Cindy D. Brogadir

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.

Congenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children.

BACKGROUND Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-aged patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay and that CCHS-related physiologic factors would impact neurocognitive test results. METHODS We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0 ± 8.5 months; range, 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them with the normative reference mean from the Bayley standardization sample; we also examined associations between Bayley scores and CCHS disease-related factors. RESULTS Preschool patients with CCHS fell significantly below the normative mean of 100 on Bayley indices of mental (mean, 83.35 ± 24.75) and motor (mean, 73.33 ± 20.48) development (P < .001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation genotypes (mental, P = .001; motor, P = .006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P < .05). CONCLUSIONS These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.

Original Research: PediatricsCongenital Central Hypoventilation Syndrome: Neurocognition Already Reduced in Preschool-Aged Children

BACKGROUND Congenital Central Hypoventilation Syndrome (CCHS) is a rare neurocristopathy characterized by severe hypoventilation and autonomic dysregulation, with typical presentation in the neonatal period, and deficient cognitive skills in school-aged patients. We hypothesized that younger (preschool) children with CCHS would also show neurocognitive delay and that CCHS-related physiologic factors would impact neurocognitive test results. METHODS We studied developmental (Bayley) test results collected during routine clinical care in 31 children (mean age 25.0 ± 8.5 months; range, 6-40 months) with PHOX2B mutation-confirmed CCHS by comparing them with the normative reference mean from the Bayley standardization sample; we also examined associations between Bayley scores and CCHS disease-related factors. RESULTS Preschool patients with CCHS fell significantly below the normative mean of 100 on Bayley indices of mental (mean, 83.35 ± 24.75) and motor (mean, 73.33 ± 20.48) development (P < .001 for both). Significantly lower Bayley mental and motor scores were associated with severe breath-holding spells, prolonged sinus pauses, and need for 24 h/d artificial ventilation. Lower Bayley motor scores were also associated with seizures. Bayley scores differed among children with the three most common polyalanine repeat expansion mutation genotypes (mental, P = .001; motor, P = .006), being essentially normal in children with the 20/25 genotype but significantly lower in the other genotype groups (P < .05). CONCLUSIONS These results confirm neurodevelopmental impairment of CCHS preschoolers, with severity related to physiologic compromise and PHOX2B genotype. These findings suggest that adverse effects begin early in the disease process, supporting the need for neurodevelopmental monitoring and intervention from early infancy.

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

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.

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. Pediatr Pulmonol. 2015; 50:1336–1345.

Congenital central hypoventilation syndrome: Broader cognitive deficits revealed by parent controls

To investigate neurocognitive deficits in children with Congenital Central Hypoventilation Syndrome (CCHS) by comparing them to their parents, since parents comprise a particularly suitable control group matched on disease‐extrinsic factors that can influence neurocognitive functioning. We compared CCHS patients to their parents and to population norms, hypothesizing that they would obtain lower intelligence test scores than both groups. We also compared patient‐parent differences against patient‐normative differences, to determine whether the two analytic approaches would yield different results.