REVIEW Cardiovascular Abnormalities and Arrhythmias in Patients with Ondine’s Curse (Congenital Central Hypoventilation) Syndrome MOHAMMAD-REZA MOVAHED,* MEHRDAD JALILI,† and NAFIZ KICIMAN‡ From the *University of California, Irvine, Department of Medicine, Division of Cardiology, †Department of Pediatrics, and ‡Division of Pediatric Intensive Care and Division of Pediatric Cardiology MOVAHED, M. R., ET AL.: Cardiovascular Abnormalities and Arrhythmias in Patients with Ondine’s Curse (Congenital Central Hypoventilation) Syndrome: A Review. Patients with congenital central hypoventi- lation syndrome (CCHS) (Ondine’s curse syndrome) have impaired autonomic control of ventilation with intact voluntary control of respiration. Autonomic dysfunction and cardiac abnormalities are common in CCHS. Bradyarrhythmias are life-threatening and often require pacemaker insertion. We presented a case of a patient with CCHS suffering from long sinus pauses requiring cardiac pacemaker insertion. Patients with CCHS are at risk for pulmonary hypertension and cor pulmonale secondary to chronic hypoxia. Diaphragmatic pacing has been beneficial in some patients with CCHS. In this article, we review concomi- tant cardiac abnormalities and the occurrence of bradyarrhythmias in patients with CCHS. (PACE 2005; 28:1226–1230) bradyarrhythmias, Ondine’s curse, congenital central hypoventilation syndrome, cardiac abnormalities, pacemaker Definition and Underlying Pathophysiology with this syndrome, including the cardiovascular Congenital central hypoventilation syndrome system which is the focus of this review. CCHS (CCHS) is a heterogeneous disorder presenting is generally thought to be secondary to insensitiv- with impaired autonomic control of ventilation. ity of the central chemoreceptors to carbon diox- Ondine was a female water sprite who fell in love ide or abnormal central integration of chemore- with a knight and married him. Once he became ceptor input. However, these children respond to unfaithful to her, he was condemned to stay awake hypercapnea with arousal suggesting that some in order to breathe. If he fell asleep, he would chemoreceptor function is intact. The most prob- forget to breathe and die. This legend remarkably able mechanism of CCHS is a brainstem lesion in matches the CCHS, thus giving the name of On- the area where input from chemoreceptors are in- 3 dine’s curse to this disorder. It usually presents tegrated. Most of these patients require mechan- with adequate ventilation while awake and ical ventilation early in childhood and some ben- 7–11 diminished respiratory effort during sleep.1–3 The efit from diaphragmatic pacing. Few patients incidence of this disorder is thought to be approx- have late onset of the disease. Noninvasive venti- 12–14 imately 1 in 50,000 live births.4 Children with this lation has been successful in some patients. condition lack perception of dyspnea, but volun- The course of this disease is variable. Some tary control of breathing is intact.5 During exer- patients survive into adulthood, but frequently cise they are at risk for hypoxia and hypercap- need multiple hospitalizations and lifelong ven- 15–17 nea.6 Most severely affected children have hy- tilatory support. There are familial cases re- poventilation both during sleep and while awake. ported and genetic abnormalities have been found 18–25 Autonomic dysfunction is the underlying patho- in patients with CCHS. Genetic abnormali- physiological abnormality in these patients. It is ties involve mutation in a polyalanine tract of 26–29 diagnosed in the absence of primary neuromuscu- PHOX2b. lar, cardiac, lung or brain abnormalities. There are Associated conditions are related to dysfunc- many other organ system abnormalities associated tion of autonomic nervous system with involve- ment of ganglia. There are many primary concomi- tant illnesses with this syndrome such as gastroe- Address for reprints: Mohammad-Reza Movahed, M.D., Ph.D., sophageal reflux, seizure disorder, Hirschsprung’s F.A.C.P., F.A.C.C., F.S.C.A.I., Assistant Clinical Professor, Uni- disease, neuroblastoma, ophthalmologic abnor- versity of California, Irvine Medical Center, 101 The City Drive, malities and developmental delay. Autonomic Bldg 53, Rm 100, Orange, CA 92868-4080. Fax: (714) 456 8895; dysfunction is widespread and includes sporadic e-mail: [email protected] profuse sweating episodes, esophageal dysmotil- Received May 20, 2005; accepted June 5, 2005. ity, diminished pupillary light response, poor 1226 November 2005 PACE, Vol. 28 CARDIOVASCULAR ABNORMALITIES IN CCHS temperature regulation, lack of fever with infec- Table I. tions, and abnormal tearing. Cardiovascular abnormalities are present in Reported Cardiovascular Abnormalities in Congenital many patients with CCHS and are thought to be Central Hypoventilation Syndrome (CCHS) or Ondine’s secondary to chronic hypoxia or autonomic dys- Curse Syndrome18,30,50 function. Autonomic dysfunction results in di- minished heart rate variability, recurrent syncope, Number of Patients cardiac arrhythmias and asystole, requiring pace- in Percent maker insertion.30 Secondary disorders are related to hypoxia such as pulmonary hypertension and Recurrent fainting episodes 12–25% 30–34 cor pulmonale. A comprehensive list of the Cardiac arrhythmias 22–39% associated disorders is reported by Vanderlaan et Cardiac pacer 4–6% 30 al., listing 59 comorbid conditions in patients Cor pulmonale/pulmonary 17–78% with CCHS. It is important to realize that the clini- hypertension cal presentation of CCHS is quite variable and de- Blurred vision with standing 14% 35 pendent on the severity of the disorder. Some in- Decrease heart rate variability 55% fants may require assisted ventilation initially but Vasovagal syncope 13% may mature to a level of adequate breathing dur- Cold finger and toes 14–43% ing wakefulness, which is thought to be secondary Dizziness 14% 36 to maturation of respiratory systems. Others may Postural hypotension 7% present at a later age with hypoxia, cyanosis, and Paroxysmal hypertension 4% right heart failure as the first symptoms of CCHS Raynaud 4% and some may present with unexplained apnea No nocturnal BP dipping 90% and life-threatening event.35 Cardiac Abnormalities long sinus pauses up to 6 seconds in patients with Autonomic Dysfunction and Cardiac CCHS undergoing broncoscopy, in comparison to Arrhythmias the control.45 Although these episodes resolved Autonomic dysfunction has been reported in spontaneously, it was severe enough to alarm many patients with CCHS. Autonomic regulation the anesthesiologist. Close monitoring of these of respiratory and cardiac function occurs simul- patients for bradyarrhythmias is recommended taneously. Abnormal hypothalamic function28 as during bronchoscopy. Aberrant neural response a regulator of respiratory and cardiac function can to cold pressor challenges has been documented partially explain this connection. Many patients in CCHS patients affected by abnormal PHOX2B with autonomic dysfunction present with abnor- gene.42 The percentage of time in respiratory sinus mal heart rate variability affecting the low- and arrhythmia, which is a signal of normal regulation high-frequency components.37–43 Furthermore, ab- of autonomic nervous system, is significantly de- normal heart rate beat-to-beat variability has been creased in CCHS patients.1 This phenomenon, to- demonstrated in patients with this disorder.38,39 gether with decreased breath-to-breath variability An increased ratio of low-frequency to high- during spontaneous breathing while asleep, is an frequency band spectral power and transient asys- indicator that the autonomic control of the cardio- tolic episodes have been seen in these patients.38,39 respiratory system is impaired. This is thought to In a series of 56 patients with CCHS, the following be a basic pathophysiology of this disorder. disorders were noted: 31 patients with heart rate Other concomitant disorders of autonomic variability, 22 with dysrthmia, 13 with vasovagal dysfunction are severe constipation, profuse syncope, 12 with loss of consciousness, 8 with cold sweating, abnormal pupillary function, and de- fingers and toes, 8 with dizziness, 4 with postural crease in body temperature. Furthermore, auto- hypotension, 2 with altered vascularity of the face, nomic crisis has been described in patient with 2 with paroxysmal hypertension and 2 with Ray- CCHS, with or without elevation of urinary cate- naud (see Table I).18 cholamines.46 Abnormal findings of neuronal loss Some patients have attenuated heart rate re- of the reticular, ambiguous nuclei, and dorsal mo- sponse to exercise.25,44 Interestingly, by using tor nuclei of the vagus nerve support the struc- spectral analysis, the low-high frequency spectra tural abnormalities involving the autonomic ner- ratios decreased in sleep, but was similar in both vous system.47 control and CCHS groups during wakefulness.43 Autonomic dysfunction can present with Silvestri et al. found significant baseline low heart neurally-mediated syncope48 which is most likely rates in patients with CCHS and higher rates of secondary to baroreflex abnormalities. Baroreflex PACE, Vol. 28 November 2005 1227 MOVAHED, ET AL. sensitivity was reduced by one-third in com- could lead to pulmonary hypertension and cor pul- parison to matched control.41 The autonomic monale.44,52 Weese-Mayer et al.50 reported 78% in- dysfunction could progress to a more severe cidence of cor pulmonale which can lead to right form of cardiac arrhythmias with overreaction