Pupillometry measures of autonomic nervous system regulation with advancing age in a healthy pediatric cohort.

PURPOSE: To determine if variables of the pupillary light response mature with age and sex in a healthy pediatric cohort and the utility of pupillometry in assessment among pediatric participants. METHODS: After 1 min in a dark room to establish baseline, pupillometry was performed on 323 healthy, pediatric participants (646 eyes; 2-21 years; 175 females). Variables included initial pupil diameter, pupil diameter after light stimulus, percent pupillary constriction, latency to onset of constriction, average constriction velocity, maximum constriction velocity, average dilation velocity, and time from light stimulus to 75% of the initial pupil diameter. Data analyses employed ANOVAs and non-linear regressions. RESULTS: Analyses of age group differences revealed that participants 12-21 years old had a larger initial pupil diameter and pupil diameter after light stimulus, with males aged 12-18 years demonstrating a larger pupil diameter than all younger participants (ps < 0.05). Participants 12-18 years old had a slower maximum constriction velocity than participants 6-11 years old, with no sex differences (ps < 0.05). Furthermore, males aged 12-18 years old had a smaller percent constriction than males 6-11 years old (ps < 0.05). Regressions revealed that percent constriction and dilation velocity seemed to mature linearly, initial pupil diameter and ending pupil diameter matured quadratically, and the constriction velocity terms matured cubically. CONCLUSIONS: Results revealed maturation of the pupillary light response by age and sex in healthy pediatric participants. Given the value of the pupillary light response as a biomarker, the results provide normative benchmarks for comparison in health and disease, including opiate-exposed and concussion patients.

Airway Obstruction during Sleep due to Diaphragm Pacing Precludes Decannulation in Young Children with CCHS.

Children with congenital central hypoventilation syndrome (CCHS) have a PHOX2B mutation-induced control of breathing deficit necessitating artificial ventilation as life support. A subset of CCHS families seek phrenic nerve-diaphragm pacing (DP) during sleep with the goal of tracheal decannulation. Published data regarding DP during sleep as life support in the decannulated child with CCHS and related airway dynamics in young children are limited. We report a series of 3 children, ages 3.3-4.3 years, who underwent decannulation. Sleep endoscopy performed during DP revealed varied (oropharynx, supraglottic, glottic, etc.) levels of complete airway obstruction despite modification of pacer settings. Real-time analysis of end tidal CO2 and SpO2 confirmed inadequate gas exchange. Because the families declined re-tracheostomy, all 3 patients rely on noninvasive mask ventilation as a means of life support while asleep. These results emphasize the need for extreme caution in proceeding with tracheal decannulation in young children with CCHS who expect to use DP during sleep as life support. Parents and patients should anticipate that they will depend on noninvasive mask ventilation (rather than DP) during sleep after undergoing decannulation. This information may improve management and guide expectations regarding potential decannulation in young paced children with CCHS.

Congenital central hypoventilation syndrome (CCHS): Circadian temperature variation.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy, which includes a control of breathing deficit and features of autonomic nervous system (ANS) dysregulation. In recognition of the fundamental role of the ANS in temperature regulation and rhythm and the lack of any prior characterization of circadian temperature rhythms in CCHS, we sought to explore peripheral and core temperatures and circadian patterning. We hypothesized that CCHS patients would exhibit lower peripheral skin temperatures (PST), variability, and circadian rhythmicity (vs. controls), as well as a disrupted relationship between core body temperature (CBT) and PST. METHODS: PST was sampled every 3 min over four 24-hr periods in CCHS cases and similarly aged controls. CBT was sampled in a subset of these recordings. RESULTS: PST was recorded from 25 CCHS cases (110,664 measures/230 days) and 39 controls (78,772 measures/164 days). Simultaneous CBT measurements were made from 23 CCHS patients. In CCHS, mean PST was lower overall (P = 0.03) and at night (P = 0.02), and PST variability (interquartile range) was higher at night (P = 0.05) (vs. controls). PST circadian rhythm remained intact but the phase relationship of PST to CBT rhythm was extremely variable in CCHS. CONCLUSIONS: PST alterations in CCHS likely reflect altered autonomic control of peripheral vascular tone. These alterations represent a previously unreported manifestation of CCHS and may provide an opportunity for therapeutic intervention. The relationship between temperature dysregulation and CCHS may also offer insight into basic mechanisms underlying thermoregulation.

Rapid-onset obesity with hypothalamic dysfunction, hypoventilation, and autonomic dysregulation (ROHHAD): Response to ventilatory challenges.

Hypoventilation is a defining feature of Rapid-onset Obesity with Hypothalamic dysfunction, Hypoventilation and Autonomic Dysregulation (ROHHAD), a rare respiratory and autonomic disorder. This chronic hypoventilation has been explained as the result of dysfunctional chemosensory control circuits, possibly affecting peripheral afferent input, central integration, or efferent motor control. However, chemosensory function has never been quantified in a cohort of ROHHAD patients. Therefore, the purpose of this study was to assess the response to awake ventilatory challenge testing in children and adolescents with ROHHAD. The ventilatory, cardiovascular and cerebrovascular responses in 25 distinct comprehensive physiological recordings from seven unique ROHHAD patients to three different gas mixtures were analyzed at breath-to-breath and beat-to-beat resolution as absolute measures, as change from baseline, or with derived metrics. Physiologic measures were recorded during a 3-min baseline period of room air, a 3-min gas exposure (of 100% O2; 95% O2, 5% CO2; or 14% O2, 7% CO2 balanced with N2), and a 3-min recovery period. An additional hypoxic challenge was conducted which consisted of either five or seven tidal breaths of 100% N2. While ROHHAD cases showed a diminished VT and inspiratory drive response to hypoxic hypercapnia and absent behavioral awareness of the physiologic compromise, most ventilatory, cardiovascular, and cerebrovascular measures were similar to those of previously published controls using an identical protocol, suggesting a mild chemosensory deficit. Nonetheless, the high mortality rate, comorbidity and physiological fragility of patients with ROHHAD demand continued clinical vigilance.

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.

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.

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.

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.

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

Sudden unexplained deaths have been reported in 13% [corrected] 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.

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.

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.

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.