Dysautonomia in Long COVID is Prevalent and Could Explain the Frequency of Symptoms.

When a person stands up, he or she assumes that the body will automatically make any changes necessary to compensate for the increased gravitational stress this change of position brings. Indeed, standing causes gravity to try to pull nearly one quarter of the body’s blood downward toward the lower arms, legs, and abdomen, reducing the amount of blood available to keep the brain supplied with oxygen. To maintain a constant oxygen supply to the brain and upper body, standing is normally accompanied by an automatic increase in heart rate and the force with which the heart contracts and, most important, a tightening of the blood vessels in the lower part of the body. The combination of these 3 actions pushes blood upward against the force of gravity, thereby maintaining an uninterrupted flow of blood to the brain. The aspect of the nervous system that governs these …

Postural Tachycardia Syndrome from a Pediatrics Perspective

A UNIQUE CASE OF CONCURRENT EHLERS DANLOS SYNDROME (EDS) AND POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME (POTS) ASSOCIATED WITH ORTHOSTATIC HYPERTENSION RESPONDING TO IV FLUIDS

1. Talha Niaz, MBBS* 2. Kelsey Klaas, MD* 1. *Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN A 15-year-old girl presents to the clinic with frequent episodes of syncope and chronic symptoms of headaches, fatigue, body aches, and abdominal discomfort. She sustained fractures of her fourth through sixth cervical vertebra due to a gymnastics injury 4 years ago, resulting in 3 months of bed rest. During recovery, she developed new onset dizziness, palpitations, and “blacking out” of her vision on standing that were later followed by syncope. Her symptoms gradually worsened over the last 4 years. Recently, she had frequent syncopal events usually associated with upright posture with episodes characterized by brief loss of consciousness for 5 to 10 seconds and then spontaneous recovery with no convulsions, postictal state, or incontinence. Spells have occurred after, but never during, exercise. She has nonrestorative sleep, low energy, and progressive tiredness throughout the day. She has diffuse body aches and occasional knee pain on activity without joint swelling, redness, or morning stiffness. She recently developed a daily headache, which is bilateral, 4/10 in intensity, pounding or throbbing, and associated with nausea without vomiting. She also has intermittent abdominal discomfort with no diarrhea or constipation. She has had normal growth and no weight loss. On examination, she has a supine heart rate of 64 beats/min that increases to 102 beats/min after standing for 3 minutes associated with some dizziness but no significant hypotension. She has a dark red to purple discoloration of her feet on standing. She has a Beighton (hypermobility) score of 4/9. The rest of her examination, including cardiac and neurologic, is normal. She has a normal electrocardiogram, head magnetic resonance imaging, and laboratory work except for serum ferritin …

Received September 14, 2004; revision received January 31, 2005; accepted March 9, 2005. “We shall not cease from exploration and the end of all our exploring will be to arrive where we started and know the place for the first time” — —T.S. Eliot, Four Quartets Syncope, defined as transient loss of consciousness and postural tone with spontaneous recovery, has both challenged and perplexed physicians since the dawn of recorded time. The earliest written accounts come from Hippocrates, and the word syncope itself is derived from an old Greek term meaning “to cut short” or “interrupt.” Recurrent episodes of syncope may result from a large number of different disorders, all of which cause a transitory reduction in cerebral blood flow sufficient to disturb the normal functions of the brain. Over the last 2 decades, considerable attention has been given to types of syncope that occur due to a centrally mediated (or “reflex”) fall in systemic blood pressure, a condition that has been referred to as vasovagal (and later neurocardiogenic) syncope. However, research into the nature of this disorder revealed that it is but one aspect of a broad and varied group of disturbances in the normal functioning of the autonomic nervous system (ANS), each of which may result in orthostatic intolerance, hypotension, and ultimately syncope. Continued investigations into the nature of these similar yet different disorders has led to the development of a system of classification that attempts to more accurately reflect our understanding of these conditions and their interrelationships.1 The present system of classification has proven both functional and clinically relevant and includes a group of disorders that most investigators have thought to be principally autonomic in nature. Because both the cardiologist and the cardiac electrophysiologist frequently are expected to both diagnose and treat these conditions, the following …

Variations in the Clinical Manifestations of Orthostatic Hypotension

Diagnostic value of 24-h ECG recording in Long COVID patients with postural orthostatic tachycardia syndrome

Background: Orthostatic hypotension (OH) is considered an important risk factor for falls, but prospective studies have been small and inconsistent. Methods: We examined the association between OH assessed at baseline in 12,661 middle-aged participants of the ARIC Study (1987-1989). OH was considered present if there was a drop in blood pressure (systolic ≥20 mm Hg or diastolic blood pressure ≥10 mm Hg) when moving from the supine to standing position after three minutes. Changes in systolic or diastolic blood pressures were also examined as continuous variables. The outcome of interest was any fall identified from ICD9 discharge codes from hospitalization records or Centers for Medicare & Medicaid Services claims data. The association of OH and risk of fall was characterized using Cox proportional hazard models. Results: At baseline, the mean age was 54 years; participants were 55% women and 47% black; 5% (N = 651) had OH. During a median follow-up of 23 years, there were 2,274 new falls. The incidence rate, using age as the time axis, was 2.8 per 1,000 person-years among participants with OH versus 2.3 per 1,000 person-years among those without OH (P = 0.03). OH was significantly associated with long-term risk of fall even after adjustment for demographics and other risk factors (Figure legend) (HR 1.25, 95% CI 1.04-1.49). Furthermore, postural change in diastolic blood pressure was more strongly associated with risk of falls (HR 1.07 per -5 mm Hg in diastolic blood pressure; P < 0.001) than postural change in systolic blood pressure (HR 1.02 per -5 mm Hg in systolic blood pressure; P = 0.01). This association appeared linear without evidence of a threshold effect (Figure). Conclusions: In an ambulatory population, OH, and in particular, postural change in diastolic blood pressure, were significant, independent risk factors for falls over a long period of time. Future studies should determine whether targeted therapies can reduce falls in persons with OH.

Postural orthostatic tachycardia syndrome (POTS) is common, and has a serious impact on children's quality of life. Midodrine hydrochloride, an α1-adrenoreceptor agonist, is an effective treatment. The study was designed to examine the therapeutic efficacy of midodrine hydrochloride by quantifying changes in blood pressure during the head-up test (HUT), in children with POTS. Overall, 104 out of 110 children with POTS were treated with midodrine hydrochloride and successfully followed-up. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) changes were analyzed during the HUT. In a retrospective analysis, a receiver operating characteristic (ROC) curve was used to analyze the therapeutic predictive value of pre-treatment changes in SBP, DBP, and a combination of both, from the supine position to standing, in the subjects. The increase of SBP and DBP from the supine position to standing in responders were significantly lower than that of the non-responders. The ROC curve showed that midodrine hydrochloride for children with POTS would be predicted to be effective when the pre-treatment increase of SBP was ≤ 0 mmHg, or when the pre-treatment increase of DBP was ≤ 6.5 mmHg (from the supine position to standing), yielding a sensitivity of 72% and specificity of 88%. The area under the curve was 0.744 and 0.809, respectively. Hence, the results suggested that looking at the changes in blood pressure during the HUT was useful in predicting the response to midodrine hydrochloride in children with POTS.

Introduction More than 500,000 people in the United States, particularly young girls, experience chronic orthostatic intolerance resulting in substantial morbidity affecting work, school, and recreational activities (11,34). Up to a third of patients with postural tachycardia syndrome (POTS) have frank syncopal episodes with almost daily presyncope (21,29). Syncope accounts for approximately 1% of hospital admissions and 3% of emergency department visits with mortality and morbidity rates of over 7% (21,27). However, identifying the definitive etiology and mechanism of syncope and presyncope is fairly uncommon, and treatment and management can be frustrating because of the heterogeneous pathophysiologic basis of orthostatic tachycardia in POTS (3). This report will discuss a 21-year-old division I field hockey player with infectious mononucleosis (IM)-induced POTS. Case Report A 21-year-old previously healthy division I field hockey player presented to her primary care physician complaining of a 2-d history of headaches. She had taken nonsteroidal anti-inflammatory drugs (NSAID) the day before evaluation, which alleviated the symptoms temporarily, allowing her to sleep. The following morning, she awoke again with a headache. Upon standing, she became light headed, nauseated, and diaphoretic. Without any recollection of the preceding events, she awoke after an unknown amount of time on the closet floor and immediately contacted her mother. Her mother arrived at her dormitory room shortly after and recalled that she was mildly confused but denied any bowel/bladder incontinence or symptoms consistent with tongue or mouth biting. Her mother contacted their primary care physician via telephone and that provider ordered an outpatient computed tomography of her head without contrast later that day, which was unremarkable. At this time, the symptoms were attributed to atypical migraines versus sinusitis and she was treated accordingly. She continued to take NSAID along with an antihistamine and took a nap for several hours that afternoon. That evening, she had a second syncopal episode while sitting on the toilet, this time witnessed by her mother. It was reported that she experienced a complete loss of consciousness for 5 to 7 s. Immediately before the episode, she appeared extremely pale. Mom denied any jerking or seizure activity, bowel/bladder incontinence, or vomiting. Before these, she had never experienced similar syncopal events. Her athletic trainers were immediately notified, and she was subsequently evaluated the following morning by the team’s primary care sports medicine physician. During her initial evaluation, the patient was found to have a lying pulse of 67, which increased to 86 with sitting and 114 with standing. Her blood pressure was 108/76 and remained stable with no evidence of orthostatic hypotension. A physical examination was significant only for 1+ tonsillar enlargement. An electrocardiogram (ECG) revealed normal sinus rhythm with no acute ischemic changes or prolonged QT interval. She was started on an antiemetic (ondansetron) for possible atypical migraine, and it was recommended that she increase her fluid and salt intake for her tachycardia, which was presumptively secondary to dehydration. Laboratory tests included a complete blood count, a metabolic profile, Epstein-Barr virus (EBV) titers, ferritin test, iron test, total iron-binding capacity, thyroid-stimulating hormone test, and vitamin D levels. It was recommended that she avoid physical activity including all participation in field hockey and follow-up in 2 to 3 d if symptoms persisted. She returned for follow-up 3 d later. Despite treating her with ibuprofen 600 mg three times daily, ondansetron 4 mg every 6 h, and increased fluids, her symptoms did not improve. She continued to report worsening nausea without any episodes of emesis. Again in the office, her pulse increased with positional changes (68 lying down, 86 sitting, and 110 standing) without evidence of orthostatic hypotension. Pregnancy test was negative and urinalysis obtained in the office was normal except for a specific gravity of >1.030. All laboratory results obtained at her previous visit were found to be within normal limits, except for her EBV titers, which were pending. Because her main complaint at that time was still a headache, she received promethazine and intramuscular ketorolac in hopes of combating an atypical migraine, as well as a normal saline 2-L bolus for her dehydration. She reported immediate symptomatic improvement and so was sent home with warning to go to the emergency department if symptoms returned. The following morning, her headache and light headedness returned and reported to be even more severe. Her primary care sports medicine physician was notified, and it was decided that further evaluation was necessary with recommendation for the athlete to be seen in the emergency department. Upon arrival in the emergency department, she received a lumbar puncture, which revealed a normal opening pressure. Magnetic resonance imaging (MRI) of the brain with and without contrast was performed and showed no abnormalities. She was admitted for intravenous fluids and evaluation by cardiology and neurology subspecialists. During her stay, all cultures including cerebrospinal fluid and blood were normal. The cardiologist and neurologist were subsequently consulted. The cardiologist obtained an ECG and performed routine laboratory tests and recommended a stress test. The neurologist was concerned for atypical migraines and ordered an MRI of the brain with and without contrast, which was unremarkable. During these workups, her EBV titers from her outpatient clinic returned and were positive for IgM antibodies. At that time, the cardiologist recommended an electrophysiology consult to perform a tilt table test (after aggressive intravenous fluid resuscitation to eliminate dehydration as a confounding variable), which was subsequently found to be positive. Findings included an increase in the heart rate from 70 to 130 and persistently stayed above 100 during the entirety of the test. After 20 min, she experienced sinus tachycardia at 160 and a systolic blood pressure drop to 101 without syncope. She was found to be symptomatic with reports of feeling diaphoretic and light headed with worsening of previous symptoms, particularly her headache and nausea. Interestingly enough, chronic headaches are a common comorbidity in patients with POTS and orthostatic headaches also occur even in the absence of intracranial hypovolemia or cerebrospinal fluid leak (3). She was subsequently diagnosed with IM-induced POTS. Her stress test was cancelled at that time and the neurologist, agreeing with the diagnosis, did not perform any additional tests. She was sent home on 2 L of fluid daily with 3 to 5 g of daily salt intake. It was postulated that her symptoms may be reversible after the acute viral infection resolved. Discussion According to current criteria for adults, POTS is defined as a heart rate increase of 30 bpm or more within 10 min of standing or head-up tilt (HUT) with a standing heart rate of 120 bpm or higher (3,9). Up to half of all documented cases have antecedent viral illness (3,35,45), and the evaluation and management of POTS should be multidisciplinary (3). Typical complaints from POTS patients include poor concentration, headache, fatigue, dizziness, chest discomfort, tremor, and shortness of breath (21). Many patients report a cyclical nature of their symptoms (21). They also may report symptoms consistent with functional gastrointestinal or bladder disorders, fibromyalgia, chronic headache, and sleep disturbances (21). Up to one-third of patients experience secondary orthostatically triggered vasovagal syncope (2,3). POTS is more frequent in women (4.5/1), and most cases occur between the ages of 15 to 25 years (3) with more than 500,000 people in the United States being affected (11,34). Although the pathophysiology is not well understood, recent research suggests that physical deconditioning and a reduced standing stroke volume may be important features (11–14,19,26,30,38). Psychological factors may play a role also. Anxiety, depression, and poor sleep may all lead to relative predominance of sympathetic over vagal control of the patient’s heart rate (3). Abnormal processing of sensory information, including somatic hypervigilance and behavioral amplification, can contribute also to persistence of symptoms, including those symptoms not triggered by orthostatic stress, such as fibromyalgia, visceral pain, and chronic dizziness. Although it is common for POTS patients to have a noticeable drop in blood pressure upon standing, some patients have no change or may even experience an increase in blood pressure upon standing (6,21). Because of the presence of multiple comorbidities not directly related to the presenting orthostases (chronic fatigue, sleep disturbances, and myofascial pain) (3), as well as the pathophysiologic heterogeneity of orthostatic intolerance, these patients are difficult to recognize and pose a particular challenge in management (3). Abnormal sympathetic nervous activity or reactivity may be central to the conditions; however, there is no definitive link between the excessive tachycardia and sympathetic nervous dysfunction (21). There are several subtypes of POTS, including neuropathic POTS, hyperadrenergic POTS, volume dysregulation, and physical deconditioning (3). In neuropathic POTS, there is indirect evidence of peripheral sympathetic denervation of the lower extremities (3,18,24). This patient population experiences venous pooling in the lower limbs secondary to impaired peripheral vasoconstriction (3). This is characterized by a loss of sweating in the feet leading to thermodysregulation and impaired increase of norepinephrine (NE) levels in response to orthostatic stress (3,18). Interestingly, there is a frequent onset after a viral illness (up to 50%), and the presence of a ganglionic acetylcholine receptor antibody in 14% of patients suggests an autoimmune etiology of neuropathic POTS (3,45). These common interacting mechanisms likely reflect changes in central nervous system areas involved in the processing of visceral and somatic nociceptive information, behavioral arousal, interoceptive awareness, and stress responses (3). Because of our patient’s recent diagnosis of IM with an acute onset (IgM+), there is high clinical suspicion that she experienced this specific subtype of POTS. In hyperadrenergic POTS, between 30% and 60% of patients have increased central sympathetic drive with plasma NE levels of 600 pg·mL−1 or more (3). They also experience fluctuating blood pressure in response to HUT, as well as episodes of tachycardia, hypertension, and hyperhidrosis (3,25,43,45). The possibility of a catecholamine-secreting tumor such as a pheochromocytoma or an autoimmune etiology such as hyperthyroidism should be considered (3). Secondary hyperadrenergic POTS also has been associated with mast cell activation disorders (3,37). Neuronal reuptake of noradrenaline via the cell membrane NET (uptake 1) is the main means of inactivation of noradrenaline and a key factor in regulation of noradrenaline to myocardial adrenoceptors (7,21). It has been demonstrated that a defect in NET may be involved in the pathophysiology of POTS (21,36). By selectively blocking NET in healthy individuals, a phenotype that resembled POTS was demonstrated (21,36). Because our patient did not demonstrate these specific symptoms and never had hypernatremia, this subtype was deemed very unlikely in our specific case. Hypovolemia secondary to volume dysregulation should be considered with the diagnosis of POTS. In one study, 28.9% of patients excreted less than 100 mEq·L−1 of sodium in 24 h (3,45) and a large subgroup experienced low plasma, total blood volumes, and red cells (3,33,42,44), illustrating a compensatory physiologic mechanism that differs from chronic dehydration in which the body retains sodium, thus retaining water, to prevent further dehydration. After saline loading, the affected patient’s urinary sodium increased and symptoms improved (23). Angiotensin-converting enzyme 2 activity has been shown to be reduced in these patients with inappropriately high plasma angiotensin II levels (3,42). Although NSAID use also can alter the angiotensin cascade, our patient was not chronically on any anti-inflammatories, nor did she ever have hyponatremia. Excessive exercise leading to dehydration as well as hypovolemia secondary to excess fluid loss from vomiting and diarrhea also should be considered (3). Again, because our patient did not experience any recent gastroenteritis or other conditions leading to dehydration with such an acute presentation, this subtype also was considered highly unlikely. Regardless of the underlying pathophysiology, physical deconditioning is an important factor in the development of orthostatic symptoms (3,19,26). These patients exhibit greater and more persistent tachycardia when upright, reduced left ventricular mass, reduced stroke volume, and reduced peak oxygen uptake during and after exercise compared with control subjects (3,12,26). The phenomenon of deconditioning also decreases the response to the vasoconstrictor baroreceptor reflex (3,4,17) and vestibulosympathetic reflex (3,6). Our patient was a highly competitive and active division I athlete making this subtype highly unlikely. She had not recently experienced any injury leading to a long period of inactivity with secondary deconditioning. Peak oxygen uptake (V˙O2 peak) is generally lower in these patients suggesting a lower physical fitness level (11). Compared with healthy, sedentary individuals matched for age and sex, POTS patients were found to have lower stroke volume and higher heart rate for each level of absolute workload (11,38). However, when expressed at the relative workload (percent of V˙O2peak), no differences in heart rate response were found, suggesting no intrinsic abnormality of heart rate regulation during exercise in POTS patients (11,17). It was found that POTS patients as well as their healthy counterparts had a similar linear correlation between cardiac output and V˙O2 during submaximal and maximal exercises indicating that POTS patients have a normal ability to increase cardiac output for the oxygen demand as well as peripheral use of oxygen (11,38). It has been postulated also that there are sex-specific differences exaggerated in POTS and that women born with small hearts, albeit normal range, were more susceptible to develop POTS (4,11,12). Conversely, decreased myocardial load and work secondary to physiologic adaptation to the reduced physical activity level also could account for these findings (11). Diagnosis POTS is one of the most common manifestations of orthostatic intolerance (3,24,25). Current criteria for adults are defined by a heart rate increase of 30 bpm or more within 10 min of standing or HUT (3,9) and a standing heart rate of 120 bpm or higher (3). For patients with a low resting heart rate or structural cardiac abnormalities, these criteria may not be applicable (3). For individuals aged 12 to 19 years, the required heart rate increment is at least 40 bpm (3,9). The observed orthostatic tachycardia may be accompanied with symptoms consistent with cerebral hypoperfusion (blurred vision, light headedness, cognitive difficulties, and generalized weakness) and sympathetic hyperactivity (chest pain, palpitations, and tremulousness) that are relieved by recumbency (3). For those patients that experience symptoms on standing or HUT but do not fulfill the heart rate criteria, the term orthostatic intolerance is used (3,30). A precise clinical history should be obtained during initial evaluation of POTS patients, which include the timing of the onset, precipitating or aggravating factors, fluid and caffeine intake, level of physical activity, current drug therapy, and sleep pattern (3). Patients should then undergo neurologic and cardiac examination in addition to orthostatic vital signs (3). It is imperative to exclude primary cardiac causes of inappropriate tachycardia with ECG, as well as possible Holter monitoring, and echocardiogram (3). Screening HUT table testing has been shown to be helpful with patients experiencing syncope of an unknown cause, including POTS (1,3), and should be ordered as an initial test. Because of limited sensitivity/specificity, this is not beneficial as a diagnostic tool but better served as a screening test in order to differentiate POTS from other forms of orthostatic intolerance. Plethysmographic blood pressure and heart rate monitoring allows examination of the beat-to-beat systolic and diastolic blood pressure and heart rate responses during HUT to improve test sensitivity and reduce false-positive rates (3). In individual cases, additional laboratory investigations may be necessary. Serum cortisol levels in both AM and PM can be considered to evaluate for any underlying hyperadrenergic states including Cushing’s disease and acute stress reactions, a thyroid cascade to evaluate for dysregulation of thyroid hormones, plasma and urinary metanephrines to detect a pheochromocytoma, serum tryptase and urinary methylhistamine to detect mast cell activation disorders, and even MRI of the head for patients with orthostatic headaches (3). For those patients with multiple associated nonorthostatic symptoms, a behavioral medicine evaluation may prove to be beneficial (3). Treatment The treatment for POTS should be focused on patient education. Many patients have unrealistic expectations about the benefits of treatments and become frustrated (3). Most patients require volume expansion with adequate daily water (1.5 to 2 L) and sodium intake (3). Diuretics should be avoided in POTS patients, most notably alcohol and caffeine (3,28). Maintaining an adequate cerebral blood flow by using vasovagal maneuvers, i.e., leg crossing, making a fist, or active contraction of abdominal or buttock muscles, can be beneficial (3) as well as wearing support garments such as compression stockings or abdominal binders (3,41). In 2014, Figueroa et al. (8) expected to show that normal saline infusion before exercise would decrease heart rate; however, no effect was observed. They postulated that an acute saline infusion was not sufficient, and more chronic treatments may be needed to improve exercise capacity (8). Furthermore, the treatment groups were not randomized so any beneficial effect of saline may have been confounded by prolonged fatigue or training effect (8). Exercise training is extremely beneficial to POTS patients by improving cardiovascular responses. In 2010 and 2011, Fu et al. (11–13) found that 53% of patients that completed a 3-month exercise training program no longer met the criteria for diagnosis of POTS; however, the severity of the POTS symptoms was a major factor limiting patients’ exercise tolerance (11). It also was noted that many patients initially exercised too vigorously leading to a worsening of symptoms (3). It has been recommended that patients start with a recumbent cycle and gradually increase over 6 to 8 wk (3). Light strengthening exercises for the major muscle groups using weight machines provide added benefit (3). Pharmacologic agents also can be used to treat POTS. The mineralocorticoid, fludrocortisone, promotes intravascular volume expansion (3,10); however, in patients with a history of migraine headaches, this can exacerbate headache and vertigo (3). The alpha1-adrenergic agonist, midodrine (5,15), elicits peripheral vasoconstriction and reduces venous pooling but can increase the risk of urinary retention in patients with bladder disorders (3). Beta-blockers such as propanolol (15,31) and bisoprolol (3,10,47) can be used to control excessive tachycardia. These medications can exacerbate fatigue and exercise intolerance and can cause hypotension in patients with preexisting low intravascular volume (3). Pyridostigmine (3,20,32,40) is a cholinesterase inhibitor which can prolong the phasic effects of acetylcholine on the autonomic ganglia, potentiating vagal effects on standing (3). Pyridostigmine potentiates muscarinic receptor activation in the gastrointestinal tract and can cause vomiting, nausea, abdominal cramps, diarrhea, and detrusor hyperactivity (3). Because of the adverse effect profile of medications and the large majority of patients being young with multiple comorbidities such as chronic fatigue syndrome, depression, and fibromyalgia, pharmacologic interventions are reserved for those cases resistant to fluid and salt loading. Conclusion In this case, conservative measures were initiated at the onset of diagnosis. The patient was discharged with strict dietary guidelines that included 2 to 3 L of water intake along with 3 g of salt daily. It was recommended she avoid caffeine and alcohol. Cardiology, neurology, and electrophysiology consults all concurred that her diagnosis of POTS would most likely be reversible with the resolution of her acute viral illness. She was treated conservatively for IM and was held from contact sports and heavy lifting until 6 wk of follow-up. Current guidelines recommend supportive therapy only for IM with steroid administration considered only in cases of airway compromise (22). Treatment with antiviral agents has not shown any benefit to date (22). At her 6 wk of follow-up, her symptoms had completely resolved and she had not experienced any additional syncopal episodes. She was cleared at that time to return to physical activity at a reduced exertional level allowing her to slowly return to her baseline. At the final follow-up, she was back to full activity with no return of symptoms.

In previous work we identified a group of children (n = 48) between the ages of 10-18 years whose diagnostic workup for chronic nausea unexplained by conventional diagnostic tests revealed that 60% had underlying cardiovascular instability (n = 30) presenting as orthostatic intolerance (OI). The OI could be sub-classified based on head up tilt (HUT) testing into three groups: Postural Orthostatic Tachycardia Syndrome (POTS), orthostatic hypotension (OH) and syncope. Children with OI in all three groups had a greater reduction in autonomic control upon HUT manifested as greater loss of baroreflex sensitivity (BRS) and heart rate variability (HRV) and higher norepinephrine levels compared to those in the non OI group. Vitamin D deficiency is associated with impaired vascular responses to vasoconstrictors and alterations in autonomic control mechanisms in adults. In this study we sought to determine if vitamin D level is lower in these pediatric OI subjects and if it correlates with the hemodynamic responses to tilt. Serum 25(OH)D tended to be lower in OI vs non OI (18.6 ± 0.7 ng/ml, n = 25, vs 22.2 ± 2.4 ng/ml, n = 15; p = 0.16). Most importantly 25(OH)D showed a high positive correlation with supine measures of BRS (seq ALL, R = 0.51, p = 0.05), HRV (rMSSD, R = 0.44, p = 0.02) only in the OI group and there was a trend for a negative correlation with sympathovagal balance ( LF/HF ratio: R =-0.35, p = 0.08). Low 25(OH)D correlated with greater loss of both BRS (R = 0.51, p = 0.01) and HRV (R = 0.44, p = 0.05) upon HUT. These findings support the concept that low vitamin D may contribute to impaired responses to tilt in OI subjects. Further work is needed to evaluate if vitamin D supplementation will improve the vascular and hemodynamic responses to tilt and help improve the OI symptoms. Our goal is to provide a safer therapeutic alternative for the treatment of OI in children.

Functional Gastrointestinal Disorders, Autonomic Nervous System Dysfunction, and Joint Hypermobility in Children: Are They Related?

Orthostatic intolerance (OI) and autonomic dysfunction (AD) are common in adolescents and young adults. Patients experience multisystem symptoms including gastrointestinal (GI), postural orthostatic tachycardia syndrome (POTS), orthostatic hypotension (OH), or only symptoms of OI (SOI) without significant findings on 70-degree head-up tilt testing (HUT). We hypothesize that patients with POTS, OH, and SOI show differences in GI symptoms and motility test and that heart rate (HR) changes on HUT predict severity of GI dysmotility. From medical records of patients (<18years) with OI, we collected demographics, presenting symptoms, GI manifestations, and GI motility testing. Data were compared between the 3 groups (POTS, OH, and SOI). We assessed changes in HR on HUT with changes on GI motility evaluation. Two hundred twenty-nine patients were included (73% females). Abdominal pain (65%), nausea (49%), vomiting (18%), and constipation (24%) were the most common GI symptoms. In patients who had motility evaluation, there were 27% (53/193) with delayed gastric emptying (GE) at 4hours, 35% (32/92) with delayed colonic transit (CT), 55% (17/31) with reduced gastric accommodation (GA), and 75% (21/28) with dyssynergic defecation (DD). Among 100 POTS, 34 OH, and 95 SOI patients, no significant differences in GI symptoms or motility tests were identified and HR changes on HUT were not associated with changes on motility tests. GI symptoms are frequent in adolescents with OI and are associated with delayed GE, reduced GA, delayed CT, and presence of DD.

There is anecdotal evidence that one or more forms of orthostatic intolerance (OI) subgroups may coexist in the same patients. However, there is a paucity of published data on the clinical features and management of patients who suffer from coexisting features of postural tachycardia syndrome (POTS) and neurocardiogenic syncope (NCS). We herein present our experience of 18 patients who we found displayed evidence of coexisting NCS and POTS. We reviewed charts of 300 POTS patients seen at the University of Toledo Syncope and Autonomic Disorders Center from 2003 to 2010 and found 18 patients eligible for inclusion in this study. Patients were included in this study if they reported clinical symptoms consistent with both POTS and NCS and then demonstrated a typical POTS pattern (a rise in heart rate without change in blood pressure [BP]) on head up tilt table (HUTT) within the first 10 minutes of upright posture followed by a neurocardiogenic pattern (a sudden fall in heart rate and/or fall in blood pressure) reproducing symptoms that were similar to the patients spontaneous episodes. We found 18 patients, mean age (30 ± 12), with 15 (84%) women and three (16%) men, who met the inclusion criterion for this study. Each of these 18 patients demonstrated a typical POTS pattern within the first 10 minutes on initial physical exam and on a HUTT. Continued tilting beyond 10 minutes resulted in a sudden decline in heart rate (which in some patients manifested as an asystole that lasted anywhere between 10 and 32 seconds [mean of 18 seconds]) and/or a fall in BP in each of these patients demonstrating a pattern consistent with neurocardiogenic subtype of OI. The mean time to the NCS pattern of a fall in BP and heart was 15 minutes with a range of 13-20 minutes. This group of patients was highly symptomatic and reported frequent clinical symptoms that were suggestive of OI. Recurrent presyncope, syncope, orthostatic palpitations, exercise intolerance, and fatigue were the principal symptoms reported. NCS may coexist with POTS in a subgroup of patients suffering from OI.

The impairment of adaptive mechanisms during orthostatic challenge may evoke orthostatic intolerance, a heterogeneous condition, in which the standing position elicits a fall in blood pressure and/or excessive tachycardia, accompanied by a wide spectrum of subjective symptoms such as dizziness, discomfort, nausea, and palpitations. Apart from chronic and potentially debilitating symptoms, orthostatic intolerance may occasionally lead to sudden loss of consciousness and fall injuries. Consequently, orthostatic intolerance should be considered as a possible cause of unexplained syncope. Two main forms of orthostatic intolerance are orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS). Clinical variants of OH include initial, classical, and delayed forms. The prevalence of OH increases with age, ranging from less than 5% under 40 years to about 20% above 70 years of age, and is higher in chronic diseases, such as hypertension and diabetes, reaching above 35% in Parkinson’s disease and advanced kidney failure. The presence of OH is associated with a higher mortality and an increased incidence of cardiovascular disease, with the majority of patients being asymptomatic in normal conditions. In contrast, POTS affects predominantly young women (70–80%) within an age range of 15–40 years and is usually accompanied by non-specific symptoms: deconditioning, headache, cognitive impairment, and gastrointestinal dysfunction. Management of orthostatic intolerance includes both non-pharmacological and pharmacological methods with limited efficacy in the severe cases. Empirical treatment with vasoactive and volume expanding drugs for OH and POTS, and rhythm controlling therapy for POTS are recommended. Future studies on syndromes of orthostatic intolerance should focus on mechanisms leading to OH and POTS, novel diagnostic methods, and more effective therapeutic options.