowel and bladder func- 11. Klein CM, Vernino S, Lennon VA, et al. The spectrum of au- toimmune autonomic neuropathies. Ann Neurol 2003;53: d) POTS frequently occurs in patients after febrile, presumably viral illnesses, immunization, sepsis, 12. Shannon JR, Flattem NL, Jordan J, et al. Orthostatic intoler- ance and tachycardia associated with norepinephrine-trans- porter deficiency. N Engl J Med 2000;342:541-549.
e) The male-female ratio of POTS is 5:1.
13. Schroeder C, Tank J, Luft FC, Jordan J. Norepinephrine trans- porter function and orthostatic syndromes. J Functional Synd 5. Common elements of treatment for POTS include all of the following except ____________.
14. Gazit Y, Nahir AM, Grahame R, et al. Dysautonomia in the joint hypermobility syndrome. Am J Med 2003;115:33-40.
a) aerobic exercise (20 min at least 3 days weekly) 15. Khurana R. Paraneoplastic autonomic dysfunction. In: Robertson DW, Low PA, Polinsky RJ, eds. Primer on the Auto- nomic Nervous System. San Diego, Calif: Academic Press; 16. Kanjwal MY, Kosinski DJ, Grubb BP. Treatment of postural orthostatic tachycardia syndrome and inappropriate sinus tachycardia. Curr Cardiol Rep 2003;5:402-406.
17. Schroeder C, Vernino S, Birkenfeld AL, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med REFERENCES
1 Streeten DH. Orthostatic intolerance. A historical introduc- tion to the pathophysiological mechanisms. Am J Med Sci ■ Answers: 1)c, 2)d, 3)c, 4)e, 5)b 30 • FAMILY PRACTICE RECERTIFICATION

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