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Ondine’s Curse

Home / For Providers & Researchers / Education / Grand Rounds, Publications, & Media / Barrow Quarterly / Volume 15, No. 2, 1999 / Ondine’s Curse
Authors

Iman Feiz-Erfan*
Paul W. Detwiler, MS, MD
Randall W. Porter, MD
Volker K. H. Sonntag, MD
Robert F. Spetzler, MD

*Georg-August-University, Göttingen, Germany, and
Division of Neurological Surgery, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona

Abstract

Percutaneous high cervical cordotomy has been used to treat intractable pain. Central sleep apnea due to a loss of the automatic respiratory drive is a potentially fatal complication. Ondine’s curse is an eponym that has been used to describe this syndrome. The anatomic substrate and etiology of this condition are reviewed.

Key Words: central sleep apnea, cervical cordotomy, Ondine’s curse, pre-Bötzinger complex

Throughout history, the legend of Ondine’s curse has been documented and interpreted differently.29,39 Probably the most famous version of this legend was created by the French novelist Jean Giraudoux.8 In his 1939 play Ondine: Piece en Trois Actes, the sea nymph Ondine falls in love and marries a human named Hans. In time Hans falls in love with another woman. Infuriated by this turn of events, Ondine’s father demands the death of Hans. In the last conversation between Hans and Ondine, he tells her of his harried existence.39

Ondine: Live Hans. You too will forget.
Hans: Live! It’s easy to say. If at least I could work up a little interest in living, but I’m too tired to make this effort. Since you left me, Ondine, all the things my body once did by itself, it does now only by special order.

It’s an exhausting piece of management I’ve undertaken. I have to supervise five senses, two hundred bones, a thousand muscles. A single moment of inattention, and I forget to breath. He died, they will say, because it was a nuisance to breath.8

In 1962, Severinghaus and Mitchell35 first coined the eponym, Ondine’s curse, to describe the symptoms of three patients whose respiratory centers failed to perform automatically after they had undergone upper bilateral cervical cordotomy for pain relief. The deficit was present when they were awake and was especially aggravated during sleep. Severinghaus and Mitchell were referring to the old German legend Der Ritter von Staufenberg where “the water nymph, Ondine, having been jilted by her mortal husband, took from him all automatic functions, requiring him to remember to breathe. When he finally fell asleep, he died.”35,39

This poem of uncertain provenance was first printed in Strasbourg in 1480. Subsequently it appeared in the writings of Paracelsus (1493-1541) who is said to have found the story in the legend Der Ritter von Staufenberg.39

Some authors29 regard the eponym Ondine’s curse as a misnomer because sea nymphs are supposed to love their humans deeply. Consequently, they question whether Ondine would have cursed her beloved mortal husband. Clinically, it has been suggested that this term be applied to patients with a central failure of automatic control of respiration as the only explanation for alveolar hypoventilation.19

Brain Stem Respiratory Center

In mammals, rhythmic respiratory activity is generated in the pre-Bötzinger complex, which is formed by a network of six physiologically different neuronal populations positioned around the rostral segment of the nucleus ambiguus.28,36 Selective lesioning of this neuronal network causes rhythmic respiratory activity to cease36 whereas rhythmicity is maintained after its isolation in brain stem slice preparations.26 The neuronal network of the pre-Bötzinger complex lies within the longitudinal cell column of the ventral respiratory group located in the ventrolateral medulla and extends from the spinomedullary junction to the level of the facial nucleus.4,36

The complex is thought to receive its primary drive either from endogenously active pacemaker neurons within the neuronal network itself or from the spontaneously active reticular formation.26 The pre-Bötzinger complex contains the highest percentage of propriobulbar interneurons34,36 and mostly lacks bulbospinal neural output compared to adjacent regions of the medulla.36 Therefore, connections between the interneurons of the pre-Bötzinger complex and more caudal medullary areas containing a high percentage of bulbospinal output neurons3 might represent the morphological substrate for the transmission pathway of the rhythmic respiratory activity generated in the pre-Bötzinger complex to the respiratory motoneurons in the spinal cord via premotoneurons of the bulbospinal tract.36

Other neuronal populations in the dorsal respiratory group participate in rhythmic respiratory function but are not essential for the generation of rhythmicity. These neurons are located in the rostral medulla within and around the nucleus of the solitary tract and are critical for reflex control of central respiratory activity. They are known to receive vagal and glossopharyngeal afferents, which are imperative for the function of important respiratory reflexes like the Hering-Breuer reflex for terminating inspiration or the coughing reflex.26,28 The pontine respiratory group, also called the pneumotaxic center,18 is located in the upper dorsolateral pontine area below the level of the inferior colliculi in the region of the parabrachial nucleus and the nucleus Kölliker-Fuse, which stabilize rhythmic respiratory activity.28

Lesioning these structures during brain stem surgery can produce pathological patterns of breathing. Inspiration is prolonged abnormally, a condition called apneustic respiration. The condition is treated by administering the selective serotonin type 1A receptor agonist, buspirone.42

Cervical Cordotomy

In 1910, Schüller33 suggested deliberately lesioning the spinothalamic tract to treat intractable pain. In 1912, Spiller and Martin37 reported the first operative treatment of persistent pain of organic origin in the lower part of the body by interrupting the anterolateral column of the spinal cord. Subsequently, Stookey38 reported the first successful high cervical unilateral and bilateral cordotomy to relieve pain caused by carcinoma of the breast.

In 1932, Foerster and Gagel5 reported a unilateral high cervical cordotomy. In 1963, Mullan and coworkers21 published the first percutaneous technique of high cervical cordotomy. High thoracic cordotomies were attempted but often were associated with an unsatisfactory level of analgesia. Consequently, high cervical cordotomy became a more popular approach for the treatment of intractable unilateral pain below the clavicle.7,10,24,25,31,32

By adding computed tomography (CT)-guidance, percutaneous cordotomy can be used to perform localized denervation of the symptomatic region.12 Complications associated with this procedure include motor weakness or paralysis, urinary retention or incontinence, transient hypotensive shock, and electrolytic abnormalities.6,11,13,16

Ondine’s Curse after High Cervical Cordotomy

Sleep apnea is a potentially fatal complication after percutaneous cervical cordotomy. It is usually reported after bilateral high cervical cordotomies, with an incidence of 3 to 5%.13,14,17,30,41 Sleep apnea has not been associated with low cervical cordotomies.2 A few cases of lethal sleep apnea after unilateral high cervical cordotomy have been reported. These cases have usually been associated with a preexisting pulmonary impairment rendering one lung insufficient to maintain adequate ventilatory activity after unilateral loss of lung function produced by a cordotomy.9,22,41

Alterations in the control of ventilation and the function of inspiratory muscles have been advocated to explain respiratory abnormality after high cervical cordotomy.13,15,22 Descending reticulospinal fibers mediating involuntary motor control of respiration are localized to the lateral surface of the ventral horn medial to the spinothalamic tract. Furthermore, it is hypothesized that afferent spinoreticular fiber tracts are present in the anterolateral column of the spinal cord. Lesioning these afferent pathways is believed to cause a deafferentation of the reticular formation with a subsequent reduction of the primary drive to the respiratory center in the brain stem.15

The close anatomical relationship of the afferent and efferent tracts for respiratory control to the spinothalamic tract suggests a possible explanation for the occurrence of sleep apnea after high cervical cordotomy.2,13,20,23,27 Moreover, a blunted carbon dioxide response and the transient postoperative dysfunction of critical respiratory nerves and muscles like the phrenic nerve and diaphragm due to surgical edema may also contribute to respiratory insufficiency.14,15,37,40

Respiratory neurons may be present in the ventral horn of C1-C2 in cats.1 If such respiratory neurons are present and functional in humans, there might, when injured, be another anatomical substrate underlying Ondine’s curse.

References

  1. Aoki M, Mori S, Kawahara K, et al: Generation of spontaneous respiratory rhythm in high spinal cats. Brain Res 202:51-63, 1980
  2. Belmusto L, Brown E, Owens G: Clinical observations on respiratory and vasomotor disturbance as related to cervical cordotomies. J Neurosurg 20:225-232, 1963
  3. Ellenberger HH, Feldman JL: Subnuclear organization of the lateral tegmental field of the rat. I: Nucleus ambiguus and ventral respiratory group. J Comp Neurol 294:202-211, 1990
  4. Feldman JL: Neurophysiology of breathing in mammals, in Bloom FE (ed): Handbook of Physiology; Section 1: The Nervous System; Volume IV: Intrinsic Regulatory Systems of the Brain. Baltimore: American Physiological Society, 463-524, 1986
  5. Foerster O, Gagel O: Die Vorderseitenstrangdurchschneidung beim Menschen. Eine klinisch-patho-physiologisch-anatomische Studie. Ztschr ges Neurol Psychiat 138:1-92, 1932
  6. Fox JL: Percutaneous stereotaxic cordotomy. I. Problems encountered. Acta Neurochir (Wien) 18:309-317, 1968
  7. French LA: High cervical tractotomy: Technique and results. Clin Neurosurg 21:239-245, 1974
  8. Giraudoux J: Ondine, a Romantic Fantasy in Three Acts, English Version by M. Valency. New York, Samuel French, Inc., 1956
  9. Hill GE, Polk SL: Hypoventilation after high unilateral cervical chordotomy in a patient with preexisting injury of the phrenic nerve. South Med J 69:718-746, 1976
  10. Horrax G, Price WT, Jr: High cervical chordotomy for relief of intractable pain in the arm, shoulder, and upper chest. Ann Surg 139:567-585, 1954
  11. Ischia S, Luzzani A, Ischia A, et al: Bilateral percutaneous cervical cordotomy: Immediate and long-term results in 36 patients with neoplastic disease. J Neurol Neurosurg Psychiatry 47:141-147, 1984
  12. Kanpolat Y, Akyar S, Caglar S, et al: CT-guided percutaneous selective cordotomy. Acta Neurochir (Wien) 123:92-96, 1993
  13. Krieger AJ, Rosomoff HL: Sleep-induced apnea. 2. Respiratory failure after anterior spinal surgery. J Neurosurg 40:181-185, 1974
  14. Krieger AJ, Standish MS, Rosomoff HL: Respiratory and autonomic dysfunction following percutaneous cervical cordotomy. Crit Care Med 2:91-95, 1974
  15. Kuperman AS, Krieger AJ, Rosomoff HL: Respiratory function after cervical cordotomy. Chest 59:128-131, 1971
  16. Long DM, Story JL: Hyponatremia following bilateral cervical cordotomy. J Neurosurg 25:623-627, 1966
  17. Lorenz R: Methods of percutaneous spinothalamic tract section, in Krayenbuhl H (ed): Advances and Technical Standards in Neurosurgery, Vol. 3. New York, Springer-Verlag (Wien):123-140, 1976
  18. Lumsden T: Observations on the respiratory centers in the cat. J Physiol 57:153-160, 1923
  19. Mellins RB, Balfour HH, Jr, Turino GM, et al: Failure of automatic control of ventilation (Ondine’s curse). Report of an infant born with this syndrome and review of the literature. Medicine (Baltimore) 49:487-504, 1970
  20. Mitchell RA: Neural regulation of respiration. Clin Chest Med 1:3-12, 1980
  21. Mullan S, Harper PV, Hekmatpanah J, et al: Percutaneous interruption of spinal-pain tracts by means of a strontium90 needle. J Neurosurg 20:931-938, 1963
  22. Mullan S, Hosobuchi Y: Respiratory hazards of high cervical percutaneous cordotomy. J Neurosurg 28:291-297, 1968
  23. Nathan PW: The descending respiratory pathway in man. J Neurol Neurosurg Psychiatry 26:487-499, 1963
  24. Ogle WS, French LA, Peyton WT: Experiences with high cervical cordotomy. J Neurosurg 13:81-87, 1956
  25. Peet MM, Kahn EA, Allen SS: Bilateral cervical chordotomy for relief of pain in chronic infectious arthritis. JAMA 100:488-489, 1933
  26. Ramirez J-M, Richter DW: The neuronal mechanisms of respiratory rhythm generation. Curr Opin Neurobiol 6:817-825, 1996
  27. Remmers JE, Tsiaras WG: Effect of lateral cervical cord lesions on the respiratory rhythm of anaesthetized, decerebrate cats after vagotomy. J Physiol (Lond) 233:63-74, 1973
  28. Richter DW: Neural regulation of respiration: Rhythmogenesis and afferent control, in Greger R, Windhorst U (eds): Comprehensive Human Physiology. Berlin, Springer-Verlag:2079-2095, 1996
  29. Rolak LA: Who was Ondine and what was his curse? J Child Neurol 11:461, 1996
  30. Rosomoff HL: Percutaneous spinothalamic cordotomy, in Wilkins RH, Rengachary SS (eds): Neurosurgery. New York, McGraw-Hill:2446-2451, 1985
  31. Roulhac GE: High cervical chordotomy. A preliminary report. Surgery 34:288-295, 1953
  32. Sanders M, Zuurmond W: Safety of unilateral and bilateral percutaneous cervical cordotomy in 80 terminally ill cancer patients. J Clin Oncol 13:1509-1512, 1995
  33. Schüller A: Uberoperative Durchtrennung der Ruckenmarksstrange (Chordotomie). Wien Med Wschr 60:2292-2295, 1910
  34. Schwarzacher SW, Smith JC, Richter DW: Pre-Bötzinger complex in the cat. J Neurophysiol 73:1452-1461, 1995
  35. Severinghaus JW, Mitchell RA: Ondine’s curse—failure of respiratory center automaticity while awake. J Clin Res 10:122, 1962
  36. Smith JC, Ellenberger HH, Ballanyi K, et al: Pre-Bötzinger complex: A brainstem region that may generate respiratory rhythm in mammals. Science 254:726-729, 1991
  37. Spiller WG, Martin E: The treatment of persistent pain of organic origin in the lower part of the body by division of the anterolateral column of the spinal cord. JAMA 58:1489-1490, 1912
  38. Stookey B: Chordotomy of the second cervical segment for relief from pain due to recurrent carcinoma of the breast. Arch Neurol Psychiatr 26:443, 1931
  39. Sugar O: In search of Ondine’s curse. JAMA 240:236-237, 1978
  40. Tenicela R, Rosomoff HL, Feist J, et al: Pulmonary function following percutaneous cervical cordotomy. Anesthesiology 29:7-16, 1968
  41. Tranmer BI, Tucker WS, Bilbao JM: Sleep apnea following percutaneous cervical cordotomy. Can J Neurol Sci 14:262-267, 1987
  42. Wilken B, Lalley P, Bischoff AM, et al: Treatment of apneustic respiratory disturbance with a serotonin-receptor agonist. J Pediatr 130:89-94, 1997