Assessment of comorbid symptoms in pediatric autonomic dysfunction.

PURPOSE: Pediatric patients with autonomic dysfunction and orthostatic intolerance (OI) often present with co-existing symptoms and signs that might or might not directly relate to the autonomic nervous system. Our objective was to identify validated screening instruments to characterize these comorbidities and their impact on youth functioning. METHODS: The Pediatric Assembly of the American Autonomic Society reviewed the current state of practice for identifying symptom comorbidities in youth with OI. The assembly includes physicians, physician-scientists, scientists, advanced practice providers, psychologists, and a statistician with expertise in pediatric disorders of OI. A total of 26 representatives from the various specialties engaged in iterative meetings to: (1) identify and then develop consensus on the symptoms to be assessed, (2) establish committees to review the literature for screening measures by member expertise, and (3) delineate the specific criteria for systematically evaluating the measures and for making measure recommendations by symptom domains. RESULTS: We review the measures evaluated and recommend one measure per system/concern so that assessment results from unrelated clinical centers are comparable. We have created a repository to apprise investigators of validated, vetted assessment tools to enhance comparisons across cohorts of youth with autonomic dysfunction and OI. CONCLUSION: This effort can facilitate collaboration among clinical settings to advance the science and clinical treatment of these youth. This effort is essential to improving management of these vulnerable patients as well as to comparing research findings from different centers.

Creating a data dictionary for pediatric autonomic disorders.

PURPOSE: Whether evaluating patients clinically, documenting care in the electronic health record, performing research, or communicating with administrative agencies, the use of a common set of terms and definitions is vital to ensure appropriate use of language. At a 2017 meeting of the Pediatric Section of the American Autonomic Society, it was determined that an autonomic data dictionary comprising aspects of evaluation and management of pediatric patients with autonomic disorders would be an important resource for multiple stakeholders. METHODS: Our group created the list of terms for the dictionary. Definitions were prioritized to be obtained from established sources with which to harmonize. Some definitions needed mild modification from original sources. The next tier of sources included published consensus statements, followed by Internet sources. In the absence of appropriate sources, we created a definition. RESULTS: A total of 589 terms were listed and defined in the dictionary. Terms were organized by Signs/Symptoms, Triggers, Co-morbid Disorders, Family History, Medications, Medical Devices, Physical Examination Findings, Testing, and Diagnoses. CONCLUSION: Creation of this data dictionary becomes the foundation of future clinical care and investigative research in pediatric autonomic disorders, and can be used as a building block for a subsequent adult autonomic data dictionary.

Arterial Baroreceptor Physiology: Differences Between Normal Subjects and Pediatric Patients with Postural Tachycardia and Neurocardiogenic Syncope.

The arterial baroreceptor reflex in children and adolescents has not been well studied in the current literature with a lack of agreed upon normal values, particularly in postural orthostatic tachycardia syndrome (POTS) or neurocardiogenic syncope (NCS). We used the sequence method and head-up tilt test (HUTT) to evaluate baroreceptor function in 3 phases: baseline supine position for 10 min, head-up position at 70° for 30 min or until syncope, and post-tilt supine reposition for 10 min. We measured the number of baroreceptor events, baroreceptor effectiveness index (BEI), and the magnitude of sensitivity of the events at each phase of HUTT. We studied 198 individuals (49 normal subjects, 67 POTS, 82 NCS) with age ranges from 8 to 21 years. The data show a statistically significant decrease in slope and BEI in patients with POTS and NCS during the head-up phase, with an increase in activity in the lag 1 and 2 portions of all phases in patients with POTS. This study provides terminology to describe baroreceptor function and identifies the slope and BEI portions of the baroreceptor reflex as the most useful objective measures to differentiate pediatric patients with POTS and NCS from normal subjects.

Orthostatic Headaches Associated With Spontaneous Intracranial Hypotension and Autonomic Dysfunction-A Case Series in Young Patients.

Background: Orthostatic headaches can be noted in spontaneous intracranial hypotension and orthostatic intolerance. We present a case series of young patients diagnosed with spontaneous intracranial hypotension and were treated for the same but subsequently developed orthostatic intolerance. Methods: We retrospectively reviewed charts for seven young patients with orthostatic headaches related to spontaneous intracranial hypotension and orthostatic intolerance. Results: Patients were diagnosed with spontaneous intracranial hypotension. Diagnosis was confirmed by identifying epidural contrast leakage and three of seven patients were noted to have early renal contrast excretion on computerized tomography myelography. Patients were treated with epidural blood patches. All patients showed persistent symptoms of autonomic dysfunction after treatment of spontaneous intracranial hypotension and orthostatic intolerance was confirmed with head-up tilt table test. Conclusions: Patients with spontaneous intracranial hypotension failing to improve following epidural blood patching should be evaluated for orthostatic intolerance.

Cutaneous manifestations of orthostatic intolerance syndromes.

Dysautonomia refers to a group of autonomic nervous system disorders that affect nearly 70 million people worldwide. One subset of dysautonomia includes syndromes of orthostatic intolerance (OI), which primarily affect adolescents and women of childbearing age. Due to the variability in disease presentation, the average time from symptom onset to diagnosis of dysautonomia is 6 years. In general, there is a paucity of dermatological research articles describing patients with dysautonomia. The objective of this review is to summarize the existing literature on cutaneous manifestations in dysautonomia, with an emphasis on syndromes of OI. A PubMed database of the English-language literature (1970-2020) was searched using the terms "dysautonomia", "orthostatic intolerance", "cutaneous", "skin", "hyperhidrosis", "hypohidrosis", "sweat", and other synonyms. Results showed that cutaneous manifestations of orthostatic intolerance are common and varied, with one paper citing up to 85% of patients with OI having at least one cutaneous symptom. Recognition of dermatological complaints may lead to an earlier diagnosis of orthostatic intolerance, as well as other comorbid conditions.

Point-of-Care Ultrasound in Sternal Notch Confirms Depth of Endotracheal Tube in Children.

OBJECTIVES: To determine if a saline-filled cuff seen at the suprasternal notch on ultrasound corresponds to correct endotracheal tube depth on a chest radiograph (tip at/below clavicle AND ≥ 1 cm above carina). DESIGN: Prospective observational study. SETTING: Tertiary Care Pediatric hospital. PATIENTS: Patients between the ages of 0-18 years requiring nonemergent cardiac catheterizations and endotracheal intubation with a cuffed endotracheal tube were included in the study. Children with anticipated or known difficult airways were excluded. INTERVENTIONS: Ultrasound evaluation of the neck following saline inflation of the endotracheal tube cuff. MEASUREMENTS AND MAIN RESULTS: Ultrasonography of the patient's neck was performed following intubation by a pediatric anesthesiologist. A linear probe was used in transverse axis to identify the saline-filled cuff starting at the suprasternal notch and moving cephalad. A cine-fluoroscopic image, similar to a chest radiograph, was obtained to ascertain the endotracheal tube depth after the cuff was identified sonographically. Endotracheal tube cuffs seen on ultrasound at the suprasternal notch were compared with the endotracheal tube depth on the cine-fluoroscopic image. A total of 75 children were enrolled in the study. The endotracheal tube was seen sonographically at the suprasternal notch in 70 patients of which 60 had complete data (an adequate chest radiograph available for review). Patient ages ranged from 2 months to 18 years with a median age of 4 years. The median endotracheal tube tip to carina distance was 2.4 cm (interquartile range, 1.75-3.3 cm.) The endotracheal tube tip to carina distance was greater than or equal to 1 cm in 57 out of the 60 patients. Endotracheal tube cuff at the suprasternal notch on ultrasound corresponded with correct endotracheal tube depth on chest radiograph with an accuracy of 95% (CI, 86-98%). CONCLUSIONS: Visualization of the cuff at the suprasternal notch by ultrasound demonstrates potential as a means of confirming correct depth of the endotracheal tube following endotracheal intubation.

Demographic and clinical features of pediatric patients with orthostatic intolerance and an abnormal head-up tilt table test; A retrospective descriptive study.

BACKGROUND: Clinical presentation varies in children with Orthostatic Intolerance. This study aimed to evaluate the epidemiological and clinical characteristics of pediatric patients with orthostatic intolerance (OI) and positive head-up tilt test (HUTT). METHODS: This study was a retrospective review of clinical data from outpatients over 18 months period. RESULTS: We included 112 patients with abnormal HUTT results. Females were 78 (70%). Mean age of presentation was 15.6 years (sd: 3.3). Fifteen percent were overweight, and 14% were obese. A headache and syncope were the most frequent presenting symptoms (46% and 29% respectively). Review of systems identified more patients with headaches (84%), Syncope (61%), presyncope (87%) and abdominal pain (29%). Except for fatigue being more prevalent during a review of systems among patients with severe OI (69%) compared to those with moderate OI (46%, p = 0.02), there was no statistically significant difference in the clinical presentation between investigator-defined moderate and severe OI. Comorbidities identified in this cohort were Chiari malformations (9%), idiopathic intracranial hypertension (9%), electroencephalographic abnormalities (8%) and patent foramen ovale (43%). CONCLUSIONS: Adolescents, mainly females had OI. Patients with OI and abnormal HUTT predominantly had a headache, syncope, and presyncope during the presentation. Eliciting review of systems and using tools such as clinical questionnaire identifies significant clinical presenting features and comorbidities.

Baroreceptor activity and sensitivity: normal values in children and young adults using the head up tilt test.

BACKGROUND: Baroreceptor function in children and adolescents has not been well studied in the current literature, with a lack of agreed upon normal values. The authors hypothesize that there is a significant increase in the baroreceptor activity with a decrease in the sensitivity during the upright phase in comparison to the supine phases of the head upright tilt test (HUTT) protocol. METHODS: Baroreceptor evaluation was performed using the sequence method in 49 subjects ages 8-21 years, during the 3 phases of HUTT: supine, head up, and post-tilt supine positions. Baroreceptor Effectiveness Index (BEI) and the number and slope of baroreceptor events were recorded. RESULTS: On study of the events and slope values, there was a significant difference between the three phases of the HUTT with regard to the baroreceptor activity and sensitivity. No significant difference was found in BEI. CONCLUSIONS: Our study presents normal values of baroreceptor activity, sensitivity, and BEI in pediatric patients under controlled supine and head up position. We also present new data regarding delayed heart rate responses to pressure changes in the Lag 1 and Lag 2 parameters, which may be beneficial in diagnosis and management of pediatric patients with orthostatic intolerance.

Comparison of skin dose measurement using nanoDot® dosimeter and machine readings of radiation dose during cardiac catheterization in children.

OBJECTIVES: Direct measurement of skin dose of radiation for children using optically stimulated luminescence (OSL) technology using nanoDot® (Landauer, Glenwood, IL, USA). BACKGROUND: Radiation dose is estimated as cumulative air kerma (AK) and dosearea product based on standards established for adult size patients. Body size of pediatric patients who undergo cardiac catheterization for congenital heart disease vary widely from newborn to adolescence. Direct, skindose measurement applying OSL technology may eliminate errors in the estimate. MATERIALS AND METHODS: The nanoDot® (1 cm × 1 cm × flat plastic cassette) is applied to patient's skin using adhesive tape during cardiac catheterization and radiation skin doses were read within 24 hrs. nanoDot® values were compared to the currently available cumulative AK values estimated and displayed on fluoroscopy monitor. RESULTS: A total of 12 children were studied, aged 4 months to 18 years (median 1.1 years) and weight range 5.3-86 kg (median 8.4 kg). nanoDot® readings ranged from 2.58 mGy to 424.8 mGy (median 84.1 mGy). Cumulative AK ranged from 16.2 mGy to 571.2 mGy (median 171.1 mGy). Linear correlation was noted between nanoDot® values and AK values (R2 = 0.88, R = 0.94). nanoDot® readings were approximately 65% of the estimated cumulative AK estimated using the International Electrotechnical Commission standards. CONCLUSIONS: Application of OSL technology using nanoDot® provides an alternative to directly measure fluoroscopic skin dose in children during cardiac catheterization. Our data show that the actual skin dose for children is approximately one-third lower than the AK estimated using international standards for adult size patients.

Pediatric Disorders of Orthostatic Intolerance.

Orthostatic intolerance (OI), having difficulty tolerating an upright posture because of symptoms or signs that abate when returned to supine, is common in pediatrics. For example, ∼40% of people faint during their lives, half of whom faint during adolescence, and the peak age for first faint is 15 years. Because of this, we describe the most common forms of OI in pediatrics and distinguish between chronic and acute OI. These common forms of OI include initial orthostatic hypotension (which is a frequently seen benign condition in youngsters), true orthostatic hypotension (both neurogenic and nonneurogenic), vasovagal syncope, and postural tachycardia syndrome. We also describe the influences of chronic bed rest and rapid weight loss as aggravating factors and causes of OI. Presenting signs and symptoms are discussed as well as patient evaluation and testing modalities. Putative causes of OI, such as gravitational and exercise deconditioning, immune-mediated disease, mast cell activation, and central hypovolemia, are described as well as frequent comorbidities, such as joint hypermobility, anxiety, and gastrointestinal issues. The medical management of OI is considered, which includes both nonpharmacologic and pharmacologic approaches. Finally, we discuss the prognosis and long-term implications of OI and indicate future directions for research and patient management.

Autologous Adipose Stem Cell Therapy for Autonomic Nervous System Dysfunction in Two Young Patients.

Postural orthostatic tachycardia syndrome and neurocardiogenic syncope are clinical manifestations of autonomic nervous system dysfunction (dysautonomia) that can lead to impaired daily functions. We report two young patients presenting with dysautonomia and autoimmune disease who both received autologous adipose stem cells (ASCs) infusions. This report is the first description of ASCs therapy for patients with combined dysautonomia and autoimmune disease. Case 1: A 21-year-old female presented at 12 years of age with escalating severe dysautonomia with weight loss and gastrointestinal symptoms. She had elevated autoantibodies and cytokines and received multiple immune modulation therapies. Her dysautonomia was treated by volume expanders, vasoconstrictors, and beta blockers with mild improvement. She received ASCs about 2 years before this report with dramatic improvement in her dysautonomia and autoimmune symptoms with a 10 kg weight gain. Case 2: A 7-year-old boy presented at 2 years of age with polyarthritis. At 5 years of age, he manifested orthostatic intolerance. He received immune modulatory therapies with mild improvement. He received ASCs and showed marked improvement of his dysautonomia and immune symptoms. Dysautonomia symptoms of these two patients improved significantly after modulation of autoimmune components by ASC therapy. Favorable clinical responses of these two cases warrant further case-control studies.

Dominant Transmission Observed in Adolescents and Families With Orthostatic Intolerance.

BACKGROUND: Orthostatic intolerance is typically thought to be sporadic and attributed to cerebral autonomic dysfunction. We sought to identify families with inherited autonomic dysfunction manifest as symptomatic orthostatic intolerance to characterize mode of inheritance and clinical features. METHODS: Sixteen families with two or more first- or second-degree relatives with autonomic dysfunction and orthostatic intolerance were enrolled. A clinical diagnosis of autonomic dysfunction defined by symptomatic orthostatic intolerance diagnosed by head-up tilt table testing was confirmed for each proband. Clinical features and evaluation were obtained from each proband using a standardized intake questionnaire, and family history information was obtained from probands and available relatives. RESULTS: Comprehensive pedigree analysis of 16 families (39 individuals with orthostatic intolerance and 40 individuals suspected of having orthostatic intolerance) demonstrated dominant transmission of autonomic dysfunction with incomplete penetrance. Affected individuals were predominantly female (71.8%, 28/39; F:M, 2.5:1). Male-to-male transmission, although less common, was observed and demonstrated to transmit through unaffected males with an affected parent. Similar to sporadic orthostatic intolerance, probands report a range of symptoms across multiple organ systems, with headaches and neuromuscular features being most common. CONCLUSIONS: Familial occurrence and vertical transmission of autonomic dysfunction in 16 families suggest a novel genetic syndrome with dominant transmission, incomplete penetrance, and skewing of the sex ratio. Elucidation of potential genetic contributions to orthostatic intolerance may inform therapeutic management and identification of individuals at risk. Adolescent evaluation should include identification and treatment of potential at-risk relatives.

Impact of isoproterenol infusion on BIS and metabolic values in pediatric patients undergoing electrophysiology studies.

STUDY OBJECTIVE: To study changes in BIS values and metabolic parameters during an infusion of isoproterenol in pediatric patients. DESIGN: Retrospective study approved By Committee For The Protection Of Human Subjects at University Of Texas Medical School at Houston. SETTING: University-affiliated children's hospital. MEASUREMENTS: The records of pediatric patients undergoing general anesthesia for electrophysiology procedures were analyzed. Electronic data collected included Bispectral Index (BIS) values, anesthetics (eg, opioids, expired concentration of inhaled anesthetics, muscle relaxants), hemodynamic values (ie, heart rate, invasive blood pressure), respiratory parameters [ie, tidal volume, respiratory rate, end-tidal CO2 (ETCO2)], and routine arterial blood gases. These parameters were analyzed 10 minutes prior to the start of the isoproterenol infusion (T-pre) and 10 minutes after isoproterenol had reduced the cardiac cycle length by 20% (T-infusion). MAIN RESULTS: Of the 29 records that were screened, 22 met the above criteria (mean age 13 ± 5 yrs). BIS values increased by an average of 8 (33 ± 8 to 41 ± 10; P < 0.001) during the isoproterenol infusion. Statistically significant increases in ETCO2 (median 33 - 36 mmHg; P = 0.01), PaCO2 (35 - 38 mmHg; P = 0.002), and lactate (1.1 -1.5 mg/dL; P < 0.001) occurred with infusion of isoproterenol. Patients undergoing controlled mechanical ventilation showed an increase in ETCO2 (mean 34 ± 6 mmHg to 37 ± 5 mmHg; P = 0.001) whereas those breathing spontaneously had an increase in minute ventilation (average increase 111 ± 30 mL/kg). CONCLUSIONS: Isoproterenol increases metabolic, respiratory, and BIS values in pediatric patients during general anesthesia. We recommend the use of BIS, close monitoring of ETCO2, and careful titration of anesthetics during isoproterenol infusion, especially when lighter planes of general anesthesia are requested for pediatric electrophysiologic procedures.

Ibn Al Nafis: his seminal contributions to cardiology.

Ibn Al Nafis, born 1213, was the first to discover the "circulation lesser" and describe the blood flow from the right ventricle to the lungs then back to the left ventricle 300 years before William Harvey. He bravely rejected the theory of Galen (130-200 AD) and Avicenna (980-1037 AD) which stated that the blood from the right ventricle passes through "invisible" holes in the ventricular septum to the left ventricle. Also was the first to note that the nourishment of the heart muscle is coming from the coronary arteries rather than from the inside of the ventricular cavity as described by earlier scholars.

Biogenic amine metabolism in juvenile neurocardiogenic syncope with dysautonomia.

OBJECTIVE: Biogenic amine brain levels and their cerebral metabolism are frequently studied by quantitation of biogenic amine metabolites in cerebrospinal fluid (CSF) compared to age-matched controls. There is a paucity of studies in adolescents and young adults investigating the potential role of disordered cerebral biogenic amine metabolism in young patients who have dysautonomia based on abnormal head-up tilt table (HUTT). METHODS: In a cohort of juvenile patients with neurocardiogenic syncope and dysautonomia documented by abnormal HUTT, biogenic amine metabolites of dopamine and serotonin were quantitated in 18 patients (15 females). HUTT testing is an effective clinical method to evaluate posturally induced physiological events in patients suspected of neurocardiogenic syncope with dysautonomia. RESULTS: Levels of the dopamine metabolite (homovanillic acid: HVA) and/or the serotonin metabolite (5-hydroxyindoleacetic acid: 5HIAA) were significantly reduced in 13 patients compared to age-matched controls. INTERPRETATION: Peripheral biogenic amines and their metabolites have been extensively studied in adults with dysautonomia due to various neurodegenerative disorders (Parkinson disease, multiple system atrophy, primary autonomic failure). Our findings indicate that more than two-thirds of this cohort of young patients with dysautonomia of variable severity have a defect in cerebral biogenic amines, particularly in dopamine and serotonin metabolism.

Noncompaction cardiomyopathy in the State of Qatar.

OBJECTIVE: To study the development of noncompaction of the ventricular myocardium (NCCM) in the state of Qatar and to highlight the prognostic parameters in those patients. METHODS: We conducted this study from 2000 to 2004 on patients who were referred to Hamad General Hospital with questionable echocardiographic features of cardiomyopathy with or without clinical manifestations of heart failure and were found to have NCCM. The diagnosis of NCCM was made according to echocardiographic criteria in 12 cases and those patients are followed up for 2-5 years. RESULTS: The mean age at diagnosis of NCCM was 6.5 years. Among them, 4 were males and 8 were females. Family history of NCCM was reported in 5 cases. Normal ejection fraction was detected in 5 patients; in this group pulsed-Tissue Doppler Imaging revealed evidence of subclinical systolic dysfunction in 4 cases. All patients showed variable degrees of diastolic dysfunction. Severely impaired ejection fraction was found in 3 cases. Progression to dilated cardiomyopathy occurred in 4 cases. Site of noncompaction included left ventricle apex in all cases, inferoposterior in 11 cases, and lateral wall in 11 cases while biventricular noncompaction was noted in 4 cases. Electrocardiogram findings included right bundle branch blocker (3) patients, left bundle branch blocker (2), left ventricular hypertrophy (6) and right ventricular hypertrophy in 3 cases. Atrial tachyarrhythmias developed in 4 cases. Wolff-Parkinson-White syndrome was detected in one patient. Associated congenital anomalies included ventricular septal defect, pulmonary stenosis, aortic coarctation, and Ebstein anomaly. The overall mortality rate was 25%. CONCLUSION: Noncompaction cardiomyopathy is so rare to be easily missed. The prognosis is poor in symptomatic cases; however, detection of subclinical systolic dysfunction is needed.

Epidemiology of idiopathic cardiomyopathy in Qatar during 1996-2003.

OBJECTIVES: To report the rates of cardiomyopathies in the population below 50 years of age in Qatar. SUBJECTS AND METHODS: We conducted a retrospective review of clinical data on patients with cardiomyopathy who were hospitalized in Hamad General Hospital, Doha. Data were collected from medical records during the 1996-2002 period and prospectively from the patients who were hospitalized during the year 2003. All cardiomyopathy patients below 50 years of age who were citizens or permanent residents in Qatar were included in this study. RESULTS: During the study period, a total of 132 cases were recorded with idiopathic cardiomyopathies. Among these, 67.4% were males and 32.6% females; Qatari 31.8%, non-Qatari 68.2%. The consanguinity rate was high among Qatari patients. In the first 7-year study period, 1996-2002, the incidence rate of all types of cardiomyopathies was 2.5/100,000 population per year (95% CI: 1.4-3.5). It increased to 5.2/100,000 population during the year 2003 (95% CI: 3.6-6.7). Dilated cardiomyopathy was most prevalent (75.8%) in all age groups, and the incidence increased remarkably with age. Lower prevalence of hypertrophic cardiomyopathy (13.6%) and left ventricle noncompaction cardiomyopathy (6.1%) was found. In children below 15 years of age, the incidence rate for all types of cardiomyopathies was 2.7/100,000 population. The overall mortality rate was 5.3%. CONCLUSION: Most cases of cardiomyopathy were identified at an early age: below 15 years and above 35 years of age. Introducing preventive and early diagnosis programs may have an impact on reducing the mortality and morbidity from idiopathic cardiomyopathy.

Blood pressure-independent attenuation of cardiac hypertrophy by AT(1)R-AS gene therapy.

Our studies have established that a single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense gene causes prolonged antihypertensive actions in the spontaneously hypertensive rat. These results suggest that antisense gene therapy is a conceptually valid strategy for the control of hypertension at the genetic level. To evaluate whether attenuation of the pathophysiological aspects of hypertension are dependent on the blood pressure lowering actions of antisense gene therapy, we chose the renin transgenic rat as a hypertensive animal model and cardiac hypertrophy as the hypertension-associated pathophysiology. A single intracardiac administration of the retroviral vector containing angiotensin II type I receptor antisense in the neonatal rat resulted in long-term expression of the antisense transgene in various cardiovascular-relevant tissues, including the heart. This expression was associated with a significant attenuation of cardiac hypertrophy despite its failure to normalize high blood pressure. Developmental studies indicated that cardiac hypertrophy was evident as early as 16 days of age in viral vector-treated control transgenic rats, despite these animals exhibiting normal blood pressure. These observations demonstrate that, in the renin-transgenic rat, the onset of cardiac hypertrophy occurs during development and is prevented without normalization of high blood pressure. Collectively, these results provide further proof of the concept and indicate that antisense gene therapy could successfully target the local tissues' renin-angiotensin system to produce beneficial cardiovascular outcomes.