Central alveolar hypoventilation

Kevin Gipson MD MS (

Dr. Gipson of Stanford University has no relevant financial relationships to disclose.

)
Payal Kenia MD (

Dr. Kenia of Stanford University has no relevant financial relationships to disclose.

)
Logan Schneider MD (

Dr. Schneider of Stanford University School of Medicine received a stock grant from Knit Health as an advisor, a stock option from Hatch Baby as an advisor, consulting fees from Jazz Pharmaceuticals as a member of an advisory board, and a consulting fee from Alphabet.

)
Michael J Howell MD, editor. (Dr. Howell of the University of Minnesota received grant support from Apnex and GE and honorariums from Inspire as a panel member.)
Originally released October 1, 1993; last updated November 3, 2018; expires November 3, 2021

This article includes discussion of central alveolar hypoventilation, also known as Ondine's curse or failure of automatic respiration. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

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 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.

Key points

 

• 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 (Mellins et al 1970; Amiel et al 2003). 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 (American Academy of Sleep Medicine 2014).

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 (Severinghaus and Mitchell 1962; Goldblatt 1995). 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.

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