Trisha Kesavan
Tamil Nadu, India

In the 16th century, philosopher Paracelsus wrote about undines as nymphs that gained souls by marrying humans.¹ According to German mythology, Ondine or Undine was a water nymph (de la Motte Fouque’s version) who married a knight, Huldbrand, and gained a soul, but would be doomed to die if he showed infidelity. Just like every other relationship, this came with a cost, but one far more deadly.¹ Her husband committed adultery with a human lover, Bertalda. Though still very much in love, Ondine visited Huldbrand one last time during his second wedding night and cursed him with a kiss, so much so that he gasped for air. He was doomed for life, and he was pushed to the dilemma of choosing to be alive or sleep for eternity.²

A fascinating mythical tale such as this in the medical field drew the attention of theatrical artists, authors, and filmmakers. Some of the noteworthy movies include The Loves of Ondine co-directed by Andy Warhol and one of Walt Disney’s most famous works, The Little Mermaid.³ There have been various adaptations of the story, which with time lost its originality by going off track. But on the medical level, Nannapaneni et al.¹ concluded in their works that “Ondine’s curse” was erratically used for conditions associated with respiration. Nowadays, it is more often related to a sleep disorder that interferes with respiration called congenital central hypoventilation syndrome (CCHS).

An extremely rare neurological disorder, CCHS is the modern counterpart of Ondine’s curse that manifests as sleep-associated alveolar hypoventilation.⁴ This disorder received the term, coined by Severingus and Mitchell in 1962, which aptly describes the failure of respiratory center automaticity that usually maintains breathing during sleep.¹ Physiologically, the chemoreceptors in the respiratory center, under the control of the autonomic nervous system, sense chemical changes in the blood, thereby altering the breathing mechanism accordingly.⁵

Respiratory failure in this disorder is primarily due to decreased chemical sensitivity to carbon dioxide, causing hypercapnia and hypoxemia.^2,4,6 To this date, there have been about 200–500 such cases every year worldwide attributed to a mutation involving the proneural HASH-1 gene or the PHOX2B gene, resulting in impaired development of noradrenergic neurons.⁶ The PHOX2B gene found on chromosome 4 codes for a protein responsible for neuronal development and differentiation. Notably, this gene mutation is not inherited and is usually sporadic.⁷

Symptoms vary based on severity, and though breathlessness can occur even in broad daylight, it is notorious for harming patients, especially during sleep.⁸ Among different phases of the sleep cycle, hypoventilation strikes typically during non-rapid eye movement sleep, where patients lack the ability to sense and show physical symptoms of respiratory compromise.² Those affected tend to present with cyanosis (bluish discoloration of skin and mucous membranes), apnea (pause in breathing for more than 20 seconds), sweating, bradycardia, and a sharp drop in blood oxygen saturation—all signs of respiratory distress.^4,9

There have been reported cases of acquired Ondine syndrome due to brainstem infections (poliomyelitis), tumors (gangliomas), trauma, encephalitis, stroke, postsurgical sequelae (high cervical chordotomy), and degenerative diseases (multisystem atrophy).^4,6,9 Other possible conditions include multiple sclerosis, Leigh syndrome, and cavernous malformation, with the most common etiology being brainstem infarction.^4,6

While diagnosing this condition, it is crucial to rule out cardiovascular, pulmonary, neuromuscular, and metabolic causes.¹⁰ CCHS is predominantly present in children of two years of age and early adolescence, and it manifests with characteristic facies of a short, flat face. In about 70% of cases, ocular findings such as abnormal pupils were positive.

Confirmation of the condition by genetic analysis of the PHOX2B mutation and other varied studies like blood gas analysis (to note carbon dioxide levels and study severity), sleep studies (like polysomnography), and imaging studies (including computed tomography, ultrasound, and magnetic resonance imaging) are essential to effectively diagnose this lethal disorder, which is relatively rare with few therapeutic options.¹⁰

The only light in this world of darkness is the in-utero identification of the affected gene through early diagnosis.⁸ This can greatly alleviate organ damage and lower the mortality rate.

With very few cases of spontaneous recoveries, pharmacological relief for Ondine’s curse is currently unavailable. This devastating condition forces patients to rely on lifelong mechanical ventilation during sleep, either by tracheostomy or using non-invasive positive pressure ventilation (NIPPV).^8,11 To improve the blood oxygen levels, oxygen therapy through a nasal cannula is advised. Medications to stimulate breathing like doxapram, metoclopromide, and cisapride can be tried in select patients.^10,12 An alternative device, the diaphragm pacemaker, serves a similar purpose. Hence, CCHS has no option for gene therapy, has no complete cure, and can only be maintained with lifelong supportive care. In a nutshell, patients can only benefit from a well-coordinated multidisciplinary team and by developing a thorough treatment plan.

In conclusion, the life of an individual surviving with Ondine’s curse can be agonizing, limiting their social interactions, travel, and leisure activities. But all is not lost. There is a ray of hope that, with appropriate management and support, patients can still lead sufficiently satisfied lives. Preserving their mental health with support groups and counseling is of utmost significance. Sensitizing health workers, researchers, patients, and the community to this condition can act as a stepping stone toward finding a cure.

References

1. “Ondine’s Curse: The Character Assassination of Undine.” Writing in Margins. August 1, 2022. https://writinginmargins.weebly.com/home/archives/08-2022.
2. Orrego-González, Eduardo, Germán José Medina-Rincón, Sofía Martínez-Gil, and Juan Sebastián Botero-Meneses. “Ondine’s Curse: The Origin of the Myth.” Arquivos De Neuro-Psiquiatria 78, no. 4 (January 31, 2020): 238–40. https://doi.org/10.1590/0004-282×20190162.
3. Nannapaneni, Ravindra, Sanjay Behari, Nick Todd, and A. D. Mendelow. “Retracing ‘Ondine’s Curse.’” Neurosurgery 57, no. 2 (August 1, 2005): 354–63. https://doi.org/10.1227/01.neu.0000166684.69422.49.
4. Zhu, Canmin, Ming Li, Jiaping Xiao, X. Y. Zhang, Mei Zhang, Qiang Li, and Wei Zeng. “Case Report: Ondine’s Curse Syndrome Secondary Brainstem Infarction.” Journal of Neurology and Neurophysiology, January 1, 2018. https://doi.org/10.4172/2155-9562.1000459.
5. Straus, Christian, Ha Trang, Marie-Hélène Becquemin, Philippe Touraine, and Thomas Similowski. “Chemosensitivity Recovery in Ondine’s Curse Syndrome under Treatment with Desogestrel.” Respiratory Physiology & Neurobiology 171, no. 2 (April 30, 2010): 171–74. https://doi.org/10.1016/j.resp.2010.03.015.
6. Demartini, Zeferino, Luana Antunes Maranha Gatto, Gelson Luis Koppe, Alexandre P. Francisco, and Ênio E. Guérios. “Ondine’s Curse: Myth Meets Reality.” Sleep Medicine: X 2 (July 13, 2020): 100012. https://doi.org/10.1016/j.sleepx.2020.100012.
7. “PHOX2B Gene: MedlinePlus Genetics,” last updated September 1, 2019. https://medlineplus.gov/genetics/gene/phox2b/.
8. Moawad, Heidi. “Ondine’s Curse: Causes, Symptoms, and Treatment.” Neurology Live, November 14, 2020. https://neurologylive.com/view/ondines-curse-causes-symptoms-and-treatment.
9. Nakajima, M., Ken-Ichiro Katsura, Yasuhiro Hashimoto, Tetsuya Terasaki, and Makoto Uchino. “[A Case of Ondine Curse Associated with a Medullary Tumor].” Rinshō Shinkeigaku 40, no. 8 (August 1, 2000): 811–15.
10. Brown, Amy, and Katherine Harwood. “Congenital Central Hypoventilation Syndrome: Practice Essentials, Background, Pathophysiology,” last updated April 21, 2021. https://emedicine.medscape.com/article/1002927-overview.
11. Ditmer, Marta, Szymon Turkiewicz, Agata Gabryelska, Marcin Sochal, and Piotr Białasiewicz. “Adolescent Congenital Central Hypoventilation Syndrome: An Easily Overlooked Diagnosis.” International Journal of Environmental Research and Public Health 18, no. 24 (December 20, 2021): 13402. https://doi.org/10.3390/ijerph182413402.
12. Aronson, Jeffrey K. Meyler’s Side Effects of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interactions. Elsevier, 2015.