Cough in children with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) is defined as failure of the chemical (autonomic) control of breathing causing alveolar hypoventilation in the absence of pulmonary, cardiac, neuromuscular or patent brainstem lesions. Hypoventilation is predominant in non-rapid-eye-movement sleep, during which breathing is primarily under chemical control. Failure of the central integration of chemosensory inputs is proposed as the putative defect. A genetic basis for CCHS is supported by lines of evidence. In some diseases of the central nervous system there is more or less complete depression of the cough reflex, whereas spontaneous ventilation is generally preserved. Little is known regarding cough in CCHS patients. Parents consistently report that their children cough 'normally' during airway infections; in contrast, experimental lines of evidence suggest that CCHS children lack a cough response following inhalation of a tussigenic agent. Although several factors may account for the discrepancy, the possibility of a weakened or even absent cough reflex remains to be fully ascertained. Conceivably, a defective cough reflex, in conjunction with the well established lack of perception of respiratory discomfort, might result in an increased risk of potentially serious respiratory complications in CCHS patients.     

Abnormal esophageal motility in children with congenital central hypoventilation syndrome

BACKGROUND & AIMS: Congenital central hypoventilation syndrome, an unexplained disorder of the central control of breathing that may reflect widespread dysfunction of brainstem structures, is regarded as a form of neuro cristopathy. Because swallowing-induced peristalsis is centrally controlled and depends on neural crest-derived esophageal innervation, we looked for esophageal dysmotility in patients with congenital central hypoventilation syndrome. METHODS: Seven patients without dysphagia or any other upper gastrointestinal tract symptoms were studied prospectively (5 girls and 2 boys; median age, 14 years; range, 11-18 years). They were compared with 7 age- and sex-matched controls. Esophageal manometry was performed using a low-compliance infusion system and the station pull-through technique. At least 10 wet swallows were analyzed in each subject. RESULTS: Pressure wave propagation was abnormal in all 7 patients (median percentage of swallows propagated, 18%, and range, 0-66; controls, 90% and 80-100; P < 0.001). Lower esophageal sphincter relaxation was abnormal in 5 patients (patients, 73% and 53-100; controls, 95% and 90-100; P = 0.01). In 2 patients, lower esophageal sphincter pressure was above the 95th percentile of control values. CONCLUSIONS: These abnormalities are strong evidence of lower esophageal dysfunction in congenital central hypoventilation syndrome. We speculate that the underlying mechanism may be dysfunction of the central structures that control swallowing.     

Cardiac rhythm disturbances among children with idiopathic congenital central hypoventilation syndrome

The objective of this study was to determine whether subjects with congenital central hypoventilation syndrome (CCHS) had an increased frequency of cardiac arrhythmias and decreased heart rate variability when compared to subjects without a known deficit in control of breathing, and that these abnormalities would be exaggerated by anesthesia. Continuous ambulatory Holter recordings were obtained in patients with CCHS and compared to two otherwise healthy control groups without a deficit in control of breathing: one with an intact airway (n = 11) and a second group with a tracheostomy (n = 6). Holter recordings were obtained before, during (under general anesthesia), and after bronchoscopy. Fourteen children with CCHS (age: 9.3 +/- 4.4 years mean +/- S.D.) were studied, and 7 underwent bronchoscopy. Seventeen control children were studied (age 6.6 +/- 3.6 years): 11 without a tracheostomy, and 6 with a tracheostomy who also underwent bronchoscopy. Maximum heart rate during baseline recording was significantly lower in the CCHS subjects as compared to controls (P = 0.0001). At baseline the difference in the number of arrhythmias/24 hr/subject in all CCHS vs. all control subjects was significant (P = 0.0002); for the subjects who had bronchoscopy, CCHS vs. control, the difference was also significant (P = 0.03). In addition, there was a significant decrease in the number of events/24 hr/subject among the CCHS subjects between baseline and post-bronchoscopy (P = 0.0288). The predominant arrhythmias were sinus bradycardia and transient asystole. The longest asystole in a CCHS subject was 6.50 sec, and in a control subject, 1.42 sec (at baseline the means of the longest asystole were 2.69 +/- 1.4 vs. 1.24 +/- 0.13; P = 0.003 in the CCHS vs. control groups). Other indices of heart rate variability were significantly reduced in the CCHS subjects (P < 0.05). These results substantiate our hypothesis that subjects with CCHS have more arrhythmias than controls, an increased frequency of bradyarrhythmias, and decreased cyclical sinus arrhythmia.     

Autonomic function in children with congenital central hypoventilation syndrome and their families

STUDY OBJECTIVES: Congenital central hypoventilation syndrome (CCHS) is a genetic disorder characterized by failure of automatic control of breathing in the absence of obvious anatomic lesions. There have been several reports suggesting that CCHS patients display autonomic dysregulation. Pulse arterial tonometry (PAT) is a novel technique that provides noninvasive moment-to-moment measurements of sympathetic tone changes to the cutaneous vascular bed. We hypothesized that autonomic function as measured by PAT would be altered in children with CCHS. DESIGN: Prospective study. SETTING: CCHS Family Conference, Orlando, FL, and the local community in Louisville, KY. PARTICIPANTS: Nineteen CCHS patients and 31 parents as well as 24 control children and 15 adult control subjects. INTERVENTIONS: Children with CCHS and their parents underwent sympathetic challenges (vital capacity sigh and cold hand pressor test) and a test of reactive hyperemia (brachial artery occlusion) while PAT was continuously monitored from the right hand. Control children and control adults underwent the same procedure. MEASUREMENTS AND RESULTS: The maximal change of the PAT signal compared to the preceding baseline was averaged and expressed as percentage change for each of the challenges. The magnitude of sympathetic discharge-induced attenuation of PAT signal following a sigh was reduced in CCHS children compared to control subjects for both the vital capacity sighs and the cold hand pressor test. There were no differences observed in the magnitude of PAT attenuation between parents of children with CCHS and control adults. No differences were observed between either CCHS and control subjects or CCHS parents and adult control subjects for the brachial artery occlusion test. CONCLUSION: CCHS patients show an attenuated response to endogenous sympathetic stimulation, supporting the presence of autonomic nervous system dysfunction as a consistent feature of this condition. No differences were found in parents of children with CCHS compared to control adults, consistent with the finding that CCHS is primarily the result of a de novo gene mutation.     

Hypoxic and hypercapnic ventilatory responses in awake children with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) has been thought to be a disorder of central chemoreceptor responsiveness. Previous studies in CCHS have shown decreased or absent ventilatory responsiveness to both hypercarbia and hypoxia. However, hypoxic responsiveness during wakefulness has not been systematically studied. We studied hypoxic and hypercapnic ventilatory responses during wakefulness in five children with CCHS (6 to 11 yr of age). To measure the hypercapnic response, the children rebreathed a hyperoxic hypercapnic mixture until PaCO2 reached 56 to 69 mm Hg. For the hypoxic response, the children rebreathed a hypoxic gas mixture, at mixed venous PCO2, until SaO2 had fallen to less than 78%. We found that the ventilatory responses to hypercapnia and hypoxia were very variable (linear correlation coefficients ranging from -0.44 to +0.63 for hypercapnic responses and from -0.15 to +0.77 for hypoxic responses), with no significant change from baseline in response to either stimulus. There was no evidence of progressive ventilatory stimulation despite increasing stimulus. Additionally, these children had no subjective sensation of dyspnea or discomfort. This establishes that hypoxic and hypercapnic ventilatory control is absent during wakefulness. Chemoreceptor control (peripheral and central) is, therefore, defective in all states in children with CCHS. We speculate that the defect in CCHS lies in central integration of the central and peripheral chemoreceptor signals.     

Diagnostic practices and disease surveillance in Canadian children with congenital central hypoventilation syndrome

OBJECTIVE:

To assess the diagnostic and surveillance practices of Canadian pediatric subspecialists for children with congenital central hypoventilation syndrome (CCHS).

METHODS:

The present analysis was a prospective cross-sectional study. A web-based survey was sent to 303 pediatric subspecialists in Canada: 85 pediatric respirologists, 77 pediatric neurologists and 141 neonatologists. The survey included 36 questions about the current diagnostic and surveillance management of pediatric CCHS. Differences in responses among respirologists, neurologists and neonatologists were evaluated for each question, where feasible, and responses were compared with the 2010 American Thoracic Society (ATS) Clinical Policy Statement for CCHS.

RESULTS:

A total of 83 (27%) participants responded to the survey; the highest survey response rate (40%) was from respirologists. For the diagnosis of CCHS, 25% of respondents did not order genetic testing, either alone or with another test, to make a diagnosis of CCHS. The criteria and tests recommended by the ATS to make a diagnosis of CCHS – genetic testing, diagnosis of exclusion, polysomnogram and plus or minus a hypercapnic challenge – were ordered by 23 (43%) of the 54 respondents. Although polysomnograms were ordered for more than 90% of children with CCHS, only 37% of respirologists aimed for a carbon dioxide range of 35 mmHg to 40 mmHg during polysomnogram titrations.

CONCLUSIONS:

The results demonstrate variability in the diagnostic and surveillance practices of pediatric subspecialists in children with CCHS across Canada. The present study provides an initial needs assessment and demonstrated that there are significant deviations in practice from the 2010 ATS guidelines.     

Alcohol use in congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) is a rare disorder where there is failure of automatic control of breathing. With improved recognition of CCHS, more children are appropriately diagnosed and treated in infancy, allowing survival into adult years. Because most of these children are able to participate in regular school, they are exposed to common adolescent behaviors, such as abusing alcohol and drugs. Alcohol and many illicit substances are known respiratory depressants. We report on 3 cases of adolescents/young adults with CCHS who had severe adverse events related to alcohol, including coma and death. This series illustrates the dangers of alcohol abuse in CCHS. We speculate that adolescents with CCHS may be less able to perceive the risks of substance abuse and impulsive behavior, leading to increased morbidity and mortality. Patients with CCHS appear to lack anxiety and the awareness that their inability to perceive physiologically dangerous levels of hypercarbia and hypoxia deprives them of important protective mechanisms.     

Mother-daughter transmission of congenital central hypoventilation syndrome

The cause of congenital central hypoventilation syndrome (CCHS) is unknown, but a genetic etiology is strongly suspected. We report a 25-year-old woman with CCHS (no Hirschsprung's disease) who gave birth to a daughter who also has CCHS. This suggests a dominant mode of inheritance for CCHS in this family. Pregnancy can be associated with physiologic challenges in CCHS. The increase in endogenous progesterone may stimulate breathing and may possibly improve symptoms of hypoventilation. Although this patient did not have any worsening in symptoms, her hyperoxic hypercapnic rebreathing ventilatory response was not different when pregnant versus when not pregnant. Ventilatory support for the patient was successfully managed with diaphragm pacing throughout the pregnancy without the need to adjust settings, despite the enlarged abdomen during pregnancy. We conclude that CCHS may be an inherited disorder. Increased endogenous progesterone during pregnancy has no effect on the ventilatory response, and diaphragm pacing can successfully provide adequate ventilation throughout pregnancy.     

Epidemiologic survey of 196 patients with congenital central hypoventilation syndrome

This study examined the cross-sectional medical and social characteristics of children diagnosed with congenital central hypoventilation syndrome (CCHS). A detailed questionnaire was mailed to all families with a child with CCHS who are affiliated with a family network or support group. The questionnaire response rate was >75% (n=196). Mean age was 10.22 years +/- 6.6 years (SD) (range, 0.4-38 years), with a 1:1 sex ratio. Multisystem involvement was almost universal among the cohort, with Hirschsprung's disease (HD) present in 16.3%; 61.7% of the children had a tracheotomy, but 14.3% were never tracheotomized, with 77 subjects (39.3%) not having a tracheostomy tube at time of survey. Respiratory support approaches varied but clearly reflected the trend towards earlier and more widespread transition to noninvasive ventilatory modalities. Significant developmental problems were noted, but attendance in regular classes occurred in the majority. Significant deficiencies in routine periodic evaluation and management were reported. In addition, the presence of CCHS was associated with a significant financial and psychosocial burden to the families. In conclusion, a comprehensive survey of 196 CCHS children and their families revealed a cross-sectional picture of substantial medical and psychosocial complexities associated with this disorder, and pointed out substantial inadequacies in routine preventive care that appear to impose stress on the families. The emerging trend of earlier transition to noninvasive ventilatory support warrants future studies. Implementation of recommended guidelines for diagnosis and multidisciplinary follow-up of CCHS should ultimately ameliorate the long-term outcome of this lifelong condition.     

Fog-induced cough with impaired respiratory sensation in congenital central hypoventilation syndrome

RATIONALE: Congenital central hypoventilation syndrome (CCHS) is a genetic disorder mainly characterized by failure of automatic control of breathing, causing alveolar hypoventilation. Little is known regarding cough in CCHS. Parental reports indicate that patients cough normally during airway infections; however, previous studies have demonstrated no cough response to fog inhalation. OBJECTIVES: To evaluate the sensory and motor components of cough, respiratory sensations, and changes in ventilation evoked by fog inhalation in children with CCHS and in sex- and age-matched control subjects. METHODS: Cough threshold was measured and cough intensity was indexed in terms of cough peak expiratory flow and integrated abdominal electromyographic activity. The pattern of breathing was recorded by inductive plethysmography. Respiratory sensations were also investigated. MEASUREMENTS AND MAIN RESULTS: All control subjects and six of seven patients coughed in response to fog inhalation. The seventh coughed with citric acid aerosol inhalation. Cough threshold values were similar in control subjects (range, 0.40-2.22 ml/min) and patients (range, 0.40-3.26 ml/min). Mean values of cough peak expiratory flow and of integrated abdominal electromyographic activity-related variables during coughing were also similar and corresponded to 80% of those recorded during maximum voluntary cough. Cough appearance was preceded by respiratory sensations and increases (P < 0.01) in ventilation in the control subjects but not in the patients. CONCLUSIONS: Children with CCHS have normal cough threshold and motor responses to fog inhalation. However, the lack of respiratory sensations and the likely related ventilatory changes typically elicited by tussigenic fog concentrations suggest a neural sensory deficit that may increase the risk of respiratory disease in these patients.     

Hypercapnic and hypoxic ventilatory responses in parents and siblings of children with congenital central hypoventilation syndrome

Children with congenital central hypoventilation syndrome (CCHS) have abnormal ventilatory responses to metabolic stimuli. As there is a genetically determined component of chemoreceptor sensitivity, parents and siblings of children with CCHS may also have blunted ventilatory responses to hypercapnea and hypoxia. To test this, we studied hypercapnic ventilatory responses and hypoxic ventilatory responses in six mothers, four fathers, and five siblings (6 to 49 yr of age) of seven children with CCHS and compared them with 15 age- and sex-matched control subjects (5 to 47 yr of age). Pulmonary function tests were not different between relatives of children with CCHS and control subjects. To measure hypercapnic ventilatory responses, subjects rebreathed 5% CO2/95% O2 until PACO2 reached 60 to 70 mm Hg. To measure hypoxic ventilatory responses (L/min/% SaO2), subjects rebreathed 14% O2/7% CO2/balance N2 at mixed venous PCO2 until SaO2 fell to 75%. All tests were completed in less than 4 min. Instantaneous minute ventilation, mean inspiratory flow (tidal volume/inspiratory time), and respiratory timing (inspiratory timing/total respiratory cycle timing) were calculated on a breath-by-breath basis. Hypercapnic ventilatory responses were 1.97 +/- 0.32 L/min/mm Hg PACO2 in children with CCHS relatives and 2.23 +/- 0.23 L/min/mm Hg PACO2 in control subjects. Hypoxic ventilatory responses were -1.99 +/- 0.37 L/min/% SaO2 in the relatives and -1.54 +/- 0.25 L/min/% SaO2 in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Presentation and treatment of monozygotic twins with congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome is a rare genetic disorder characterized by hypoventilation during sleep secondary to a blunted response to hypercapnia and hypoxia. The current case report describes developmentally normal four-year-old monozygotic twin boys who presented in infancy with variable presentations and clinical severity of congenital central hypoventilation syndrome. Both were managed with noninvasive positive pressure ventilation.     

Ventilatory effects of almitrine bismesylate in congenital central hypoventilation syndrome

Patients with congenital central hypoventilation syndrome (CCHS) lack hypercapnic and hypoxic stimulation of ventilation but have demonstrated carotid body function in response to hyperoxia and to pharmacological stimulation with doxapram. This study investigated the ventilatory effects of almitrine bismesylate, a carotid body stimulant, in 12 patients with CCHS. Measurements of minute ventilation, tidal volume (VT), respiratory rate (RR) and transcutaneous PO2 (TCPO2) were taken before and after administration of 4.5 mg/kg and 6 mg/kg of almitrine. Twenty-four hour pharmacokinetic studies were performed in 7 patients who received 4.5 mg/kg and in 6 patients who received 6 mg/kg almitrine. There was no significant improvement in ventilatory and gas exchange parameters at either dose of almitrine despite appropriate peak serum concentration of the drug at the time of the studies. These results suggest that almitrine is not a useful ventilatory stimulant in children with CCHS.     

Noninvasive ventilatory strategies in the management of a newborn infant and three children with congenital central hypoventilation syndrome

Four children with congenital central hypoventilation syndrome (CCHS) treated with noninvasive techniques of ventilation are presented. Two infants (one in the newborn period) were treated with nasal mask bilevel positive airway pressure (BiPAP), and then both were transitioned to negative pressure chamber ventilation at several years of age because of possible midface hypoplasia. Tracheostomies were not performed. Two older children were transitioned from mechanical ventilation via tracheostomy to nasal mask BiPAP, and then in one case to negative pressure chamber ventilation, and in the other to phrenic nerve pacing. Their tracheostomies were removed.     

Brainstem anomalies in two patients affected by congenital central hypoventilation syndrome

Congenital central hypoventilation syndrome (CCHS) is a rare neurocristopathy characterized by absence of automatic control of respiration; decreased sensibility to hypoxia and hypercapnia, mainly during sleep; and autosomal dominant inheritance due to heterozygous polyalanine expansions and frameshift mutations in the PHOX2B gene. Because the CCHS phenotype could hide other neurologic diseases, the American Thoracic Society established that the initial evaluation of suspected CCHS should exclude neuroanatomic impairments as the structural basis of the reduced autonomic system function. In this work, we describe the clinical history of two unrelated patients with hypoventilation during sleep and harboring hypoplasia of the pons and a Chiari I malformation, respectively. In both patients, CCHS was diagnosed by detection of PHOX2B polyalanine expansion, suggesting that the American Thoracic Society diagnostic criteria may be too restrictive. Moreover, to exclude a putative role of PHOX2B in non-CCHS neurologic diseases, we have performed PHOX2B mutation screening in a group of individuals with Chiari I malformation, confirming the exclusive role of PHOX2B in the pathogenesis of CCHS.