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Postural Tachycardia Syndrome (POTS) and the GI Tract: A Primer for the Gastroenterologist John K. DiBaise, MD, FACG1, Lucinda A. Harris, MS, MD1 and Brent Goodman, MD2
Postural tachycardia syndrome (POTS) is one of the most common causes of orthostatic intolerance and is being increasingly recognized in clinical practice. Gastrointestinal (GI) symptoms are reported commonly in patients with POTS and pose a considerable management challenge, making it imperative that gastroenterologists be aware of this condition and its GI comorbidities. Although the evidence presented herein does not prove causation, it does support an association between GI symptoms, GI dysmotility, and POTS. At present, the evaluation and treatment of GI symptoms in patients with POTS remains largely empirical. General measures to treat POTS may lead to improvement in both GI and non-GI symptoms. GI symptoms refractory to these measures should prompt further diagnostic evaluation of gastrointestinal dysmotility and appropriate dietary and pharmacologic management. This review focuses its attention on the involvement of the GI tract in POTS including a discussion of GI symptoms and conditions associated with POTS, followed by an analysis of abnormalities in gut physiology described in POTS, and concluding with an overview of management and suggestions for research directions. Am J Gastroenterol https://doi.org/10.1038/s41395-018-0215-4
Introduction Orthostatic intolerance describes symptoms that develop in response to upright posture and, classically, resolve upon recumbency. Although orthostatic intolerance due to generalized autonomic failure (e.g., from diabetes mellitus, amyloidosis, or multiple system atrophy) is well recognized, orthostatic intolerance more commonly results from other conditions. It is estimated that over 500,000 persons in the United States have some form of orthostatic intolerance [1]. Postural tachycardia syndrome (POTS) is considered the most common cause of chronic orthostatic intolerance [2]. Orthostatic hemodynamic dysregulation occurs when the normal physiologic gravitational regulatory mechanism is impaired. Patients with such impairment may present with both orthostatic hypotension and tachycardia or with orthostatic tachycardia alone as seen in POTS. Indeed, the cardinal hemodynamic feature in POTS is an excessive heart rate increase without a corresponding decrease in blood pressure and is associated with multiple symptoms on standing that, classically, improve with recumbency. Consensus criteria (Table 1) for POTS include an increase in heart rate of at least 30 beats per minute (bpm) within 10 min of standing or head-up-tilt testing (>40 bpm in children), in the absence of orthostatic hypotension and any precipitating factors [3–5]. POTS is more common among young women with a female:male ratio of at least 4.5:1 and an age range between 15 and 50 years [3, 6]. A family history of orthostatic intolerance has been reported in 13% of POTS patients [7]. While the underlying etiology is unknown, multiple pathophysiologic
mechanisms are thought to converge as a final common pathway to result in the clinical syndrome known as POTS [8]. Like all types of orthostatic intolerance, common presenting symptoms in POTS are caused by cerebral hypoperfusion and/ or sympathetic overactivity, and include lightheadedness, blurred vision, difficult cognition/brain fog, lower extremity or generalized weakness, syncope, palpitations, chest pain, dyspnea, tremors/ shakiness, and paresthesias. Classically, symptoms of orthostatic intolerance improve with recumbency, but resolution may be incomplete or delayed. The symptoms of orthostatic intolerance frequently coexist with a number of symptoms and comorbid conditions that are not necessarily orthostatic in nature. Nonorthostatic symptoms commonly seen in POTS include dry eyes or mouth, and a variety of urinary and gastrointestinal (GI) complaints. Both orthostatic and non-orthostatic symptoms can be severe and contribute considerably to diminished quality of life [9–13]. Common comorbidities include chronic fatigue syndrome, fibromyalgia, migraine headaches, and the hypermobile form of Ehlers–Danlos syndrome. Because of pathophysiologic heterogeneity, diversity of clinical presentation seemingly unrelated to orthostatic stress, and unpredictability of clinical response, POTS patients pose a considerable management challenge and, optimally, require a multidisciplinary approach to both evaluation and management. The primary purpose of this narrative review is to increase the awareness of this condition to gastroenterologists who are increasingly being referred to these complex patients, often under the pretense of a
1 Division of Gastroenterology and Hepatology, Mayo Clinic, Scottsdale, AZ, 85259, USA. 2Department of Neurology, Mayo Clinic, Scottsdale, AZ, 85259, USA. Correspondence: J.K.D. (email:
[email protected]) Received 29 March 2018; accepted 16 July 2018
© 2018 the American college of Gastroenterology
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Table 1 Consensus criteria to diagnose POTS
Review Article
• Heart rate increase ≥30 bpm within 10 min of upright posture in adults (≥40 bpm in adolescents 12–19 years) • Absence of orthostatic hypotension (sustained drop-in blood pressure ≥20/10 mmHg within minute of upright posture) • Orthostatic intolerance symptoms for ≥6 months • Absence of other causes such as dehydration, other medical conditions, medications, and dietary influences
primary disorder of brain–gut function. Herein, we will focus on the involvement of the GI tract in POTS including a discussion of GI symptoms and conditions associated with POTS, followed by an analysis of abnormalities in gut physiology that may contribute to the GI problems described. We conclude with an overview of management and suggestions for research directions. First, a brief examination of the pathophysiology of POTS and its comorbidities is presented.
Pathophysiology Orthostatic intolerance may occur in the setting of physical deconditioning, intravascular volume depletion, impaired sympathetic vasoconstriction in the lower extremities, and excessive cardiac sympathoexcitatory response [6]. POTS has been classified into two major subtypes, neuropathic and hyperadrenergic, based primarily on autonomic testing and plasma norepinephrine levels. Neuropathic POTS is thought to reflect partial autonomic denervation characterized by reduced total peripheral resistance with exaggerated orthostatic venous pooling in the lower limbs [14, 15]. It is speculated that the cerebral hypoperfusion occurring in the neuropathic form of POTS results from peripheral pooling of blood volume and resultant blood pressure instability. The common occurrence of an acute onset of symptoms (e.g., persistent lightheadedness and fatigue or postprandial bloating and vomiting) after a viral-like illness in up to 50% of the patients suggests an autonomic immune-mediated pathogenesis [2, 11]. In contrast, hyperadrenergic POTS is thought to be a centrally driven sympathetic activation characterized by supine vasoconstriction and tachycardia, pale and cold skin, and increased supine muscle sympathetic nerve activity [15]. These patients often present with episodes of tachycardia, hypotension, and hyperhidrosis, which may be triggered by orthostatic stress, emotional stimuli, and physical activity. The presence of multiple symptoms that are severe and result in significant disability without demonstrable cause frequently raises the suspicion of a psychogenic origin. This has led to controversy regarding the organic nature of POTS and diagnostic confusion leading to inappropriate testing and treatment. A recent report by Khurana attempted to better understand the nature of POTS by studying the genesis of palpitations, a common symptom in patients with POTS that involves visceral, somatic, cognitive, and affective components [16]. In comparing 11 POTS patients and 10 control subjects, they found that POTS patients discriminated more types of palpitations in response to several types of individual stimuli than did controls, suggesting central visceral sensitization. In addition, the palpitations in POTS patients were mediated The American Journal of
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mainly by sympathoexcitatory stimuli and were independent of tachycardia. No difference was observed in somatosensory amplification or heartbeat perception, indicating that POTS patients are not predisposed to exaggerating every symptom and favoring an organic source of palpitations. POTS shares a number of symptoms with panic disorder and anxiety including palpitations, lightheadedness, dyspnea, and tremulousness. Somatization, depression, and anxiety have all been observed in patients with POTS [17–19]. In a study by Raj et al., 21 POTS patients were compared with 20 normal controls and 18 patients with attention-deficit hyperactivity disorder (ADHD); all patients completed a variety of questionnaires that assessed depression, anxiety, and ADHD characteristics [20]. Although POTS patients did not have an increased prevalence of psychiatric disorders compared to the general population, they tended to be mildly depressed, moderately anxious, and experienced significant inattention. Nonetheless, others have found no such association [21, 22]. While the current evidence fails to support a primarily psychological origin of symptoms in POTS, psychological distress is often present in POTS patients, similar to others with chronic medical conditions. A substantial percentage of POTS patients experience a variety of symptoms referred to the gut, urinary bladder, and other organs. The GI symptoms are similar to those seen in patients with functional GI disorders. The underlying pathophysiology of these disorders includes visceral hypersensitivity, central sensitization, somatic hypervigilance, and behavioral amplification—processes that may also explain the heterogeneity of multiple etiologies of POTS, the poor correlation between symptom severity and extent of hemodynamic changes and other objective testing, and the persistence of orthostatic symptoms despite control of heart rate. Although a therapeutic approach focusing on enhancing central inhibition or reducing excitation may be useful, because POTS is a heterogeneous disorder, a single mechanism such as visceral sensitivity is unlikely to apply to all patients.
Comorbidities in POTS Table 2 lists a number of chronic conditions/comorbidities frequently seen in patients with POTS that contribute to symptom burden and reduced quality of life. Because many of these conditions are not attributable to orthostatic intolerance, it has been suggested that they should not necessarily be considered part of the syndrome. Indeed, many of these same symptoms occur commonly in patients with functional GI disorders and in patients without POTS or other forms of orthostatic intolerance. This raises the question of whether any association between functional GI disorders and POTS reflects an epiphenomenon rather than a causal relationship. Based on our clinical experience with POTS patients, we suggest that these comorbid conditions be evaluated and appropriately managed, as they often exacerbate symptoms of orthostatic intolerance and may significantly impair quality of life in patients with POTS. No studies have rigorously examined the rates of comorbid GI disease in POTS patients. In one small study, however, nearly one-third of POTS patients reported a diagnosis of irritable bowel syndrome [23]. Previous reports have also found inflammatory www.nature.com/ajg
Table 2 Non-gastrointestinal conditions/comorbidities that mimic or may be associated with POTS
Table 3 GI symptoms, functional/motility disorders, and other diseases described in patients with POTS
Non-GI conditions that may mimic POTS
Non-GI conditions associated with POTS
GI symptoms
Motility/functional GI disorders
Other GI diseases
Adrenal insufficiency
Antiphospholipid antibody syndrome
Abdominal bloating
Autism spectrum disorder
Chronic intestinal pseudoobstruction
Celiac disease
Anemia Carcinoid
Chronic fatigue
Chronic abdominal pain
Esophageal hypomotility
Median arcuate ligament syndrome
Cardiomyopathy
Chronic migraine
Constipation
Functional dyspepsia
Deconditioning
Concussion
Inflammatory bowel disease
Hyperthyroidism
Fibromyalgia
Diarrhea
Mastocytosis
Hashimoto’s thyroiditis
Gastric electrical activity abnormalities
Pheochromocytoma
Hypermobile form of Ehlers–Danlos syndrome
Dysphagia
Gastroparesis
Early satiety
Gastroesophageal reflux disease
Heartburn/regurgitation
Irritable bowel syndrome
Nausea
Pelvic floor dysfunction
Vomiting
Rapid gastric emptying
Interstitial cystitis Mast cell activation disorder Psychiatric disorders Sjogren’s syndrome Sleep difficulties
bowel disease in 7% and celiac disease in 3% of POTS patients [23, 24]. Table 3 lists GI symptoms and conditions described in patients with POTS. Future studies should incorporate comprehensive GI evaluations to determine the prevalence of comorbid GI disease in these patients.
Unique comorbidities associated with POTS Hypermobile form of Ehlers–Danlos syndrome
The hypermobile form of Ehlers–Danlos syndrome (EDS) is a non-inflammatory heritable disorder of connective tissue characterized by hyperflexible joints, hyperelastic skin, and musculoskeletal symptoms [25, 26]. GI symptoms appear to occur commonly among EDS patients [27]. Furthermore, there is a well-recognized association between EDS and functional GI disorders. Previous studies involving secondary and tertiary care patients report that about 50% of patients with functional dyspepsia have EDS, while 40% of patients with IBS have EDS, suggesting that this might represent a distinct phenotype [28, 29]. Epidemiologic studies also suggest that patients with EDS are more likely to have functional, compared to organic, GI disorders [30]. EDS appears to be common in patients with POTS, suggesting that the connective tissue matrix in the gut, which is responsible for the passive mechanical properties of the gut, might be impaired in POTS patients with EDS [31]. Many POTS patients, however, have similar GI symptoms and disorders without having EDS. In a recent report, Wallman and colleagues found a prevalence of EDS of 18% in patients with POTS, a prevalence much higher than the suggested prevalence in both the general population (0.02%) and in patients with dysautonomia but without POTS [32]. Mechanisms implicated to explain dysautonomia in EDS include adrenoreceptor hyperresponsiveness, molecular defects in blood vessel connective tissue, and peripheral neuropathy [33]. In an attempt © 2018 the American college of Gastroenterology
to explore the relationship between POTS and EDS, Fikree et al. recently compared pathophysiologic mechanisms in 30 EDS patients with (n = 18) and without (n = 12) POTS who presented with esophageal symptoms [34]. They found that patients with both EDS and POTS had more severe dysphagia and reflux symptoms and were more likely to have pathologic reflux and esophageal dysmotility, although some patients with JHS and no POTS also had pathologic reflux and esophageal dysmotility. Furthermore, there was no linear relationship between severity of reflux/ dysphagia symptom scores and physiologic testing. Thus, symptom severity cannot be reliably used to predict whether patients will have abnormal esophageal physiology. While intriguing, the relationship between POTS and EDS remains unclear and further studies are needed. Mast cell activation disorders
Based on the description of flushing episodes associated with orthostatic intolerance in some POTS patients, mast cell activation disorders (MCAD) have also been suggested to occur in association with hyperadrenergic POTS raising the possibility that mast cell mediators might play a role in the pathogenesis of POTS. Unlike mastocytosis, idiopathic mast cell activation occurs in the absence of mast cell proliferation but with episodic accumulation of mast cell mediators in the plasma or urine, usually present during symptom episodes. Mast cells are located near the blood vessels and peripheral nerves, making them well positioned to modulate sympathetic activity, vascular tone, and angiogenesis [35]. Mast cell activation may affect the sympathetic and parasympathetic function by modulation of the immune system and/ or inflammatory processes. These patients typically present with episodic “attacks” of flushing accompanied by lightheadedness, dizziness, dyspnea, nausea, headache, diarrhea, and/or syncope; symptoms representative of the hyperadrenergic type of POTS with biochemical evidence of MCAD. In our clinical experience, however, signs and symptoms of mast cell activation can occur in The American Journal of
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neuropathic forms of POTS and in individuals where the POTS subtype cannot be characterized. Shibao et al. compared 8 patients with POTS + MCAD (flushing episode with simultaneously increased urine methylhistamine levels) to 16 POTS patients with flushing but without MCAD, 5 patients with orthostatic hypotension + MCAD and to 12 healthy individuals [36]. In this report, the spectrum of symptoms, triggering events, and response to treatment in patients with POTS + MCAD were described. Symptoms during episodes included flushing, palpitations, postural lightheadedness, nausea, diarrhea, abdominal cramping, and polyuria. Patients often exhibited hypersomnia after the episode. Triggering events included prolonged standing, exercise, menses, meals, sexual intercourse, and certain medications (e.g., aspirin and β-blockers). They found no evidence of a primary diffuse autonomic neuropathy as the cause of this syndrome. Instead, they found an exaggerated sympathetic activation consistent with the hyperadrenergic form of POTS. It was concluded that MCAD should be considered in POTS patients presenting with flushing as should treatment directed against mast cell mediators (e.g., H1 and H2 histamine receptor blockers, central sympatholytics, and cromolyn). Diagnosis of MCAD requires biochemical documentation because other causes of flushing may occur in patients with POTS. GI symptoms such as abdominal pain, bloating, and diarrhea are often present in patients with mast cell activation involving the GI tract, and we have observed that these patients may respond favorably to mast cell stabilization therapies. We, therefore, recommend that POTS patients reporting prominent flushing, hives, diarrhea, itchy skin, and urinary irritability should undergo laboratory testing to evaluate for possible mast cell activation. Testing is more likely to be abnormal during times of active symptoms or symptom flares.
Gastrointestinal issues in POTS It has been suggested that since POTS may result from dysautonomia, this same impairment in autonomic nerves may be the cause of abnormal gut motility and the symptoms that result [23]. GI symptoms have been shown to occur more commonly in POTS patients with dysautonomia than those without [37]. GI motility disorders have frequently been associated with autonomic dysfunction and, in some instances, GI symptoms seem to fluctuate along with autonomic symptoms [38]. A shared trigger, such as a prior infectious episode, may be responsible for POTS and GI dysfunction. Alternatively, GI symptoms may lead to a reduction in nutrient and fluid intake resulting in volume shifts and dehydration, further aggravating the autonomic symptoms. However, others argue that despite the prevalence of GI symptoms in POTS patients, they should not necessarily be considered to be a manifestation of the POTS (or dysautonomia) as these symptoms/conditions may be mediated by visceral afferents leading to visceral sensitivity rather than due to primary involvement of the enteric nerves or efferent autonomic (sympathetic or parasympathetic) output [6]. Because GI disorders associated with POTS may result in insufficient fluid intake or excess fluid loss leading to hypovolemia with subsequent orthoThe American Journal of
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static symptoms and tachycardia, in some instances, orthostatic intolerance might be better considered a consequence of the GI disorder. Future studies should evaluate the association between hypovolemia, GI symptoms, and POTS and the effects of restoring fluid status in these patients. Finally, it was recently suggested that median arcuate ligament syndrome (MALS), also known as celiac artery compression syndrome, may be responsible for GI symptoms in some patients with POTS. MALS is characterized by a variety of dyspeptic symptoms often accompanied by weight loss attributed to impingement and compression of the celiac artery and/or celiac plexus by the median arcuate ligament. Recent preliminary findings from a case series suggest that MALS occurs commonly in POTS patients (>50%) and that improvement may occur in not only GI symptoms, but also orthostatic symptoms and quality of life following surgical division of the median arcuate ligament [39, 40]. We urge a conservative view of these reports; however, as this radiographic finding may occur as a consequence of weight loss and not be the cause of the symptoms, leading to unnecessary surgery [41]. Gastrointestinal symptoms
GI complaints appear to be common in the POTS population; however, the range of the symptoms has not been fully described (Table 3). Wang et al. used a 30-item survey of GI symptoms to query 28 adult POTS patients seen in an autonomic disorders clinic [23]. The most commonly reported symptoms were nausea (86%), irregular bowel movements (71%), abdominal pain (70%), constipation (70%), heartburn (64%), and bloating (59%). The vast majority reported multiple symptoms that occurred more than once weekly and did not improve with supine positioning. GI symptoms also appear to be common in pediatric patients with orthostatic intolerance. In a study of 24 patients who presented to a pediatric gastroenterologist with symptoms suggestive of orthostasis, all were found to have orthostatic intolerance; four had POTS alone, eight had both POTS and neurally-mediated hypotension, and 12 had neurally-mediated hypotension alone [42]. The most common GI symptoms were abdominal pain (71%), nausea (56%), and vomiting (50%); multiple GI symptoms were common in individual patients and nearly one-half had symptoms for more than 3 years. Interestingly, while treatment with conventional GI medications (e.g., antisecretory, antispasmodic, and prokinetic) did not lead to symptom resolution, most of these patients had resolution or improvement in their GI symptoms with measures directed at the orthostatic intolerance (e.g., increased fluid and dietary salt intake, fludrocortisone, and midodrine). Another report in children with POTS found that 80% had abdominal pain and 60% had recurrent nausea and vomiting [43]. Migraine headaches, myalgias/arthralgias, and disturbed sleep were also common in these children. Gastrointestinal transit disturbances
An understanding of the relationship among GI symptoms, GI dysmotility, and POTS is important because these symptoms result in substantial disability from both the reduced quality of life www.nature.com/ajg
experienced by these patients and an impaired intake of nutrition and hydration. Abnormalities in both gastric emptying and gastric electrical activity have been described in patients with POTS. Rapid gastric emptying appears to be more common than delayed gastric emptying in POTS; however, the mechanism remains unclear. The rapid delivery of nutrients to the small intestine is well known to cause a variety of GI and vasomotor symptoms, including postprandial orthostasis (i.e., dumping syndrome) [44]. While the association between delayed gastric emptying and autonomic neuropathy is well recognized, rapid gastric emptying may be more common in autonomic neuropathy [45] and may be a consequence of sympathetic denervation in POTS [13]. The more common occurrence of rapid emptying in POTS differs from functional dyspepsia and diabetic dyspepsia where delayed emptying is more common, but is similar to that occurring with cyclic vomiting syndrome [45, 46]. Future studies using pancreatic polypeptide response to sham feeding as an index of vagal function and superior mesenteric arterial flow to evaluate sympathetic function have been suggested to evaluate the mechanism involved. Park et al. retrospectively reviewed the results of autonomic function and gastric emptying testing, and upper GI and autonomic symptoms in 22 patients (86% female; mean age 28.5 years) with POTS [47]. The most frequent upper GI symptoms were nausea and/or vomiting (82%), abdominal pain (59%), and post-prandially fullness/early satiety (46%). Fourteen (64%) had normal emptying, two (9%) had delayed emptying, and six (27%) had rapid emptying; symptoms were not associated with abnormal emptying. There was no association between gastric emptying and autonomic symptoms or dysfunction. Loavenbruck and colleagues retrospectively reviewed the records of 163 adult patients (140 female; mean age 30 years) with POTS who also had undergone testing of gastrointestinal transit and autonomic functions [48]. Gastric emptying was normal in 55 (34%), delayed in 30 (18%), and rapid in 78 (48%). The most common GI symptoms were nausea (21%), nausea/vomiting (10%), constipation (19%), and dyspepsia (18%). One hundred forty-one (84%) had chronic pain and 58 (36%) had features of physical deconditioning. Symptoms were not associated with gastric emptying; however, vomiting was more common in those with delayed emptying. Among 121 patients who underwent colonic scintigraphy, transit was normal in 80 (66%), slow in 33 (36%), and accelerated in 8 (7%). Physical deconditioning was associated with rapid emptying while anxiety/ depression was present less commonly with delayed emptying. The tilt-associated increase in heart rate and reduction in blood pressure at 1 min was also associated with delayed emptying. Except for more severe adrenergic impairment in patients with delayed gastric emptying, the pattern of autonomic dysfunction did not discriminate among gastric emptying groups. In the pediatric population, Antiel et al. retrospectively reviewed patients who came to a pediatric referral center because of nausea and dyspepsia and had undergone both autonomic reflex and gastric emptying testing; 21 of 31 total patients met criteria for POTS [49]. There was no significant difference between the POTS and non-POTS groups with regard to presenting symptoms. Overall, 13 (42%) individuals had abnormal gastric emptying results (delayed in 6, accelerated in 7), but gastric emptying scores were © 2018 the American college of Gastroenterology
similar between the POTS and non-POTS groups. Furthermore, there was no correlation between an individual’s gastric emptying results at 1, 2, and 4 h and that person’s heart rate change on tilt table testing. Thus, while altered gastric emptying and POTS were common in a referral population of adolescents with nausea and/ or abdominal discomfort, the clinical presentation was not predictive of test results. Huang et al. reported on a series of 12 POTS patients (11 female; mean age 32 years) who presented to a GI clinic for evaluation of GI symptoms and underwent a variety of GI motility tests [50]. The most common GI symptoms were each experienced by more than 70% of patients and included bloating, constipation, abdominal pain, and nausea/vomiting. On gastroduodenal manometry, 93% (11/12) demonstrated signs of intestinal neuropathy; the most common findings being bursts of uncoordinated phasic activity in both fasting (58%) and postprandial (42%) states, low contractility in the fed state (67%), and lack of development of the fed state (42%). Gastric emptying was delayed in 60% (3/5) while colon transit was slow in 80% (4/5). Esophageal manometry and anorectal manometry studies showed abnormalities in 67% (4/6) and 86% (6/7), respectively. Abdominal imaging showed signs of pseudo-obstruction in 58% (7/12) such as dilated bowel loops and/or air-fluid levels. These data suggest that the perturbations in POTS involve multiple segments of the gut. Abnormalities in gastric electrical activity
Gastric electrical activity has been shown to change during upright positioning in children with POTS [51]. Seligman et al. recorded transcutaneous gastric myoelectrical activity in 15 POTS patients (7 with GI symptoms and 8 without; 11 with features suggestive of EDS) and in 11 healthy individuals [52]. An increased variability of gastric pacemaker rhythm (i.e., instability coefficient of the dominant function [ICDF]) was present both pre- and post-prandially in the POTS group compared to controls. POTS patients with GI symptoms had significantly higher postprandial ICDF than those without GI symptoms. It was speculated that the altered gastric myoelectrical activity may be due to a heightened level of sympathetic nerve activity, either independent of or related to anxiety [53]. No significant differences were found in dominant function or the low, normal, or high-range power percentages of the total power before and after the meal between the POTS patients and controls or between the POTS patients with and without GI symptoms. These findings suggest increased variability of the gastric slow wave frequency rather than arrhythmia of the slow waves, and support the involvement of autonomic/ enteric nerve activities in POTS.
Overview of the approach to management in POTS Given the heterogeneity and complexity of their clinical presentation, POTS patients would benefit from a multidisciplinary evaluation. A modification of the basic evaluation of POTS as recommended by the Heart Rhythm Society is shown in Table 4 [5]. When POTS is suspected, referral for appropriate testing and/ or referral to a specialist in POTS (e.g., neurologist and cardiThe American Journal of
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Table 4 Recommendations for the general evaluation of suspected POTS
Table 5 Testing considerations when POTS comorbidities suspected
Evaluation
Comment
Condition
Testing
Medical history
Medications, comorbidities, diet, exercise, family history, details on nature of tachycardia (e.g., chronicity, triggers, modifying factors, syncope/presyncope, symptoms, and impact on daily activities)
Mast cell activation disorder
Tryptase; 24-h urine collection for n-methylhistamine, leukotriene E4 and 11-beta prostaglandin F2 alpha preferably during a flare
Physical exam
Cardiovascular, neurologic, autonomic, musculoskeletal, and others based on symptoms
Hypermobile type— Ehlers–Danlos syndrome
Screen by calculating Beighton score for generalized joint hypermobility; if vascular EDS suspected, an echocardiogram prior to referral to a cardiologist
Orthostatic vitals
Blood pressure and heart rate while supine (>5 min) and again after 1, 3, 5, and 10 min of standing
Autoimmunity
Electrocardiogram
To exclude prior cardiac condition or existing conduction defects
Paraneoplastic autoantibody profile, collagen vascular disease screening especially for Sjogren’s syndrome,? celiac disease
Blood testing
When suspected dehydration, anemia, hyperthyroidism, or carcinoid. Also, supine and standing norepinephrine levels when hyperadrenergic POTS suspected
Median arcuate ligament syndrome
Radiographic (duplex ultrasound and CT/MR angiography) imaging of the celiac artery using respiratory maneuvers
Dysautonomia
Autonomic reflex screen including testing of cardiovagal, sudomotor, and adrenergic functions
a
Cardiovascular testinga
When suspected structural or conduction defects (e.g., Holter monitor, echocardiogram, and exercise stress test)
Head-up tilt table testinga
When normal orthostatic vitals but high clinical suspicion, or in those with known/suspected seizure disorder
Autonomic function testsa
When symptoms of autonomic neuropathy, or in those whose symptoms do not markedly improve with treatment
Autoimmune testinga
When concomitant autonomic neuropathy or GI dysmotility
Should be considered based on individual patient characteristics only; other evaluation essential in all patients
a
ologist) is encouraged. An awareness of the unique associations with POTS, particularly MCAD, EDS, and autoimmunity, should prompt an assessment of these conditions when the appropriate history, signs, and/or symptoms are present (Table 5). Importantly, we also recommend a nutritional assessment and counseling for all POTS patients, but particularly those with the moderate to severe symptoms. Given the limitations in the existing knowledge of the GI complications in POTS, the evaluation and management of associated GI symptoms and disorders is, by necessity, based upon consensus and expert opinion. From a GI perspective, the testing performed should be based upon the symptoms present and will often include endoscopic, radiographic, and motility tests. Appropriate motility testing should be guided by the most prominent GI symptom(s). Table 6 summarizes an approach to GI evaluation in POTS.
Treatment considerations The heterogeneity of POTS makes it difficult to design a treatment algorithm to fit all patients. Establishing an effective provider–patient relationship along with reassurance and education are essential steps in management. The general approach to managing orthostatic symptoms in POTS includes volume restitution, physical conditioning, exercise training, support garments, and pharmacotherapies. Patient education should include information about symptoms due to orthostatic intolerance and those that are not, as well as factors that may exacerbate their The American Journal of
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symptoms. Increasing fluid (2 L/day) and salt intake (10 g/day) are an important first step in management of all POTS patients. Mild to moderate symptoms may respond to simple measures including avoidance of circumstances that precipitate symptoms and use of pressure garments. More severely affected individuals will require medications such as fludrocortisone, midodrine, beta-blockers, pyridostigmine, and/or selective serotonin reuptake inhibitors. A discussion of the goals of treatment and setting realistic expectations is critical in the management of this challenging condition. Of additional importance is a focus on the simultaneous treatment of the non-orthostatic symptoms and associated conditions (Table 7). In particular, patients with symptoms suggestive of mast cell activation (e.g., flushing and pruritus) may benefit from treatment with a mast cell stabilizing “cocktail” consisting of an H1-receptor antagonist, H2-receptor antagonist, and cromolyn sodium. The role of immune-modulating medications in patients with suspected immune-mediated/autoimmune contribution to their condition remains to be clarified [54]. Similar to the benefits of a multidisciplinary approach to the evaluation of POTS, a multidisciplinary approach to treatment is also important. For the gastroenterologist treating the varied GI symptoms in POTS, specific treatment guidelines do not exist; however, the emphasis is similar to management of functional GI disorders, which focuses on treating the most prominent symptoms [55–57] (Table 7). Antiemetics are commonly employed in POTS patients given the prevalence of nausea; combinations of antiemetics are sometimes needed. Although randomized controlled trials have not been performed in POTS, carbidopa, which inhibits the decarboxylation of peripheral levodopa, has been employed in this population based on its success in patients with dysautonomia [58]. The utility of prokinetic and anti-dumping treatments in POTS patients with delayed or rapid gastric emptying, respectively, requires further study. Pyridostigmine, a cholinesterase inhibitor primarily employed in the treatment of autonomic symptoms, has the additional benefit of improving intestinal transit. Pyridostigmine has been shown to be well tolerated and improve orthostatic symptoms in POTS [59]. Its benefit in POTS patients with GI symptoms requires further study but our anecdotal experience www.nature.com/ajg
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Gut segment
Indication
Tests to consider
Esophagus
Dysphagia, heartburn/regurgitation Belching Globus Chest pain
Endoscopy Barium esophagram Esophageal manometry Ambulatory impedance-pH testing
Stomach
Nausea/vomiting Gas-bloating Distension Early satiety Abdominal pain/discomfort Dyspepsia
Endoscopy Gastric emptying testing Gastric accommodation testing
Small bowel
Nausea/vomiting Gas-bloating Diarrhea Abdominal pain/discomfort
Cross-sectional imaging Small bowel transit testing (?) Small bowel bacterial overgrowth testing Lactose/fructose breath testing
Colon and pelvic floor
Constipation Diarrhea Gas-bloating Distension Abdominal pain/discomfort
Colonoscopy Colon transit testing Anorectal manometry Balloon expulsion testing Evacuation proctography
suggests a benefit in some patients. When chronic pain is present, an attempt should be made to avoid or eliminate the use of opioids whenever possible as their use increases the risk of opioid-induced bowel dysfunction and the narcotic bowel syndrome. The use of neuromodulating agents (e.g., tricyclic antidepressants) can then be considered, although the utility of these medications in this setting also requires additional study. In patients who do not respond to standard medical therapies, treatment is empirical and not evidence-based. For more refractory cases, the use of a combination of gut-directed and central pharmacological agents is often used and the combination of medications with psychological treatment should also be considered. Importantly, because of the number of conditions associated with POTS, there is the danger of unnecessary testing. Therefore, psychological support is critical and biobehavioral strategies and cognitive behavioral therapy may help with symptom management [60]. These patients require special attention to their nutrition and hydration because of associated GI symptoms and gut dysmotility. A gastroparesis diet is often employed; the benefit of other specialized diets (e.g., low FODMAP) requires further study. Finally, as weight loss and dehydration are common in those with severe symptoms, parenteral fluid and/or enteral or parenteral nutrition support is occasionally required.
Prognosis The natural history of POTS remains unclear but is thought to reflect a chronic condition without an increased risk of mortality [5]. It has been suggested that those POTS patients with a limited autonomic neuropathy are more apt to improve over time because peripheral nerve can recover, a situation seen in other autonomic neuropathies [61]. An improvement in orthostatic symptoms was common and over one-third no longer met criteria for POTS in a prospective study of adult POTS patients followed for 1 year [62]. In a similar study of adolescents with POTS followed for an average © 2018 the American college of Gastroenterology
of 5 years, 19% reported resolution of their symptoms, while 51% had persistent but improved symptoms and 16% had only intermittent symptoms [63]. Fourteen percent reported symptoms of similar or worsening severity and a significant proportion reported ongoing functional disability. In a retrospective review, 80% of POTS patients treated with general measures and followed for 18 months or longer reported improved orthostatic intolerance, while 60% were functionally normal, and 90% were able to return to work [9]. Patients who had antecedent event (e.g., viral illness) and a more acute onset seemed to do better than those with spontaneous POTS. Those without an antecedent event were more likely to have a family history of similar symptoms and a less favorable outcome. Overall, these data suggest that while cure is uncommon, many POTS patients improve over time. Further study of the natural history and prognosis of POTS is crucial to better understand factors associated with both clinical improvement and more profound disability.
Suggestions for future research The evidence presented has many limitations including the small number patients studied, the retrospective, uncontrolled study designs, use of non-validated surveys and different methods used to measure gastric emptying, and lack of data on treatment and their impact on symptoms and features of GI dysmotility. In order to develop a more complete understanding the relationship between POTS and GI symptoms/disorders, it will be critical to demonstrate objective pathophysiological abnormalities. Because of the rather weak evidence of causality to date and the limitations described, which are prone to bias and confounding, it remains difficult to ascertain a clear role of POTS in the GI symptoms and functional GI/motility disorders seen. This provides a great opportunity to prospectively study the relevant areas of importance including epidemiology, pathophysiology, evaluation, and management of GI issues in POTS. The American Journal of
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Table 6 Suggested approach to GI evaluation in POTS
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Table 7 Treatment strategies for POTS-associated GI symptoms and conditions Symptom
Medication or therapy
Nausea/vomiting
Antiemeticsa—ondansetron, promethazine, prochlorperazine, aprepitant, and off-label use of carbidopa Prokinetic agents—metoclopramide, domperidone, pyridostigmine, and off-label use of prucalopride Complementary medicine treatments—ginger tea, aromatherapy, and STW5
Chronic abdominal pain
Acid suppression—proton pump inhibitor and H2 receptor antagonist Antispasmodics—dicyclomine, hyoscyamine, and peppermint oil Pain modulators—tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, and anti-epileptic agents Psychological therapy—cognitive behavioral therapy and hypnotherapy
Constipation
Osmotic laxative—PEG3350, lactulose, and milk of magnesia Stimulant laxative—bisacodyl and senna Chloride channel activator—lubiprostone Guanylate cyclase-C agonist—linaclotide and plecanatide
Diarrhea
Diet modification—soluble fiber, low FODMAP, and gluten-free Microbiome modification—rifaximin, Bifidobacterium infantis 35624 Antidiarrheals—loperamide and diphenoxylate Bile acid sequestrants—cholestyramine, colestipol, and colesevelam μ- and κ-opioid receptor agonist and δ-opioid receptor antagonist—eluxadolineb 5-HT3 receptor antagonist—alosetron (female pts only)
Autoimmunity
Corticosteroids Intravenous immunoglobulin
Mast cell activation
H2 receptor antagonist—famotidine and ranitidine 2nd generation H1 antagonist—fexofenadine, loratadine and cetirizine Mast cell stabilizer—cromolyn sodium, and ketotifen
Patients may require multiple agents and care should be taken to monitor the electrocardiographic QT interval Contraindicated in patients post cholecystectomy, patients having ≥3 alcoholic beverages/day, and moderate to severe hepatic insufficiency
a
b
Areas of future prospective study should include: • Epidemiology—timing of onset of GI symptoms and comorbid GI diseases relative to the diagnosis of POTS; prevalence of nutritional deficits; natural history; and, the relationship between EDS and MCAD in POTS patients with and without GI symptoms. • Pathophysiology—further investigation of the pathogenesis of GI symptoms in POTS including the relevance of autonomic testing, EDS, MCAD, autoimmune testing, GI physiologic testing, and MALS; and, studies using pancreatic polypeptide response to sham feeding as an index of vagal function and superior mesenteric arterial flow to evaluate sympathetic function. • Clinical evaluation—prospective, controlled study of the role of autonomic testing, evaluation of EDS and MCAD, autoimmune testing, and GI physiologic testing in identifying clinically useful management strategies. • Treatment—controlled trials of GI-centric medications (e.g., prokinetics and antisecretory), neuromodulating agents and immune-modifying medications (e.g., intravenous immunoglobulin); management of nutritional deficits; and, long-term outcomes.
Conclusion Postural tachycardia syndrome (POTS) is one of the most common causes of orthostatic intolerance and is being increasingly encountered in clinical practice. POTS has been suggested to be The American Journal of
Gastroenterology
the cause of a variety of symptoms and a number of comorbidities are seen in POTS patients. GI symptoms are reported commonly in patients with POTS and pose a considerable management challenge. Indeed, they often represent a source of considerable frustration and disability for patient and provider alike. Although the evidence presented herein does not prove causation, it does support an association between GI symptoms, GI dysmotility, and POTS. Furthermore, while the exact nature of the pathophysiological abnormalities in POTS remain to be established, awareness of this association may facilitate an earlier consideration of the diagnosis of POTS, thereby reducing the duration of symptoms and costs/risks associated with their evaluation. POTS patients require a multidisciplinary approach to their management. At present, the evaluation and treatment of GI symptoms in patients with POTS remains largely empirical. General measures to treat POTS may lead to improvement in both GI and non-GI symptoms. GI symptoms refractory to these measures should prompt further diagnostic evaluation of gastrointestinal dysmotility and appropriate dietary and pharmacologic management. CONFLICT OF INTEREST
Guarantor of the article: John K DiBaise, MD, FACG Specific author contributions: JKD performed the literature search and composed the manuscript. LAH and BG provided significant intellectual input, reference selection, and critical review of the manuscript. The final draft of this manuscript was reviewed and approved by JKD, LAH, and BG. Financial support: None. Potential competing interests: None. www.nature.com/ajg
References 1. 2. 3. 4. 5.
6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28.
Robertson D. The epidemic of orthostatic tachycardia and orthostatic hypotension. Am J Med Sci. 1999;317:75–77. Schondorf R, Low PA. Idiopathic postural tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology. 1993;43:132–7. Low PA, Opfer-Gehrking TL, Textor SC, et al. Postural tachycardia syndrome (POTS). Neurology. 1995;45(Suppl 5):S19–S25. Singer W, Sletten DM, Opfer-Gehrking TL, et al. Postural tachycardia in children and adolescents: what is abnormal? J Pediatr. 2012;160:222–6. Sheldon RS, Grubb BP II, Olshansky B, et al. 2015 heart rhythm society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm. 2015;12:e41–63. Benarroch EE. Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin Proc. 2012;87:1214–25. Thieben MJ, Sandroni P, Sletten DM, et al. Postural tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc. 2007;82:308–13. Arnold AC, Ng J, Raj SR. Postural tachycardia syndrome - diagnosis, physiology, and prognosis. Auton Neurosci. 2018. https://doi. org/10.1016/j.autneu.2018.02.005. (Epub ahead of print). Sandroni P, Opfer-Gehrking TL, McPhee BR, Low PA. Postural tachycardia syndrome: clinical features and follow-up study. Mayo Clin Proc. 1999;74:1106–10. Grubb BP, Kosinkski DJ, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head-up tilt table testing. Pacing Clin Electrophysiol. 1997;20:2205–12. Low PA, Opfer-Gehking RL, Textor SC, et al. Comparison of the postural tachycardia syndrome (POTS) with orthostatic hypotension due to autonomic failure. J Auton Nerv Syst. 1994;50:181–8. Deb A, Morgenshtern BS, Culbertson CJ, Wang LB, DePold Hohler A. A survey-based analysis of symptoms in patients with postural tachycardia syndrome. Proc (Bayl Univ Med Cent). 2015;28:157–9. Benrud-Larson LM, Dewar MS, Sandroni P, et al. Quality of life in patients with postural tachycardia syndrome. Mayo Clin Proc. 2002;77:531–7. Jacob G, Costa F, Shannon JR, et al. The neuropathic postural tachycardia syndrome. N Engl J Med. 2000;343:1008–14. Stewart JM, Montgomery LD. Regional blood volume and peripheral blood flow in postural tachycardia syndrome. Am J Physiol Circ Physiol. 2004;28:H1319–H1327. Khurana RK. Visceral sensitization in postural tachycardia syndrome. Clin Auton Res. 2014;24:71–76. Low PA, Sandroni P, Joyner M, Win-Kuang S. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol. 2009;20:352–8. Esler M, Alvarenga M, Pier C, et al. The neuronal nonadrenaline transporter, anxiety and cardiovascular disease. J Psychopharmacol. 2006;20:60–66. Benrud-Larson LM, Sandroni P, Haythornthwaite JA, et al. Correlates of functional disability in patients with postural tachycardia syndrome: preliminary cross-sectional findings. Health Psychol. 2003;22:643–8. Raj V, Haman KL, Raj SR, et al. Psychiatric profile and attention deficits in postural tachycardia syndrome. J Neurol Neurosur Psychiatry. 2009;80:339–44. Khurana RK. Experimental induction of panic-like symptoms in patients with postural tachycardia syndrome. Clin Auton Res. 1995;16:371–7. Masuki S, Eisenach JH, Johnson CP, et al. Excessive heart rate response to orthostatic stress in postural tachycardia syndrome is not caused by anxiety. J Appl Physiol. 2007;102:896–903. Wang LB, Culbertson CJ, Deb A, et al. Gastrointestinal dysfunction in postural tachycardia syndrome. J Neurol Sci. 2015;359:193–6. Blitshteyn S. Autoimmune markers and autoimmune disorders in patients with postural orthostatic tachycardia syndrome (POTS). Lupus. 2015;24:1364–69. Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers–Danlos syndromes. Am J Med Genet Part C Semin Med Genet. 2017;175:8–26. Fikree A, Aziz Q, Grahame R. Joint hypermobility syndrome. Rheum Dis Clin North Am. 2013;39:419–30. Zeitoun JD, Lefevre JH, de Parades V, et al. Functional digestive symptoms and quality of life in patients with Ehlers-Danlos syndromes: results of a national cohort study on 134 patients. PLoS ONE. 2013;8:e80321. Fikree A, Grahame R, Aktar R, et al. A prospective evaluation of undiagnosed joint hypermobility syndrome in patients with gastrointestinal symptoms. Clin Gastroenterol Hepatol. 2014;12:1680–7.
© 2018 the American college of Gastroenterology
29. Nelson AD, Mouchli MA, Valentin N, et al. Ehlers Danlos syndrome and gastrointestinal manifestations: a 20-year experience at Mayo Clinic. Neurogastroenterol Motil. 2015;27:1657–66. 30. Fikree A, Aktar R, Grahame R, et al. Functional gastrointestinal disorders are associated with the joint hypermobility syndrome in secondary care: a case-control study. Neurogastroenterol Motil. 2015;27:569–79. 31. Mathias CJ, Low DA, Iodice V, et al. Postural tachycardia syndrome – current experience and concepts. Nat Rev Neurol. 2011;8:22–34. 32. Wallman D, Weinberg J, Hohler AD. Ehlers-Danlos syndrome and postural tachycardia syndrome: a relationship study. J Neurol Sci. 2014;340:99–102. 33. Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med. 2003;44:93–100. 34. Fikree A, Aziz Q, Sifrim D. Mechanisms underlying reflux symptoms and dysphagia in patients with joint hypermobility syndrome, with and without postural tachycardia syndrome. Neurogastroenterol Motil. 2017;29. https://doi.org/10.1111/nmo.13029. 35. Feoktistov I, Tyzhowv S, Goldstein AE, Biaggioni I. Mast cell-mediated stimulation of angiogenesis: cooperative interaction between A2B and A3 adenosine receptors. Circ Res. 2003;92:485–92. 36. Shibao C, Arzubiaga C, Jackson Roberts L II, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension. 2005;45:385–90. 37. Al-Shekhlee A, Linderberg JR, Hachwi RN, Chelimsky TC. The value of autonomic testing in postural tachycardia syndrome. Clin Auton Res. 2005;15:219–22. 38. Bharucha AL, Camilleri M, Low PA, Zinsmeister AR. Autonomic dysfunction in gastrointestinal motility disorders. Gut. 1993;34:397–401. 39. Ashangari C, Suleman A, Le TH. Median arcuate ligament syndrome in postural tachycardia syndrome (POTS). Auton Neurosci. 2015;192:124(abstract P17.16). 40. Abdallah H, Thammineni K, Hartas G, Kane K. Median arcuate ligament syndrome presenting as POTS. Auton Neurosci. 2015;192:123(abstract P17.111). 41. Ho KKF, Walker P, Smithers BM, et al. Outcome predictors in median arcuate ligament syndrome. J Vasc Surg. 2017;65:1745–52. 42. Sullivan SD, Hanauer J, Rowe PC, et al. Gastrointestinal symptoms associated with orthostatic intolerance. J Ped Gastroenterol Nutr. 2005;40:425–8. 43. Ojha A, Chelimsky TC, Chelimsky G. Comorbidities in pediatric patients with postural orthostatic tachycardia syndrome. J Pediatr. 2011;158:119–22. 44. Tack J, Arts J, Caenepeel P, De Wulf D, Bisschops R. Pathophysiology, diagnosis and management of postoperative dumping syndrome. Nat Rev Gastroenterol Hepatol. 2009;6:583–90. 45. Lawal A, Barboi A, Krasnow A, et al. Rapid gastric emptying is more common than gastroparesis in patients with autonomic dysfunction. Am J Gastroenterol. 2007;102:618–23. 46. Namin F, Patel J, Lin Z, et al. Clinical, psychiatric and manometric profile of cyclic vomiting syndrome in adults and response to tricyclic therapy. Neurogastroenterol Motil. 2007;19:196–202. 47. Park K.-J, Singer W, Sletten DM, Low PA, Bharucha AE. Gastric emptying in postural tachycardia syndrome: a preliminary report. Clin Auton Res. 2013;23:163–7. 48. Loavenbruck A, Iturrino J, Singer W, et al. Disturbances of gastrointestinal transit and autonomic functions in postural tachycardia syndrome. Neurogastroenterol Motil. 2015;27:92–98. 49. Antiel RM, Risma JM, Grothe RM, Brands CK, Fischer PR. Orthostatic intolerance and gastrointestinal motility in adolescents with nausea and abdominal pain. J Pediatr Gastroenterol Nutr. 2008;46:285–8. 50. Huang RJ, Chun CL, Friday K, Triadafilopoulos G. Manometric abnormalities in the postural orthostatic tachycardia syndrome: a case series. Dig Dis Sci. 2013;58:3207–11. 51. Safder S, Chelimsky TC, O’Riordan MA, Chelimsky G. Gastric electrical activity becomes abnormal in the upright position in patients with postural tachycardia syndrome. J Pediatr Gastroenterol Nutr. 2015;51:314–8. 52. Seligman WH, Low DA, Asahina M, Mathias CJ. Abnormal gastric myoelectrical activity in postural tachycardia syndrome. Clin Auton Res. 2013;23:73–80. 53. Bonyhay I, Freeman R. Sympathetic nerve activity in response to hypotensive stress in the postural tachycardia syndrome. Circulation. 2004;110:3193–8. 54. Weinstock LB, Brook JB, Myers TL, Goodman B. Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. BMJ Case Rep. 2018;2018:bcr-2017–221405.
The American Journal of
Gastroenterology
9
Review Article
Postural Tachycardia Syndrome (POTS) and the Gi Tract: A Primer...
Review Article
10
DiBaise et al.
55. Camilleri M, Bueno L, Andresen V, et al. Pharmacologic, pharmacokinetic, and pharmacogenomic aspects of functional gastrointestinal disorders. Gastroenterology. 2016;150:1318–31. 56. Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Engl J Med. 2017;376:2566–78. 57. Talley NJ, Ford AC. Functional dyspepsia. N Engl J Med. 2015;373:1853–63. 58. Norcliffe-Kaufmann L, Martinez J, Axelrod F, et al. Hyperdopaminergic crisis in familial dysautonomia: a randomized trial of carbidopa. Neurology. 2013;80:1611–17. 59. Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardic syndrome: a single center experience. Pacing Clin Electrophysiol. 2011;24:750–5.
The American Journal of
Gastroenterology
60. Kizilbash SJ, Ahrens SP, Bruce BK, et al. Adolescent fatigue, POTS, and recovery: a guide for clinicians. Curr Probl Pediatr Adol Health Care. 2014;44:108–33. 61. Suarez GA, Fealey RD, Camilleri M, Low PA. Idiopathic autonomic neuropathy: clinical, neurophysiologic, and follow-up studies on 27 patients. Neurology. 1994;44:1675–82. 62. KimpinskiK FigueroaJJ, Singer W, et al. A prospective, 1-year follow-up study of postural tachycardia syndrome. Mayo Clin Proc. 2012;87:746–52. 63. Bhatia R, Kazilbash SJ, Ahrens SP, et al. Outcomes of adolescent postural orthostatic tachycardia syndrome. J Pediatr. 2016;173: 149–53.
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