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Evaluation of postural tachycardia syndrome (POTS)

      Abstract

      The diagnostic evaluation of a patient with suspected postural tachycardia syndrome (POTS) requires a thoughtful diagnostic approach utilizing a careful clinical history and examination, laboratory, and autonomic testing. This article outlines the importance of a thorough history in identifying mechanism of symptom onset, clinical features, associated clinical conditions or disorders, and factors that may result in symptom exacerbation. The clinical examination involves an assessment of pupillary responses, an evaluation for sudomotor and vasomotor signs, and an assessment for joint hypermobility. Laboratory testing helps to exclude mimics of autonomic dysfunction, recognize conditions that may exacerbate symptoms, and to identify conditions that may cause or be associated with autonomic nervous system disease. The purpose of autonomic testing is to confirm a POTS diagnosis, exclude other causes of orthostatic intolerance, and may provide for characterization of POTS into neuropathic and hyperadrenergic subtypes. Other diagnostic studies, such as epidermal skin punch biopsy, exercise testing, radiographic studies, sleep studies, gastrointestinal motility studies, and urodynamic studies should be considered when clinically appropriate.

      Keywords

      1. Introduction

      The evaluation of suspected postural tachycardia syndrome (POTS) requires a careful history, thorough clinical examination, and a thoughtful diagnostic evaluation. Delays in diagnosis and misdiagnoses are commonplace prior to establishing a definitive diagnosis of POTS. Data from a large survey of nearly 700 patients with POTS patients, self-reported a median time to diagnosis of just under 6 years, with 27% of the respondents reporting having been seen by >10 physicians prior to diagnosis, and 83% of respondents reported being given a psychiatric diagnosis prior to being diagnosed with POTS (). While precise prevalence rates are not known, it has been suggested that POTS is one of the most common conditions to affect young females (
      • Robertson D.
      • Shannon J.R.
      • Biaggioni I.
      • et al.
      Orthostatic intolerance and the postural tachycardia syndrome: genetic and environment pathophysiologies. Neurolab Autonomic Team.
      ). POTS has been estimated to affect over 500,000 individuals in the United States alone (
      • Robertson D.
      The epidemic of orthostatic tachycardia and orthostatic hypotension.
      ).
      The purpose of the diagnostic evaluation of a patient with suspected POTS is to confirm the presence of an excessive postural tachycardia, exclude other conditions that have the potential to mimic autonomic nervous system impairment (see Table 1), identify conditions that may be associated with or causative of autonomic dysfunction, and to exclude conditions that may exacerbate autonomic nervous system impairment. A careful history is necessary to establish the timing and mechanism of symptom onset, involves a thorough autonomic review of systems (see Table 2), and a careful medication and family history. Identification of other co-morbid conditions, particularly those commonly reported by POTS patients is another critical aspect of the evaluation. Given the heterogeneity of the clinical features associated with POTS, an individualized approach to the diagnostic evaluation is warranted.
      Table 1Conditions that mimic, cause or are associated with postural tachycardia syndrome (POTS).
      Conditions that may mimic POTS
       Mastocytosis
       Adrenal insufficiency
       Anemia
       Pheochromocytoma, Paraganglioma
       Carcinoid
       Thyroid disease
       Deconditioning
       Cardiomyopathy
       Panic disorder
      Conditions that may be associated with POTS
       Ehlers-Danlos syndrome
       Concussion
       Celiac disease
       Hashimotos thyroiditis
       Antiphospholipid antibody syndrome
       Sjögren syndrome
       Systemic lupus erythematosis
       Mast cell activation syndrome
       Mitochondrial cytopathy
       Autism Spectrum Disorder
       Gastroparesis
       Gastrointestinal dysmotility
       Chronic migraine
       New daily persistent headache
      Table 2Autonomic review of systems.
      Sudomotor
       Hyperhidrosis
       Hypohidrosis
       Anhidrosis
       Heat intolerance
      Secretomotor
       Dry eyes
       Dry mouth
      Adrenergic
       Postural lightheadedness
       Near-syncope
       Syncope
      Gastrointestinal
       Dysphagia
       Early satiety
       Abdominal bloating
       Constipation
       Diarrhea
      Genitourinary
       Nocturia
       Incomplete bladder emptying
       Urinary retention
       Impotence

      2. History

      A major focus of the clinical history is to establish the timing and mechanism of symptom onset. The majority of POTS patients report symptom onset from early teens through the 5th decade (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ). It is not uncommon for patients to report more modest symptoms of orthostatic intolerance, such as postural lightheadedness or rare episodes of vasovagal syncope in their teens, prior to developing more fulminant and severe symptoms in their late teens or twenties. POTS is more frequent in females; with a female to male ratio of at least 4.5:1 (
      • Benarroch E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ). Symptoms may develop acutely (<1 month), subacutely (1–3 months), or more insidiously (>3 month) (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ). A meticulous review of symptom onset is necessary to identify conditions that may have precipitated POTS. An antecedent history of infection is the most commonly reported (potential) precipitating event, occurring in upwards of 50% of patients (
      • Low P.A.
      • Opfer-Gehrking T.L.
      • Texor S.C.
      • et al.
      Postural tachycardia syndrome (POTS).
      ;
      • Sandroni P.
      • Opfer-Gehrking T.L.
      • McPhee B.R.
      • Low P.A.
      Postural tachycardia syndrome: clinical features and follow-up study.
      ;
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ). These infections are most typically upper respiratory or gastrointestinal viral illnesses (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ). Onset following a surgical procedure is sometimes reported (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ;
      • Mathias C.J.
      • Low D.A.
      • Iodice V.
      • Owens A.P.
      • Kirbis M.
      • Grahame R.
      Postural tachycardia syndrome – current experience and concepts.
      ) but is significantly less common than a post-infectious onset. Rarely, symptoms may begin during or following pregnancy. Symptom onset with or following concussion has been scarcely reported (
      • Kanjwal K.
      • Saeed B.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Comparative clinical profile of postural tachycardia patients with and without joint hypermobility syndrome.
      ) though is an under-recognized precipitating event. Notably, autonomic testing in concussion patients has demonstrated findings typical of those seen in POTS (
      • Goodman B.P.
      • Vargas B.V.
      • Dodick D.W.
      ;
      • Heyer G.L.
      • Fischer A.
      • Wilson J.
      • et al.
      Orthostatic intolerand autonomic dysfunction in youth with persistet postconcussion symptoms: a head-upright tilt table study.
      ). A substantial number of POTS patients will have no identifiable antecedent event or precipitant for their condition, even in those with acute-subacute symptom onset. A minority of patients will report a family history of orthostatic intolerance (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ).

      2.1 Orthostatic symptoms

      POTS patients by definition (see Table 3) should have symptoms of orthostatic intolerance. These symptoms typically include postural lightheadedness, near-syncope, heart racing (tachycardia), and palpitations. A history of vasovagal syncope is not uncommon. However, it is critical to recognize that any symptom present when upright, that resolves or improves with recumbency may reflect orthostatic intolerance and must be recognized as a potential symptom associated with POTS. Examples of such symptoms include nausea, chest pain, vertigo, unsteadiness, leg weakness, extremity paresthesias, dyspnea, headache, neck pain, visual symptoms, anxiety, tremor, diaphoresis, flushing, and cognitive symptoms. Failure to recognize these symptoms as a form of orthostatic intolerance is likely a major reason for delays in establishing a diagnosis of POTS. Furthermore, the aforementioned symptoms may not necessarily be solely postural. It is not uncommon, for example, for tachycardia in POTS patients to occur nocturnally and even awaken patients from sleep.
      Table 3POTS criteria.
      • 1.
        Heart Rate increment ≥30 beats/min within 10 min of standing or head-up tilt in individuals
      • 2.
        Heart Rate increment ≥40 beats/min in children/adolescents
      • 3.
        Absence of orthostatic hypotension (decrease in systolic blood pressure of 20 mm Hg and diastolic blood pressure of 10 mm Hg)
      • 4.
        Postural symptoms
      Factors other than postural change may exacerbate or even precipitate the aforementioned symptoms (
      • Mathias C.J.
      • Low D.A.
      • Iodice V.
      • Owens A.P.
      • Kirbis M.
      • Grahame R.
      Postural tachycardia syndrome – current experience and concepts.
      ). Many patients report that symptoms are worse in the morning, particularly upon awakening. Other common exacerbating factors include showering, dehydration, heat, food ingestion, menses, physical exertion, alcohol, and deconditioning. Insomnia may exacerbate symptoms or contribute to persistent fatigue. Exacerbation of or persistent headache or migraine may be associated with symptom worsening. Regardless of the initial mechanism of symptom onset, a surgical procedure, concussion, or infection may result in a period of transient POTS symptom exacerbation. A careful medication history is also critical, as certain medications may result in symptom exacerbation. Examples of medications (and substances) that might mimic or exacerbate POTS include stimulant medications, α and β blockers, calcium channel blockers, serotonin and norepiphrine reuptake inhibitors, monoamine oxidase inhibitors, and phenothiazines (
      • Agarwal A.K.
      • Garg R.
      • Ritch A.
      • Sarkar P.
      Postgard.
      ;
      • Cheshire W.P.
      Stimulant medication and postural orthostatic tachycardia syndrome: a tale of two cases.
      ).

      2.2 Non-orthostatic, non-autonomic symptoms

      As noted above, a number of non-orthostatic, non-autonomic symptoms, may be reported by POTS patients. Fatigue is a prominent symptom in many patients, adversely impacting quality of life and activity level. It is not uncommon for POTS patients to be diagnosed with chronic fatigue syndrome at some point during their clinical course. Fatigue may be impacted by sleep complaints, which are also common in POTS patients. Indeed, 1 study of 44 POTS patients identified more severe sleep disturbances, higher fatigue, and excessive daytime somnolence relative to normal controls (
      • Bagai K.
      • Song Y.
      • Ling J.F.
      • Malow B.
      • Black B.K.
      • Biaggioni I.
      • et al.
      Sleep disturbances and diminished quality of life in postural tachycardia syndrome.
      ). Cognitive complaints (often characterized by patients as “brain fog”) are present in a significant majority of POTS patients and is disabling for some. Neuropsychological testing in 28 POTS patients identified significant impairment in selective attention, executive function, and cognitive processing speed relative to healthy controls (
      • Arnold A.C.
      • Haman K.
      • Garland E.M.
      • et al.
      Cognitive dysfunction in postural tachycardia syndrome.
      ). Notably, memory function, sustained attention, psychomotor speed, and verbal fluency were not significantly different in POTS patients relative to controls in this study.

      2.3 Autonomic review of systems

      An autonomic review of systems is necessary to establish the extent of autonomic system involvement. While delineating the presence and extent of orthostatic intolerance symptomatology is critical in establishing a diagnosis of POTS, significant impairment of other autonomic systems occurs (particularly gastrointestinal) and may be a source of significant disability for patients. Patients should be queried as to the presence of dry eyes and dry mouth, which can be seen in patients with autonomic neuropathy and other conditions associated with autonomic failure. Gastrointestinal symptoms are commonly reported in POTS patients (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ). All patients should be questioned about dysphagia, early satiety, nausea, vomiting, abdominal pain, constipation, and diarrhea. Urinary symptoms such as increased frequency, difficulty initiating urination, nocturnal enuresis, and incomplete bladder emptying, may be reported by POTS patients. Thermoregulatory or sweating impairment may be suggested by symptoms such as heat intolerance, cold intolerance, hyperhidrosis, or hypohidrosis.

      2.4 Co-morbid conditions

      The clinical history should also focus on establishing whether any associated (non-autonomic) conditions are present. In the author's experience, migraine and hypermobile Ehlers-Danlos syndrome are the most common co-morbid conditions. These conditions must be identified if present, as they may influence POTS management (
      • Kanjwal K.
      • Saeed B.
      • Karabin B.
      • Kanjwal Y.
      • Grubb B.P.
      Comparative clinical profile of postural tachycardia patients with and without joint hypermobility syndrome.
      ;
      • Miglis M.G.
      • Schultz B.
      • Muppidi S.
      Postural tachycardia in hypermobile Ehlers-Danlos syndrome: A distinct subtype?.
      ). Clinical features such as hypermobile joints, “double-jointedness”, joint dislocations, and clicking joints, are suggestive of EDS (Mathias). The recently revised hypermobile EDS criteria has established a 5 point questionnaire for assessing hypermobility, with affirmative responses of 2 or more of these items considered positive for hypermobility (see Table 4) (
      • Malfait F.
      • Francomano C.
      • Byers P.
      • Belmont J.
      • Berglund B.
      • Black J.
      • Bloom L.
      • Bowen J.M.
      • Brady A.F.
      • Burrows N.P.
      • Castori M.
      • Cohen H.
      • Colombi M.
      • Demirdas S.
      • De Backer J.
      • De Paepe A.
      • Fournel-Gigleux S.
      • Frank M.
      • Ghali N.
      • Giunta C.
      • Grahame R.
      • Hakim A.
      • Jeunemaitre X.
      • Johnson D.
      • Juul-Kristensen B.
      • Kapferer-Seebacher I.
      • Kazkaz H.
      • Kosho T.
      • Lavallee M.E.
      • Levy H.
      • Mendoza-Londono R.
      • Pepin M.
      • Pope F.M.
      • Reinstein E.
      • Robert L.
      • Rohrbach M.
      • Sanders L.
      • Sobey G.J.
      • Van Damme T.
      • Vandersteen A.
      • van Mourik C.
      • Voermans N.
      • Wheeldon N.
      • Zschocke J.
      • Tinkle B.
      The 2017 international classification of the Ehlers–Danlos syndromes.
      ). This questionnaire is particularly useful in those who have physical limitations that may preclude calculation of a Beighton score.
      Table 4Hypermobility 5-point questionnaire.
      1) Can you now (or could you ever) place your hands flat on the floor without bending your knees?
      2) Can you now (or could you ever) bend your thumb to touch your forearm?
      3) As a child, did you amuse your friends by contorting your body into strange shapes, or could you do the splits?
      4) As a child or teenager did your shoulder or kneecap dislocate on more than one occasion?
      5) Do you consider yourself double-jointed?
      An answer of yes, to 2 or more of these questions suggests joint hypermobility with 80–85% sensitivity and 80–90% specificity.
      • Malfait F.
      • Francomano C.
      • Byers P.
      • Belmont J.
      • Berglund B.
      • Black J.
      • Bloom L.
      • Bowen J.M.
      • Brady A.F.
      • Burrows N.P.
      • Castori M.
      • Cohen H.
      • Colombi M.
      • Demirdas S.
      • De Backer J.
      • De Paepe A.
      • Fournel-Gigleux S.
      • Frank M.
      • Ghali N.
      • Giunta C.
      • Grahame R.
      • Hakim A.
      • Jeunemaitre X.
      • Johnson D.
      • Juul-Kristensen B.
      • Kapferer-Seebacher I.
      • Kazkaz H.
      • Kosho T.
      • Lavallee M.E.
      • Levy H.
      • Mendoza-Londono R.
      • Pepin M.
      • Pope F.M.
      • Reinstein E.
      • Robert L.
      • Rohrbach M.
      • Sanders L.
      • Sobey G.J.
      • Van Damme T.
      • Vandersteen A.
      • van Mourik C.
      • Voermans N.
      • Wheeldon N.
      • Zschocke J.
      • Tinkle B.
      The 2017 international classification of the Ehlers–Danlos syndromes.
      .
      Migraine without aura is the most common headache type associated with POTS (
      • Khurana R.K.
      • Eisenberg L.
      Orthostatic and non-orthostatic headache in postural tachycardia syndrome.
      ); but other types of headache may occur, including migraine with aura, chronic migraine, tension type headache, new daily persistent headache, and an orthostatic headache that mimics a cerebrospinal fluid leak (
      • Mokri B.
      • Low P.A.
      Orthostatic headaches without CSF leak in postural tachycardia syndrome.
      ). Headache may develop prior to, concomitant with, or subsequent to the development of POTS (Khurana et al., 2010). Diffuse pain symptoms/syndromes may be reported by POTS patients, including arthralgias and myalgias, the latter of which are not uncommonly attributed to fibromyalgia (
      • Staud R.
      Autonomic dysfunction in fibromyalgia syndrome: postural orthostatic tachycardia.
      ). Mast cell activation syndrome (MCAS), discussed in a later chapter in this issue, is a common co-morbid condition in POTS patients (
      • Shibao C.
      • Arzubiaga C.
      • Roberts L.J.
      • Raj S.
      • Black B.
      • Harris P.
      • Biaggioni I.
      Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders.
      ). Symptoms particularly suggestive of MCAS in POTS patients include flushing, hives, diarrhea, itchy skin, and urinary irritability. Chronic fatigue is a commonly reported symptom in POTS patients, and there may be similar clinical characteristics in POTS and chronic fatigue syndrome (
      • Rowe P.C.
      • Bou-Holaigah I.
      • Kan J.S.
      • Calkins H.
      Is neurally mediated hypotension an unrecognised cause of chronic fatigue?.
      ;
      • Stewart J.M.
      • Gewitz M.H.
      • Weldon A.
      • et al.
      Orthostatic intolerance in adolescent chronic fatigue syndrome.
      ). Other clinical conditions present in a minority, but substantial number of POTS patients include celiac disease, Hashimotos thyroiditis, Sjögren syndrome, and irritable bowel syndrome.

      3. Physical examination

      The general physical examination is a critical component of the evaluation of suspected POTS, and should include a careful cardiac, dermatologic, and neurological examination (
      • Benarroch E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ). Supine and standing heart rate and blood pressure measurements may demonstrate an excessive increase in heart rate of >30 beats per minute (bpm) in adults 18 years of age or older, >40 bpm when younger than age 20, or a heart rate of >120 bpm with standing. POTS patients by definition should not have sustained orthostatic hypotension. A careful cardiac examination is necessary to exclude structural heart disease. Pupillary responses to light should be assessed, and if abnormal (sluggish or absent responses), are typically a sign of an autonomic neuropathy. Fundoscopic examination to exclude papilledema in a patient with headache is necessary to rule out intracranial hypertension. The neurological examination may rarely show evidence of a small fiber neuropathy (diminished pinprick or temperature sensation in the extremities) but should be otherwise normal in POTS patients.
      Excessive resting sweat on the palms and feet may suggest hyperhidrosis or excessive sympathetic activation. Conversely, dry skin and dry oral mucosa may indicate secretomotor impairment as can occur with medication effect (particularly anticholinergic medications) or with Sjögren syndrome. Excessive swelling in the distal lower limbs, and rarely the hands and abdomen with standing, may reflect excessive venous pooling. The presence of postural, color change in the feet and hands reflects vasomotor instability, and may manifest as blotchy, marbled, mauve or purple skin. The presence of flushing, typically present on the face and upper chest and hives, should alert the clinician to possible MCAS. Livedo reticularis may be seen in POTS patients with antiphospholipid antibody syndrome (
      • Schofield J.R.
      • Blitshteyn S.
      • Shoenfeld Y.
      • Hughes G.R.V.
      Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS).
      ).
      The examination should also involve an assessment of skin and joints for hypermobile EDS. Dermatologic signs of EDS include soft or velvety skin, mild skin hyperextensibility, unexplained striae (no history of significant weight change), bilateral piezogenic papules of the heel, and atrophic scarring of at least 2 sites (Malfait). Assessment of joint hypermobility may be quantified by calculating a Beighton score, with a score ≥ 5 in those ranging from post-puberty up to age 50 suggestive of hypermobility (
      • Malfait F.
      • Francomano C.
      • Byers P.
      • Belmont J.
      • Berglund B.
      • Black J.
      • Bloom L.
      • Bowen J.M.
      • Brady A.F.
      • Burrows N.P.
      • Castori M.
      • Cohen H.
      • Colombi M.
      • Demirdas S.
      • De Backer J.
      • De Paepe A.
      • Fournel-Gigleux S.
      • Frank M.
      • Ghali N.
      • Giunta C.
      • Grahame R.
      • Hakim A.
      • Jeunemaitre X.
      • Johnson D.
      • Juul-Kristensen B.
      • Kapferer-Seebacher I.
      • Kazkaz H.
      • Kosho T.
      • Lavallee M.E.
      • Levy H.
      • Mendoza-Londono R.
      • Pepin M.
      • Pope F.M.
      • Reinstein E.
      • Robert L.
      • Rohrbach M.
      • Sanders L.
      • Sobey G.J.
      • Van Damme T.
      • Vandersteen A.
      • van Mourik C.
      • Voermans N.
      • Wheeldon N.
      • Zschocke J.
      • Tinkle B.
      The 2017 international classification of the Ehlers–Danlos syndromes.
      ).

      3.1 POTS subtypes

      It has been suggested that POTS is a “final common pathway” resulting from a number of different pathophysiologic mechanisms (
      • Raj S.R.
      The postural tachycardia syndrome (POTS): pathophysiology, diagnosis, & management.
      ). It is notable that symptoms attributed to POTS resulting from concussion, and presumably impairment of central autonomic control, are often indistinguishable from those resulting from an (peripheral) autonomic neuropathy. Identification of different subtypes of POTS may be useful, though it must be recognized that these classification schemes are descriptive, and different POTS subtypes may be concomitantly present. Primary POTS subtypes include: Hyperadrenergic POTS, Neuropathic POTS, and POTS with Volume dysregulation (
      • Benarroch E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ).
      Hyperadrenergic POTS may be identified by observing orthostatic hypertension, excessive phase IV overshoot on the Valsalva maneuver, and a standing norepinephrine level that exceeds 600 pg/mL (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ;
      • Raj S.R.
      Postural tachycardia syndrome (POTS).
      ). There are currently no consensus criteria for what constitutes neuropathic POTS, though abnormal results on quantitative sudomotor axon reflex testing, distal impairment on thermoregulatory sweat testing, and abnormal epidermal skin punch biopsy may provide evidence in favor of a peripheral process affecting autonomic and small fiber nerves (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ;
      • Gibbon C.H.
      • Bonhay I.
      • Benson A.
      • Wang N.
      • Freeman R.
      Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.
      ). Many POTS patients have been demonstrated to have low plasma, red cell, and total blood volumes (
      • Streeten D.H.
      • Thomas D.
      • Bell D.S.
      The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome.
      ;
      • Raj S.R.
      • Robertson D.
      Blood volume perturbations in the postural tachycardia syndrome.
      ;
      • Stewart J.M.
      • Ocon A.J.
      • Clarke D.
      • Taneja I.
      • Medow M.S.
      Defects in cutaneous angiotensin-converting enzyme 2 and angiotensin-(1–7) production in postural tachycardia syndrome.
      ). Some POTS patients with hypovolemia have been demonstrated to have reduced standing renin and aldosterone levels relative to normal controls with normovolemia. Furthermore, some patients have had inappropriately high angiotensin II levels without an increase in the metabolite angiotensin, suggesting abnormal angiotensin II metabolism (
      • Stewart J.M.
      • Ocon A.J.
      • Clarke D.
      • Taneja I.
      • Medow M.S.
      Defects in cutaneous angiotensin-converting enzyme 2 and angiotensin-(1–7) production in postural tachycardia syndrome.
      ). Additionally, POTS patients have been demonstrated to have an impaired vasopressor response to angiotensin II (
      • Mustafa H.I.
      • Raj S.R.
      • Diedrich A.
      • et al.
      Altered systemic hemodynamic & baroreflex response to angiotensin II in postural tachycardia syndrome.
      ); a finding that may contribute to blood pressure instability and postural tachycardia in POTS patients.

      4. Diagnostic evaluation

      Given that there is not a single test that is sufficiently or exclusively diagnostic of POTS, much of the diagnostic evaluation is focused on excluding conditions that may mimic or exacerbate POTS and identifying co-morbid conditions that impact management. Ideally, formal autonomic testing may suggest potential mechanisms of symptom manifestation, which better inform treatment decisions. The following discussion is not intended to suggest that all diagnostic studies be done on all POTS patients, but rather to serve as a guide for test selection in particular clinical circumstances, and is also intended to serve as a review of the current state of diagnostic testing in POTS patients.

      4.1 Laboratory studies

      Basic laboratory studies should be considered in all POTS patients, including a complete blood count, thyroid cascade, am cortisol, plasma and urinary metanephrines, vitamin B12, celiac testing, antinuclear antibody testing, and Sjögren antibody testing (ssa, ssb), (see Table 5) (
      • Benarroch E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ). Assessment of plasma supine and standing catecholamines may be helpful in elucidating baroreflex sympathoexcitation and in providing evidence of hyperadrenergic POTS (
      • Benarroch E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ). The extent of laboratory testing should be influenced by the duration, severity, and treatment responsiveness of the patient's condition. In patients with chronic, severe, and refractory symptoms, more extensive laboratory testing may be indicated, and particularly in individuals with significant systemic symptoms, the author recommends aggressive pursuit of autoimmune causes. Additional autoantibody testing can be considered, including voltage-gated potassium channel complex antibodies, N-type calcium channel antibodies, ganglionic acetylcholine receptor antibodies, and P/Q-type calcium channel antibodies. The prevalence of these autoantibodies in POTS patients may not be increased relative to the general population (this is the author's experience); however, these autoantibodies have been associated with autonomic neuropathy and autoimmune gastrointestinal dysmotility (
      • Flanagan E.P.
      • Saito Y.A.
      • Lennon V.A.
      • et al.
      Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility.
      ), both conditions that may share some clinical resemblance to POTS. Whether these autoantibodies have clinical significance in POTS, in the absence of autonomic neuropathy or gastrointestinal dysmotility is not clear at this time.
      Table 5Laboratory evaluation of POTS.
      Consider in all suspected POTS patients
       Complete blood count
       Thyroid cascade
       Vitamin B12
       Am cortisol
       Serum and urine metanephrines
       Antinuclear antibody
       ssa, ssb
      Consider in POTS patients with chronic, refractory symptoms; particularly those with autonomic neuropathy or GI dysmotility
       Dysautonomia autoantibodies: voltage gated potassium channel complex, N-type calcium channel antibodies, P/Q-type calcium channel antibodies, ganglionic AChR antibodies
       Antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies, beta-2-glycoprotein antibodies
       Complement: total, C3, C4
       Supine and standing catecholamines
       Serum tryptase
       24 h urine studies: n-methylhistamine, 11-beta prostaglandin F2, leukotriene E4
      A number of novel autoantibodies have been reported in association with POTS patients, though additional research is necessary to determine the role and clinical significance of these antibodies in clinical practice. A study of 14 POTS patients demonstrated the presence of α1 adrenergic receptor and β1 adrenergic receptor autoantibodies in all patients, presence of β2 adrenergic autoantibodies in half of the POTS patients, and absence of these antibodies in normal controls (
      • Li H.
      • Yu X.
      • Liles C.
      • et al.
      Autoimmune basis for postural tachycardia syndrome.
      ). The authors suggest that antagonistic antibodies to α1 AR receptors may result in failure of peripheral vasoconstriction to orthostatic demands, and that activating, agonistic antibodies to β1 and β2 adrenergic receptors may accentuate the compensatory tachycardia in these patients. More recently the presence of these antibodies in a cohort of 17 European patients with POTS was reported, with 8 patients demonstrating α1 adrenergic autoantibodies, 11 with β1 adrenergic antibodies, and 12 with β2 adrenergic antibodies (
      • Fedorowski A.
      • Li H.
      • Yu X.
      • et al.
      Antiadrenergic autoimmunity in postural tachycardia syndrome.
      ). Additional research is necessary to validate these findings in larger POTS cohorts.
      POTS has been associated with antiphospholipid antibody syndrome (
      • Schofield J.R.
      • Blitshteyn S.
      • Shoenfeld Y.
      • Hughes G.R.V.
      Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS).
      ), as well as Sjögren syndrome (
      • Goodman B.P.
      Immunoresponsive autonomic neuropathy in Sjögren syndrome – case series and literature review.
      ;
      • Goodman B.P.
      • Crepeau A.
      • Dhawan P.S.
      • Khoury J.A.
      • Harris L.
      Spectrum of autonomic nervous system impairment in Sjögren syndrome.
      ). Further research is necessary to determine whether these conditions are causative of autonomic (and systemic) signs and symptoms in POTS, and most importantly whether there is a role for immunotherapy in these conditions. Sjögren syndrome is a common autoimmune disorder characterized by keratoconjunctivitis sicca and xerostomia (dry eyes and dry mouth), and the development of systemic, extraglandular involvement occurs in at least 1/3 of patients. Establishing a diagnosis of Sjögren syndrome can be problematic given that sicca symptoms not infrequently develop after neurological or autonomic signs develop (
      • Goodman B.P.
      Immunoresponsive autonomic neuropathy in Sjögren syndrome – case series and literature review.
      ), and the significantly suboptimal sensitivity of standard Sjögren syndrome (ss-a, ss-b) antibodies (
      • Birnbaum J.
      Peripheral nervous system manifestations of Sjogren syndrome. Clinical patterns, diagnostic paradigms, etiopathogenesis, and therapeutic strategies.
      ). A novel Sjögren syndrome antibody panel includes antibodies to salivary gland protein-1, parotid secretory protein, and carbonic anhydrase VI; may have a role in establishing a diagnosis in patients with suggestive signs and symptoms (
      • Suresh L.
      • Malyavantham K.
      • Shen L.
      • Ambrus J.L.
      Investigation of novel autoantibodies in Sjogren's syndrome utilizing Sera from the Sjogren's international collaborative clinical alliance cohort.
      ). While more research is necessary to validate and determine the significance and role of these antibodies in clinical practice, minor salivary gland biopsy is an accepted diagnostic tool used to confirm a diagnosis of Sjögren syndrome (
      • Shiboski C.H.
      • Shiboski S.C.
      • Seror R.
      • et al.
      International Sjögren's syndrome criteria working group. 2016 American College of Rheumatology/European league against rheumatism classification criteria for primary Sjögren's syndrome: a consensus and data-driven methodology involving three international patient cohorts.
      ). Further studies are necessary to determine the role of minor salivary gland biopsy in POTS patients.
      A history of multiple, repeated infections should prompt consideration of immunoglobulin quantification and possibly, immunology referral for evaluation of possible immunodeficiency. Patients with a strong family history of autonomic dysfunction and a POTS phenotype, particularly those with significant gastrointestinal dysmotility, might benefit from genetics consultation and consideration of genetic testing for mitochondrial disorders. Genetic testing is not at this point recommended for hypermobile EDS.

      4.2 Cardiac testing

      Cardiac testing should be considered in all patients, including electrocardiogram, echocardiogram, and 24-h Holter monitoring. The purpose of this testing is to exclude significant, structural cardiac disease and inappropriate sinus tachycardia (IST) or other forms of cardiac dysrhythmia. IST may be difficult to distinguish from POTS, as this condition is also characterized by high heart rates and symptoms of orthostatic intolerance, predominantly in young women. Tachycardia in IST is typically not posturally-mediated and resting heart rate commonly exceeds 100 bpm (
      • Nwazue V.C.
      • Paranjape S.Y.
      • Black B.K.
      • et al.
      Postural tachycardia syndrome and inappropriate sinus tachycardia: role of autonomic modulation and sinus node automaticity.
      ). Most patients with POTS become deconditioned at some point during their symptom course, and formal exercise testing can be considered to assess exercise capacity. A comprehensive study involving formal exercise testing in 184 patients with orthostatic intolerance, identified deconditioning (defined as VO2max < 85%) in 90% of the patients in this cohort (
      • Parsaik A.
      • Allison T.G.
      • Singer W.
      • Sletten D.M.
      • Joyner M.J.
      • Benarroch E.E.
      • Low P.A.
      • Sandroni P.
      Deconditioning in patients with orthostatic intolerance.
      ).

      4.3 Neurologic testing

      A brain MRI with and without contrast should be considered in patients with chronic migraine, orthostatic headache, and new daily persistent headache. While many POTS patients have at least a modest postural component to their headaches (
      • Khurana R.K.
      • Eisenberg L.
      Orthostatic and non-orthostatic headache in postural tachycardia syndrome.
      ), a headache that is primarily orthostatic should prompt an investigation for spontaneous intracranial hypotension, resulting from a cerebrospinal fluid (CSF) leak. Individuals with hypermobile EDS may be at increased risk for spontaneous CSF leaks (
      • Reinstein E.
      • Pariani M.
      • Bannykh S.
      • Rimoin D.L.
      • Schievink W.L.
      Connective tissue spectrum abnormalities associated with spontaneous cerebrospinal fluid leaks: a prospective study.
      ;
      • Schievink W.I.
      Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.
      ). Brain MRI findings in patients with spontaneous intracranial hypotension may demonstrate sagging of the brain, subdural fluid collections, pachymeningeal enhancement, pituitary hyperemia, subdural fluid collections, and engorgement of venous structures (
      • Schievink W.I.
      Spontaneous spinal cerebrospinal fluid leaks and intracranial hypotension.
      ). Treatment options for spontaneous intracranial hypotension range from bed rest and caffeine, to injection of autologous blood into the spinal epidural space (epidural blood patch), application of fibrin sealant, and ultimately surgical repair, if more conservative approaches are unsuccessful.
      Nerve conduction studies and needle electromyography should be considered in patients with both symptoms and signs of a large-fiber peripheral neuropathy. Significant large-fiber peripheral neuropathy is uncommon in POTS patients, and if identified should prompt an aggressive diagnostic evaluation for an underlying condition responsible for both, particularly Sjögren syndrome. POTS patients may more commonly demonstrate signs and symptoms suggestive of small-fiber peripheral neuropathy (SFN). Such symptoms may include numbness, tingling, and burning extremity symptoms, along with abnormal sensory testing to pinprick and temperature. In cases of suspected SFN, epidermal skin punch biopsy should be considered. This technique involves 3 mm skin punch biopsies from proximal and distal sites in the lower limb, with application of protein gene product 9.5 that stains intraepidermal nerve fibers, and allows for calculation of intraepidermal nerve fiber density (IENFD). Decreased IENFD may be seen in patients with SFN, and abnormal findings on skin biopsy were reported in 9 of 24 POTS patients in one study (
      • Gibbon C.H.
      • Bonhay I.
      • Benson A.
      • Wang N.
      • Freeman R.
      Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.
      ). Abnormal IENFD may indicate a neuropathic form of POTS as previously discussed.

      4.4 Autonomic testing

      Autonomic testing should be considered in cases of suspected POTS in order to confirm the diagnosis and to provide for more precise categorization into different pathophysiologic POTS subtypes (
      • Benarroch E.
      Postural tachycardia syndrome: a heterogeneous and multifactorial disorder.
      ). Tilt-table testing (TTT) at 60° for at least 10 min, ideally with noninvasive plethysmographic blood pressure and heart rate monitoring, allows for continuous beat-to-beat assessment during head-up tilt (HUT). A sustained heart rate increment ≥ 30 bpm with HUT or heart rate ≥ 120 bpm in the absence of orthostatic hypotension suggests a diagnosis of POTS in the appropriate clinical context (see Fig. 1). A careful medication review is necessary to ensure that medication effects have not influenced HUT. Stimulant medications (or substances), calcium channel blockers, beta blockers, beta adrenergic agonists (such as isoproterenol), and nitroglycerin can affect blood pressure and heart rate during HUT, and may potentially result in a misdiagnosis of POTS or OH (
      • Cheshire W.P.
      Stimulant medication and postural orthostatic tachycardia syndrome: a tale of two cases.
      ). Orthostatic hypertension, as defined by an increase in systolic blood pressure > 10 mm Hg on HUT may suggest a hyperadrenergic form of POTS (
      • Grubb B.P.
      Postural tachycardia syndrome.
      ) (see Fig. 1). Beat-to-beat heart rate and blood pressure measurements often demonstrate considerable variability.
      Fig. 1
      Fig. 1Tilt-table testing in POTS.
      Top tracing depicts excessive heart rate increment with head-up tilt, while the lower tracing depicts collapse in pulse pressure with marked blood pressure instability in POTS patient.
      Top tracing depicts excessive heart rate increment head-up tilt; while lower tracing showing increase in blood pressure in hyperadrenergic form of POTS with associated Sjögren syndrome.
      Assessment of cardiovagal reflexes involves an analysis of heart rate variability with deep breathing and the Valsalva ratio (
      • Low P.A.
      • Denq J.C.
      • Opfer-Gehrking T.L.
      • et al.
      Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects.
      ). Cardiovagal function is only rarely abnormal in POTS patients; with only 9.9% of 152 POTS patients demonstrating abnormal cardiovagal function in 1 study (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ). Analysis of blood pressure response to the Valsalva maneuver, provides an assessment of adrenergic function (
      • Low P.A.
      • Denq J.C.
      • Opfer-Gehrking T.L.
      • et al.
      Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects.
      ), and in POTS patients may demonstrate excessive early phase II, attenuation of late phase II, and an exaggerated phase IV overshoot. An excessive phase IV overshoot may be seen in patients with hyperadrenergic POTS (
      • Raj S.R.
      The postural tachycardia syndrome (POTS): pathophysiology, diagnosis, & management.
      ;
      • Raj S.R.
      Postural tachycardia syndrome (POTS).
      ).
      Sudmotor function is most commonly assessed through analysis of quantitative sudomotor axon reflex testing (QSART) and much less commonly, thermoregulatory testing (TST). The QSART involves the iontophoresis of acetylcholine at 4 sites, which includes the forearm, proximal-lateral leg, medial-distal leg, and proximal foot, and provides an assessment of postganglionic sympathetic sudomotor function (
      • Low P.A.
      • Denq J.C.
      • Opfer-Gehrking T.L.
      • et al.
      Effect of age and gender on sudomotor and cardiovagal function and blood pressure response to tilt in normal subjects.
      ). Abnormal QSART testing was reported in 42.8% of 152 POTS patients in 1 series (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ), and other smaller series reported abnormalities ranging from 33%–63% of patients (
      • Al-Shekhlee A.
      • Lindenberg J.R.
      • Hachwi R.N.
      • et al.
      ;
      • Peltier A.C.
      • Garland E.
      • Raj S.R.
      • et al.
      ;
      • Gibbon C.H.
      • Bonhay I.
      • Benson A.
      • Wang N.
      • Freeman R.
      Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome.
      ). Abnormal postganglionic sympathetic sudomotor function is generally considered to reflect a neuropathic form of POTS. TST involves the application of an indicator powder, followed by placement of the patient in a humidity-controlled cabinet used raise body temperature and demonstrate sweating. Abnormal findings on TST were seen in 53.8% of POTS patients in a large cohort, with most in this group demonstrating a distal pattern of sweat loss (
      • Thieben M.J.
      • Sandroni P.
      • Sletton D.M.
      • et al.
      Postural orthostatic tachycardia syndrome: the Mayo clinic experience.
      ).

      4.5 Gastrointestinal evaluation

      As noted above, gastrointestinal symptoms are common in POTS patients, with nearly 70% of patients in 1 series reporting gastrointestinal symptoms (
      • Al-Shekhlee A.
      • Lindenberg J.R.
      • Hachwi R.N.
      • et al.
      ). While these symptoms may reflect a visceral motility disorder, primary gastrointestinal disorders such as celiac disease, gastroesophageal reflux, esophagitis, gastritis, eosinophilic disorders, and inflammatory bowel disease must be considered and excluded through diagnostic testing, when appropriate. Lactose intolerance, fructose intolerance, cyclic vomiting, and MCAS may also contribute to significant gastrointestinal symptomatology.
      Gastrointestinal symptoms in POTS patients are commonly under-recognized and suboptimally investigated, resulting in frustratingly few treatment options for patients. It is not yet known precisely how or to what extent hypermobile EDS impacts gastrointestinal function in POTS patients, though gastrointestinal involvement in EDS has been well described (
      • Beckers A.B.
      • Keszthelyi D.
      • Fikree A.
      • et al.
      Gastrointestinal disorders in joint hypermobility syndrome/Ehlers-Danlos syndrome hypermobility type: a review for the gastroenterologist.
      ;
      • Fikree A.
      • Chelimsky G.
      • Collins H.
      • Kovacic K.
      • Aziz Q.
      Gastrointestinal involvement in the Ehlers–Danlos syndromes.
      ). It is not known whether the presence or severity of gastrointestinal dysmotility in POTS patients is predictive of an underlying autoimmune condition, though given the recent description of immunoresponsive autoimmune gastrointestinal dysmotility (
      • Flanagan E.P.
      • Saito Y.A.
      • Lennon V.A.
      • et al.
      Immunotherapy trial as diagnostic test in evaluating patients with presumed autoimmune gastrointestinal dysmotility.
      ), the author recommends an aggressive autoantibody assessment in POTS patients with dysmotility. Esophageal, gastric, and intestinal motility testing should be considered in POTS patients, as indicated by the nature of symptoms. Esophageal dysmotility may be demonstrated in POTS patients with dysphagia, and gastroparesis may be seen in patients with early satiety, abdominal pain, nausea, and post-prandial abdominal bloating. Gastric emptying studies in 163 POTS patients identified rapid gastric emptying in 48% and a delay in gastric emptying in 18% of patients (
      • Loavenbruck A.
      • Iturrino J.
      • Singer W.
      • et al.
      Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome.
      ). In this cohort, vomiting was significantly associated with delayed gastric emptying, and delayed colonic transit was noted in 27% of 121 patients tested (
      • Loavenbruck A.
      • Iturrino J.
      • Singer W.
      • et al.
      Disturbances of gastrointestinal transit and autonomic functions in postural orthostatic tachycardia syndrome.
      ).
      A number of different modalities may be utilized to establish the presence of an esophageal, gastric, or intestinal motility disorder (see Table 6). While plain radiograph, computerized tomography, and MR enterography may demonstrate dilated intestinal loops and are helpful to exclude mechanical obstruction, they lack adequate sensitivity in identifying a motility disorder. Gastric emptying scintigraphy involves the ingestion of a radiolabeled meal, and ideally, an assessment of retention at 0, 1, 2, and 4 h (
      • Rao S.S.C.
      • Camilleri M.
      • Hasler W.L.
      • et al.
      Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.
      ). Likewise, small intestine motility can be assessed through scintigraphic studies, typically as a component of whole gut transit study (
      • Rao S.S.C.
      • Camilleri M.
      • Hasler W.L.
      • et al.
      Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.
      ). Colonic transit using radiopaque markers allows for calculation of transit times through the colon, and has been widely adopted to assess constipation and unexplained diarrhea in patients with a suspected motility disorder (
      • Hinton J.M.
      • Lennard-Jones J.E.
      • Young A.C.
      A new method for studying gut transit times using radioopaque markers.
      ). Colonic transit scintigraphy is an alternative method for assessing motility in patients with regional colonic or whole gut motility disorders (
      • Camilleri M.
      Scintigraphic biomarkers for colonic dysmotility.
      ;
      • Rao S.S.C.
      • Camilleri M.
      • Hasler W.L.
      • et al.
      Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.
      ). Wireless motility capsule is an alternative technique that involves a single-use, ingested but non-digestible capsule that measures pH, pressure, and temperature throughout the GI tract (
      • Rao S.S.C.
      • Camilleri M.
      • Hasler W.L.
      • et al.
      Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.
      ). Whole gut transit time, gastric emptying, small bowel transit time, and colonic transit time can be calculated using the wireless motility capsule (
      • Rao S.S.C.
      • Camilleri M.
      • Hasler W.L.
      • et al.
      Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.
      ;
      • Paine P.
      • McLaughlin J.
      • Lal S.
      Review article: the assessment and management of chronic severe gastrointestinal dysmotility in adults.
      ). Wireless motility capsule may be suboptimal in assessing gastric function relative to scintigraphic studies and is contraindicated in cases of severe dysmotility or pseudo-obstruction given a risk of capsule retention (
      • Paine P.
      • McLaughlin J.
      • Lal S.
      Review article: the assessment and management of chronic severe gastrointestinal dysmotility in adults.
      ). Manometry studies may distinguish myopathic from neuropathic conditions in the small intestine (
      • Stanghellini V.
      • Cogliandro R.
      • Cogliandro L.
      • et al.
      Clinical use of manometry for the diagnosis of intestinal motor abnormalities.
      ;
      • Smout A.J.
      Manometry of the gastrointestinal tract: toy or tool?.
      ), may demonstrate esophageal dysmotility, and anorectal manometry may provide evidence of pelvic floor dysfunction. Breath testing involves ingestion of a non-digestible carbohydrate such as lactulose, which upon contact with enteric mucosa generates gases that transverse the mucosa, are transported to the lungs, and are exhaled, providing an assessment of small bowel tansit time (
      • Rao S.S.C.
      • Camilleri M.
      • Hasler W.L.
      • et al.
      Evaluation of gastrointestinal transit in clinical practice: position paper of the American and European Neurogastroenterology and Motility Societies.
      ).
      Table 6Indications & testing modalities for motility assessment in POTS patients.
      RegionIndications for testingTesting modalities
      EsophagusDysphagia, vomiting, chest pain,Esophageal manometry
      Regurgitation, reflux, nausea,Esophageal scintigraphy
      Globus
      GastricEarly satiety, Nausea, vomiting,Gastric emptying scintigraphy
      Bloating, post-prandial fullness,Wireless motility capsule
      Upper abdominal painBreath test
      Small bowelNausea, vomiting, bloating,Breath test
      Diarrhea, abdominal painScintigraphy
      Wireless motility capsule
      Large bowelConstipation, diarrhea,Wireless motility capsule
      Abdominal pain, bloatingRadioopaque markers
      Colonic scintigraphy
      Patients with gastrointestinal dysmotility are at risk for small intestinal bacterial overgrowth (SIBO), which is defined as a bacterial population in the small intestine exceeding 105–106 organisms/mL (
      • Corrazza G.R.
      • Menozzi M.G.
      • Strocchi A.
      • et al.
      The diagnosis of small bowel bacterial overgrowth: reliability of jejunal culture and inadequacy of breath hydrogen testing.
      ). While diminished gastric acid secretion and small intestine dysmotility are most commonly associated with SIBO, other risk factors include anatomical problems or anomalies, celiac disease, diabetes mellitus, cirrhosis, renal failure, inflammatory bowel disease, immunodeficiency states, malnutrition, and recurrent antibiotic use (
      • Dukowicz A.C.
      • Lacy B.E.
      • Levine G.M.
      Small intestinal bacterial overgrowth: a comprehensive review.
      ). Clinicians must have a high index of suspicion for SIBO given that symptoms are nonspecific and may include bloating, abdominal distension, abdominal pain, diarrhea, and fatigue (
      • Dukowicz A.C.
      • Lacy B.E.
      • Levine G.M.
      Small intestinal bacterial overgrowth: a comprehensive review.
      ). Breath testing as discussed above is the primary study used to identify SIBO. Treatment of SIBO involves correction of the underlying cause (if possible), nutritional support, and treatment of the overgrowth (
      • Dukowicz A.C.
      • Lacy B.E.
      • Levine G.M.
      Small intestinal bacterial overgrowth: a comprehensive review.
      ). SIBO treatment often requires broad spectrum antimicrobial therapy, which in some patients may require repeat or cyclical therapy, along with dietary modifications (
      • Rezaie A.
      • Pimentel M.
      • Rao S.S.
      How to test and treat small intestinal bacterial overgrowth: an evidence-based approach.
      ).

      4.6 Genitourinary evaluation

      A recent study of 19 POTS patients reported findings from a quantitative overactive bladder (OAB) screening questionnaire, and found that 13 of 19 patients met clinical criteria for a diagnosis of probable clinically significant OAB, with nocturia, increased daytime frequency, and urgency most problematic for patients (
      • Kaufman M.R.
      • Chang-Kit L.
      • Raj S.R.
      • Black B.K.
      • Milam D.F.
      • Reynolds W.S.
      • Biaggioni I.
      • Robertson D.
      • Dmochowski R.R.
      Overactive bladder and autonomic dysfunction: lower urinary tract symptoms in females with postural tachycardia syndrome.
      ). Urodynamic studies might be considered in POTS patients with significant lower urinary tract symptoms that suggest urinary retention. The components of urodynamic testing include uroflowmetry, postvoid residual measurements, cystometry, leak point pressure measurements, pressure flow studies, and in some centers, electromyography and video urodynamic studies. A video of 16 POTS patients referred for evaluation of lower urinary tract symptoms, identified a pattern of impaired sensation of bladder fullness, inefficient emptying with straining pattern of voiding, and no loss of bladder compliance (Fuare, Walker).

      4.7 Sleep evaluation

      As previously noted, fatigue, daytime sleepiness, and sleep disturbances are common in POTS patients. Other complaints often reported by POTS patients that may reflect a sleep disorder include headache upon awakening, repeated nocturnal awakening, nocturnal sweating, nocturnal palpitations and tachycardia. Polysomnography in 25 POTS patients was compared to that performed in 31 control subjects, demonstrating similar sleeping times between the groups, but a higher percentage of stage 2 sleep was noted in POTS patients, and no statistically significant difference in REM sleep and percentage of slow wave sleep was seen in the POTS group relative to controls (
      • Mallien J.
      • Isenmann S.
      • Mrazek A.
      • Haensch C.-A.
      Sleep disturbances and autonomic dysfunction in patients with postural orthostatic tachycardia syndrome.
      ). It was noted by the authors, however, that 4 POTS patients in this cohort did not achieve REM sleep during polysomnography.

      5. Conclusions

      POTS is a common, though under-recognized, heterogeneous disorder that requires a thorough clinical history and examination, and a thoughtful diagnostic approach, in order to identify relevant clinical features and associated conditions. An individualized diagnostic approach is necessary given the multi-system heterogeneity of the condition, which can better inform treatment decisions in POTS patients. In the author's opinion, present and future clinical research aimed at understanding the pathogenesis of POTS, should ideally involve much larger case series than those previously reported with more optimal identification of comorbid conditions, and a focus on the interplay between autoimmunity and genetics.

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