Anna S. Kenny

Autonomic Nervous System Dysregulation: Breathing and Heart Rate Perturbation During Wakefulness in Young Girls with Rett Syndrome

This study characterizes cardiorespiratory dysregulation in young girls with MECP2 mutation–confirmed Rett syndrome (RS). Respiratory inductance plethysmography of chest/abdomen and ECG was obtained during daytime wakefulness in 47 girls with MECP2 mutation–confirmed RS and 47 age-, gender-, and ethnicity-matched controls (ages 2–7 y). An in-home breath-to-breath and beat-to-beat characterization was conducted and revealed that breathing was more irregular, with an increased breathing frequency, mean airflow, and heart rate in RS versus controls. There was a decreased correlation between normal breathing and heart rate variability, and an exaggerated increase in heart rate response to breathholds in RS versus controls. We conclude that girls with RS have cardiorespiratory dysregulation during breathholds as well as during “normal” breaths and during breaths before and subsequent to breathholds. This dysregulation may offer insight into the mechanisms that render girls with RS more vulnerable to sudden death.

Diaphragm Pacing with a Quadripolar Phrenic Nerve Electrode: An International Study

We sought to determine the international experience with the quadripolar diaphragm pacer system and to test two hypotheses: the incidence of pacer complications would be (1) increased among pediatric as compared to adult patients; and (2) highest among active pediatric patients with idiopathic congenital central hypoventilation syndrome (CCHS). Data were collected via a questionnaire coupled with the Atrotech Registry data for a total of 64 patients (35 children and 29 adults) from 14 countries. Thoracic implantation of electrodes and bilateral pacer use each occurred in 94% of all subjects. Tetraplegic (vs pediatric CCHS) patients were more typically paced 24 hours/day (P = 0.001). Pacing duration averaged 2.0 ± 1.0 years among children and 2.2 ± 1.1 years among adults. Infections occurred among 2.9% of surgical procedures, all in pediatric CCHS patients (vs pediatric tetraplegic patients, P = 0.01). The incidence of mechanical trauma was 3.8%, without significant differences among patient groups. The incidence of presumed electrode and receiver failure were 3.1% and 5.9%, respectively, with internal component failure greater among pediatric CCHS than pediatric tetraplegic patients (P < 0.01). Intermittent or absent function of 0–4 electrode combinations occurred among 19% of all patients, with increased frequency among pediatric CCHS than pediatric tetraplegic patients (P < 0.03). Complication‐ free successful pacing occurred in 60% of pediatric and 52% of adult patients. In all, 94 % of the pediatric and 86% of the adult patients paced successfully after the necessary intervention. Although pacer complications were not increased among pediatric as compared to adult patients, the incidence of complications was highest among the active pediatric patients with CCHS. Longitudinal study of these patients will provide invaluable information for modification and improvement of the quadripolar system.

Autonomic dysregulation in young girls with Rett Syndrome during nighttime in‐home recordings

This study was designed to specifically characterize the autonomic phenotype of cardiorespiratory dysregulation during the nighttime in young girls with MECP2 mutation-confirmed Rett Syndrome (RS), studied in their home environment. Computerized breath-to-breath and beat-to-beat characterization of at-home continuously recorded respiratory inductance plethysmography of chest/abdomen and ECG (VivoMetrics, Inc.) was obtained during overnight recordings in 47 girls with MECP2 mutation-confirmed RS and 47 age-, gender-, and ethnicity-matched screened controls (ages 2-7 years). We determined that although the breathing and heart rate appear more regular during the night compared to the day, young girls with RS demonstrate apparent nocturnal irregularities. Comparing daytime versus nighttime, breathing was more irregular, with an increased breathing frequency (and irregularity), mean amplitude of respiratory inductance plethysmography sum (AMP)/T(I), and heart rate and decreased AMP in girls with RS. Comparing girls with RS versus controls during nighttime recording, breathing was more irregular, with an increased breathing frequency (and irregularity), mean AMP/T(I), and heart rate. An increased uncoupling between measures of breathing and heart rate control indicates malregulation in the autonomic nervous system, and is apparent during the day as well as the night. This uncoupling may represent a mechanism that renders the girls with RS more vulnerable to sudden death.

Facial Phenotype in Children and Young Adults with PHOX2B-Determined Congenital Central Hypoventilation Syndrome: Quantitative Pattern of Dysmorphology

Congenital central hypoventilation syndrome (CCHS) is caused by mutations in PHOX2B, which is essential for maturation of the neural crest into the autonomic nervous system and is expressed in the dorsal rhombencephalon, a region that gives rise to facial structures. Digital photographs of 45 individuals with PHOX2B-confirmed CCHS, and 45 matched controls were analyzed for 17 linear and 6 angular measurements, and 9 derived indices. Paired t tests were used to compare group means, correlation was calculated between PHOX2B polyalanine expansion number and facial measures, and stepwise logistic regression was used to predict case-control and genotype status. CCHS cases differed significantly from controls on 13 variables (6 after p value correction: nasolabial angle, upper lip height, lateral lip height, facial index, upper facial index, and presence of inferior inflection of the lateral segment of the upper lip vermillion border). Five variables were able to predict correctly 85.7% of CCHS cases and 82.2% of controls: upper lip height, biocular width, upper facial height, nasal tip protrusion, and inferior inflection of the upper lip vermillion border. A negative relationship between number of repeats and four anthropometric measures was observed: mandible breadth, nasolabial angle, lateral lip height, and mandible-face width index. These results suggest a characteristic facial phenotype in children and young adults with CCHS, due to an expansion mutation in PHOX2B.

Pupillometry in congenital central hypoventilation syndrome (CCHS): quantitative evidence of autonomic nervous system dysregulation

Introduction:Congenital central hypoventilation syndrome (CCHS) is characterized by alveolar hypoventilation, autonomic nervous system (ANS) dysregulation (ANSD), and mutations in the paired-like homeobox 2B (PHOX2B) gene. ANSD in CCHS affects multiple systems and includes ophthalmologic abnormalities. We hypothesized that quantitative pupil measures, obtained using pupillometry, would vary between cases with CCHS and controls and within those with CCHS by PHOX2B genotype.Results:Measures known to be illustrative of sympathetic and parasympathetic response (prestimulus, maximum pupil diameter, percentage of pupil constriction after light stimulus, and average constriction and dilation velocities) were significantly reduced in those with CCHS as compared with controls (all P < 0.05).Discussion:These reductions are indicative of both sympathetic and parasympathetic deficits in CCHS, which is in keeping with the role of PHOX2B in ANS development. An inverse linear relationship was apparent in pupil diameter and velocity measurements among the cases with CCHS with the most common heterozygous PHOX2B polyalanine expansion repeat mutations, suggesting a graded phenotype/genotype dose response based on polyalanine repeat length. These results confirm our central hypotheses while offering the first objective measures of pupillary dysfunction and ophthalmologic-specific ANSD in CCHS.Methods:A total of 316 monocular measurements were taken under dark-adapted conditions with a fixed light stimulus from 22 PHOX2B mutation-confirmed cases with CCHS and 68 healthy controls.

Residual chemosensitivity to ventilatory challenges in genotyped congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) is a neurodevelopmental disorder characterized by life-threatening hypoventilation, possibly resulting from disruption of central chemosensory integration. However, animal models suggest the possibility of residual chemosensory function in the human disease. Cardioventilatory function in a large cohort with CCHS and verified paired-like homeobox 2B (PHOX2B) mutations was assessed to determine the extent and genotype dependence of any residual chemosensory function in these patients. As part of inpatient clinical care and evaluation, 64 distinct studies from 32 infants, children, and young adults with the disorder were evaluated for physiological response to three different inspired steady-state gas exposures of 3 min each: hyperoxia [100% oxygen (O2)]; hyperoxic hypercapnia [95% O2 and 5% carbon dioxide (CO2)]; and hypoxic hypercapnia [14% O2 and 7% CO2 balanced with nitrogen (N2)]. These were followed by a hypoxia challenge consisting of five or seven breaths of N2 (100% N2). In addition, a control group of 15 young adults was exposed to all but the hypoxic challenge. Comprehensive monitoring was used to derive breath-to-breath and beat-to-beat measures of ventilatory, cardiovascular, and cerebrovascular function. On average, patients showed a residual awake ventilatory response to chemosensory challenge, independent of the specific patient PHOX2B genotype. Graded dysfunction in cardiovascular regulation was found to associate with genotype, suggesting differential effects on different autonomic subsystems. In addition, differences between cases and controls in the cerebrovascular response to chemosensory challenge may indicate alterations in cerebral autoregulation. Thus residual cardiorespiratory responses suggest partial preservation of central nervous system networks that could provide a fulcrum for potential pharmacological interventions.

Familial dysautonomia: frequent, prolonged and severe hypoxemia during wakefulness and sleep.

Sudden unexplained deaths have been reported in 32% of Familial Dysautonomia (FD) subjects. To characterize cardiorespiratory dysregulation in children with FD that might contribute to potential sudden death, respiratory inductance plethysmography (chest/abdomen), ECG, hemoglobin saturation, and pulse waveform (VivoMetrics, Inc.) were recorded in the home during daytime wakefulness and overnight sleep in 25 children with IKBKAP mutation‐confirmed FD and 25 age‐, and gender‐matched controls. Breath‐to‐breath and beat‐to‐beat characterization of breathing, hemoglobin saturation, and heart rate was conducted. Children with FD had more frequent, prolonged, and severe episodes of hypoxemia than matched controls, awake and asleep. Though a small percent of the study time revealed bradycardia and apnea, the hypoxemia was the most prevalent pattern in FD and rarely occurred with related bradycardia. Though infrequent with desaturation or bradycardia, apnea was more prevalent in FD subjects than controls, and more apparent during sleep than wakefulness. Children with FD have cardiorespiratory dysregulation during wakefulness and sleep, likely representing alveolar hypoventilation. We hypothesize that the related repeated hypoxemia (and presumed related hypercarbia) may render individuals with FD more vulnerable to sudden death. Pediatr Pulmonol. 2008; 43:251–260.

Respiratory and cardiovascular indicators of autonomic nervous system dysregulation in familial dysautonomia

Familial dysautonomia (FD) is a profound sensory and autonomic nervous system disorder associated with an increased risk for sudden death. While bradycardia resulting from loss of sympathetic tone has been hypothesized to play a role in this mortality, extended in‐home monitoring has failed to find evidence of low heart rates in children with FD. In order to better characterize the specific cardio‐respiratory pathophysiology and autonomic dysregulation in patients with FD, 25 affected children and matched controls were studied with in‐home technology, during day and night. Respiratory and heart rate timing and variability metrics were derived from inductance plethysmography and electrocardiogram signals. Selective shortening of inspiratory time produced an overall increase in respiratory frequency in children with FD, with higher daytime respiratory variability (vs. controls), suggesting alterations in central rhythm generating circuits that may contribute to the heightened risk for sudden death. Overall heart rate was increased and variability reduced in FD cases, with elevated heart rates during 20% of study time. Time and frequency domain measures of autonomic tone indicated lower parasympathetic drive in FD patients (vs. controls). These results suggest withdrawal of vagal, rather than sympathetic tone, as a cause for the sustained increase and dramatic lability in respiration and heart rates that characterize this disorder. Pediatr Pulmonol. 2012; 47:682–691.

Characterization of Dermatoglyphics in PHOX2B-Confirmed Congenital Central Hypoventilation Syndrome

OBJECTIVE. Individuals with congenital central hypoventilation syndrome have characteristic variants in the PHOX2B gene (primarily polyalanine expansion mutations). The PHOX2B gene acts as a transcriptional activator in the promotion of pan-neuronal differentiation in the autonomic nervous system during early embryologic development, with a primary role in the sympathetic noradrenergic phenotype in vertebrates. Because sympathetic innervation has been hypothesized to affect the development of dermatoglyphic pattern types, we hypothesized that individuals with PHOX2B-confirmed congenital central hypoventilation syndrome would have characteristic dermatoglyphic patterning and that the dermatoglyphic phenotype would be related to the disease-defining PHOX2B genotype. METHODS. Dermatoglyphic pattern type frequency, left/right symmetry, and genotype/phenotype correlation were assessed for 33 individuals with PHOX2B-confirmed congenital central hypoventilation syndrome and compared with published control data. RESULTS. Dermatoglyphic pattern type frequencies were altered in congenital central hypoventilation syndrome cases versus controls. In particular, there was an increase of arches in females and ulnar loops in males, with the largest differences for the left hand and for individuals with both congenital central hypoventilation syndrome and Hirschsprung disease. Dissimilarity scores between the congenital central hypoventilation syndrome and congenital central hypoventilation syndrome + Hirschsprung disease cases were not significantly different, nor were dissimilarity scores between all of the female and all of the male cases. No significant association was found between the number of polyalanine repeats in the PHOX2B genotypic category and dermatoglyphic pattern frequencies in the congenital central hypoventilation syndrome study groups. CONCLUSIONS. These results represent the first report describing specific dermatoglyphic patterning in congenital central hypoventilation syndrome and suggest a relationship between PHOX2B and the expression of dermatoglyphic pattern types. An expanded congenital central hypoventilation syndrome data set to include the full spectrum of PHOX2B mutations is necessary to further delineate the role of PHOX2B in dermatoglyphic patterning.

Prolonged cardiorespiratory monitoring of children more than twelve months of age: characterization of events and approach to discontinuation.

We assessed children referred to our apnea program who were > or = 12 months of age, beyond the at-risk period for sudden infant death syndrome (SIDS), but for whom home cardiorespiratory monitoring had continued. Our objectives were to (1) determine reasons for initiation and continuation of monitoring, (2) apply documented monitoring of transthoracic impedance, electrocardiographic signals, and, in a subset of patients, pulse oximetry, to determine the types of cardiorespiratory events that these children experienced, and (3) describe how documented monitoring was applied for eventual discontinuation of monitoring. Among 45 patients (median age, 22 months), 263 disks were collected, representing 2982 monitor days. Indications for initiation of monitoring included an apparent life-threatening event in 51.1% of patients, apnea of prematurity in 35.5%, history of SIDS or apparent life-threatening event in a relative in 9%, and intrauterine drug exposure in 4.4%. Continuation of monitoring had been based on continued alarms and, in 31% of patients, documented apnea, bradycardia, or hemoglobin desaturation. In 40 of 45 patients, 2292 episodes of apnea (17.5% of all events) were recorded (range, 16 to 31 seconds). Five patients had 223 episodes of bradycardia (1.7% of all events). Of all 13,075 recorded events, 76.8% resulted in audible alarms, but only 3.9% of these alarms were for apnea and 2.2% were for bradycardia. Of 19 patients studied with pulse oximetry, 18 had 663 episodes of hemoglobin desaturation <90%. All children were thriving at the time of referral. Discontinuation of monitoring was based on a childs ability to resume breathing spontaneously or on normalization of heart rate or hemoglobin saturation before the audible alarm sounded, for a minimum of 2 to 3 months. By extension of the audible apnea alarm to 25 or 30 seconds, lowering of the cutoff point for bradycardia alarm, or lowering of the cutoff point for the oximetry alarm, a recommendation to discontinue monitoring could be made for 41 patients. Of these, no child had a recurrence of cardiorespiratory events or died of SIDS. Documented monitoring proved to be a useful clinical tool for investigation of the clinical and physiologic importance of these cardiorespiratory events in children beyond the at-risk period for SIDS; recommendations about discontinuation of monitoring could be made knowledgeably and safely.