CCHS •Congenital Central Hypoventilation Syndrome •Odi’Ondine’s curse Case report • New born te rm m al e, becam e cyan oti c ~2h aatebfter bir th , 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 isod es 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

Hypo pnea This is an 18 second hypo pneic 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 approximatel y 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 approximatel y 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 • גנט יקה

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 • גנט יקה 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 bein g 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 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 • Recent studies have shown that: 1) PHOX2B is the main disease-causing gene for CCHS, an autosomal dominant disor der w ith i ncompl et e penet rance; 2) PHOX2B is the first gene for which germline mutations have been dem on str ated to p red ispose to neuroblastoma; 3) Hirschsprung disease is associated with an intronic single-nucleotide polhifthPHOXlymorphism of the PHOX2BiB gene in a case-control study. CCHS – Progress? • עד 2003 המידע התבסס כמעט רק על תאורי מקרה (לפעמים כמה) • שנת 2004 ה יוותה מהפך, ומה היום?

• קליניקה • גנט יקה CCHS – Progress? • עד 2003 המידע התבסס כמעט רק על תאורי מקרה (לפעמים כמה) • שנת 2004 ה יוותה מהפך, ומה היום?

• קליניקה, גנטיקה • טיפול? CCHS Survey Japan 2012 Pediatr Int. 2012 Feb;54(1):123-6. Eppgypidemiologic survey of patients with CCHS in Jap an. Hasegawa H et al. Tokyo, Japan. [email protected] • 37 patients with CCHS were reported from 23 hospitals. • 18 were male, 19 were flfemale • Age range 4 months to 34 years. • Diagnosis was based on clinical symptoms in 37/37 patients; ventilatory response to inhaled CO2 in 14/37; and genetic analysis (PHOX2B) in 11/37. •Hirschsprung's disease in 13/37 and CNS disorders in 15/37. • Prognoses: 3/37 died in hospital, 1/37 remained in hospital, 33/37 were on hhiltilti(didhome mechanical ventilation (died 4/33)d), and 0/37 were cured. Tracheostomy (21/37), use of a nasal mask (9/37), use of a facemask (5/37), and diaphragmatic pacing (1/37). החדרת מוטציה PHOX2B לעכברים פוגעת ברג ישות לדו תחמוצת הפחמן. אחרי כמה ימים מתחיל תהליך אדפטציה בעקר דרך הגברת רגישות להיפוקסיה עכברים בריאים גיל יומיים (עיגולים פתוחים) לעומת 9 ימים מוטנטים (עיגולים 22 יום מלאים) לפי גיל פוסטנטלי בוגרים CCHS Genetics

החדרת הגן לעוברי עכברים גרמה לטריאדה של CCHS, הירשפרונג ונוירובלסטומה CCHS Genetics Case report CSA Tx Daily Dose (mg) Comments AtAcetazol am ide 1000 diuresi s and me tab o lic acidosis Theoph ylli ne 5–10 mg/kg RittiltRespiratory stimulant adenosine antagonist NlNaloxone 1–3 OitOpiate ant agoni itst Respiratory stimulant MdMedroxy 50–120 IilIncreases ventilatory progesterone response to co2,o2 Clomipramine 10–100 Tricyclic antidepres. Reduce REM Nasal CPAP Pressure titrated May reduce OSA and break cycling Oxygen Titrated (1-3 l/min) May remove the initiating factor (as altitude) CCHS Tx Daily Dose Comments (mg) Acetazolamide 1000 diuresis and metabolic acidosis Theophylline 5–10 mg/kg Respiratory stimulant adenosine antagonist Almitrine 200 Respiratory stimulant

Doxapram 4-6 mg/kg Respiratory stimulant Diappghragmatic pacin g – Phrenic nerve stimulation

• Diaphragm pacing (DP) by bilateral electrical stimulation of the phrenic nerves offers important advantages • The ppqy()atient wears an external radiofrequency (RF) transmitter over an implanted receiver, and a stimulating current is induced without the need for any transcutaneous wires. • Infants and children require tracheostomy to avoid upper airway obstruction • The stimulus pppppparameters most appropriate for pediatric patients have been characterized as low stimulus frequency, short inspiratory time, and moderate respiratory rate. Diappghragmatic pacin g – Phrenic nerve stimulation

• In 33 pediatric patients, representing 96 patient-years of use, there were 26 failures of the pacing systems requiring removal and/or replacement of the internal components (technical problems, “diaphragmatic fatigue”. • MiMean time to filfailure was 56 months. • Of our 33 patients, 26 are alive and 22 are currently using the pacing systems.

Brouilette & Marzocchi, Diaphragm pacing: clinical and experimental results, Biol Neonate 65: 265-71, 1994. AJRCCM 2000

Passive Movement of low extremity

Control: feet held with no motion

Physical Exercise AK, Nov 2005 סיכום • CCHS מחלה נדירה (בערך 1:50000) • הגן האחראי הינו Phox2B האחראי על התפתחות חלקים במערכת העצבים האוטונומית מה – neural crest • לחולים סיכון יתר להירשפרונג ונוירובלסטומה • יש קשת רחבה של ביטוי קליני • הטיפולים מותאמים אישית לפי הקליניקה • אין החלמה אך תיתכן מעט הסתגלות ושיפור