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A Heterogeneous and Multifactorial Disorder Postural tachycardia syndrome (POTS) is defined by a heart rate increment of 30 beats/min or more within 10 minutesof standing or head-up tilt in the absence of orthostatic hypotension; the standing heart rate is often 120 beats/min orhigher. POTS manifests with symptoms of cerebral hypoperfusion and excessive sympathoexcitation. The pathophys-iology of POTS is heterogeneous and includes impaired sympathetically mediated vasoconstriction, excessive sympa-thetic drive, volume dysregulation, and deconditioning. POTS is frequently included in the differential diagnosis ofchronic unexplained symptoms, such as inappropriate sinus tachycardia, chronic fatigue, chronic dizziness, or unex-plained spells in otherwise healthy young individuals. Many patients with POTS also report symptoms not attributable toorthostatic intolerance, including those of functional gastrointestinal or bladder disorders, chronic headache, fibromyalgia,and sleep disturbances. In many of these cases, cognitive and behavioral factors, somatic hypervigilance associated withanxiety, depression, and behavioral amplification contribute to symptom chronicity. The aims of evaluation in patients withPOTS are to exclude cardiac causes of inappropriate tachycardia; elucidate, if possible, the most likely pathophysiologic basisof postural intolerance; assess for the presence of treatable autonomic neuropathies; exclude endocrine causes of ahyperadrenergic state; evaluate for cardiovascular deconditioning; and determine the contribution of emotional andbehavioral factors to the patient’s symptoms. Management of POTS includes avoidance of precipitating factors, volumeexpansion, physical countermaneuvers, exercise training, pharmacotherapy (fludrocortisone, midodrine, ␤-blockers,and/or pyridostigmine), and behavioral-cognitive therapy. A literature search of PubMed for articles published fromJanuary 1, 1990, to June 15, 2012, was performed using the following terms (or combination of terms): POTS; posturaltachycardia syndrome, orthostatic; orthostatic; syncope; sympathetic; baroreceptors; vestibulosympathetic; hypovolemia; vis-ceral pain; chronic fatigue; deconditioning; headache; Chiari malformation; Ehlers-Danlos; emotion; amygdala; insula; anteriorcingulate; periaqueductal gray; fludrocortisone; midodrine; propranolol; ␤-adrenergic; and pyridostigmine. Studies werelimited to those published in English. Other articles were identified from bibliographies of the retrieved articles.
2012 Mayo Foundation for Medical Education and Research Ⅲ Mayo Clin Proc. 2012;87(12):1214-1225 From the Department ofNeurology, Mayo Clinic,Rochester, MN.
P osturaltachycardiasyndrome(POTS)isone drenandadolescents,andnewcriteriaforthesedis- of the most common manifestations of ortho- orders in this age group have been recently static intolerance.1,2 According to current proposed.5 POTS is more frequent in women criteria for adults,3 POTS is defined by a heart rate (female:male ratio, 4.5:1), and most cases occur be- increment of 30 beats/min or more within 10 min- tween the ages of 15 and 25 years. Up to 50% of utes of standing or head-up tilt (HUT) in the absence cases have antecedent viral illness, and 25% have a of orthostatic hypotension; the standing heart rate is family history of similar complaints.1,6,7 The expe- often 120 beats/min or higher. These criteria may rience from extensive series indicates that POTS is not be applicable for individuals with low resting pathophysiologically heterogeneous. Many patients heart rate. For individuals aged 12 to 19 years, the with POTS present with multiple chronic symptoms required increment is at least 40 beats/min.3 The that are not directly related to orthostatic stress, and orthostatic tachycardia may be accompanied by only a small subgroup of patients with POTS have a symptoms of cerebral hypoperfusion and sympa- defined autonomic disorder. Physical decondition- thetic hyperactivity that are relieved by recum- ing and psychological factors have an important role bency. Symptoms of cerebral hypoperfusion include in these patients. Therefore, the evaluation and light-headedness, blurred vision, cognitive difficul- management of POTS should be multidisciplinary.
ties, and generalized weakness; symptoms of exces- These patients pose a particular challenge in man- sive sympathoexcitation include palpitations, chest agement, which reflects the pathophysiologic hetero- pain, and tremulousness. The term orthostatic intol- geneity of orthostatic intolerance, the presence of erance is used to describe a condition in which pa- multiple comorbidities not directly related to ortho- tients develop symptoms on standing or HUT but static stress, and the lack of recognition that patients do not fulfill the heart rate criteria for the diagnosis with POTS frequently require exercise training and of POTS.4 The diagnostic criteria for orthostatic in- behavioral-cognitive approaches to obtain long- tolerance and POTS in adults are unsuitable for chil- term control of their symptoms. There have been Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 www.mayoclinicproceedings.org Ⅲ 2012 Mayo Foundation for Medical Education and Research many recent reviews on POTS.2,8,9 This review willfocus on (1) the pathophysiologic heterogeneity of POTS, (2) comorbid conditions commonly associ- Postural tachycardia syndrome (POTS) is not a unique nosological ated with POTS, (3) an expanded view of POTS entity, and its treatment should be individualized.
pathophysiology, and (4) the evaluation and ratio-nale for a multimodal approach to these patients.
The pathophysiologic mechanisms of orthostatic intolerance in POTS A literature search of PubMed for articles pub- are multifactorial and include hypovolemia, venous pooling, hyperad- lished from January 1, 1990, to June 15, 2012, was renergic states, and restricted adrenergic neuropathies in the lower performed using the following terms (or combina- tion of terms): POTS; postural tachycardia syndrome, Many symptoms reported by patients with POTS, including visceral orthostatic; orthostatic; syncope; sympathetic; barore-ceptors; vestibulosympathetic; hypovolemia; visceral symptoms and chronic pain disorders, are not due to orthostatic pain; chronic fatigue; deconditioning; headache; Chiari intolerance and therefore are not, in the strict sense, part of the malformation; Ehlers-Danlos; emotion; amygdala; in- sula; anterior cingulate; periaqueductal gray; fludrocor- Most patients with POTS and evidence of a sympathetic neuropathy tisone; midodrine; propranolol; ␤-adrenergic; and pyri- restricted to the lower limbs have no identifiable cause of neuropathy; dostigmine. Studies were limited to those published pheochromocytoma should be excluded in patients with excessive in English. Other articles were identified from bib-liographies of the retrieved articles.
Except for effects of chronic pain and physical deconditioning, there is no clear mechanistic relationship between Ehlers-Danlos syndrome or POTS AS A SYNDROME OF ORTHOSTATICINTOLERANCE The management of POTS includes patient education, volume restitution, Symptoms Reflecting Orthostatic Intolerance physical countermaneuvers, graded exercise training, and pharmacotherapy POTS is one of the most common syndromes of (fludrocortisone, midodrine, ␤-blockers, and/or pyridostigmine).
orthostatic intolerance; others include reflex (neu- Cognitive-emotional factors, including behavioral conditioning and am- rally mediated, vasovagal) syncope and orthostatichypotension in its several forms.3,10 The manifesta- plification, have a key role in POTS.
tions of POTS that reflect orthostatic intolerance(POTS in the strict sense) include those of cerebralhypoperfusion and reflex sympathetic activation.
of sweating in the feet on thermoregulatory sweat Up to one-third of patients may develop secondary tests and quantitative sudomotor axon reflex test- orthostatically triggered vasovagal (reflex, neurally ing17 and impaired increase of NE release in the mediated) syncope.11 As in all types of orthostatic lower limb in response to orthostatic stress.17 In a intolerance, typical exacerbating factors include large series,7 54% of patients had evidence of pe- heat exposure, physical exertion, heavy meals, pro- ripheral sudomotor denervation. The primary longed recumbency, menses, and drugs such as di- pathophysiologic mechanism of postural intoler- ance in this subgroup of patients is presumed to beimpaired peripheral vasoconstriction, leading to ve- Classic Pathophysiology and POTS Subtypes nous pooling in the lower limbs. Consistent with Exaggerated postural tachycardia may reflect several this possibility, a subgroup of patients with POTS pathophysiologically distinct mechanisms2,4,6,8,9,13-16 have impaired indirect measures of sympathetic va- (Table 1). Based on autonomic testing and plasma soconstriction assessed by the blood pressure profile norepinephrine (NE) levels, POTS has been classi- during the Valsalva maneuver or HUT7 and venous fied into several subtypes, including neuropathic pooling in the absence of venous compliance defects and hyperadrenergic POTS2,13 and, based on mea- in the lower limbs.18 This neuropathic subgroup surement of leg venous pressure and calf blood flow, corresponds to the so-called high-flow POTS sub- as low-flow, high-flow, and normal-flow POTS.8,16 group, characterized by reduced total peripheral re- ␤ -Adrenoreceptor polymorphisms may contribute sistance while supine and venous pooling in the legs to the hemodynamic diversity of patients with on standing.8,16 Reduced myocardial meta-iodo- benzylguanidine uptake has been reported in pa-tients with POTS.19 However, the relationship be-tween this finding and peripheral adrenergic Neuropathic POTS. The term neuropathic POTS1,17 denervation of the lower limb is still undeter- describes a subgroup of patients with indirect evi- mined. The frequent onset after a viral illness and dence of peripheral sympathetic denervation in the the presence of a ganglionic acetylcholine recep- lower limbs. This condition is characterized by loss tor antibody in 14% of patients suggest an auto- Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 TABLE 1. Pathophysiologic Mechanisms of Orthostatic Intolerance in POTS Impaired sympathetically mediated vasoconstriction Restricted postviral or autoimmune neuropathies Excessive cardiac sympathoexcitatory responses Impaired renal control of fluid secretion HUT ϭ head-up tilt; MIBG ϭ meta-iodobenzylguanidine; NE ϭ norepinephrine; POTS ϭ postural tachycardia syndrome; RAA ϭ renin-angiotensin-aldosterone; VGKC ϭvoltage-gated potassium channel; VM ϭ Valsalva maneuver; V˙O possibility of hyperthyroidism or a catecholamine-se- creting tumor, such as pheochromocytoma, should beconsidered. Laboratory studies should include deter-mination of plasma and urinary metanephrine levels, Hyperadrenergic POTS. Between 30% and 60% of and if they are elevated, imaging studies to detect patients with POTS have evidence of increased cen- tral sympathetic drive, as reflected by standing Hyperadrenergic states may also be secondary plasma NE levels of 600 pg/mL or more (to convert to immune disorders associated with antibodies to pmol/L, multiply by 5.911); fluctuating blood against components of the voltage-gated potas- pressure or hypertensive response during HUT; and sium channel complex in the setting of limbic episodes of tachycardia, hypertension, and hyperhi- encephalitis or Morvan syndrome.25 However, drosis.2,7,20 In these patients, the episodes can be hyperadrenergic POTS as the only manifestation triggered not only by orthostatic stress but also by of anti–voltage-gated potassium channel complex emotional stimuli and physical activity. This sub- autoimmunity has not yet been convincingly group of patients may correspond to the so-called low-volume POTS characterized by supine vasocon-striction, supine tachycardia, pale and cold skin,and increased supine muscle sympathetic nerve ac- POTS and Volume Dysregulation. Many patients tivity.16 These patients have been categorized into a with POTS have low plasma, red cell, and total primary or central hyperadrenergic subgroup with blood volumes as assessed using various tech- plasma NE levels often between 1000 and 2000 niques.26-28 In one study, 28.9% of patients ex- pg/mL that compromises approximately 5% to 10% creted less than 100 mEq/L of sodium in 24 hours, of cases and a heterogeneous group of secondary which was interpreted as consistent with a hypovo- hyperadrenergic POTS.21 Loss-of-function se- lemic status.7 In many cases, these patients have low quence variation of the norepinephrine transporter levels of standing plasma renin activity and aldoste- (NET) and reduced clearance of synaptic NE were rone compared with controls. However, some pa- found in a case of hyperadrenergic POTS.22 How- tients have a low-flow phenotype associated with ever, increased NE levels more commonly reflect inappropriately high plasma angiotensin II levels, pharmacological NET blockade by drugs such as reflecting reduced estimated angiotensin-convert- tricyclic antidepressants, selective NET inhibitors, ing enzyme 2 activity.28 Functional gastrointestinal and amphetaminelike drugs such as methylpheni- disorders associated with poor water intake due to date. Secondary hyperadrenergic POTS has also nausea or excess fluid loss due to diarrhea may re- been associated with mast cell activation disor- sult in hypovolemia with secondary orthostatic ders.23 In patients with hyperadrenergic POTS, the symptoms and tachycardia. In this case, POTS Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 should be considered a consequence of the gastro- parasympathetic or sympathetic output via the vagus, pelvic, or splanchnic nerves.
POTS and Physical Deconditioning. Most patients Chronic Fatigue, Insomnia, and Fibromyalgia with POTS exhibit greater and more persistent Chronic fatigue,43-45 fibromyalgia,46 and sleep dis- tachycardia, reduced stroke volume, reduced left turbances44 have been frequently associated with ventricular mass, and reduced peak oxygen uptake POTS. In a large series of adult patients with POTS, when upright and during and after exercise com- many reported chronic fatigue (48%), sleep distur- pared with control subjects.29,30 These findings in- bance (32%), and myofascial pain (16%).7 There is an dicate the presence of physical deconditioning, overlap between chronic fatigue syndrome and POTS.
which may be an important factor in the develop- Patients with POTS who have chronic fatigue syn- ment of orthostatic symptoms, regardless of the un- drome have higher laboratory markers of sympathetic derlying pathophysiology.30,31 Bed rest or decondi- activation than patients without chronic fatigue.43,45 tioning also decreases the gain of the vasoconstrictorbaroreceptor reflex32,33 and the vestibulosympa- thetic reflex,34 which could also predispose patients Ehlers-Danlos syndrome (EDS) is a heterogeneous dis- to orthostatic intolerance. However, there is evi- order that includes several forms, all linked to se- dence that bed rest or deconditioning does not pri- quence variations in genes encoding for fibrillar pro- marily affect the reflex control of muscle sympa- teins and/or collagen processing enzymes leading to reduced structural integrity of connective tissue.
Joint hypermobility, which is characteristic of EDStype III associated with sequence variations in tenas- cin X, has been frequently associated with Many patients with POTS experience chronic symp- POTS.47-49 However, the mechanistic relationship toms that cannot be mechanistically explained by pos- between these 2 entities is incompletely defined.
tural intolerance or excessive tachycardia.2,37 Many of Whereas tenascin X sequence variations affect car- these symptoms are also prevalent in patients without diovascular tissue leading to valvular disease,50 the orthostatic intolerance; in these cases, excessive pos- hypothesis that impaired integrity of vascular con- tural tachycardia is secondary to hypovolemia, pro- nective tissue leads to impaired venous return and longed bed rest, physical deconditioning, and anxiety, secondary orthostatic tachycardia has not yet been convincingly tested. EDS III is also characterized byearly onset of chronic pain, particularly in the shoul-ders, hands, and knees,51 which may be disabling due to associated anxiety, depression, and a somato- A percentage of patients with POTS experience vis- sensory amplification state52; this may lead to sec- ceral symptoms referred to the upper or lower gas- ondary hypersympathetic responses triggered by trointestinal tract, bladder, and other organs. In a large series of adult patients with POTS,7 nausea waspresent in 39%, bloating in 24%, diarrhea in 18%,constipation in 15%, abdominal pain in 15%, and bladder symptoms in 9% of cases. These symptoms Chronic headache, including migraine, is a common are similar to those typically reported by patients comorbidity in patients with POTS.7,37,53 Ortho- with functional motility disorders such as functional static headaches also occur in patients with dyspepsia, gastric emptying disorders, irritable POTS,53,54 even in the absence of intracranial hypo- bowel syndrome, and interstitial cystitis, among volemia or cerebrospinal fluid leak.55 The relation- others.38,39 The underlying pathophysiology of ship between POTS and orthostatic headache is un- these disorders includes mucosal inflammation, vis- certain because treatment of orthostatic tachycardia ceral hypersensitivity, secondary visceromotor dys- with volume expansion is only partially effective in function, and, in most cases, behavioral amplifica- these patients.55 Orthostatic tachycardia has also tion.39-42 Although these symptoms may be more been reported in patients with type I Chiari malfor- frequently reported in patients with neuropathic mation,56,57 in some cases associated with syringo- POTS,2 they should not necessarily be considered myelia.58 However, a direct relationship between a manifestation of a primary underlying auto- incidental type I Chiari malformation and ortho- nomic disorder (dysautonomia) because these are static intolerance has not been convincingly dem- disorders of visceral sensitivity mediated by vis- onstrated.59 POTS has also been shown in pa- ceral afferents and not due to primary involve- tients with a remote history of traumatic head ment of the enteric nervous system or efferent injury,60 but this does not necessarily implicate Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 direct damage of central autonomic areas as the dulla.70-74 Information from visceral mechanore- primary cause of orthostatic intolerance.
ceptors (including cardiovascular, gastrointestinal,and genitourinary receptors) as well as visceral and somatic nociceptors is conveyed to this network viathe dorsal horn of the spinal cord, nucleus of the solitary tract, and parabrachial nucleus of the pons70; vestibular receptors activate this network The persistence of orthostatic symptoms despite via relay in the vestibular nuclei.75 This information adequate control of the heart rate and the coexis- is referred to as interoception because it reflects the tence of many nonorthostatic symptoms com- physiological state of the body.71 These inputs trig- monly reported by patients with POTS suggest that ger homeostatic reflexes integrated at the level of the impaired processing of viscerosensory (including medulla, including the baroreflex76 and vestibulo- cardiovascular) information, conditioning, and be- sympathetic reflexes63 that are initiated by ortho- havioral amplification also play a contributory role static stress and mediated by sympathoexcitatory in this disorder. For example, many triggers, such as neurons of the rostral ventrolateral medulla.77 viral illness (particularly if associated with gastroin- These interoceptive inputs also relay, either directly or testinal fluid loss), prolonged bed rest, or both, may via the thalamus, to forebrain areas such as the hypo- result in relatively rapid development of symptoms thalamus, amygdala, insular cortex, and anterior cin- of orthostatic intolerance and sympathoexcitation.
gulate cortex.70-72 All these areas are reciprocally inter- This pattern of responses may become conditioned, connected and control sympathetic cardiovascular leading to failure of the viscerosensory and sympa- output via projections to the rostral ventrolateral me- thetic systems to readapt to the routine demands dulla.77 The amygdala automatically attributes emo- of standing and exercise after the acute illness.
tional valence to the stimulus and is involved in This situation would be akin to the case of chronic associative learning and conditioned fear re- subjective dizziness, in which there is failure of the sponses.78 The anterior insular cortex is required for postural and ocular motor control systems to re- conscious awareness of bodily sensations.71 For ex- adapt to the routine demands of locomotion after an ample, functional magnetic resonance imaging acute episode of vertigo and postural instabil- studies showed increased activity of the anterior in- ity.61,62 Because standing up not only produces ac- sula during tasks in which subjects attend to the tivation of the baroreflex but also triggers a vestibu- timing of their heartbeats.79 The dorsal anterior cin- losympathetic reflex,63 exaggerated conditioned gulate (also called the midcingulate) cortex is acti- responses to vestibular inputs and lack of readapta- vated during tasks that involve awareness, attention, tion of the vestibulosympathetic responses may also and behavioral engagement that are associated with contribute to persistence of posture-induced symp- an increase in sympathetic drive.72 These areas proj- toms and tachycardia in these patients. Abnormal ect to the hypothalamus and periaqueductal gray processing of sensory information, including so- region, which orchestrate coordinated autonomic matic hypervigilance64 and behavioral amplifica- and pain modulatory responses in the setting of tion, may also contribute to persistence of symp- emotion and stress. Functional neuroimaging stud- toms, including those not triggered by orthostatic ies also indicate that the insular and anterior cingu- stress, such as visceral pain,41 fibromyalgia,65,66 late cortex may also be involved in modulation of and chronic dizziness. Furthermore, decondition- baroreflex-mediated sympathetic and cardiovascu- ing, poor sleep, and psychological factors such as anxiety or depression may all lead to relative pre- There is a reciprocal interaction between these dominance of sympathetic over vagal control the areas and areas of the prefrontal cortex involved in focused attention and emotional modulation.81 Theinsular, midcingulate, and dorsolateral prefrontal cortex are also components of the cortical network The central circuits involved in visceral sensation, that is activated in response to pain and visceral aversive conditioning, behavioral arousal, stress re- sensations, referred to as the pain matrix.82,83 This sponses, and pain processing and modulation may network exhibits considerable use-dependent syn- all be involved in the maintenance of the symptoms aptic plasticity, which may be maladaptive, for ex- in patients with POTS (Figure). Key components of ample in the setting of chronic stress or pain.82,83 this network include the brainstem sensory relay nu- Functional neuroimaging studies also show that the clei, amygdala, insula, anterior cingulate cortex, hy- connectivity among the amygdala, cingulate, and pre- pothalamus (particularly the paraventricular nu- frontal cortex is affected in disorders such as anxiety cleus and lateral hypothalamic area), periaqueductal and depression,81 which are common comorbid con- gray region, medullary raphe, and ventrolateral me- ditions in patients with symptoms associated with Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 Anterior cingulate cortex (behavioral arousal) Amygdala (emotional tagging of sensation) -Visceral pain/dysmotility-Myofascial pain FIGURE. Complex pathophysiology of postural tachycardia syndrome (POTS). The mechanisms of orthostatic intolerance inPOTS include impaired sympathetic vasoconstriction leading to venous pooling, hypovolemia, deconditioning, and hyperadrenergicstate. Excessive reflex sympathoexcitation may be triggered by orthostatic stress via reduced baroreceptor input to the nucleusof the solitary tract (NTS) and activation of vestibulosympathetic reflexes (VSR) relayed via the medial vestibular nucleus (MVN),resulting in increased activity of sympathoexcitatory neurons of the rostral ventrolateral medulla. Many comorbidities of POTS,including visceral pain and dysmotility, other chronic pain conditions, and dizziness may reflect abnormal processing of interoceptiveinformation, relayed via the NTS and parabrachial nucleus (PBN) via the ventromedial portion of the thalamus to a central networkthat includes the anterior cingulate cortex, insula, amygdala, hypothalamus, and periaqueductal gray region.
POTS, including those of visceral pain and dysmotility, tating or aggravating factors; presence of associated chronic fatigue, fibromyalgia, and insomnia.
nonorthostatic symptoms; fluid and caffeine intake;level of physical activity; sleep pattern; response toprevious attempted treatments; and current drug EVALUATION AND MANAGEMENT OF PATIENTSWITH POTS therapy. The patient should undergo a comprehen-sive cardiac and neurologic examination in addition Patients with POTS require a multidisciplinary eval- to measurements of supine and standing heart rate and blood pressure. Examination could also revealindirect evidence of venous pooling (such as lower extremity edema) or excessive sympathetic activity Elicitation of the clinical history of patients with (such as cold, clammy hands). The main aspects of POTS should address the trigger, timing of onset, laboratory evaluation in patients with POTS are and progression of orthostatic symptoms; precipi- summarized in Table 2. The aims are to exclude Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 TABLE 2. Laboratory Evaluation in Patients With POTS Cardiac evaluation (ECG, echocardiogram, Holter monitoring) Head-up tilt (at a 60° angle for 10 min) Plasma catecholamine, both supine and during standing or Assessment of baroreflex sympathoexcitation 24-Hour blood pressure and heart rate monitoring Correlate the timing of the patient’s symptoms Autoantibodies (VGKC complex, ganglionic AChR) AChR ϭ acetylcholine receptor; ECG ϭ electrocardiogram; MRI ϭ magnetic resonance imaging; OI ϭ orthostatic intolerance; POTS ϭpostural tachycardia syndrome; VGKC ϭ voltage-gated potassium channel.
primary cardiac causes of inappropriate tachycardia; into the different pathophysiologic subtypes determine, if possible, the most likely primary (neuropathic, hyperadrenergic, or hypovolemic).
pathophysiologic basis of postural intolerance;identify treatable causes of autonomic neuropathy in patients with neuropathic POTS; exclude endo-crine or other systemic causes of a hyperadrenergic The management of POTS involves nonpharmaco- state in patients with hyperadrenergic POTS; assess logical (Table 3) and pharmacological (Table 4) the degree of cardiovascular conditioning; investi- gate the mechanisms of gastrointestinal and otherassociated symptoms; and address possible psychi- atric comorbidities. The basic evaluation should in- Patient education is a fundamental aspect of POTS clude a cardiac evaluation, autonomic reflex testing, management. Patients should be informed about the and measurement of supine and standing plasma differences between the symptoms that are due to catecholamine levels. Screening HUT table testing orthostatic intolerance and those that are not and has been shown to be helpful in the evaluation of about potential aggravating or precipitating factors patients with syncope of unknown cause, including that may exacerbate their postural and exercise POTS.84 Noninvasive plethysmographic blood pressure and heart rate monitoring allows a carefulexamination of the beat-to-beat systolic and dia-stolic blood pressure and heart rate responses dur- ing HUT. Data regarding stroke index and total Regardless of the basic pathophysiologic mecha- peripheral resistance, as well as heart rate vari- nism, most patients require volume expansion with ability, can also be obtained from these record- adequate daily water (1.5-2 L) and sodium intake. This ings. This information provides a more thorough is particularly important on awakening or before a pre- picture of the hemodynamic and reflex responses dictable orthostatic stress. Excessive caffeine intake associated with orthostatic stress and allows a should be avoided because it may increase diuresis more precise categorization of patients with POTS Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 TABLE 3. Nonpharmacological Management of POTS Physical countermaneuvers, such as leg crossing,bending forward and placing a foot on a chair, mak- ing a fist, or active contraction of abdominal or but- tock muscles may produce small increases in mean arterial pressure to maintain an adequate cerebral blood flow and prevent fainting in patients with all forms of orthostatic intolerance, including neuro- Avoid blood pooling in mesenteric vessels genic orthostatic hypotension,85 vasovagal syn- Because blood pooling on standing occurs both in the abdomen and lower limbs, some patients with POTS may benefit from wearing support garments, such as thigh- or waist-high tight support stockings As in all causes of physical deconditioning, reduced stroke volume is a key component in the pathogen- esis of POTS.29 As described by Shibata et al,89 short-term exercise training improves physical fit- ness and cardiovascular responses during exercise NE ϭ norepinephrine; POTS ϭ postural tachycardia syndrome.
in patients with POTS. Given that deconditionedpatients with POTS may rapidly become symptom-atic during exercise, they should begin with a verysmall amount of exercise, using either a recumbent intravascular volume. Pyridostigmine may poten- cycle or treadmill and gradually increasing the reg- tiate muscarinic receptor activation in the gastro- imen over the next 6 to 8 weeks. Patients also benefit intestinal tract, exacerbating nausea, vomiting, from light strengthening exercises for the major abdominal cramps, and diarrhea, and in the blad- muscle groups using weight machines.
der, potentiating the symptoms of detrusorhyperactivity.
Pharmacological TherapyDrug therapy of POTS includes the mineralocorti- Why Are Some Patients With POTS So Difficult to coid fludrocortisone90 to promote intravascular vol- ume expansion, the ␣ -adrenergic agonist mido- Several factors contribute to the difficulties in the drine87,91 to elicit peripheral vasoconstriction and management of patients with POTS. First is the lack reduce venous pooling, ␤-blockers including pro- of patient education (or, worse, patient misinforma- pranolol87,92 and cardioselective agents such as bis- tion) about the disorder. This leads to unrealistic prostol90,93 to control the excessive sinus tachycardia, expectations about the beneficial effects of treatment and the cholinesterase inhibitor pyridostigmine94-96 to aimed to correct the postural tachycardia and sec- prolong the phasic effects of acetylcholine on the ondary frustration and symptom amplification. A autonomic ganglia, leading to peripheral sympa- second factor is the failure to recognize the hetero- thetic vasoconstrictor output (and potentiating va- geneous pathophysiologic basis of orthostatic tachy- gal effects) on standing (Table 3). However, adverse cardia in POTS. Drug treatment may need to be in- effects of these drugs can limit their use in patients dividualized, depending on whether impaired with POTS because of the presence of comorbid peripheral vasoconstriction and venous pooling, hy- symptoms. Fludrocortisone may exacerbate head- peradrenergic state, or hypovolemia is thought to be ache and vertigo, particularly in patients with mi- the most prominent trigger. A complicating factor is graine. Midodrine can increase the risk of urinary that the doses of fludrocortisone, midodrine, retention in patients with functional bladder disor- ␤-blockers, or pyridostigmine used for treatment of ders by increasing contraction of the smooth muscle other conditions such as neurogenic orthostatic hy- of the bladder neck. Propranolol and other ␤-block- potension or inappropriate sinus tachycardia may ers may exacerbate fatigue and exercise intolerance not be tolerated by many patients with POTS, par- and may produce hypotension in patients with low ticularly those with physical deconditioning and Mayo Clin Proc. Ⅲ December 2012;87(12):1214-1225 Ⅲ http://dx.doi.org/10.1016/j.mayocp.2012.08.013 TABLE 4. Pharmacological Management of POTS Special considerations in patients with POTS Vasoconstriction (reduces venous pooling) May worsen GI symptoms or urinary retention Reduce sympathetic influence on the sinus node Propranolol may be potentially useful to treat comorbidities All ␤-blockers should be started at low doses because patients may have ␤-adrenoceptor supersensitivity ␤-Blockers may exacerbate fatigue or produce hypotension if used without concomitant nonpharmacological Potentiates ganglionic sympathoexcitation during May help visceral hypomotility but may exacerbate GI ϭ gastrointestinal; POTS ϭ postural tachycardia syndrome.
comorbid conditions. Drugs used to treat POTS eas involved in processing of interoceptive (vis- comorbidities may also exacerbate orthostatic ceral and somatic nociceptive) information, tachycardia; these include amphetaminelike psy- interoceptive awareness, behavioral arousal, and chostimulants used to treat chronic fatigue and an- tidepressants such as amitriptyline used to treat in- somnia, migraine, fibromyalgia, or visceral pain.
drome; HUT ؍ head-up tilt; NE ؍ norepinephrine; NET ؍ Another reason for symptom persistence is the fail- norepinephrine transporter; POTS ؍ postural tachycardia ure to address physical deconditioning with a grad- ual exercise program. Although many patients are Correspondence: Address to Eduardo E. Benarroch, MD, motivated to exercise, they may initially exercise too Department of Neurology, Mayo Clinic, 200 First St SW, vigorously, leading to worsening of symptoms. Fi- Rochester, MN 55905 ([email protected]).
nally and perhaps most importantly is the funda-mental role of somatic hypervigilance, behavioralarousal, and emotional conditioning in the main- tenance of the patient’s orthostatic, as well as non- Low PA, Opfer-Gehrking TL, Textor SC, et al. Postural tachy- orthostatic, symptoms. Both the patient and the cardia syndrome (POTS). Neurology. 1995;45(4, suppl 5):S19- physician should realize that, as in many other chronic conditions, realistic expectations and be- Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia havioral-cognitive approaches are more likely syndrome (POTS). J Cardiovasc Electrophysiol. 2009;20(3):352- than pharmacotherapy to improve the patient’s Freeman R, Wieling W, Axelrod FB, et al. Consensus state- ment on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Clin Parsaik AT, Allison TG, Singer W, et al. Deconditioning in POTS is a prototypical chronic, potentially disabling patients with orthostatic intolerance [published online ahead condition with no clear pathologic substrate and of print September 19, 2012]. Neurology. 2012. In press.
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