Obstructive Apneas in a Mouse Model of Congenital Central Hypoventilation Syndrome.

Rationale: Congenital central hypoventilation syndrome (CCHS) is characterized by life-threatening sleep hypoventilation and is caused by PHOX2B gene mutations, most frequently the PHOX2B27Ala/+ mutation, with patients requiring lifelong ventilatory support. It is unclear whether obstructive apneas are part of the syndrome. Objectives: To determine if Phox2b27Ala/+ mice, which present the main symptoms of CCHS and die within hours after birth, also express obstructive apneas, and to investigate potential underlying mechanisms. Methods: Apneas were classified as central, obstructive, or mixed by using a novel system combining pneumotachography and laser detection of abdominal movement immediately after birth. Several respiratory nuclei involved in airway patency were examined by immunohistochemistry and electrophysiology in brainstem-spinal cord preparations. Measurements and Main Results: The median (interquartile range) of obstructive apnea frequency was 2.3 (1.5-3.3)/min in Phox2b27Ala/+ pups versus 0.6 (0.4-1.0)/min in wild types (P < 0.0001). Obstructive apnea duration was 2.7 seconds (2.3-3.9) in Phox2b27Ala/+ pups versus 1.7 seconds (1.1-1.9) in wild types (P < 0.0001). Central and mixed apneas presented similar significant differences. In Phox2b27Ala/+ preparations, the hypoglossal nucleus had fewer (P < 0.05) and smaller (P < 0.01) neurons, compared with wild-type preparations. Importantly, coordination of phrenic and hypoglossal motor activities was disrupted, as evidenced by the longer and variable delay of hypoglossal activity with respect to phrenic activity onset (P < 0.001). Conclusions: The Phox2b27Ala/+ mutation predisposed pups not only to hypoventilation and central apneas, but also to obstructive and mixed apneas, likely because of hypoglossal dysgenesis. These results thus demand attention toward obstructive events in infants with CCHS.

[Clinical and neuropsychological characteristics in congenital central hypoventilation syndrome]. / Aspectos clinicos y neuropsicologicos del sindrome de hipoventilacion central congenita.

INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) syndrome is a rare disease caused by mutations in the PHOX2B gene. Patients show a reduced response to hypercapnia and hypoxia accompanied by diffuse disturbances of the autonomic nervous system and occasionaly also disturbances in neuroimaging. A specific neuropsychological profile has not been described in children and adolescents with CCHS. CASE REPORTS: We describe three cases (aged between 4 and 19 years) with different profiles of affectation in cognitive and functionality. These profiles are compared with the features described in the literature about neuropsychology in CCHS. CONCLUSIONS: The profile of functional impairment in the CCHS is variable: in case 1, a severe global developmental delay with autistic features and marked functional involvement is described. In case 2, bilateral atrophy of the hippocampus is associated with involvement in social cognition and in executive functions with moderate functional repercussion. Case 3 shows difficulties in some cognitive executive functions (planning and non-verbal fluency), but without functional repercussion. Neuropsychological assessment can help in the clinical management of these patients by determining and guiding the need for rehabilitation treatments.

TITLE: Aspectos clinicos y neuropsicologicos del sindrome de hipoventilacion central congenita.Introduccion. El sindrome de hipoventilacion central congenita (SHCC) es una enfermedad rara producida por mutaciones en el gen PHOX2B. Los pacientes muestran una reducida respuesta a la hipercapnia e hipoxia acompañada de alteraciones difusas del sistema nervioso autonomo y ocasionalmente alteraciones en neuroimagen. No se ha descrito un perfil neuropsicologico especifico en los niños y adolescentes con SHCC. Casos clinicos. Se presentan tres casos (de edades comprendidas entre 4 y 19 años) con diferente perfil de afectacion cognitiva y funcional. Se comparan los perfiles de los tres casos con los hallazgos descritos en la bibliografia sobre neuropsicologia en el SHCC. Conclusiones. El perfil de afectacion funcional en el SHCC es variable: en el caso 1 se describe un grave retraso global en el desarrollo con rasgos autistas y acusadas implicaciones funcionales. En el caso 2, la atrofia bilateral del hipocampo se asocia a deficit en cognicion social y alteraciones en funciones ejecutivas con moderada repercusion funcional. El caso 3 muestra dificultades en algunas funciones ejecutivas cognitivas (planificacion y fluidez no verbal), pero sin repercusion funcional. La evaluacion neuropsicologica puede ayudar en el manejo clinico de estos pacientes determinando y orientando la necesidad de tratamientos rehabilitadores.

A case of congenital central hypoventilation syndrome.

We encountered a 2-year-old female infant with congenital central hypoventilation syndrome (CCHS) who underwent an abdominal operation for strangulated ileus. Prior to the surgery, at home, the infant had been receiving non-invasive positive-pressure ventilation (NPPV) support only during sleep. However, after postoperative extubation, the blood oxygen saturation (SpO(2)) decreased to approximately 90 % with NPPV during sleep alone, necessitating the use of biphasic cuirass ventilation (BCV) along with NPPV for 2 days. The infant was weaned from the BCV on hospital day 9, and was discharged from the intensive care unit (ICU) on hospital day 13. Although it has been said that CCHS is not under the control of the respiratory center, there are no reports of the true CO(2) response curves in these patients. Therefore, during respiratory management in the ICU post-surgery, we examined (with the consent of the mother) the relationship of the end-tidal carbon dioxide (ETCO(2)) to the tidal volume and respiratory rate, for a period of 6 min in the absence of sedation, using a respiratory profile monitor. Electrocardiographic and SpO(2) monitoring was also conducted at the same time, to ensure the patient's safety. In this patient, while the ETCO(2) increased, the tidal volume and respiratory rate remained unchanged. No relationship was found between the tidal volume and the respiratory rate. Various modalities have been used for the treatment of CCHS (tracheotomy, NPPV, and diaphragmatic pacing). Treatment of these patients in the ICU should be tailored to the needs of individual patients and their families.

Congenital central hypoventilation syndrome in a full-term baby presenting with repeated extubation failure.

Congenital central hypoventilation syndrome (CCHS) is a rare condition. The main characteristic is respiratory insufficiency during sleep. Patients who have CCHS need varying degrees of ventilation support during sleep, or even all day long, according to its severity. We report a term baby with repeated extubation failure, CCHS and Hirschsprung's disease diagnosed at 1 month of age. This patient was discharged at 5 months old with a home ventilator and reached normal developmental milestones.

Progressive gray matter changes in patients with congenital central hypoventilation syndrome.

INTRODUCTION: Patients with congenital central hypoventilation syndrome (CCHS) show brain injury in areas that control chemosensory, autonomic, motor, cognitive, and emotion functions, which are deficient in the condition. Many of these abnormal characteristics are present from the neonatal period; however, it is unclear whether tissue injury underlying the characteristics progressively worsens with time. We hypothesized that several brain areas in subjects with CCHS would show increased gray matter volume loss over time. METHODS: We collected high-resolution T1-weighted images twice (4 years apart) from seven subjects with CCHS (age at first study, 16.1 ± 2.7 years; four males) and three control subjects (15.9 ± 2.1 years; three males) using a 3.0-Tesla magnetic resonance imaging (MRI) scanner, and evaluated regional gray matter volume changes with voxel-based morphometry (VBM) procedures. RESULTS: Multiple brain sites in CCHS, including frontal, prefrontal, insular, and cingulate cortices; caudate nuclei and putamen; ventral temporal and parietal cortices; and cerebellar cortices showed significantly reduced gray matter volume over time. Only limited brain areas, including sensory, temporal, and medullary regions, emerged with increased gray matter at the later age. DISCUSSION: Patients with CCHS show reduced gray matter volume with age progression in autonomic, respiratory, and cognitive regulatory areas, an outcome that may contribute to deterioration of functions found in the syndrome with increasing age.

Vagal nerve stimulator placement for medically refractory seizures in a child treated with phrenic nerve pacing for congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) is a rare, idiopathic disorder characterized by a failure of automatic respiration. Abnormalities such as seizure disorder, failure to thrive, and Hirschsprung disease have been associated with CCHS. In this report, the authors discuss the use of vagal nerve stimulation (VNS) to treat a medically refractory seizure disorder in a child who had previously undergone placement of bilateral phrenic nerve stimulators for treatment of CCHS. Concomitant use of phrenic and vagal nerve stimulators has not previously been reported in the literature. No adverse reactions were noted with both devices working. Diaphragmatic pacing (DP) was clinically unaffected by VNS. The patient experienced a marked reduction in seizure frequency and severity following vagal nerve stimulator placement. Based on this case, the authors conclude that VNS is a potentially safe and efficacious treatment option for seizure disorder associated with CCHS in patients undergoing DP.

Congenital central hypoventilation syndrome and the PHOX2B gene: a model of respiratory and autonomic dysregulation.

The paired-like homeobox 2B gene (PHOX2B) is the disease-defining gene for congenital central hypoventilation syndrome (CCHS). Individuals with CCHS typically present in the newborn period with alveolar hypoventilation during sleep and often during wakefulness, altered respiratory control including reduced or absent ventilatory responses to hypercarbia and hypoxemia, and autonomic nervous system (ANS) dysregulation; however, a subset of individuals present well into adulthood. Thermoregulation is altered and perception of shortness of breath is absent, but voluntary breathing is retained. Structural and functional magnetic resonance imaging (MRI) and limited post-mortem studies in subjects with CCHS reveal abnormalities in both forebrain and brainstem. MRI changes appear in the hypothalamus (responsible for thermal drive to breathing), posterior thalamus and midbrain (mediating O(2) and oscillatory motor patterns), caudal raphé and locus coeruleus (regulating serotonergic and noradrenergic systems), the lateral medulla, parabrachial pons, and cerebellum (coordinating chemoreceptor and somatic afferent activity with breathing), and insular and cingulate cortices (mediating shortness of breath perception). Structural and functional alterations in these sites may result from PHOX2B mutations or be secondary to hypoxia/perfusion alterations from suboptimal management/compliance. The study of CCHS, with collaboration between physician-scientists and basic scientists, offers a rare opportunity to investigate control of breathing within the complex physiological network of the ANS.

Central autonomic regulation in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show significant autonomic dysfunction in addition to the well-described loss of breathing drive during sleep. Some characteristics, for example, syncope, may stem from delayed sympathetic outflow to the vasculature; other symptoms, including profuse sweating, may derive from overall enhanced sympathetic output. The dysregulation suggests significant alterations to autonomic regulatory brain areas. Murine models of the genetic mutations present in the human CCHS condition indicate brainstem autonomic nuclei are targeted; however, the broad range of symptoms suggests more widespread alterations. We used functional magnetic resonance imaging (fMRI) to assess neural response patterns to the Valsalva maneuver, an autonomic challenge eliciting a sequence of sympathetic and parasympathetic actions, in nine CCHS and 25 control subjects. CCHS patients showed diminished and time-lagged heart rate responses to the Valsalva maneuver, and muted fMRI signal responses across multiple brain areas. During the positive pressure phase of the Valsalva maneuver, CCHS responses were muted, but were less so in recovery phases. In rostral structures, including the amygdala and hippocampus, the normal declining patterns were replaced by increasing trends or more modest declines. Earlier onset responses appeared in the hypothalamus, midbrain, raphé pallidus, and left rostral ventrolateral medulla. Phase-lagged responses appeared in cerebellar pyramis and anterior cingulate cortex. The time-distorted and muted central responses to autonomic challenges likely underlie the exaggerated sympathetic action and autonomic dyscontrol in CCHS, impairing cerebral autoregulation, possibly exacerbating neural injury, and enhancing the potential for cardiac arrhythmia.

Rostral brain axonal injury in congenital central hypoventilation syndrome.

Brain injury underlying the state-related loss of ventilatory drive, autonomic, cognitive, and affective deficits in congenital central hypoventilation syndrome (CCHS) patients appears throughout the brain, as demonstrated by magnetic resonance (MR) T2 relaxometry and mean diffusivity studies. However, neither MR measure is optimal to describe types of axonal injury essential for assessing neural interactions responsible for CCHS characteristics. To evaluate axonal integrity and partition the nature of tissue damage (axonal vs. myelin injury) in CCHS, we measured water diffusion parallel (axial diffusivity) and perpendicular (radial diffusivity) to rostral brain fibers, indicative of axonal and myelin changes, respectively, with diffusion tensor imaging (DTI). We performed DTI in 12 CCHS (age 18.5 + or - 4.9 years, 7 male) and 30 control (17.7 + or - 4.6 years, 18 male) subjects, using a 3.0-Tesla MR imaging scanner. Axial and radial diffusivity maps were calculated, spatially normalized, smoothed, and compared between groups (analysis of covariance; covariates, age and gender). Significantly increased radial diffusivity, primarily indicative of myelin injury, emerged in fibers of the corona radiata, internal capsule, corpus callosum, hippocampus through the fornix, cingulum bundle, and temporal and parietal lobes. Increased axial diffusivity, suggestive of axonal injury, appeared in fibers of the internal capsule, thalamus, corona radiata, and occipital and temporal lobes. Multiple brain regions showed both higher axial and radial diffusivity, indicative of loss of tissue integrity with a combination of myelin and axonal injury, including basal ganglia, bed nucleus, and limbic, occipital, and temporal areas. The processes underlying injury are unclear, but likely stem from both hypoxic and developmental processes.

Cerebral MRI abnormalities in a premature infant with later confirmed congenital central hypoventilation syndrome.

We present a premature infant with an inability to ventilate spontaneously during sleep periods. In addition, the patient showed general hypotonia. The child had a delayed passage of stool and increased anal muscle tone, indicating Hirschsprung's disease. The combination of these symptoms suggested congenital central hypoventilation syndrome, which was confirmed postmortem by DNA analysis showing a mutation in the PHOX2B gene. MRI of the brain showed damage to the white matter, including the internal capsula. This type of damage to the white matter has not been described before in a premature infant, who did not experience birth asphyxia.

Dilated basilar arteries in patients with congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) patients show hypoventilation during sleep and severe autonomic impairments, including aberrant cardiovascular regulation. Abnormal sympathetic patterns, together with increased and variable CO(2) levels, lead to the potential for sustained cerebral vasculature changes. We performed high-resolution T1-weighted imaging in 13 CCHS and 31 control subjects using a 3.0-T magnetic resonance imaging scanner, and evaluated resting basilar and bilateral middle cerebral artery cross-sections. Two T1-weighted image series were acquired; images were averaged and reoriented to common space, and regions containing basilar and both middle cerebral arteries were oversampled. Cross-sections of the basilar and middle cerebral arteries were manually outlined to calculate cross-sectional areas, and differences between and within groups were evaluated. Basilar arteries in CCHS were significantly dilated over control subjects, but both middle cerebral artery cross-sections were similar between groups. No significant differences appeared between left and right middle cerebral arteries within either group. Basilar artery dilation may result from differential sensitivity to high CO(2) over other vascular beds, damage to serotonergic or other chemosensitive cells accompanying the artery, or enhanced microvascular resistance, and that dilation may impair tissue perfusion, leading to further neural injury in CCHS.

Congenital Central Hypoventilation syndrome (Ondine's curse): prenatal diagnosis and fetal breathing characteristics.

We report a case of Congenital Central Hypoventilation syndrome (CCHS), diagnosed in utero at 18 weeks' gestation analysis of repeats in the PHOX2b gene in fetal amniocytes and confirmed at delivery. Prenatal diagnosis allowed for serial detailed assessment of fetal breathing characteristics. Fetal breathing in this affected fetus was indistinguishable from breathing characteristics in the non-affected fetus.

PHOX2B in respiratory control: lessons from congenital central hypoventilation syndrome and its mouse models.

Phox2b is a master regulator of visceral reflex circuits. Its role in the control of respiration has been highlighted by the identification of heterozygous PHOX2B mutations as the cause of Central Congenital Hypoventilation Syndrome (CCHS), a rare disease defined by the lack of CO(2) responsiveness and of breathing automaticity in sleep. Phox2b(27Ala/+) mice that bear a frequent CCHS-causing mutation do not respond to hypercapnia and die in the first hour after birth from central apnoea. They are therefore a reliable animal model for CCHS. Neurons of the retrotrapezoïd nucleus/parafacial respiratory group (RTN/pFRG) were found severely depleted in these mice and no other neuronal loss could be identified. Physiological experiments show that RTN/pFRG neurons are crucial to driving proper breathing at birth and are necessary for central chemoreception and the generation of a normal respiratory rhythm. To date, the reason for the selective vulnerability of RTN/pFRG neurons to PHOX2B protein dysfunction remains unexplained.

Mammillary body and fornix injury in congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS) is accompanied by reduced ventilatory sensitivity to CO2 and O2, respiratory drive failure during sleep, impaired autonomic, fluid, and food absorption regulation, and affective and cognitive deficits, including memory deficiencies. The deficits likely derive from neural injury, reflected as structural damage and impaired functional brain responses to ventilatory and autonomic challenges. Brain structures playing essential memory roles, including the hippocampus and anterior thalamus, are damaged in CCHS. Other memory formation circuitry, the fornix and mammillary bodies, have not been evaluated. We collected two high-resolution T1-weighted image series from 14 CCHS and 31 control subjects, using a 3.0-Tesla magnetic resonance imaging scanner. Image series were averaged and reoriented to a standard template; areas containing the mammillary bodies and fornices were over sampled, and body volumes and fornix cross-sectional areas were calculated and compared between groups. Both left and right mammillary body volumes and fornix cross-sectional areas were significantly reduced in CCHS over control subjects, controlling for age, gender, and intracranial volume. Damage to these structures may contribute to memory deficiencies found in CCHS. Hypoxic processes, together with diminished neuroprotection from micronutrient deficiencies secondary to fluid and dietary absorption issues, may contribute to the injury.

Cor pulmonale due to congenital central hypoventilation syndrome presenting in adolescence.

OBJECTIVE: To report the first case of congenital central hypoventilation syndrome (CCHS) presenting with severe cor pulmonale in an adolescent. METHODS AND DESIGN: Case report and literature review. Our Institutional Review Board waived the need for consent. SETTING: Pediatric intensive care unit in a tertiary care children's hospital. PATIENT: A 12-year-old girl who developed profound hypoxia following routine dental extraction under intravenous opiate sedation and became progressively obtunded due to marked hypoventilation without hypoxic arousal, requiring mechanical ventilation. She had evidence of severe right heart failure, but no cardiac, pulmonary, neurologic, or neuromuscular cause was identified. The diagnosis of CCHS was suspected and subsequently confirmed by blood polymerase chain reaction analysis that revealed a heterozygous polyalanine expansion mutation of the PHOX2B gene (five polyalanine repeats). CONCLUSIONS: This report describes the unusual presentation of severe cor pulmonale in an adolescent with so-called "late-onset" CCHS. CCHS was previously thought to be a disease affecting only neonates, but the late-onset phenotype has now been well described in adults. It should be considered in any child presenting with unexplained right heart failure without an identifiable cause, particularly if central sleep apnea is present, because early initiation of ventilatory support can prevent cardiac and neurologic sequelae and improve outcome.