Association between the severity of chronic spontaneous urticaria and sleep-disordered breathing.

BACKGROUND: Chronic spontaneous urticaria (CSU) is a common mast cell-driven disease, presenting with wheals, angioedema, or both. Sleep-disordered breathing (SDB) is also a common condition and contributes to various diseases by causing chronic inflammation. Recent studies have suggested an association between CSU and SDB. METHODS: To determine the association between the severity of SDB and that of CSU, we studied consecutive patients with CSU who visited the Sagamihara National Hospital allergy department or dermatology department between April 1 and October 31, 2018. The severity of CSU and SDB was evaluated based on the urticaria activity score 7 (UAS7) and peripheral arterial tone apnea-hypopnea index (pAHI) derived from out-of-center sleep testing (OCST) findings, respectively; their correlation was examined. RESULTS: Of the 37 patients studied, 19 had symptom-free-to-mild CSU (UAS7 ≤15) and 18 had moderate-to-severe CSU (UAS7 ≥16). The pAHI in the latter group was significantly higher than that in the former group (18 vs. 4.2, p = 0.001). In multivariate logistic analysis, moderate-to-severe SDB (pAHI ≥15) was significantly associated with moderate-to-severe CSU even after adjusting for the BMI (adjusted odds ratio 22 [95% confidence interval, 1.7-285]). CONCLUSIONS: The severity of SDB is correlated with that of CSU independently of the BMI. Physicians should consider comorbid SDB when treating patients with CSU.

Beneficial effects of adaptive servo ventilation in patients with chronic heart failure.

BACKGROUND: Sleep-disordered breathing (SDB) is thought to be a state of inflammation caused by hypoxic stress. Whether adaptive servo ventilation (ASV) attenuates the inflammatory response and improves the cardiac function of patients with congestive heart failure (CHF) accompanied by SDB was not been investigated. METHODS AND RESULTS: Seventeen inpatients with New York Heart Association (NYHA) II or III underwent polysomnography. There was a positive correlation between the apnea hypopnea index and high-sensitivity C-reactive protein (hs-CRP) level (r=0.753, P=0.016). The patients were divided into ASV (n=10) and non-ASV groups (n=7), and CHF-parameters were measured before and after ASV treatment. Improvement was noted for the NYHA class in the ASV group but not in the non-ASV group. In contrast to the non-ASV group, the level of brain natriuretic peptide (BNP), ejection fraction, and hs-CRP levels in the ASV group significantly improved (BNP, 212.1 ± 181.2 to 77.3 ± 54.0 pg/ml [P<0.05]; ejection fraction, 43.5 ± 6.4 to 53.3 ± 6.1% [P=0.002]; hs-CRP, 0.85 ± 0.58 to 0.21 ± 0.19 mg/dl, [P=0.008]). The increase in ejection fraction was correlated with a decrease in the hs-CRP level (r=-0.753, P=0.001). CONCLUSIONS: Anti-inflammatory effects of ASV are important contributors for improving cardiac function in patients with CHF accompanied by SDB.

Anxiety and congenital central hypoventilation syndrome.

OBJECTIVE: It has been hypothesized that individuals who cannot perceive elevations of CO2 will be less anxious than individuals with intact CO2 perception. To test this hypothesis, children with congenital central hypoventilation syndrome, who have a potentially lethal chronic illness associated with lack of CO2 perception and thus provide a natural experimental group, were studied. METHOD: Rates of anxiety symptoms and disorders in children with congenital central hypoventilation syndrome (N = 13) were compared with rates in an age-matched, nonreferred group of community subjects (N = 292) that included subgroups of children with asthma (N = 15) and other chronic medical illnesses (N = 66). Anxiety symptoms were assessed with information obtained from structured interviews of the parents, which provided both total symptom scores and DSM-III-R diagnoses. RESULTS: The children with congenital central hypoventilation syndrome exhibited significantly fewer anxiety symptoms than all other comparison subjects. Two of these children (15%) met criteria for anxiety disorders, a rate lower than that of the whole community group (24%) and of the chronically ill comparison subgroups (32%-47%). The largest difference in the prevalence of disorder emerged between the children with congenital central hypoventilation syndrome (15%) and those with asthma (47%). In the comparison of children with congenital central hypoventilation syndrome and children with other chronic illnesses, a priori analysis showed that the former had significantly lower rates of disorders that have been linked to panic in the literature. CONCLUSIONS: This study supports theories of anxiety that implicate CO2 perception in the pathophysiology of panic and related anxiety states.

Congenital central hypoventilation and sleep state.

Congenital central hypoventilation (Ondine's curse) is described in an infant with persistant symptoms throughout the first nine months of life. Respiratory control was most severely affected in quiet sleep, although abnormalities were present in rapid eye movement (REM) sleep and while awake. Failure of metabolic control in quiet sleep led to profound hypoventilation. Behavioral or "behavioral-like" inputs in the awake state and REM sleep increased ventilation, but not to expected normal levels. The ventilatory response to inhaled 4% CO2 was markedly depressed in all states.

Hypercapneic arousal responses in children with congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome (CCHS, Ondine's curse) is generally thought to be due to insensitivity of the central chemoreceptors to carbon dioxide. Children with CCHS have absent ventilatory responses to both hypercapnea and hypoxia, suggesting either abnormal central and peripheral chemoreceptor function or abnormal central integration of chemoreceptor input. Because ventilatory and arousal responses to respiratory stimuli are distinct from each other, if children with CCHS have complete chemoreceptor dysfunction, one would predict that both ventilatory and arousal responses to respiratory stimuli would be abnormal. However, if they have abnormal central integration of chemoreceptor input for ventilation, they may still arouse to respiratory stimuli despite the absence of a ventilatory response. Hypercapneic arousal responses were tested in eight children with CCHS, aged 5.8 +/- 1.2 (SEM) years, and seven healthy control subjects, aged 4.4 +/- 1.1 years. Children were studied during sleep while normal ventilation was maintained using their home ventilators. Hypercapneic challenges were performed by rapidly increasing the inspired carbon dioxide tension to 60 mm Hg and maintaining this level until the child aroused or for a maximum of 3 minutes. Of children with CCHS, 87.5% aroused to hypercapnea, compared with 100% of control children. There was no significant difference in arousal between children with CCHS and normal control subjects. It is concluded that most children with CCHS arouse to hypercapnea, indicating the presence of some central chemoreceptor function. It is speculated that because these children do respond to hypercapnea, the most probable mechanism for CCHS is a brainstem lesion in the area where input from both chemoreceptors is integrated.

Long-term follow-up of children with congenital central hypoventilation syndrome.

The long-term clinical course of six patients with congenital central hypoventilation syndrome is described. During the neonatal period, the patients had prolonged apneas and hypoventilation, in the absence of cardiac, pulmonary, or neuromuscular disease. After an initial period of respirator dependency, they became able to sustain normal gas exchange while awake. During sleep, however, profound hypoventilation developed, and tracheostomy and mechanical ventilation were required. Ventilatory responses to hypercapnia and hypoxia were depressed or absent and did not improve with time. One patient was able, at 2 years of age, to breathe spontaneously during sleep with only moderate hypoventilation. The others, now 4 to 14 years of age, still need ventilatory support during sleep. Complications, such as cardiac failure and hypoxic seizures, mostly occurred early in the course and resolved with correction of insufficient mechanical ventilation. Speech acquisition was possible with the use of a special stoma plug. All patients were managed at home, and with appropriate support, the parents were able to provide safe ventilatory care with low morbidity and no mortality.

Congenital central alveolar hypoventilation syndrome in six infants.

Six infants with congenital alveolar hypoventilation syndrome (CCHS) were seen and observed over several years. Two had an association of CCHS with Hirchsprung's disease. All infants were treated by tracheostomy and mechanical ventilation. Three infants have survived (including one with CCHS and Hirchsprung's disease). However, all survivors have required frequent rehospitalization. The infant with the longest survival (now 4 years of age) has developed significant daytime problems involving the "behavioral control" of ventilation. One infant was considered as a "near miss for sudden infant death syndrome" and became significantly symptomatic after establishment of delta (stage 3-4 non-rapid eye movement) sleep, which normally develops between 2 and 4 months of age. CCHS involves autonomic nervous system dysfunction, and the question of a defect involving the integration of chemoreceptor information more than a direct defect of the central chemoreceptor is discussed.

Congenital central hypoventilation syndrome: mutation analysis of the receptor tyrosine kinase RET.

Congenital central hypoventilation syndrome (CCHS) usually occurs as an isolated phenotype. However, 16% of the index cases are also affected with Hirschsprung disease (HSCR). Complex segregation analysis suggests that CCHS is familial and has the same inheritance pattern with or without HSCR. We postulate that alteration of normal function of the receptor tyrosine kinase, RET, may contribute to CCHS based on RET's expression pattern and the identification of RET mutations in HSCR patients. To further explore the nature of the inheritance of CCHS, we have undertaken two main routes of investigation: cytogenetic analysis and mutation detection. Cytogenetic analysis of metaphase chromosomes showed normal karyotypes in 13 of the 14 evaluated index cases; one index case carried a familial pericentric inversion on chromosome 2. Mutation analysis showed no sequence changes unique to index cases, as compared to control individuals, and as studied by single strand conformational polymorphism (SSCP) analysis of the coding region of RET. We conclude that point mutations in the RET coding region cannot account for a substantial fraction of CCHS in this patient population, and that other candidate genes involved in neural crest cell differentiation and development must be considered.

Congenital central hypoventilation syndrome associated with multiple ganglioneuromas.

A five-year-old girl had congenital central hypoventilation syndrome and mediastinal and adrenal tumors. The mediastinal mass was though to be present, retrospectively, for at least four years prior to surgery. Pathology of the excised tumors revealed benign ganglioneuromas. This is the first case reported of an association between CCHS and multiple ganglioneuromas. This suggests that CCHS, like neural crest tumors, may result from maldevelopment of the embryonic neural crest.

Congenital central hypoventilation syndrome: cardiorespiratory responses to moderate exercise, simulating daily activity.

Children with congenital central hypoventilation syndrome (CCHS) lack normal awake ventilatory responses to hypoxia and hypercarbia, yet engage in daily activities typical of similarly aged children. Our patients with CCHS are assessed annually with a walking treadmill protocol to assess physiologic responses to different levels of simulated daily activity. We hypothesized that children with CCHS (compared with age- and sex-matched healthy controls) would 1) exercise for shorter durations and reach lower peak speed and incline on the treadmill; 2) become more hypoxemic, more hypercarbic, and develop less tachycardia during activity; and 3) take longer to return to baseline oxygenation, ventilation, and heart rate than normal children. Seven children with CCHS [mean age, 6.9 +/- 3.0 (SD) years] who required 24 h/day ventilatory support (diaphragm pacers while awake and mechanical ventilation asleep) and 7 controls performed a walking protocol on a treadmill with progressive increments in speed and incline. Hemoglobin saturations (SaO2), end-tidal carbon dioxide concentrations (ETCO2), and heart rates (HR) were recorded at baseline conditions, during activity and during recovery. There were no significant differences between children with CCHS and controls in baseline values, duration of activity, peak speed, and incline achieved during walking and recovery time to baseline once the treadmill had stopped. However, children with CCHS became significantly more hypoxemic and hypercarbic during activity (P < 0.05), and they had a lower percent increase in HR during treadmill walking than controls (P < 0.05). These results offer the clinician an opportunity to adjust clinical management in children with CCHS by providing specific recommendations to parents about appropriate levels of activity for their children with CCHS.(ABSTRACT TRUNCATED AT 250 WORDS)

Resolution of obstructive sleep apnea syndrome after adenoidectomy in congenital central hypoventilation syndrome.

We report on a 2 1/2-year-old boy who is currently ventilated at home by positive pressure ventilation through a nasal mask during the night because of congenital central hypoventilation syndrome (CCHS). Up to age 2 he had developed normally. A reevaluation was performed because of symptoms suggestive of obstructive sleep apnea syndrome (OSAS), including snoring, nocturnal sweating, frequent nighttime awakenings, speech impairment, daytime fatigue, and failure to thrive. A sleep study indicated obstructive apnea episodes lasting up to 40 s and arterial desaturations below 50% during spontaneous sleep. During mechanical ventilation snoring persisted, and capillary PCO2 rose to 60 mm Hg. Partial upper airway obstruction, leaking around the mask, and arousal movements developed on passive flexion of the neck to 20 degrees. After adenoidectomy, symptoms of OSAS resolved. There were no more obstructive apneas during spontaneous sleep, but obstructive apneas could be provoked by neck flexion to 20 degrees. During ventilation, neck flexion of 20 degrees was tolerated, but a 40 degrees flexion led to partial obstruction. In CCHS patients, the problem of upper airway obstruction is rarely noted because most patients are ventilated through a permanent tracheostomy. Today, noninvasive ventilation strategies are becoming more common. Reduced activity of upper airway muscles and impaired reflex mechanisms could lead to upper airway obstruction during face mask positive pressure ventilation in children with CCHS. Enlarged adenoids worsened this problem in our patient, leading to insufficient ventilation and OSAS. Adenoidectomy resolved symptoms of OSAS and enabled successful nasal mask ventilation. Close follow-up of the patient avoided hypoxia and sequelae from OSAS such as pulmonary hypertension.

Congenital central hypoventilation syndrome: an update.

Awareness of the existence of CCHS has led to increasingly frequent reports of such patients from all over the world. However, the exact pathophysiologic mechanisms underlying the clinical manifestations of this congenital disease entity remain unknown. For the respiratory physiologist, CCHS can be viewed as an experiment of nature that provides an important and unique window into central cardiorespiratory regulation. For the pediatrician, CCHS children represent an unique clinical challenge in coordinating the diagnostic and therapeutic procedures required to enhance the patients' quality of life.

Upper airway function in Ondine's curse.

Congenital central alveolar hypoventilation (Ondine's curse) is a rare disorder with absence of automatic control of ventilation but preservation of voluntary breathing. Phrenic pacing, used to treat this condition, is usually not successful without a tracheotomy. We performed fiberoptic videoendoscopy on an affected infant airway. During wakefulness and ventilation by a negative pressure ventilator, the airway was normal, but with sleep onset, passive inspiration produced phasic epiglottic collapse. This case demonstrates the importance of central control in maintaining upper airway patency.

Congenital difficulties with swallowing and breathing associated with maternal polyhydramnios: neurocristopathy or medullary infarction?

Two babies with congenital difficulties in swallowing and breathing are presented and contrasted. Both were associated with maternal polyhydramnios, but one was due to medullary infarction and the other to a malformation ("neurocristopathy"). In the former case, isolated tenth and twelfth cranial nerve palsies provided the clue as to the correct etiology, whereas the latter baby had dyscoordination of swallowing and breathing with sleep apnea ("Ondine's curse"). It is somewhat ironic that the case without a difficult delivery had the infarct, probably prenatal in onset, whereas the one with a difficult delivery had the congenital malformation. Neural crest cells are known to migrate widely and to develop greatly different functions, but the fact that their central associations of neural tube origin may also be affected has not previously been emphasized in the etiopathogenesis of the congenital malformation. A variety of syndromes with combinations of many defects may be seen in which too many or too few cells are formed, with more or less serious consequences especially for the respiratory and gastrointestinal systems.

The complete spectrum of neurocristopathy in an infant with congenital hypoventilation, Hirschsprung's disease, and neuroblastoma.

Neuroblastoma, Hirschsprung's disease, and central hypoventilation (Ondine's curse) are considered aberrations of neural crest cell growth, migration, or differentiation, and as such are considered to be under the general heading of neurocristopathy. Their combined occurrence in a newborn infant presenting with total colonic aganglionosis, central hypoventilation, and multifocal neuroblastoma had not been reported previously. A 2.3-kg white full-term girl required endotracheal intubation because of persistent apnea in the first hours of life. She had progressive abdominal distension and failure to pass meconium; a barium enema was performed, which showed microcolon with meconium pellets at the distal ileum. During laparotomy the distal ileum was found to be obstructed with inspissated meconium; an ileostomy and appendectomy were performed. The resected specimens were aganglionic. An additional 20 cm of aganglionic ileum was removed, and a normally innervated ileostomy was constructed. Numerous attempts at extubation failed because of apnea. The results of an extensive apnea workup, including electroencephalogram, magnetic resonance imaging (MRI), bronchoscopy, and pH probe study, were normal. Sleep studies showed congenital central hypoventilation syndrome, and the patient underwent a tracheostomy. At 3 months, an abdominal ultrasound examination performed within a septic workup showed a right suprarenal mass extending across the midline. Thoracic and abdominal MRI scans showed large bilateral adrenal and posterior mediastinal masses. The serum catecholamines and ferritin level were markedly elevated, suggestive of neuroblastoma. In light of the child's multiple problems, the family chose to forgo further workup (including a tissue biopsy) and therapy. In the following 2 months her tumor load rapidly progressed, and she died of respiratory insufficiency.(ABSTRACT TRUNCATED AT 250 WORDS)

Congenital central hypoventilation syndrome: ocular findings in 37 children.

BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare cause of central sleep apnea. Although ophthalmic abnormalities have been reported, the ocular findings have not been discussed in detail. METHODS: We examined or obtained the records of 37 children with CCHS. RESULTS: Twenty-seven patients were found to have abnormal pupils, most of which were miotic and reacted poorly to light. In 18 cases, the anterior surface of the iris was unusually smooth. Ten of the children with abnormal pupils also demonstrated light-near dissociation. Twenty had strabismus of various types, and 18 showed evidence of convergence insufficiency. CONCLUSIONS: The high incidence of strabismus, pupillary abnormalities, and convergence insufficiency may be a result of neurologic defects in the midbrain.

Anesthetic care for the child with congenital central alveolar hypoventilation syndrome (Ondine's curse).

Idiopathic congenital central alveolar hypoventilation syndrome, otherwise known as Ondine's curse, is a rare neuropathologic syndrome characterized by an inadequate respiratory drive with hypoventilation and periods of prolonged apnea resulting in hypercarbia and hypoxemia. Although no definite pathologic abnormality has been identified to account for the disorder, it is thought to represent a primary defect related to altered function of central chemoreceptors resulting in defective control of minute ventilation. Associated problems related to neural crest cell migration, including neuroblastoma formation and Hirschsprung's disease, suggest that the primary defect is defective neural crest cell migration and function. Problems that may impact on perioperative care include the defective central control of ventilation and defective control of upper respiratory musculature, which may lead to upper airway obstruction. Although many patients will have previously undergone tracheostomy and chronic mechanical ventilation, problems in other organ systems can impact on perioperative care. Cardiovascular issues include the possible presence of cor pulmonale and autonomic nervous system dysfunction. Central nervous system issues include the frequent occurrence of seizures and mental retardation. The preoperative work-up, premedication, and the intraoperative/postoperative care and monitoring of these patients is reviewed.

Association of misoprostol, Moebius syndrome and congenital central alveolar hypoventilation. Case report.

We report a case showing the association of Moebius syndrome, the use of misoprostol during pregnancy and the development of central congenital alveolar hypoventilation. Pathophysiological aspects of these three diseases are discussed and also the unfavorable prognosis of this association.

[From tracheostomy to non-invasive mask ventilation: a study in children with congenital central hypoventilation syndrome]. / Vom Tracheostoma zur nasalen Maskenbeatmung--Erfahrungen bei Kindern mit zentralem Hypoventilationssyndrom.

BACKGROUND: Children with congenital central hypoventilation syndrome (CCHS) have to be ventilated during sleep due to respiratory insensitivity to CO2. This long-term mechanical ventilation sometimes requires a tracheostomy during infancy, leading to increased risk of infections and of tracheal problems, and later on to stigmatization and restrictions in social life. PATIENTS AND METHOD: We therefore evaluated non-invasive mask ventilation in 4 children between 6 and 15 years of age, who had been ventilated via tracheal canula since early infancy under polysomnographic control. RESULTS: Best results were obtained with standard face masks in connection with pressure controlled timed ventilation. In 1 child we used a volume-controlled ventilator. The lack of dyspnea in these patients can worsen the acceptance of a face mask, which is more uncomfortable than a tracheal cannula. In 2 children we waited with the definite closure of the tracheostomy due to pavor-like symptoms and laryngeal closure during sleep and problems in acceptance of the mask, respectively. In the other 2 children we could demonstrate effective non-invasive mask ventilation during temporary tracheal closure for several nights. Therefore the tracheostomy was definitely closed. Long-term follow-up with home monitoring showed effectiveness of non-invasive ventilation in these cases.

[Sleep-phase-related home therapy in congenital central hypoventilation syndrome (CCHS)]. / Schlafphasenbezogene Atemtherapie bei Kindern mit angeborener Unempfindlichkeit für CO2.

PATIENTS AND METHOD: Eight children with congenital central hypoventilation syndrome (CCHS) (aged 3 to 16 years) underwent repeated polysomnographic recordings (sleep-EEG, induction plethysmography, PtcO2, PtcCO2, PACO2, FO2, SaO2, ECG) during spontaneous breathing and during therapy. The result led to individual therapeutic plans. RESULT: During NREM sleep a close relationship between increasing EEG-delta-activity and increasing PCO2 could be observed (PCO2 max. 107 mm Hg in NREM IV). A similar effect was seen during mechanical ventilation with decreasing spontaneous respiratory activity during increasing sleep depth (PCO2 max. 89 mm Hg in NREM IV). Associated with NREM I/II and REM sleep strong variations in spontaneous breathing with consecutive variations of blood gases were observed. Hyperventilation during REM sleep (PCO2 min. 20 mm Hg) could occur with continuous mechanical ventilation. A continuous blood gas monitoring improved home therapy since blood gas adapted control of mechanical ventilation was possible now. This caused a stabilization of blood gases in sleep. CONCLUSION: Patients with CCHS show a vigilance-dependent, enlarged variability of blood gases which should be considered in the management of home therapy. Continuous monitoring and blood gas adapted mechanical ventilation obtain a stabilization of acid-base balance during sleep. Preliminary data suggest a positive effect on sleep-wake quality and mental performance.