Assessment of Desogestrel in Ondine Syndrome

Rationale of the study The congenital central hypoventilation syndrome (CCHS), also called Ondine syndrome or Ondine's curse, is a rare orphan disease associated with mutations of the PHOX 2B gene. It is characterized by an absence or a deep reduction in the ventilatory response to hypercapnia and hypoxia. As a consequence, life-threatening hypoventilation or apneas occur during sleep and, in some patients, also during wakefulness. Survival thus depends on mechanical ventilatory assistance (or on phrenic pacing), all life long. There is no pharmacological treatment.

We have fortuitously observed two cases of recovery of ventilatory response to hypercapnia in patients taking desogestrel, a very potent progestin, as a contraceptive treatment ("Straus, C., et al. Respir. Physiol. Neurobiol. 2010 ; 171 : 171-174").

The hypothesis of the research project stems from these observations. It assumes that desogestrel will restore a chemosensitivity to hypercapnia in Ondine patients that will allow them to breath sufficiently without mechanical ventilatory assistance during sleep.

The primary goal of the study will be to assess whether a treatment with desogestrel will restore a ventilatory response to hypercapnia. The secondary goal will be to evaluate whether this response will allow the patients to be weaned from mechanical ventilatory assistance during sleep.

Methods The study will take place in one unique hospital, the Pitie-Salpetriere Hospital in Paris, France. It will be conducted in volunteer pubescent female patients. Patients with contra-indications to desogestrel will not be included.

The ventilatory response to hypercapnia will be assessed through the rebreathing method and through a blinded procedure specifically designed for the study. Sleep and breathing during sleep will be assessed through polysomnography. Blood gas analysis as well as hormonal and ionic analysis of the blood will be performed. The ventilatory response to hypoxia will also be assessed. Changes in cerebral activation will be looked for using functional magnetic resonance imaging (fMRI).

Protocol Patients will be first assessed with all the tests mentioned in the above paragraph, except fMRI. Polysomnography will be performed under mechanical ventilation.

Patients who will not take any contraceptive oral treatment with estrogens or progestin and whose response to hypercapnia will be low enough will immediately continue the study. An fMRI will be performed and the patients will be prescribed desogestrel 75 µg daily.

Patients who will be under an oral contraceptive treatment with estrogens or progestin will have to stop it and to use mechanical contraception (condom). All the patients taking an oral contraceptive treatment will be assessed after having stopped these drugs, with all the tests mentioned in the "methods" paragraph, except fMRI. Polysomnography will be performed under mechanical ventilation. If their ventilatory response to hypercapnia will be low enough an fMRI will be performed and the patients will be prescribed desogestrel 75 µg daily.

All the patients will be assessed under treatment with desogestrel. If the slope of the ventilatory response to hypercapnia is more than 1L/min/mmHg, an attempt of weaning from mechanical ventilation during sleep will replace the usual polysomnography under mechanical ventilation. The patients will be admitted in an intensive care unit where they will sleep without ventilatory assistance. Polysomnographic recordings will be performed with a portable device. In case of prolonged hypopneas or apneas or in case of arterial desaturation, patients will be awakened and mechanical ventilation will be resumed. The attempt of weaning will be regarded as a failure. In the absence of those criteria, the weaning will be regarded as a possible success. However, the investigators will not prescribe to the patient to sleep without ventilatory assistance. Their attending physician will have to take the final decision regarding this issue.

Inclusion criteria

• Ondine syndrome
• Pubescent female

Exclusion criteria

• Contra-indications to a treatment with desogestrel.
• Other treatment with estrogens or progestin that cannot be stopped.