Central alveolar hypoventilation, a disorder of impaired ventilatory response to hypercapnia and hypoxemia, may be congenital, acquired, or idiopathic. Congenital central hypoventilation syndrome (CCHS) is most often caused by mutation of the gene PHOX2B and generally presents during the first year of life as respiratory failure in a neonate necessitating mechanical ventilation. These patients exhibit hypoventilation, which is generally worsened in sleep, and they may also suffer from varying degrees of dysautonomia. Rarely, these mutations are associated with neurocristopathies including Hirschsprung disease and malignancies of neural crest origin. Evidence is emerging linking PHOX2B mutations to structural changes within the central nervous system in patients affected by congenital central hypoventilation syndrome. The idiopathic form is characterized by decreased alveolar ventilation that leads to nocturnal hypercapnia in individuals who have no lung disease, obesity, skeletal malformation, or neuromuscular disorder to account for the hypoventilation. Central hypoventilation may also arise as an acquired disease in the context of brainstem injury or structural disorder.
| || |
• Central alveolar hypoventilation may be congenital (genetic), acquired, or idiopathic.
| || |
• The underlying neurologic disorder involves an absent or reduced response to carbon dioxide resulting in hypercapnia and hypoxemia.
| || |
• A thorough evaluation should be performed in all cases to rule out other identifiable neuromuscular, cardiopulmonary, and skeletal etiologies.
| || |
• Genetic testing and neurologic imaging are indicated in all suspected cases.
| || |
• Early diagnosis and initiation of nocturnal noninvasive positive pressure ventilation is a key therapeutic strategy.
Historical note and terminology
Congenital central alveolar hypoventilation syndrome was first described in 1970, and the genetic etiology was finally elucidated in 2003 (63; 04). A full description may be found in the 2014 International Classification of Sleep Disorders—Third Edition (ICSD-3) under the name congenital central alveolar hypoventilation syndrome (01).
The term Ondine’s curse, which was first applied to the condition of central alveolar hypoventilation in a 1962 case series of 3 adult patients with high cervical and brainstem lesions following surgery, is derived both from an 1811 novella, Undine, by the German writer Friedrich de la Motte Fouqué and from a subsequent reimagining of the story in the 1938 play “Ondine” by Jean Giradoux (85; 31). In this play, Ondine, a water nymph, falls in love with a knight named Hans. However, their love is ill-fated, and when Ondine is jilted by Hans, her uncle, the King of the Sea, curses Hans. Hans loses all automaticity: “I don’t see unless I tell my eyes to see… A moment of inattention and I forget to hear, to breathe…” When he finally falls asleep, Hans stops breathing and dies. Ondine’s curse, therefore, properly refers only to the condition where hypoventilation is restricted to the sleeping state.
The idiopathically acquired form of central alveolar hypoventilation is also described in the ICSD-3 under Sleep-Related Nonobstructive Alveolar Hypoventilation, Idiopathic. It is characterized by blunted chemoresponsiveness in the absence of identifiable abnormalities (pulmonary, cardiac, neurologic, or muscular). When hypoventilation occurs during the day (in addition to nocturnal sleep), the condition is referred to as idiopathic (primary) alveolar hypoventilation.