Central hypoventilation syndrome

Central hypoventilation syndrome (CHS) is a sleep-related breathing disorder that causes ineffective breathing, apnea, or respiratory arrest during sleep (and during wakefulness in severe cases). CHS can either be congenital (CCHS) or acquired (ACHS) later in life. The condition can be fatal if untreated. CCHS was once known as Ondine's curse.

Not to be confused with Central sleep apnea.

Central hypoventilation syndrome
Other names	Ondine's curse, primary alveolar hypoventilation, alveolar hypoventilation secondary to neurologic disease, idiopathic acquired central hypoventilation syndrome
Ondine by John William Waterhouse (1849–1917)
Specialty	Neurology

ACHS can develop as a result of severe injury or trauma to the brain or brainstem.[1] Congenital cases are very rare and involve a failure of autonomic control of breathing. In 2006, there were only about 200 known cases worldwide. As of 2008, only 1000 total cases were known.[2] 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.[3] However, as there have been cases where asymptomatic family members also were found to have CCHS, it may be that these figures only reflect those found to require mechanical ventilation. In all cases, episodes of apnea occur in sleep, but in a few patients, at the most severe end of the spectrum, apnea also occurs while awake.

Although rare, cases of long-term untreated CCHS have been reported and are termed late onset CCHS (LO-CCHS).[4] There have, however, even been cases of LO-CCHS where family members found to have it have been asymptomatic.[5] Again, lack of awareness in the medical community may cause such a delay.[6] CCHS susceptibility is not known to be affected by gender.[3]

Signs and symptoms

CHS is associated with respiratory arrests during sleep and, in some cases, to neuroblastoma (tumors of the sympathetic ganglia), Hirschsprung disease (partial agenesis of the enteric nervous system),[7] dysphagia (difficulty swallowing) and anomalies of the pupilla. Other symptoms include darkening of skin color from inadequate amounts of oxygen, drowsiness, fatigue, headaches, and an inability to sleep at night. Patients with CHS also have a sensitivity to sedatives and narcotics, which makes respiration even more difficult. A low concentration of oxygen in the red blood cells also may cause hypoxia-induced pulmonary vasoconstriction and pulmonary hypertension, culminating in cor pulmonale or a failure of the right side of the heart.[8] Associated complications may also include gastro-esophageal reflux, ophthalmologic issues, seizures, recurrent pneumonia, developmental delays, learning disabilities, episodes of fainting, and temperature disregulation.[9]

Causes

CHS is exhibited typically as a congenital disorder, but in rare circumstances, can also result from severe brain or spinal trauma or injury (such as after an automobile accident, stroke, asphyxiation, brain tumor, encephalitis, poisoning, as a complication of neurosurgery) or due to particular neurodegenerative conditions such as Parkinson's disease, multiple system atrophy, or multiple sclerosis. Long and Allen (1984) were the first to report the abnormal brainstem auditory evoked responses in an alcoholic woman who recovered from Ondine's curse. These investigators hypothesized that their patient's brainstem was poisoned — not destroyed — by her chronic alcoholism.[10]

Medical investigation of patients with this syndrome has led to a deeper understanding of how the body and brain regulate breathing on a molecular level. PHOX2B, a transcription factor involved in the development of neurons,[11] can be associated with this condition.[12][13][14][15] This homeobox gene is important for the normal development of the autonomic nervous system.

The disease used to be classified as a "neurocristopathy",[16][17] or disease of the neural crest because part of the autonomic nervous system (such as sympathetic ganglia) derives from the neural crest. However, this denomination is no longer favored because essential neurons of the autonomic nervous system, including those that underlie the defining symptom of the disease (respiratory arrests), are derived from the neural tube (the medulla), not from the neural crest, although such mixed embryological origins are also true for most other neurocristopathies.

Diagnosis

Children with CCHS develop life-threatening episodes of apnea with cyanosis, usually in the first months of life. Medical evaluation excludes lesions of the brain, heart, and lungs but demonstrates impaired responses to build-up of carbon dioxide (hypercapnia) and decreases of oxygen in the circulation (hypoxia), the two strongest stimuli to increase breathing rate.

Polysomnography shows that hypoventilation is most marked during slow-wave sleep. In the most severe cases, hypoventilation is present during other nonrapid eye movement sleep stages and even wakefulness. A subset of CCHS patients are at very high risk for developing malignant neural crest-derived tumors, such as neuroblastoma.

The sequence of PHOX2B reveals mutations in 91% of the cases.[7]

As in many disorders that are very rare, an infant with this unusual form of sleep apnea suffers from the probability that their physician has most likely never seen another case and will not recognize the diagnosis. In some locations, such as France, optimal management of patients, once identified, has been aided by the creation of a national registry and the formation of a network of centers.

Treatment

People generally require tracheostomy and lifetime mechanical ventilation on a ventilator in order to survive. However, it has now been shown that biphasic cuirass ventilation can effectively be used without the need for a tracheotomy. Other potential treatments for CHS include oxygen therapy and medicine for stimulating the respiratory system. Currently, problems arise with the extended use of ventilators, including fatal infections and pneumonia.[18]

Prognosis

Most people with CCHS (unless they have the Late Onset form) do not survive infancy, unless they receive ventilatory assistance during sleep. An alternative to a mechanical ventilator is diaphragm pacing.[19]

History

CCHS was first described in 1962 by Severinghaus and Mitchell in three patients following surgery to the upper cervical spinal cord and brainstem.[20]

Etymology

Its name is a reference to the story of Ondine and Hans, characters in Ondine, a 1938 play by Jean Giraudoux based on traditions tracing back through Undine (a novella of 1811) to earlier European folk tales. The water-spirit Ondine tells her future husband Hans, whom she had just met, that "I shall be the shoes of your feet ... I shall be the breath of your lungs". Ondine makes a pact with her uncle the King of the Ondines that if Hans ever deceives her he will die. After their honeymoon, Hans is reunited with his first love Princess Bertha and Ondine leaves Hans only to be captured by a fisherman six months later. On meeting Ondine again on the day of his wedding to Bertha, Hans tells her that "all the things my body once did by itself, it does now only by special order ... A single moment of inattention and I forget to breathe". Hans and Ondine kiss, after which he dies.

See also

• Our Curse, an Oscar-nominated 2013 short documentary film about a child with Ondine's curse

References

1. Jazeela Fayyaz, DO (2017-12-05). Zab Mosenifar, M (ed.). "Hypoventilation Syndromes". Medscape.
2. "Congenital central hypoventilation syndrome". Genetics Home Reference. U.S. National Library of Medicine. Retrieved 5 June 2015.
3. Congenital Central Hypoventilation Syndrome at eMedicine
4. Windisch W, Hennings E, Storre J, Matthys H, Sorichter S (2004). "Long-term survival of a patient with congenital central hypoventilation syndrome despite the lack of continuous ventilatory support". Respiration. 71 (2): 195–8. doi:10.1159/000076685. PMID 15031579.
5. Bygarski, Elizabeth; Paterson, Melanie; Lemire, Edmond G. (April 26, 2013). "Extreme intra-familial variability of congenital central hypoventilation syndrome: a case series". Journal of Medical Case Reports. 7 (1): 117. doi:10.1186/1752-1947-7-117. PMC 3651317. PMID 23622117.
6. Lovell BL, Bullock RE, Anderson KN (March 2010). "An unusual presentation of congenital central hypoventilation syndrome (Ondine's Curse)". Emerg Med J. 27 (3): 237–8. doi:10.1136/emj.2009.072215. PMID 20304901.
7. Trang H, Dehan M, Beaufils F, Zaccaria I, Amiel J, Gaultier C (2005). "The French Congenital Central Hypoventilation Syndrome Registry: general data, phenotype, and genotype". Chest. 127 (1): 72–9. doi:10.1378/chest.127.1.72. PMID 15653965.
8. "Primary alveolar hypoventilation: Ondine's curse". A.D.A.M. Medical Encyclopedia. U.S. National Library of Medicine. September 17, 2010.
9. "CCHS Family Network".
10. Long, K. J.; Allen, N. (October 1984). "Abnormal brain-stem auditory evoked potentials following Ondine's curse". Arch. Neurol. 41 (10): 1109–10. doi:10.1001/archneur.1984.04050210111028. PMID 6477223.
11. Longo, Dan L. (2012). "Chapter 264. Disorders of Ventilation". Harrison's principles of internal medicine (18th ed.). New York: McGraw-Hill. ISBN 9780071748896.
12. Gaultier C; Amiel J.; Dauger S; et al. (2004). "Genetics and early disturbances of breathing control". Pediatr. Res. 55 (5): 729–33. doi:10.1203/01.PDR.0000115677.78759.C5. PMID 14739359.
13. Gaultier C, Trang H, Dauger S, Gallego J (2005). "Pediatric disorders with autonomic dysfunction: what role for PHOX2B?". Pediatr. Res. 58 (1): 1–6. doi:10.1203/01.PDR.0000166755.29277.C4. PMID 15901893.
14. Todd ES, Weinberg SM, Berry-Kravis EM, et al. (2006). "Facial phenotype in children and young adults with PHOX2B-determined congenital central hypoventilation syndrome: quantitative pattern of dysmorphology". Pediatr. Res. 59 (1): 39–45. doi:10.1203/01.pdr.0000191814.73340.1d. PMID 16327002.
15. "Gene secret of 'mythical curse'". BBC News. 5 May 2003. (The article misspells PHOX2B as "Thox2b".)
16. Kincaid PK, Dietrich RB, Pais MJ (1994). "Pediatric case of the day. Neurocristopathy (Ondine-Hirschsprung syndrome)". Radiographics. 14 (5): 1139–43. doi:10.1148/radiographics.14.5.7991820. PMID 7991820.
17. Poceta, J. S.; Strandjord, T. P.; Badura, R. J.; Milstein, J. M. (1987). "Undine curse and neurocristopathy". Pediatr. Neurol. 3 (6): 370–2. doi:10.1016/0887-8994(87)90011-7. PMID 3508086.
18. "Death by Nap: Boy Risks Death if He Nods off". 2010-08-17.
19. Takeda, S.; Fujii, Y.; Kawahara, H.; Nakahara, K.; Matsuda H (1996). "Central alveolar hypoventilation syndrome (Undine's curse) with gastroesophageal reflux". Chest. 110 (3): 850–852. doi:10.1378/chest.110.3.850. PMID 8797441.
20. Severinghaus JW; Mitchell, R. A. (1962). "Undine's curse — failure of respiratory center automaticity while awake". Clin Res. 10: 122.

External links

Classification	D ICD-10: G47.35 ICD-9-CM: 327.25 OMIM: 209880 MeSH: D020182 DiseasesDB: 32976
External resources	MedlinePlus: 000078 eMedicine: article/1002927 GeneReviews: Congenital central hypoventilation syndrome