Ondine's curse

Ondine's curse, also called congenital central hypoventilation syndrome (CCHS) or primary alveolar hypoventilation, is a respiratory disorder that is fatal if untreated. People afflicted with Ondine's curse classically suffer from respiratory arrest during sleep.

CCHS is congenital or developed due to severe neurological trauma to the brainstem. 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. There are also cases when the diagnosis is made in later life and middle age, although the symptoms are usually obvious in retrospect. Again, lack of awareness in the medical community may cause such a delay.

This is a very rare and serious form of central nervous system failure, involving a failure of autonomic control of breathing. About 1 in 200,000 live born children have the condition. In 2006, there were only about 200 known cases worldwide. 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.

CCHS susceptibility is not known to be affected by gender.

Signs and symptoms
Ondine's curse 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), 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. Those suffering from Ondine's curse 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.

Causes
Ondine's curse is exhibited typically as a congenital disorder, but in rare circumstances, can also result from severe brain or spinal trauma (such as after an automobile accident, stroke, or as a complication of neurosurgery). Long and Allen (1984) reported 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.

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, can be associated with this condition. This homeobox gene is important for the normal development of the autonomic nervous system.

The disease used to be classified as a "neurocristopathy", 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 Congenital Central Hypoventilation Syndrome 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 demonstrate 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.

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 and prognosis
Patients generally require tracheotomies 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 Ondine's curse include oxygen therapy and medicine for stimulating the respiratory system. Currently problems arise with the extended use of ventilators, including fatal infections and pneumonia

Most people with Ondine's curse do not survive infancy, unless they receive ventilatory assistance during sleep. An alternative to a mechanical ventilator is Phrenic Nerve Pacing/diaphragm pacing.

Although rare, cases of long-term untreated CCHS have been reported and are termed Late Onset CCHS (LO-CCHS).

History and etymology
Ondine's curse was first described in 1962 by Severinghaus and Mitchell in three patients following surgery to the upper cervical spinal cord and brainstem.

Its name is a reference to the myth of Ondine, a water nymph who had an unfaithful mortal lover. He swore to her that his "every waking breath would be a testimony of [his] love", and upon witnessing his adultery, she cursed that if he should fall asleep, he would forget to breathe. Eventually, he fell asleep from sheer exhaustion, and his breathing stopped.