eMedicine Specialties > Pediatrics: General Medicine > Pulmonology

Congenital Central Hypoventilation Syndrome

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Cyrus M Shahriary, MD, Fellow, Pediatric Pulmonology, University of California at Irvine, Miller Children's Hospital; David Gozal, MD, Vice-Chairman of Research and Director, Kosair Children's Hospital Comprehensive Sleep Medicine Center, Professor, Department of Pediatrics, University of Louisville

Updated: Dec 19, 2008

Introduction

Background

The preferred nomenclature for the disorder known as Ondine curse is congenital central hypoventilation syndrome (CCHS). The literary misnomer "Ondine's curse" has been used in prior literature. In the story of Ondine, a German folk epic, the nymph Ondine falls in love with a mortal. When the mortal is unfaithful to the nymph, the king of the nymphs places a curse on the mortal. The king's curse makes the mortal responsible for remembering to perform all bodily functions, even those that occur automatically, such as breathing. When the mortal falls asleep, he "forgets" to breathe and dies.

Congenital central hypoventilation syndrome should be considered in children with episodic or sustained hypoventilation and hypoxemia in the first months of life without obvious cardiopulmonary or neuromuscular disease. Most patients breathe normally while awake but hypoventilate during sleep. In 1962, Severinghaus and Mitchell coined the term Ondine curse to describe a syndrome that manifested in 3 adult patients after high cervical and brainstem surgery. When awake and summoned to breathe, these patients did so; however, they required mechanical ventilation for severe central apnea when asleep. In 1970, Mellins and colleagues first reported an infant with the clinical features of congenital central hypoventilation syndrome.

Children with congenital central hypoventilation syndrome have progressive hypercapnia and hypoxemia when asleep, particularly during quiet sleep and, to a lesser extent, during rapid eye movement (REM) sleep. Unfortunately, patients with congenital central hypoventilation syndrome also lack an arousal response to hypoxemia and hypercapnia. Therefore, mechanical ventilation is the only therapeutic option. However, ventilation can be adequate while the patient is awake.

Pathophysiology

Remarkable progress has been made in determining the genetic basis of congenital central hypoventilation syndrome and in recognizing that this disordered respiratory control syndrome actually represents a more global phenomenon of autonomic nervous syndrome (ANS) dysregulation.

A genetic defect for congenital central hypoventilation syndrome has been speculated because of its occurrence in certain families, suggesting a codominant Mendelian inheritance of a major gene. Vertical transmission has been reported in at least 5 women, and symptoms of ANS dysfunction in families are prevalent. Approximately 20% of all reported congenital central hypoventilation syndrome cases are accompanied by Hirschsprung disease. The association of these 2 relatively rare clinical entities suggests a possible common pathogenetic basis.

Initial attempts at identifying the gene were directed at genes known to be associated with Hirschsprung disease, including receptor tyrosine kinase (ret), endothelin-signaling pathway genes, glial-derived neurotrophic factor, and other genes involved in neural crest cell migration and ANS development. However, many of these mutations occur in family members who do not have congenital central hypoventilation syndrome. Although initial studies show mutation of PHOX2B in 62% of patients with congenital central hypoventilation syndrome in France and 40% in Japan, more recent studies have identified mutations of the PHOX2B gene in almost 93-100% of probands with congenital central hypoventilation syndrome.^1,2 PHOX2B is located on chromosome 4p12 and was initially identified in mice deficient in PHOX2B that died in utero with absent ANS circuits. The specific mutation appears to be a polyalanine repeat expansion in the second polyalanine repeat sequence in exon3of PHOX2B.

Weese-Mayer et al (2004) reported on 20 individuals with unique protein-altering mutations in other genes, as follows:³

• Eight unrelated individuals had ret mutations.
• One individual had a GDNF mutation.
• One individual had an EDN3 mutation.
• One individual had a BDNF mutation.
• Five individuals had HASH1 mutations.
• One individual had a PHOX2A mutation.
• One individual had a GFRA1 mutation.
• One individual had a BMP2 mutation.
• One individual had an ECE1 mutation.

Nine of 16 individuals evaluated had PHOX2B polyalanine repeat expansion mutations. Three of these 9 patients were identified as having ret mutations, 3 with HASH1 mutations, one with a GDNF mutation, one with a BDNF mutation, and one with a GFRA1 mutation. The PHOX2B repeat expansion mutations were associated with congenital central hypoventilation syndrome. Parental samples from these families were analyzed. The ret, GDNF, BDNF, and HASH1 mutations were not associated with congenital central hypoventilation syndrome. Therefore, the role of mutations in genes other than PHOX2B in congenital central hypoventilation syndrome causation is unclear. 

Whether family members of people with congenital central hypoventilation syndrome are also affected is unclear. On one hand, family members of people with congenital central hypoventilation syndrome do not have evidence of respiratory control dysfunction. On the otherhand, many family members have some derangement in ANS function.

ANS dysfunction

Structural CNS abnormalities

Physiologic abnormalities of ventilatory control

Interestingly, despite absent rebreathing ventilatory responses to both hypercapnia and hypoxia, most patients with congenital central hypoventilation syndrome are able to maintain adequate spontaneous ventilation during wakefulness, and this ability probably relates to residual peripheral chemoreceptor function in these patients (ie, positive response to transient changes in carbon dioxide or oxygen concentration in respired gas).

Because chemoreceptors are considered to be important controllers of ventilation during exercise and because parents of children with congenital congestive hypoventilation syndrome do not report major limitations in the ability of their children to participate in regular physical activities, incremental exercise tests on a treadmill were performed in children with congenital central hypoventilation syndrome. These studies showed that movement of the lower limbs exerts a dominant influence on the respiratory rate and, consequently, on the increase of minute ventilation during exercise.

These findings were confirmed when similar increases in ventilation were found during application of passive motion in these children. Thus, in a setting of deficient integration of respiratory control inputs, mechanoreceptor afferent input from muscles and joints, rhythmic entrainment of respiration, or both take over and play a significant role in the modulation of breathing during exercise in children with congenital central hypoventilation syndrome.

Congenital central hypoventilation syndrome is characterized by dysfunction in the metabolic control of breathing; therefore, more severe gas-exchange disturbances occur during non-REM sleep. This is clearly in contrast with other sleep-disordered breathing, such as obstructive asleep apnea syndrome, in which gas-exchange abnormalities preferentially occur during REM sleep. These unique findings during non-REM sleep suggest that the intrinsic defect in congenital central hypoventilation syndrome is always present but becomes more prominently expressed at times when other overlapping mechanisms are less active or inoperative.⁶

Because ventilatory and arousal responses to respiratory stimuli may at least partially involve separate neural pathways, if children with congenital central hypoventilation syndrome have a disorder of chemoreceptor input integration, they may still arouse to respiratory stimuli. Marcus et al (1991) showed that most children with congenital central hypoventilation syndrome aroused to hypercapnia.⁷ This suggests that the most probable mechanism for congenital central hypoventilation syndrome is a brainstem lesion in the area where input from chemoreceptors is integrated.

Frequency

United States

Congenital central hypoventilation syndrome is a very rare disorder with an estimated prevalence of 1 case per 200,000 live births.⁸

International

Some speculate that about 300 children worldwide have congenital central hypoventilation syndrome.³

Mortality/Morbidity

The clinical outcome of children with congenital central hypoventilation syndrome has markedly changed since the description of the disorder. In the past, most patients presented with neurocognitive deficits of varying severity, stunted growth, cor pulmonale, and/or seizure disorders; however, early diagnosis and institution of adequate ventilatory support to prevent recurrent hypoxemic episodes clearly offers the potential for improved growth and development and should be associated with normal longevity. Mortality is primarily due to complications that stem from long-term mechanical ventilation or from the extent of bowel involvement when Hirschsprung disease is present. Nevertheless, stressing that the characteristic central hypoventilation during sleep is a life-long symptom is important.

Neural crest tumors have also been associated with congenital central hypoventilation syndrome. Therefore, the prognosis depends on adequate treatment of the underlying tumor.

Race

No differences in the occurrence of congenital central hypoventilation syndrome are evident based on race.

Sex

Both sexes appear to be equally affected.

Age

Congenital central hypoventilation syndrome is present at birth, although the diagnosis may be delayed because of variations in the severity of the manifestations or lack of awareness in the medical community, particularly in milder cases.

Clinical

History

The clinical presentation of patients with congenital central hypoventilation syndrome (CCHS) may widely vary and depends on the severity of the hypoventilation disorder. Some infants do not breathe at birth and require assisted ventilation in the newborn nursery. Most infants with congenital central hypoventilation syndrome who present in this manner do not spontaneously breathe during the first few months of life but may mature and have a pattern of adequate breathing during wakefulness over time; however, apnea or central hypoventilation persists during sleep. This apparent improvement over the first few months of life is believed to result from normal maturation of the respiratory system (eg, improved respiratory mechanics, postnatal development and compensation) and does not represent a true change in the basic deficit in respiratory control.

Other infants may present at a later age, with cyanosis, edema, and signs of right heart failure as the first indications of congenital central hypoventilation syndrome. These symptoms in infants have often been mistaken for those of cyanotic congenital heart disease; however, cardiac catheterization reveals only pulmonary hypertension. Infants with less severe congenital central hypoventilation syndrome may present with tachycardia, diaphoresis, and/or cyanosis during sleep.

Presumably, if the diagnosis is not made, right heart failure develops as a consequence of repeated hypoxemic and hypercapnic episodes during sleep. Still others may present with unexplained apnea or an apparent life-threatening event; some may even die and be categorized as having sudden infant death syndrome. Thus, the wide spectrum of severity in clinical manifestations dictates the age at which recognition of congenital central hypoventilation syndrome takes place. Increased awareness of this unusual clinical entity and a comprehensive evaluation of every patient are critical for early diagnosis and appropriate intervention.

• Sleep-dependent hypoventilation in the absence of neuromuscular, heart, or lung disease is the hallmark of congenital central hypoventilation syndrome.
  • The severity of hypoventilation widely varies. In severe cases, hypoventilation is also present during wakefulness. Late-onset central hypoventilation syndrome has also been described.
  • Patients with congenital central hypoventilation syndrome have an absent or blunted ventilatory response to sustained hypercapnia. They also have a depressed ventilatory response to sustained hypoxia.
• Patients with congenital central hypoventilation syndrome have disorders of autonomic nervous syndrome (ANS) control, with abnormalities in heart rate, blood pressure, and pupil diameter control. Although baseline heart rate in persons with congenital central hypoventilation syndrome does not differ from controls, the relative increase above the mean heart rate at rest and with exercise is attenuated and heart rate variability is decreased.⁸ Children with congenital central hypoventilation syndrome exhibit an increased frequency of arrhythmia, primarily sinus bradycardia, and transient asystole, with documented pauses as long as 6.5 seconds in congenital central hypoventilation syndrome compared with 1.4 seconds in controls. Children with congenital central hypoventilation syndrome exhibited lower blood pressure values during wakefulness and higher blood pressure values during sleep compared with controls, indicating attenuation of the normal sleep-related blood pressure decrement.
• The enteric nervous system may also be abnormal; about 15-20% of patients with congenital central hypoventilation syndrome also have Hirschsprung disease.
• Neural crest–derived tumors such as neuroblastoma are present in about 5% of patients with congenital central hypoventilation syndrome. The PHOX2B gene is speculated to be the first gene for which germline mutations can be shown to predispose to neuroblastoma.⁹ In 1978, the co-occurrence of Hirschsprung disease and central hypoventilation was named Haddad syndrome and was later expanded to include neuroblastoma, a triad currently known as the neurocristopathy syndrome.¹⁰

Physical

Unless Hirschsprung disease is present, no major diagnostic findings are present upon physical examination; in most cases, only subtle manifestations are present.

• Infants may be hypotonic, display thermal lability, and have occasional and sudden hypotensive events that are unexplainable based on the surrounding circumstances. These manifestations usually improve over time.
• Gastroesophageal reflux and decreased intestinal motility with constipation are often present in younger patients.
• Ocular findings (eg, abnormal pupils that are miotic, anisocoric, or abnormally responsive to light) can be found in 70% of cases. Abnormal irides (60% of cases); strabismus (50% of cases); and, on occasion, lack of tears during crying, can also be found. Thus, referring children with congenital central hypoventilation syndrome for a thorough ophthalmologic evaluation is important.
• In congenital central ventilation syndrome, ventilation is most severely affected during quiet sleep, the state in which automatic neural control is predominant. Ventilatory patterns are also abnormal during active sleep and even during wakefulness, although to a milder degree. The severity of respiratory dysfunction may range from relatively mild hypoventilation during quiet sleep with fairly good alveolar ventilation during wakefulness to complete apnea during sleep with severe hypoventilation during wakefulness.
• Other signs indicative of brainstem dysfunction, such as poor swallowing, may be present but are not essential to the diagnosis of congenital central hypoventilation syndrome.
• Congenital central hypoventilation syndrome is diagnosed in individuals with the following:¹¹
  • Hypoventilation with absent or negligible ventilatory sensitivity to hypercarbia and absent or variable ventilatory sensitivity to hypoxemia
  • Generally adequate ventilation while awake, but hypoventilation with normal respiratory rate and shallow breathing (diminished tidal volume) during sleep
  • Hypoventilation both while awake and asleep
  • Absent perception of asphyxia (ie, absent behavioral awareness of hypercarbia and hypoxemia) and absent arousal
  • No evidence of primary neuromuscular, lung, or cardiac disease or identifiable brain stem lesion that might account for the constellation of symptoms

Causes

PHOX2B is the main disease-causing gene for congenital central hypoventilation syndrome, an autosomal dominant disorder with incomplete penetrance. Secondary central hypoventilation syndrome may result from other conditions or occurrences (eg, brainstem tumor or other space-occupying lesions, vascular malformations, CNS infection, stroke, neurosurgical procedures to the brain stem).

• Correlations with genotype and phenotype have been described in patients with congenital central hypoventilation syndrome. An association with the number of PHOX2B repeats and the number of ANS dysfunction symptoms and the severity of respiratory disorders have been reported.
• Patients with congenital central hypoventilation syndrome who develop malignant neural crest–derived tumors have either a missense or a frameshift heterozygous mutation in the PHOX2B gene. Therefore, a subset of patients with congenital central hypoventilation syndrome who are at risk for developing malignant tumors may be identified.

Differential Diagnoses

Other Problems to Be Considered

A structural hindbrain or brainstem abnormality
Congenital myasthenic syndrome
Diaphragm dysfunction
Mobius syndrome

Workup

Laboratory Studies

• In patients with suspected congenital central hypoventilation syndrome (CCHS), perform urine collection for amino acids and organic acids to evaluate for metabolic disorders that may occur as recurrent apparent life-threatening events or cyanotic spells.
• For PHOX2B testing, contact Rush University Genetics Laboratory at (312) 942-6298.

Imaging Studies

• Imaging studies of the CNS are strongly recommended. Computerized axial tomographic scans of the brain have been used in the past but have a low yield in the evaluation of brainstem regions because of bone-air interface reconstruction artifacts. Thus, when congenital central hypoventilation syndrome is suspected, T1 and T2 MRI testing is currently the recommended imaging approach for anatomic evaluation of the CNS. Using a 3.0-Tesla MRI unit, increased mean diffusivity (MD) values suggest regional alterations or injury.
• Perform cardiac evaluation, including chest radiography and echocardiography.
• Perform diaphragm fluoroscopy, ultrasonography, or both to rule out unilateral or bilateral diaphragmatic paralysis or paresis. On occasion, measuring maximal transdiaphragmatic pressures against an occluded airway when the patient is crying and breathing 100% oxygen or, preferentially, a mixture that contains 95% oxygen and 5% carbon dioxide may be useful.

Other Tests

• Although specific methods for establishing the diagnosis of congenital central hypoventilation syndrome vary among medical centers, the following guidelines for evaluation of a patient exemplify a typical approach in a tertiary center:  
  • Administer a polysomnographic study in a well-equipped laboratory to carefully determine respiratory patterning and gas-exchange abnormalities during different behavioral states. Because many infants may not be sufficiently stable to undergo polysomnographic studies while spontaneously breathing, documenting the changes in cardiorespiratory behavior and related consequences by performing brief discontinuations of mechanical ventilatory support during each sleep stage is important. Periodically repeat these studies because significant developmental changes occur in sleep and respiratory patterns during the first year of life. A sleep study needs to be performed every 3-4 months during the first 2 years of life and every 6 months until the child is aged 5-6 years. Annual evaluation after age 6 years is usually adequate if the patient is stable.
  • Although hypercapnic ventilatory challenges are not specifically included in the proposed diagnostic criteria, they are an essential component for the diagnosis of congenital central hypoventilation syndrome. Steady-state or rebreathing approaches are similarly valid. For steady-state challenges, the use of 3%, 5%, and 7% carbon dioxide balance in oxygen for 20-30 minutes at each level is usually appropriate; it is also easier to deliver when patients are mechanically ventilated. In infants, the use of calibrated respiratory inductance plethysmography is helpful to determine, in a semiquantitative fashion, whether a ventilatory increase is apparent during spontaneous breathing, during wakefulness in milder patients, or as a ventilatory change from the stable ventilation provided by the mechanical ventilatory settings.
  • At a later stage, pursue more quantitative measurements with a mask and pneumotachograph if the patient is awake or by incorporating a pneumotachograph to the ventilator circuit if the patient is asleep. These studies must be conducted in each of the defined states (ie, waking, rapid eye movement [REM], non-REM) so they can be incorporated into the polysomnographic evaluation described above.
• Obtain an electrocardiography as part of the cardiac evaluation.
• If extensive hypotonia is present, nerve conduction studies and electromyography (EMG) may be required after extensive clinical neurologic assessment.
• Perform an ophthalmologic examination (ie, careful pupillary assessment) to assess for autonomic ophthalmologic abnormality.
• Neurocognitive assessment is used to determine baseline function.

Procedures

• If extensive hypotonia is present, muscle biopsy may be required after extensive clinical neurologic assessment.
• If Hirschsprung disease is suspected, consider rectal biopsy.

Treatment

Medical Care

Congenital central hypoventilation syndrome (CCHS) is a lifelong condition. A multidisciplinary approach to provide for comprehensive care and support of every child is needed.

• General measures
  • Infants with congenital central hypoventilation syndrome may have significant hypotonia and temporary feeding difficulties. In addition, moderate-to-severe gastroesophageal reflux is frequently present. Initiate early administration of prokinetic agents and antireflux medications in patients with hypotonia, temporary feeding difficulties, and gastroesophageal reflux; furthermore, begin nasogastric feeding to provide adequate nutrition. More radical approaches (eg, percutaneous gastrostomy tube feeding insertion, antireflux surgical procedures, or both) may be necessary if these problems are severe or persistent.
  • For patients with Hirschsprung disease, surgical intervention and, sometimes, colostomy to relieve the distal intestinal obstruction may be required. Although little attention has been given to the visual system of children with congenital central hypoventilation syndrome, ophthalmoplegia, and other ocular anomalies have long been recognized to be occasionally present; therefore, a thorough and periodic (ie, every year) ophthalmologic evaluation is necessary.
• Respiratory stimulants: Attempts to enhance the respiratory stability and promote eucapnia in patients with congenital central hypoventilation syndrome failed when pharmacologic approaches were used. Trials with doxapram in 2 infants and with the carotid body stimulant almitrine bismesylate in 13 patients did not show consistent improvements in spontaneous ventilatory or gas-exchange parameters. Therefore, respiratory stimulants have no current role in the treatment of congenital central hypoventilation syndrome.
• Invasive mechanical ventilatory support
  • To date, most centers that provide long-term home care for children with congenital central hypoventilation syndrome use positive-pressure ventilation through a permanent tracheotomy. The types of positive-pressure ventilators used in the home vary among centers and have gradually evolved, reflecting the dynamic needs of the population of patients with congenital central hypoventilation syndrome and the technical developments in the field.
  • Ventilators should be used in the spontaneous intermittent mandatory ventilation (SIMV) mode. Because an uncuffed tracheostomy should be used to minimize granuloma formation, ventilator settings should compensate for air leaks around the tracheotomy tube by increasing volume and peak airway pressure as necessary.
  • Pressure plateau ventilation is suggested to be a useful alternative in home mechanical ventilation of children with congenital central hypoventilation syndrome who are not receiving adequate ventilation with standard volume ventilation using demand compressor ventilators. The pressure-limited plateau ventilatory technique uses a volume ventilator but in a pressure-limit assist/control mode. Therefore, large volumes can be dialed as tidal volume into the ventilator. Because pressure is limited, the excess volume, which was not used to achieve the pressure plateau with each breath, is discarded via the pressure relief valve. This approach allows for breath-by-breath compensation of variable leaks. Pressure plateau ventilation is particularly useful in young patients and obviates the need for cuffed tubes or the use of ventilators that require continuous gas flow.
  • The recent availability of continuous-delivery compressors in home ventilators now permits domiciliary and ambulatory administration of ventilator modes traditionally reserved for intensive care units. Mildly hyperventilating patients with CCHS during their sleep to achieve PCO₂ near 30-35 mm Hg is recommended. Mild nighttime hyperventilation results in better daytime spontaneous ventilation and gas exchange ("sprinting").
• Noninvasive ventilatory support
  • Experience with negative-pressure ventilation (NPV) in patients with congenital central hypoventilation syndrome has been favorable; however, it is restricted to only a few centers in the United States and the world. This ventilatory modality is cumbersome and requires significant equipment adjustments over time. In addition, noninvasive ventilatory support may be associated with upper airway obstruction during sleep in younger children with congenital central hypoventilation syndrome, most probably elicited by absent pharyngeal dilator activation during non-centrally mediated inspiration. Also, NPV relies on the ability of chest wall movement. Hence patients with chest wall deformity may not be good candidates for NPV.
  • More recently, transition from invasive mechanical ventilation to nasal mask ventilation has been reported in patients with congenital central hypoventilation syndrome who are older than 7-8 years and who were nocturnally dependent on the ventilator. One study showed that mask ventilation can be safely commenced at an early age in children affected with congenital central hypoventilation syndrome. It is not only effective but is the preferred mode of ventilatory support by parents and patients, and even children who are established on other modes of ventilatory support can also be successfully weaned on to mask ventilation within a short period.¹²
  • Mask desensitization is important for compliance with bilevel positive airway pressure (BiPAP) use, especially in younger patients. However, BiPAP use 24 h/d disrupts daily activities and social interaction and may cause mid-face hypoplasia.
• Diaphragm pacing
  • Daytime diaphragm pacing in children with congenital central hypoventilation syndrome provides greater mobility than mechanical ventilation.¹³ Thus, candidates for diaphragm pacing are potentially ambulatory patients who require ventilatory support 24 h/d via tracheotomy and who do not exhibit significant ventilator-related lung damage. Diaphragm pacer settings must provide adequate alveolar ventilation and oxygenation during rest and daily activities.
  • Aside from cost, potential discomfort may be associated with surgical implantation and possible need for surgical revisions because of pacer malfunction. Diaphragm pacing requires increased level of fitness of the diaphragm. This is achieved by gradually increasing the length of time the child is paced. Most children can tolerate approximately 12-14 hours of pacing per day. Despite these limitations, most parental reports regarding diaphragm pacing are favorable. Development of a quadripolar electrode offers several advantages that primarily include greater durations of diaphragmatic pacer support at diminished risk of phrenic nerve damage, decreased diaphragmatic fatigue, and optimization of pacing requirements during exercise. Therefore, as equipment improves, the need to replace components is lessened.¹⁴
  • Deciding on the most appropriate type of ventilatory support requires referral to specialized centers with personnel experienced in diaphragm pacing.

Surgical Care

Surgical interventions include traditional procedures.

• Tracheotomy may be indicated for ventilatory support.
• Colostomy is sometimes required when Hirschsprung disease is present.
• When feeding problems arise, particularly during infancy, gastrostomy tube placement with or without antireflux procedures may be required.
• Usual postoperative follow-up care for these procedures is necessary but does not differ from the care needed by any other patient.

Consultations

The diagnostic evaluation of patients with congenital central hypoventilation syndrome requires a multidisciplinary approach involving many specialists.

• Neurologist: Consultation with a pediatric neurologist is recommended in the evaluation of hypotonia or or seizure activity (seizures can occur in some children with congenital central hypoventilation syndrome spontaneously or as a result of acute hypoxia). Nerve conduction studies, electromyography (EMG), muscle biopsy, auditory-evoked potentials, EEG, and imaging studies of the CNS may be necessary.
• Cardiologist: Evaluation by a cardiologist is suggested to exclude any cardiac involvement.
• Gastroenterologist: Evaluation by a gastroenterologist is suggested to rule out bowel hypomotility, to evaluate for gastroesophageal reflux, and to assist in management of Hirschsprung disease.
• Ear, nose, and throat (ENT) specialist: Evaluation by an otolaryngologist is suggested for tracheostomy evaluation, surgery, and regular postoperative and long-term care.
• Social worker, speech therapist, respiratory therapist, and other health care specialists: Evaluation by these specialists is suggested to provide multidisciplinary care and follow-up.
• Child behavior specialist: Periodic developmental assessment by a child behavior specialist is suggested.

Activity

Children with congenital central hypoventilation syndrome can lead active lives and are not restricted from any of the usual activities engaged by healthy children. In water activities, such as swimming, special protective devices are required for the tracheostomy tube to prevent aspiration. Nevertheless, many children with congenital central hypoventilation syndrome participate in aquatic activities without any identifiable adverse consequence. Patients require close supervision by the parents or caretakers while swimming or while playing in swimming pools or similar situations. This is because these children do not sense air hunger while diving and can therefore become severely hypoxic underwater and lose consciousness.

Medication

As noted in Treatment, the use of medications is restricted to the treatment of associated diseases rather than the primary disorder, which requires some sort of ventilatory support. These patients frequently have problems with gastroesophageal reflux.

Prokinetic agents

These agents are useful in the management of gastroesophageal reflux, which is a frequent manifestation in patients with congenital central hypoventilation syndrome (CCHS), particularly during their younger years.

Metoclopramide (Reglan, Clopra, Maxolon)

Improves GI motility by releasing acetylcholine from myenteric plexus resulting in contraction of the smooth muscle. Available in 5-mg and 10-mg tabs, 5 mg/mL syrup, and 5 mg/mL injection. Administer 30 min ac.

Dosing

Adult

5-10 mg PO or 5-20 mg IV/IM tid

Pediatric

0.1-0.2 mg/kg/dose PO/IV/IM up to qid; not to exceed 0.8 mg/kg/d

Interactions

Anticholinergics may antagonize effects of metoclopramide; opioid analgesics may increase CNS toxicity

Contraindications

Documented hypersensitivity; pheochromocytoma or GI hemorrhage, obstruction, or perforation; history of seizure disorders

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in history of mental illness, renal impairment, and Parkinson disease; may cause extrapyramidal symptoms, especially at higher doses; adverse effects include sedation, headache, anxiety, leukopenia, and diarrhea

Cisapride (Propulsid)

Indirectly improves GI motility by promoting acetylcholine release from postganglionic nerve endings in the myenteric plexus. Accelerates gastric emptying and enhances LES tone.
Withdrawn from US market on July 14, 2000. Manufacturer may make available to certain patients who meet clinical eligibility criteria for limited-access protocol only.
Available in 10-mg and 20-mg tabs and an oral susp (1 mg/mL).

Dosing

Adult

10 mg PO qid 15 min ac

Pediatric

<1 month: 0.1-0.2 mg/kg/dose PO q6-12h 15 min ac; not to exceed 0.8 mg/kg/d
>1 month: 0.2-0.3 mg/kg/dose PO tid/qid 15 min ac; not to exceed 10 mg/dose

Interactions

Do not use in conjunction with drugs that prolong QT interval (eg, quinidine, TCAs, phenothiazines); concurrent use with drugs that inhibit CYP3A4 (eg, ketoconazole, itraconazole, miconazole, erythromycin, fluconazole, clarithromycin, indinavir, ritonavir, nefazodone) may increase levels and induce fatal cardiac arrhythmias; decreases effects of atropine and digoxin; increases toxicity of warfarin, diazepam, cimetidine, ranitidine, and CNS depressants

Contraindications

Documented hypersensitivity; GI perforation, hemorrhage, or mechanical obstruction; history of prolonged electrocardiographic QT intervals or known family history of congenital long QT syndrome; medications that prolong QT interval and increase risk of arrhythmia including certain antipsychotics, antiarrhythmics, and antidepressants; uncorrected hypokalemia or hypomagnesemia or patients who may experience rapid reduction of plasma potassium such as those administered potassium-wasting diuretics and/or insulin in acute settings; concomitant administration with drugs that inhibit CYP3A4 (eg, fluconazole, erythromycin, ketoconazole, itraconazole, miconazole, clarithromycin, troleandomycin, indinavir, amprenavir, ritonavir) may lead to elevated blood levels

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in neonates because of increased risk for cardiac arrhythmias; adverse effects include headaches, cramps, colic, and diarrhea; ECG and measurement of QTc interval recommended before and 2 wk after treatment initiation

Follow-up

Further Outpatient Care

• Periodic follow-up is necessary and is usually more frequent in younger children with congenital central hypoventilation syndrome (CCHS). Follow-up incorporates multidisciplinary approaches, aiming to determine that all areas receiving care are addressed. In addition, adequacy of ventilatory support must be established based on an overnight sleep study in the laboratory.
• The CCHS family network provides community support.

Complications

• Major complications of congenital central hypoventilation syndrome relate to delay in diagnosis or to complications associated with procedures (eg, tracheostomy, gastrostomy tube, colostomy).
• Rarely, patients may develop neural crest–derived tumors (eg, ganglioneuroma, neuroblastoma, ganglioneuroblastoma).

Prognosis

• Overall, the prognosis of patients with congenital central hypoventilation syndrome is excellent if the diagnosis is prompt and medical management is appropriate; however, neurocognitive deficits of varying severity, stunted growth, cor pulmonale, and/or seizure disorders are frequent in older patients who may not have benefited from prompt recognition or intervention.

Patient Education

• For excellent patient education resources, visit eMedicine's Children's Health Center. Also, see eMedicine's patient education article Sudden Infant Death Syndrome (SIDS).

Miscellaneous

Medicolegal Pitfalls

• The major medicolegal situations that may develop primarily involve the delayed diagnosis of congenital central hypoventilation syndrome (CCHS) or the assignment of causal relationships between congenital central hypoventilation syndrome and any type of fetal exposure.
• For example, legal issues may arise from the potential association between ingestion of any given medication or exposure to a particular environmental situation; however, no current evidence links a particular teratogen to congenital central hypoventilation syndrome. Thus, although the embryology of the neural crest is still actively researched and is clearly linked to congenital central hypoventilation syndrome, no associations between exposure to chemicals during a particular phase of pregnancy and ultimate development of congenital central hypoventilation syndrome are noted.
• A more frequent, albeit less argumentative, issue involves the recognition and diagnosis of congenital central hypoventilation syndrome. Infants who develop apnea or apparent life-threatening events during early postnatal life could have a mild variant of the wide clinical spectrum of congenital central hypoventilation syndrome and ultimately die of sudden infant death syndrome. Because the manifestations in cases of sudden infant death syndrome/congenital central hypoventilation syndrome are subtle, diagnosing congenital central hypoventilation syndrome and preventing sudden infant death syndrome would be impossible.
• On the other side of the severity spectrum, multiple unsuccessful trials to wean mechanical ventilation in an otherwise full-term baby should raise the suspicion for central hypoventilation syndrome, either congenital or secondary to other conditions. Early recognition of the appropriate diagnostic entity using the diagnostic approach elaborated in Workup prevents unnecessary delays in tracheotomy and in the institution of mechanical ventilatory support using a home ventilator, thereby accelerating the discharge process and preventing iatrogenic complications (eg, self extubation, acute and chronic tracheal injury) that arise from ventilatory support using an endotracheal tube.

Special Concerns

• Congenital central hypoventilation syndrome is a diagnosis of exclusion. This means that cardiac, neurologic, pulmonary, and generalized disorders need to be excluded before the diagnosis of congenital central hypoventilation syndrome is established.

References

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Keywords

congenital central hypoventilation syndrome, CCHS, Ondine curse, Ondine's curse, sleep-induced apnea, central apnea, central hypoventilation, autonomic nervous system dysregulation, ANS dysregulation, Hirschsprung disease, Hirschsprung's disease, obstructive sleep apnea syndrome, sudden infant death syndrome, Rett syndrome, stunted growth, cor pulmonale, neural crest tumors, apnea, heart failure, apparent life-threatening event, SIDS, neuroblastoma, gastroesophageal reflux

Contributor Information and Disclosures

Author

Terry Chin, MD, PhD, Associate Professor of Pediatrics, Pediatric Allergy/Immunology/Pulmonology, Department of Pediatrics, University of California Irvine School of Medicine; Associate Director, Miller Children's Hospital at Long Beach Memorial Medical Center
Terry Chin, MD, PhD is a member of the following medical societies: American Academy of Allergy Asthma and Immunology, American Association of Immunologists, American College of Allergy, Asthma and Immunology, American College of Chest Physicians, American Thoracic Society, California Thoracic Society, Clinical Immunology Society, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Cyrus M Shahriary, MD, Fellow, Pediatric Pulmonology, University of California at Irvine, Miller Children's Hospital
Cyrus M Shahriary, MD is a member of the following medical societies: American Academy of Pediatrics, Iran Medical Council, and Iranian Society of Pediatrics
Disclosure: Nothing to disclose.

David Gozal, MD, Vice-Chairman of Research and Director, Kosair Children's Hospital Comprehensive Sleep Medicine Center, Professor, Department of Pediatrics, University of Louisville
David Gozal, MD is a member of the following medical societies: Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Girish D Sharma, MD, Associate Professor, Department of Pediatrics, Rush University Medical Center, Rush Children's Hospital; Director of Pediatric Pulmonary Section and Rush Cystic Fibrosis Center
Girish D Sharma, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, American Thoracic Society, and Royal College of Physicians of Ireland
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Heidi Connolly, MD, Associate Professor of Pediatrics and Psychiatry, University of Rochester; Director, Pediatric Sleep Medicine Services, Strong Sleep Disorders Center
Heidi Connolly, MD is a member of the following medical societies: American Academy of Pediatrics, American Thoracic Society, and Society of Critical Care Medicine
Disclosure: Nothing to disclose.

CME Editor

Mary E Cataletto, MD, Associate Director, Division of Pediatric Pulmonology, Winthrop University Hospital; Professor of Clinical Pediatrics, State University of New York at Stony Brook; Director of Children's Sleep Services, Winthrop University Hospital
Mary E Cataletto, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Chest Physicians
Disclosure: Shering Plough Pharmaceuticals Honoraria Consulting

Chief Editor

Michael R Bye, MD, Professor of Clinical Pediatrics, Division of Pulmonary Medicine, Columbia University College of Physicians and Surgeons; Attending Physician, Pediatric Pulmonary Medicine, Columbia University Medical Center
Michael R Bye, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Chest Physicians, and American Thoracic Society
Disclosure: Merck Honoraria Speaking and teaching

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Mariam M Ischander, MD, to the development and writing of this article.

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