CCHS •Congenital Central Hypoventilation Syndrome •Odi’Ondine’s curse Case report • Newbo rn te rm ma le, beca m e cyan oti c ~2h aatebfter birt h, required mechanical ventilation • Several attempts to wean failed between 0-16h following disconnection from the ventilator • Lung+heart examination including chest X ray , ABG on ventilation, ECG, cardiac US were normal • NiditifNo indication for i iftinfection • Blood work including muscle enzymes was normal. • Neurological examination was normal. • Constipation Differential Diagnosis • CNS ((,,,ygy,brain stem CVA, AVM, tumor, Syringomyelia, Leigh’s encephalomyelopathy, Olivo-Ponto_cerebellar degeneration, Mobius Syn) • Neuro-muscular (Muscular dystrophy, Spinal muscular atroppy,yphy, myopath y,yy, myesthenia gravis , Guillain Barre, Poliomyelitis) • Pulmonary (congenital lung disease: agenesis, emphysema, sequestration, bronchogenic cysts, cystic adenomatoid malformation, diaphragmatic hernia…, pneumonia, edema-CHF) • Others ((,Botulism, achondrop p,lasia, Some inborn errors of metabolism) CCHS •Congenital Central Hypoventilation Syndrome •Odi’Ondine’s curse The condition is named after a mythological story. The water nymph Ondine was punished by the gods after falling in love with a kn ig ht by be ing condemned to stay awake in order to breathe. • A rare lifelonCCHSggy multisystem disorder characterized by autonomic nervous system dysfunction , which most dramatically manifests as failure to maintain ventilatory homeostasis during sleep. Described at 1970. • Mellins RB, Balfour HH Jr, Turino GM, Winters RW. Failure of autonomic control of ventilation (Ondine’s curse). Medicine (Baltimore) 1970;49:487–526. • A rare lifelonCCHSggy multisystem disorder characterized by autonomic nervous system dysfunction , which most dramatically manifests as failure to maintain ventilatory homeostasis during sleep. Described at 1970. • Mellins RB, Balfour HH Jr, Turino GM, Winters RW. Failure of autonomic control of ventilation (Ondine’s curse). Medicine (Baltimore) 1970;49:487–526. Sleep Related Breathing Disorders • In the late 60s the Sleep Apnea term was introduced (to replace the term Pickwickian Syndrome). • The syndrome is caused by the presence of obstructive sleep apnoeas, contrary to obesity respiratory overload • In the early 1970s the obstruction of the upper airways was establish as a continuum stretching from snoring to full-blown sleep apnoea syndrome Definition SAS is descr ibe as repe titive ep iso des of complete or partial cessation of breathing during sleep. OSA is describe as repetitive episodes oflttilif complete or partial upper airway obstruction during sleep. As a result affected persons have unrestful sleep and excessive daytime sleepiness. Categorization • Obstruct ive • Central • Mixed ECG Airflow Thor. Effort Abd. Effort SAO2 Central Apnea These are central apneas ( 2) with minimal oxygen desaturation. Notice the low SAO2 at the beginning of this tracing. This is associated with a previous apnea. Both of these events are between 13-16 seconds in duration. Exhale Airflow reduction Inhale > effort with paradox Paradox ends SAO2 desaturation Hypop nea This is an 18 second hypop neic event. The airflow signal is reduced by approximately 50% during this event. EKG Airflow Thoracic Effort Abdominal Effort SAO2 Mixed Apnea – has both central and obstructive components CCHS Resp Care 2004 CCHS Resp Care 2004 CCHS Genetics CCHS - Associates • Hirschsprung’s disease (neural crest dysfunction). • Haddad et al. Congenital failure of autonomic control of ventilation, ggyastrointestinal motility and heart rate. Medicine (Baltimore) 1978;57:517–526. • El-Halaby E , Coran AG . Hischsprung’s disease associated with Ondine’s curse: report of three cases and review of the literature. J Pediatr Surg 1994;29:530–535. CCHS - incidence •Thihe estimated diidf incidence of CCHS i s approximately 1 in 50,000 live births. • CCHS was identified 30 yygears ago, and at 2002 there were estimated 400 sufferers worldwide. • Gaultier C. Congenital central hypoventilation alveolar syndrome: an orphan disorder . Lecture abstracts, Second International Symposium on CCHS, Faculte ´ de Me´decine Bichat, Universite´ Paris, February 2002. Central Sleep Apnea • Idiopathi c cent ral sl eep apnoea: A wak e PCO2 illis normal or low Ventilatory hypercapnic response is normal or increased • Cheyne–Stokes respiration: Awake PCO2 is normal or low, Ventilatory hypercapnic response is normal or increased. Common in neurological disorders and congestive heart failure • High-altitude associated resp cycling: acute exposure to altitude. AkAwake PCO2 illVtilthiis normal or low. Ventilatory hypercapnic response is normal or increased. Reduced during REM sleep • Central hypoventilation syndrome: Awake hypoxaemia and hypercapnia that are worsened by sleep. Worst during REM sleep. Decreased ventilatory response to hypercapnia (Obesity). • CCHS Awake PCO2 is normal or high, Ventilatory hypercapnic response is normal or decreased. Worsened by sleep, worst during REM sleep CCHS - incidence •Thihe estimated diidf incidence of CCHS i s approximately 1 in 50,000 live births. • CCHS was identified 30 yygears ago, and at 2002 there were estimated 400 sufferers worldwide. • Gaultier C. Congenital central hypoventilation alveolar syndrome: an orphan disorder. Lecture abstracts, Second International Symposium on CCHS, Faculte ´ de Me´decine Bichat, Universite´ Paris, February 2002. CCHS - Associates • Hirschsprung’s disease (neural crest dysfunction). • Haddad et al. Congenital failure of autonomic control of ventilation, gastrointestinal motility and heart rate. Medicine (()Baltimore) 1978;57:517–526. • El-Halaby E , Coran AG . Hischsprung’ s disease associated with Ondine’s curse: report of three cases and review of the literature. J Pediatr Surg 1994;29:530–535. CCHS – Progress? • עד 2003 המידע התבסס כמעט רק על תאורי מקרה (לפעמים כמה) • שנת 2004 היוותה מהפך • קליניקה • גנטיקה CCHS - Clinical • Pediatric Pulmonology 37:217–229 (2004) • Questionnaires to family network of CCHS, 5 languages, 19 countries, 75% return rate. CCHS - Clinical • Mean age 10±26 years (range 0.4–38 years), with 13 of the 196 over 20 years. • 1:1 sex ratio , • 42 (21.4%) of the children were born prematurely. • Height and weight averaged in the 45th percentile, with only 7 children at less than 5%. • 94% lived at home full time. 3% were adopted . Four children (2.5%) lived in a long-term care facility. • The population included two sets of identical twins (both twins affected), and one pair of siblings with CCHS. CCHS - Clinical • Twenty (10%) CCHS subjects were 24-hr ventilator-dependent. • 82% (160) were identified as requiring mechanical ventilatory support only while asleep. • 8%idhiltilti% received mechanical ventilation during sleep plus 1-3 hours sometime during the day. CCHS - Clinical • Nearly two -thirds ( 62%) of the subjects had a tracheostomy, but • 14% (28) of the children had never been tracheotomized • 77 subjects (39.3%) not having a thttracheotomy t tbttifube at time of survey. • 47 of 82 of the CCHS subjjpects in Europe were ventilated without tracheotomy (53%) vs only (22 of 90) US CCHS patients (24%), P<0.0001) Discharggpe from hospital after birth מונשמים רצוף מונשמים רק בשינה • Paradoxicallyyq children who required 24 hour ventilation were discharged from hospital earlier than the sleep-only ventilated • At 1 yygear of age 25% of the children were still hospitalized. Additional diseases • Hirschsprung disease: 15% of sleep-only (SO) ventilated, 25% of 24-hours ventilated • Seizures: 39% of SO ventilated , 70%of% of 24- h • CdiCardiac arrh hthiythmias: 17%fSO% of SO ventilated, 35% of 24-h ventilated • Ophthalmological problems: 46% of sleep- onlyy, ventilated, 50% of 24-hours ventilated • Speech delay: 48% of SO ventilated, 75% of 24h CCHS – Progress? • עד 2003 המידע התבסס כמעט רק על תאורי מקרה (לפעמים כמה) • שנת 2004 היוותה מהפך • קליניקה • גנטיקה מה חדש בדנ"ש? 1.CCHS – Phox2b, passive movementits, pacing 2.Airway length 3.Mandibular distraction Scientists have found the gene responsible for the rare condition Ondine's Curse - (BBC News 5/5/2003). The condition is named after a mythological story. Some accounts say the water nymph Ondine was punished by the gods after falling in love with a kniggyht by being condemned to sta y awake in order to breathe. In this condition where the central nervous system fails to control over breathing while asleep. PHOX2B gene in CCHS. Ped Res 55: 729-33, 2004. • PHOX2B mutation causes apneas and decreased hypercapnic ventilatory response (in knock-out newborn mice). • PHOX2B is expressed in the ANS during human embryonic development. There is an essential role of PHOX2B in the normal patterning of the autonomous ventilation system. • Ret mutation (and others) is associated with Hirschsprung Gaultier Nature Genetics 2003, Ped Res 2004, Ped Res 2005 CCHS Genetics • CCHS, Hirschsprung and neuroblastomas can occur in combination . Familial cases have been reported. • This suggest s vari abl e expressi on of a single genetic abnormality as the common cause to these neural crest disorders. • PHOX2B gen e i s piv otal in th e development of most relays of the autonomic nervous system, including all autonomic neural crest derivatives, it is considered th e gene responsibl e f or th e above conditions (2008). CCHS Genetics • CCHS, Hirschsprung and neuroblastomas can occur in combination . Familial cases have been reported. • This suggest s vari abl e expressi on of a single genetic abnormality as the common