2.3. Diagnostic approaches and biomarkers

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Etiology and Contributing Factors]] → -------- ##### Summary >[!Summary] >|BASIC EVALUATION|DESCRIPTION| >|:---------------------------------------------------------------------------------------------------------------------------------------------- |:------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ | >|elicitation of clinical history| trigger timing of onset, progression of orthostatic symptoms, precipitating and aggravating factors, presence of associated nonorthostatic symptoms, fluid and caffeine intake, level of physical activity, sleep pattern, response to previous attempted treatments, current drug therapy[[#^1]], validated questionnaires to explore the presence of autonomic features and track severity of symptoms[[#^36]][[#^03]][[#^05]]| >|noninvasine plethysmographic BP and HR monitoring in head-up tilt (HUT)[[#^6]][[#^22]][[#^23]][[#^33]]|to distinguish POTS from other forms of OI ; stroke index and total peripheral resistance provides picture of hemodynamic and reflex reponses, which allow for more precise categorization into different pathophysiologic subtypes[[#^5]] | >|active standing test[[#^24]]| HR and BP measured when the patient has been supine for 5-10 mins, and then after standing for 1 min, 3 mins, 5 mins, 8 mins and 10 mins[[#^32]] ; used for initial screening in clinics that lack access to fully equipped autonomic laboratory[[#^24]] | >|comprehensive cardiac evaluation (ECG[[#^6]][[#^24]][[#^011]], echocardiogram[[#^6]], 24 (48)-hr ECG holter monitoring[[#^24]], 24-h ambulatory BP holter monitoring[[#^6]])|to exclude primary cardiac causes of inappropriate tachycardia[[#^6]] ; to correlate timing of symptoms with presence of tachycardia| >|exercise ECG[[#^24]] testing with VO₂ max[[#^6]]| assess degree of cardiovascular conditioning | >--------------- >| AUTONOMIC TESTING | DESCRIPTION | >|:------------------------------------------------------------------------------------------------------------------------ |:------------------------------------------------------------------------------------------------------------------------- | >| quantitative sudomotor axon reflex test (QSART)[[#^9]][[#^16]][[#^28]] , quantitative sensory testing (QST)[[#^9]][[#^28]] or thermoregulatory sweat test (TST)[[#^9]][[#^21]][[#^28]] | to demonstrate sudomotor denervation to foot and toes[[#^9]][[#^02]] ; adrenergic impairment to lower extremity seen in neuropathic POTS | >| composite autonomic severity score (CASS)[[#^20]][[#^22]] | combines results of 3 subsets of autonomic tests (sudomotor, cardiovagal and adrenergic) | >| blood pressure and heart rate responses to Valsalva maneuver[[#^17]][[#^18]][[#^19]][[#^24]][[#^012]] | suggest presence of 'hyperadrenergic type of POTS'[[#^19]][[#^02]] | >- To interpret autonomic function tests, it is important to have a basic understanding of the baroreceptor reflex.[[#^35]] >-------------------------------------- >| LABORATORY TESTS | DESCRIPTION | >|:-------------------------------------------------------------------------------------------------------- |:---------------------------------------------------------------------------------------------------------------------------- | >| supine & standing plasma catecholamine levels[[#^4]][[#^6]][[#^25]][[#^04]] | supine and after standing for 10[[#^29]]-15[[#^7]] minutes ; plasma norepinephrine levels of >600 pg/mL considered hyperadrenergic response[[#^7]][[#^10]][[#^02]] | >| skin biopsy[[#^28]] | to determine whether an autonomic neuropathy exists[[#^28]] | >| vitamin B12 levels, iron indices, serological markers for celiac disease[[#^11]] , anaemia[[#^25]], electrolyte disorders[[#^25]][[#^34]], renal function[[#^34]], hemoglobin[[#^34]] | | >| thyroid cascade[[#^6]][[#^25]][[#^34]] | evaluate for hyperadrenergic state[[#^6]] | >| adrenal hormone abnormalities[[#^25]] | | >| AM & PM cortisol[[#^6]][[#^34]] | evaluate for chronic fatigue | >|plasma and urinary metanephrine[[#^6]] | detect pheochromocytoma[[#^6]] | >| serum tryptase, urinary methylhistamine[[#^6]] | to detect mast cell activation disorders | >| autoantibodies (VGKC complex, ganglionic AChR)[[#^6]] | to detect autoimmune causes of POTS[[#^6]] | >| 24-hr urine sodium[[#^8]][[#^15]] | to determine volume status[[#^15]][[#^02]][[#^04]] ; goal is volume of 1,500 - 2,500 mL and sodium excretion of 170 mmol/24 hours[[#^8]] | >--------------- >| ADDITIONAL TESTS | DESCRIPTION | >|:-------------------------------------------- |:--------------------------------------------------------------------------------------------- | >| MRI of head with gadolinium[[#^6]] | patients with orthostatic headache[[#^6]] | >| gastrointestinal[[#^25]] or urologic evaluations[[#^6]] | if suspected functional visceral dysmotility syndrome[[#^6]] | >| behavioral medicine evaluation[[#^6]] | patients with multiple associated nonorthostatic symptoms[[#^6]] | >| external or implantable loop recorder (ILRs)[[#^24]] | reserved under restriction for very difficult patients with spontaneous fainting spells, etc.[[#^24]] | > >- recommended that postural testing be performed in the morning (to optimize diagnostic sensitivity)[[#^27]] > - If a clinician has a high suspicion of POTS, but a patient does not meet the criterion for orthostatic tachycardia at their initial evaluation, reassessment at a later date is prudent, preferably in the morning[[#^30]] > - patients with POTS have sinus tachycardia, not another supraventricular tachyarrhythmia. Clinicians should consider paroxysmal supraventricular tachycardia, especially if the tachycardia is not always positional, if it has a sudden onset and offset (the heart rate usually increases more gradually in POTS), or if the tachycardia stops with a Valsalva manoeuvre[[#^31]] -------- ##### Diagnostic Approaches >_“Elicitation of the clinical history of patients with POTS should address the trigger, timing of onset, and progression of orthostatic symptoms; precipitating or aggravating factors; presence of associated nonorthostatic symptoms; fluid and caffeine intake; level of physical activity; sleep pattern; response to previous attempted treatments; and current drug therapy.”_ ([[Benarroch-2012]], [p. 6](zotero://open-pdf/library/items/WEZLT9QC?page=6&annotation=8LQ5QUDN))^1 >_“The patient should undergo a comprehensive cardiac and neurologic examination in addition to measurements of supine and standing heart rate and blood pressure. Examination could also reveal indirect evidence of venous pooling (such as lower extremity edema) or excessive sympathetic activity (such as cold, clammy hands).”_ ([[Benarroch-2012]], [p. 6](zotero://open-pdf/library/items/WEZLT9QC?page=6&annotation=FGXLNN5R))^2 >_“The aims are to exclude ([p. 6](zotero://open-pdf/library/items/WEZLT9QC?page=6&annotation=MKDYJRTF)) primary cardiac causes of inappropriate tachycardia; determine, if possible, the most likely primary pathophysiologic basis of postural intolerance; identify treatable causes of autonomic neuropathy in patients with neuropathic POTS; exclude endocrine or other systemic causes of a hyperadrenergic state in patients with hyperadrenergic POTS; assess the degree of cardiovascular conditioning; investigate the mechanisms of gastrointestinal and other associated symptoms; and address possible psychiatric comorbidities.”_ ([[Benarroch-2012]], [p. 7](zotero://open-pdf/library/items/WEZLT9QC?page=7&annotation=TFK2XFPS))^3 >_“The basic evaluation should include a cardiac evaluation, autonomic reflex testing, and measurement of supine and standing plasma catecholamine levels.”_ ([[Benarroch-2012]], [p. 7](zotero://open-pdf/library/items/WEZLT9QC?page=7&annotation=US92IQTB))^4 >_“Noninvasive plethysmographic blood pressure and heart rate monitoring allows a careful examination of the beat-to-beat systolic and diastolic blood pressure and heart rate responses during HUT. Data regarding stroke index and total peripheral resistance, as well as heart rate variability, can also be obtained from these recordings. This information provides a more thorough picture of the hemodynamic and reflex responses associated with orthostatic stress and allows a more precise categorization of patients with POTS ([p. 7](zotero://open-pdf/library/items/WEZLT9QC?page=7&annotation=7KMUDUD3)) into the different pathophysiologic subtypes (neuropathic, hyperadrenergic, or hypovolemic).”_ ([[Benarroch-2012]], [p. 7](zotero://open-pdf/library/items/WEZLT9QC?page=7&annotation=SHH7H3SK))^5 >![[Benarroch-2012-7-x138-y375.png#invert_B| 700]] >([[Benarroch-2012]], [p. 7](zotero://open-pdf/library/items/WEZLT9QC?page=7&annotation=YE8YBFXV))^6 >*“Plasma catecholamines should be measured supine and after standing for 15 minutes. The primary interest is in norepinephrine. In about half the patients standing, norepinephrine exceeds 600 pg/mL, considered a hyperadrenergic response.” *([[Low-2009]], [p. 4](zotero://open-pdf/library/items/I4WAD8AG?page=4&annotation=TY9L38T5))^7 >*“A 24-hour urine sodium is a simple and helpful test that provides documentation that the patient is taking sufficient fluids and sodium. The goal is a volume of 1,500–2,500 mL and sodium excretion of 170 mmol/24 hours. The latter indicates that the patient is taking adequate sodium and likely has a normal plasma volume.” *([[Low-2009]], [p. 4](zotero://open-pdf/library/items/I4WAD8AG?page=4&annotation=JNF8CE7G))^8 >*“Distal postganglionic sudomotor denervation can be demonstrated with the quantitative sudomotor axon reflex test (QSART)21 or the thermoregulatory sweat test.22 These tests demonstrate sudomotor denervation to the foot and toes. Adrenergic impairment to the lower extremity can be seen in neuropathic POTS demonstrable as impaired norepinephrine spillover in the leg while the arm response remains normal” *([[Low-2009]], [p. 4](zotero://open-pdf/library/items/I4WAD8AG?page=4&annotation=VY4W5PUE))^9 >![[Low-2009-14-x43-y101.png#invert_B| 800]] >([[Low-2009]], [p. 14](zotero://open-pdf/library/items/I4WAD8AG?page=14&annotation=5IB2DGET))^10 >*“Some physicians specializing in POTS will also assess Vitamin B12 levels, iron indices, and serological markers for celiac disease” *([[Raj-2013]], [p. 5](zotero://open-pdf/library/items/CCJLQKRB?page=5&annotation=X5EMXQ7Y))^11 >*“The supine norepinephrine is often within the normal range in POTS patients, while the upright norepinephrine is frequently elevated (>600 pg/ml), reflecting the exaggerated neural sympathetic tone that is present in these patients while upright.” *([[Raj-2013]], [p. 5](zotero://open-pdf/library/items/CCJLQKRB?page=5&annotation=V6QMFUTJ))^12 >*“The blood volume is low in many patients with POTS 14. This can be objectively assessed with nuclear medicine tests to directly measure either the plasma volume or the red cell volume.” *([[Raj-2013]], [p. 5](zotero://open-pdf/library/items/CCJLQKRB?page=5&annotation=97EBN7QI))^13 >![[Thieben-2007-3-x115-y472.png#invert_B| 800]] >([[Thieben-2007]], [p. 3](zotero://open-pdf/library/items/5WXWEQWX?page=3&annotation=FFL5HUYR))^14 >*“An important first step in the assessment and treatment of patients with POTS is to determine their volume status and institute salt and fluid replacement in those with hypovolemia. El Sayed and Hainsworth15 reported that 24-hour urinary sodium excretion correlated significantly with plasma volume as measured with Evans blue dye.” *([[Thieben-2007]], [p. 6](zotero://open-pdf/library/items/5WXWEQWX?page=6&annotation=XKKVIU4V))^15 >*“If a clinician has a high suspicion of POTS, but a patient does not meet the criterion for orthostatic tachycardia at their initial evaluation, reassessment at a later date is prudent, preferably in the morning.”* ([[Raj-2022]], [p. 1](zotero://open-pdf/library/items/YN8BG2FZ?page=1&annotation=6QVBVIES))^30 >*“The evaluation of POTS requires a focused history and examination, followed by tests that should include HUT, some estimation of volume status and preferably some evaluation of peripheral denervation and hyperadrenergic state.” *([[Low-2009]], [p. 1](zotero://open-pdf/library/items/I4WAD8AG?page=1&annotation=C44QYR3A))^02 >*“All patients need a detailed history to document the severity of orthostatic intolerance, its modifying factors and influence on activities of daily living. It is helpful to grade the severity of orthostatic intolerance, based on symptoms, standing time, and effect on activities of daily living (Table 2). A full autonomic system review should document autonomic systems involved and whether there are symptoms to suggest an autonomic neuropathy. Commonly associated disturbances such as fatigue, sleep disturbance, and migraine should be documented.” *([[Low-2009]], [p. 3](zotero://open-pdf/library/items/I4WAD8AG?page=3&annotation=Y9JCXR4W))^03 >![[Low-2009-13-x65-y494.png#invert_B| 600]] >([[Low-2009]], [p. 13](zotero://open-pdf/library/items/I4WAD8AG?page=13&annotation=JL7SC9H3))^04 >![[Low-2009-12-x61-y363.png#invert_B| 1000]] >([[Low-2009]], [p. 12](zotero://open-pdf/library/items/I4WAD8AG?page=12&annotation=NSJI6RJN))^05 >*“An electrocardiogram (ECG), 24-hr Holter monitor and echocardiogram might be needed to rule out a cardiac etiology for the tachycardia in suspected cases of POTS. The tachycardia of POTS is a sinus tachycardia. An ECG should be done= to rule out= the presence of an accessory bypass tract or any abnormalities of cardiac conduction [11]. Chest pain in POTS is rarely from coronary artery obstruction but it may be associated with ECG changes when patients are upright [20]. A Holter monitor can supply information on mean HR and its variability during various prescribed or routine activities that precipitate orthostatic symptoms. It might be used to exclude a re-entrant dysrhythmia, especially when the patient reports paroxysmal tachycardia with a sudden onset and offset” *([[Garland-2015]], [p. 3](zotero://open-pdf/library/items/CAWTWYLR?page=3&annotation=GYMX7AJ6))^011 >*“Cardiovascular autonomic function tests [30] to evaluate sympathetic vasoconstriction and cardiac parasympathetic responses should be performed in presumed POTS patients to rule out more severe forms of autonomic failure. Intact vagal function can be demonstrated by a normal sinus arrhythmia ratio in response to deep breathing. A Valsalva maneuver is useful to assess both vagal and sympathetic components of the baroreflex” *([[Garland-2015]], [p. 4](zotero://open-pdf/library/items/CAWTWYLR?page=4&annotation=28H5PZWN))^012 ##### Autonomic Function Test >*“Cardiovagal, adrenergic, and postganglionic sudomotor functions were assessed as follows.[10] The quantitative sudomotor axon reflex test (QSART) evaluates the postganglionic sympathetic sudomotor axon [11] and is performed at 4 sites (forearm, proximal lateral aspect of the leg, medial distal aspect of the leg, and proximal foot). Acetylcholine is iontophoresed as a stimulus, and responses are recorded in a single compartment of a multicompartmental sweat cell separate from the stimulus compartment. The axon reflex is mediated by postganglionic sympathetic sudomotor fibers.” *([[Thieben-2007]], [p. 2](zotero://open-pdf/library/items/5WXWEQWX?page=2&annotation=PETA48TI))^16 >*“Cardiovagal function is assessed on the basis of heart rate response to deep breathing and the Valsalva ratio.[12] The heart rate response to deep breathing is the range of heart rate with the subject supine and breathing 6 times per minute. This technique assesses the degree of sinus arrhythmia.” *([[Thieben-2007]], [p. 2](zotero://open-pdf/library/items/5WXWEQWX?page=2&annotation=8KUYB8EU))^17 >*“To test the Valsalva maneuver, the subject was recumbent and asked to maintain a column of mercury at 40 mm Hg for 15 seconds. The ratio of the maximal to minimal heart rate defines the Valsalva ratio.” *([[Thieben-2007]], [p. 2](zotero://open-pdf/library/items/5WXWEQWX?page=2&annotation=M2VELEVH))^18 >*“Adrenergic function is assessed by the blood pressure and heart rate responses to the Valsalva maneuver and head-up tilt. Beat-to-beat blood pressure was monitored continuously (Finapres Monitor, Ohmeda, Englewood, Colo), and a computer console continuously displayed systolic, diastolic, and mean blood pressure.[10] Manual measurement of the blood pressure using a sphygmomanometer cuff and mercury manometer was used to assess the accuracy of beat-to-beat blood pressure.” *([[Thieben-2007]], [p. 2](zotero://open-pdf/library/items/5WXWEQWX?page=2&annotation=2GU4ULBA))^19 >*“The composite autonomic severity score (CASS) is a semiquantitative score from 0 (no deficit) to 10 (maximal deficit) that combines the results of 3 subsets of autonomic tests and corrects for the effects of age and sex: sudomotor (range, 0-3), cardiovagal (range, 0-3), and adrenergic (range, 0-4).” *([[Thieben-2007]], [p. 2](zotero://open-pdf/library/items/5WXWEQWX?page=2&annotation=3MV8NMKN))^20 >*“The thermoregulatory sweat test is performed in a cabinet with a hot and humid environment (45∞-50∞C air temperature; 35%-40% relative humidity). The mean skin temperature was kept at 39.0∞C. Oral temperature increased at least 1.0∞C or to 38.0∞C (whichever was higher). Maximal sweating was achieved in 30 to 65 minutes. An indicator powder was used to demonstrate sweating, and the percentage of anhidrosis on the anterior body surface was calculated from images created from digital photographs of the sweat distribution.” *([[Thieben-2007]], [p. 2](zotero://open-pdf/library/items/5WXWEQWX?page=2&annotation=CY345ATK))^21 >![[Thieben-2007-4-x316-y436.png#invert_B| 500]] >([[Thieben-2007]], [p. 4](zotero://open-pdf/library/items/5WXWEQWX?page=4&annotation=676EH6SG))^22 >![[Fedorowski-2019-6-x44-y413.png#invert_B| 850]] >([[Fedorowski-2019]], [p. 6](zotero://open-pdf/library/items/BZ35QDLR?page=6&annotation=HMPYZHZN))^23 >![[Fedorowski-2019-7-x63-y86.png#invert_B| 800]] >([[Fedorowski-2019]], [p. 7](zotero://open-pdf/library/items/BZ35QDLR?page=7&annotation=GRDXVP66))^24 >![[Fedorowski-2019-8-x50-y430.png#invert_B| 800]] >([[Fedorowski-2019]], [p. 8](zotero://open-pdf/library/items/BZ35QDLR?page=8&annotation=4HKNQS7G))^25 >*“An active standing test that can be easily performed may immediately give a diagnostic clue if supported by a history of characteristic chronic orthostatic intolerance, postural heart rhythm acceleration and varying panorama of accompanying complaints (Table 2). Further diagnostic process should be optimally delegated to a centre or specialist with a good experience of POTS. The golden standard for POTS diagnosis is head-up tilt test with a non-invasive beat-to-beat haemodynamic monitoring (Fig. 2). A panel of additional tests may be performed to explore the haemodynamic profile of patient, differentiate between the ‘hyperadrenergic’ and ‘neuropathic’ form, and to grade the symptoms (Table 4; Fig. 3). In some dedicated autonomic centres, which are not widely available, a battery of autonomic tests can be offered to better categorize the affection and dysfunction of the entire autonomic nervous system [34, 61–63], not only of its cardiovascular branch.” *([[Fedorowski-2019]], [p. 8](zotero://open-pdf/library/items/BZ35QDLR?page=8&annotation=XIKQUKPL))^26 >*“To optimize diagnostic sensitivity, it is recommended that postural testing be performed in the morning” *([[Garland-2015]], [p. 3](zotero://open-pdf/library/items/CAWTWYLR?page=3&annotation=2PQ7JGGC))^27 >*“A thermoregulatory sweat test or a Quantitative Sudomotor Axon Reflex Test (QSART), quantitative sensory testing, or a skin biopsy can also be used to determine whether an autonomic neuropathy exists” *([[Garland-2015]], [p. 6](zotero://open-pdf/library/items/CAWTWYLR?page=6&annotation=JHRWFIZ7))^28 >*“Plasma norepinephrine levels should be determined in patients with POTS while in steady state in the supine and upright positions (at least 10 min in each position)” *([[Garland-2015]], [p. 7](zotero://open-pdf/library/items/CAWTWYLR?page=7&annotation=A9H43ARK))^29 >*“patients with POTS have sinus tachycardia, not another supraventricular tachyarrhythmia. Clinicians should consider paroxysmal supraventricular tachycardia, especially if the tachycardia is not always positional, if it has a sudden onset and offset (the heart rate usually increases more gradually in POTS), or if the tachycardia stops with a Valsalva manoeuvre”* ([[Raj-2022]], [p. 2](zotero://open-pdf/library/items/YN8BG2FZ?page=2&annotation=77NEJMSU))^31 >*“Heart rate and blood pressure must be measured when the patient has been supine for 5–10 minutes to allow fluid equilibration, and then after standing for 1 minute, 3 minutes, 5 minutes, 8 minutes and 10 minutes.”* ([[Raj-2022]], [p. 4](zotero://open-pdf/library/items/YN8BG2FZ?page=4&annotation=9J4GTM5D))^32 >*“The tilt table test leads to a slightly greater increase in heart rate than the stand test,39 which increases its diagnostic sensitivity.”* ([[Raj-2022]], [p. 4](zotero://open-pdf/library/items/YN8BG2FZ?page=4&annotation=BAWYMCEN))^33 >*“Core laboratory investigations5 should screen for secondary causes of orthostatic tachycardia, including hemoglobin, electrolytes, renal function, ferritin, thyroid-stimulating hormone and morning cortisol.”* ([[Raj-2022]], [p. 5](zotero://open-pdf/library/items/YN8BG2FZ?page=5&annotation=FYJEJGQ9))^34 >*“To interpret autonomic function tests, it is important to have a basic understanding of the baroreceptor reflex. Baroreceptors ([p. 5](zotero://open-pdf/library/items/HLELIN7I?page=5&annotation=G66DK76H)) are stretch-sensitive mechanoreceptors located in the aortic arch and carotid sinuses. They monitor changes in blood pressure and provide a rapid negative feedback loop between HR and blood pressure. Elevated blood pressure activates the baroreflex, leading to decreases in HR and blood pressure. A drop in blood pressure will inhibit the baroreflex, leading to increases in HR and blood pressure. Baroreflex-induced changes in blood pressure are mediated by both branches of the autonomic nervous system: the parasympathetic and sympathetic systems. Rapid baroreflex adjustments are critical for regulation of HR and peripheral vascular resistance during orthostatic stress.35,36 In individuals with reduced venous return during orthostasis but an intact baroreflex, persistent reduction in stretch of the baroreceptors results in an exaggerated and sustained tachycardia. During deep inspiration and expiration while supine, however, individuals with POTS generally have a normal variation in HR variability (preserved vagal function) as the baroreflex responds to changes in intrathoracic pressure. Immediately following a Valsalva maneuver, however, the normal rebound in blood pressure (phase IV) is exaggerated, reflecting a vigorous pressor response. A reduced ability to buffer a fall in activation (stretch) of the baroreceptors may occur in a subgroup of “hyperadrenergic” POTS patients with high background sympathetic tone.”* ([[Wells-2017]], [p. 6](zotero://open-pdf/library/items/HLELIN7I?page=6&annotation=7GTZWVVI))^35 >![[Zotero/Zotero Images/Wells-2017-5-x66-y484.png]] >([[Wells-2017]], [p. 5](zotero://open-pdf/library/items/HLELIN7I?page=5&annotation=GWXXCQIA)) > >*“Several validated questionnaires may be useful to explore the presence of autonomic features and track severity of symptoms in patients with POTS (Table 2).”* ([[Wells-2017]], [p. 4](zotero://open-pdf/library/items/HLELIN7I?page=4&annotation=6TL9RZI7))^36 -------- Tags: #diagnosis #biomarkers #test