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Congenital Central Syndrome (CCHS)

Indra Narang, MBBCH, MD

Director of Medicine, Hospital For Sick Children, Toronto

Associate Professor University Of Toronto

Financial Interest Disclosure

I have no conflicts of interest

Indra Narang Objectives

. To highlight the pathophysiology of congenital central hypoventilation syndrome (CCHS) in children

. To review the ventilatory control of in CCHS

. To discuss the diagnosis, management and outcomes of CCHS in children Control of Breathing

. Highly coordinated and integrated control of breathing Gas Exchange in Infancy

. Newborn: median nadir SaO2 = 83%

. At one year: median nadir SaO2 = 92%

. Normal CO2= 35-45mmHg

. Nocturnal (Sleep) Hypoventilation

. transcutaneous CO2 and/or end-tidal CO2 > 50mmHg for more than 25% of total sleep time

Hunt CE, J Paediatr 1999 Scholle S, 2011

Congenital Central Hypoventilation Syndrome (CCHS)

Characterised by:

. Alveolar Hypoventilation . Autonomic Nervous System Disorders (ANSD) . Both anatomical and physiological

CCHS caused by genetic mutations in PHOX2B gene

Weese-Mayer D, ATS Statement, ARJCCM 2010 Trang H, Chest 2005

CCHS Prevalence

. Prevalence - unclear . First described in 1970 in a newborn . More than 1000 cases worldwide . 1 in 200,000 in France

Weese-Mayer D, ATS Statement, ARJCCM 2010 Trang H, Chest 2005

CCHS Presentation

At birth or soon after birth

. and /or respiratory failure . Recurrent central . Apparent life threatening episode

* In the absence of respiratory/cardiac/neurological abnormalities CCHS Presentation

Late-onset CCHS (LO-CCHS)

. In infancy, childhood, adulthood with unexplained alveolar hypoventilation following;

. Anaesthetic . CNS depressants . Pulmonary infections Atypical CCHS Presentation

. Damage 2O to chronic and

. Cor pulmonale . Seizures . Developmental delays . motor . speech . learning Ventilation in CCHS

Low tidal volumes Monotonous RR Central apneas

Hypoxia Hypercapnia

Impaired Sensitivity to Hypoxia and Hypercapnia

Alveolar Hypoventilation Ventilation in CCHS

. Spectrum of ventilatory dysfunction . More marked hypoventilation in NREM vs REM sleep . CAs commonly co-exist in both NREM and REM . Inadequate ventilatory response to infections/distress . Movement during sleep can improve ventilation

Weese-Mayer D, ARJCCM 2010. Huang J. J App Physiol 2008. Paton JY, Am Rev Respir Dis 1993. Gozal D, ARJCCM 2000.

CCHS: Ventilation During Sleep

Study design . 9 CCHS children, 5 trach, 4 NIPPV NREM . Ventilator disconnected during REM and NREM sleep during a PSG

. Reconnected once CO2 > 60mmHg or >55mmHg for > 5 mins

REM Results . Severe hypoventilation which was worse in NREM . More central apneas in NREM . Arousals were frequent Huang J, JAP 2008. PSG in Child with Suspected CCHS

tcCO2 50 CCHS: Ventilation During Sleep

Study Design . 6 children, all trach and vent . Disconnected from ventilator during N3 sleep . Passive motion of lower extremities (PLME) for up to 3 minutes

. CO2 allowed to increase to 55mmHg

Results

. CO2 decreased, 59mmHg to 41mmHg . Increase in respiratory rate

Gozal D, AJRCCM 2000. Molecular Mechanisms for CCHS

. Cluster of PHOX2B expressing excitatory neurons in the retrotrapezoid nucleus (RTN) are a key site for chemoreception - detect CO2 and/or H+

. Increased levels of CO2 and/or H+ is sensed by GPR4 (proton-activated receptor) and causes PHOX2B containing RTN neurons to secrete excitatory neurotransmitters Science 2015 Science 2015

Genetic deletion of GPR4 caused loss of activation of RTN neurons, increased and blunted

ventilatory response to CO2 as seen in CCHS ANSD in CCHS

ANATOMICAL PHYSIOLOGICAL

. Hirschsprungs (20%) .. Esophageal Breath holding dysmotility spells . Tumors of neural crest (5%) .. Breath Lack of holding perception spells to dyspnea . neuroblastomas .. Reduced Bradycardia body temperature . ganglioneuroma .. Diaphoresis Esophageal dysmotility .. Lack Reduced of perception body temperature to dyspnea .. Abnormal Diaphoresis pupillometry .. Altered Abnormal perception pupillometry of anxiety

CCHS Inheritance PHOX2B mutations on 4p12 Most de novo Autosomal Dominant

PARMS (Polyalanine repeat expansion mutations) . Normal genotype - 20 alanines . Heterozygous expansion . Genotypes 20/24 to 20/33 . 90% of PHOX2B mutations

CCHS Inheritance PHOX2B mutations on 4p12 Most de novo Autosomal Dominant

PARMS (Polyalanine repeat NPARMS expansion mutations ) . NON-polyalanine repeat expansion . Normal genotype - 20 alanines mutations . Heterozygous expansion . Missense, nonsense, frameshift or stopcodon mutations and deletions . Genotypes 20/24 to 20/33 . 10% of PHOX2B mutations . 90% of PHOX2B mutations

Genotype and CCHS Phenotype

Weese-Mayer D, ARJCCM 2010 PARMS Genotype and Ventilation

20/24- 20/25 • Rarely require 24 hour ventilation

• Variable awake needs, depends on 20/26 activity • Require nocturnal ventilation

20/27- 20/33 • Typically require continuous ventilation Diagnosis and Management of CCHS CCHS Evaluation

. PHOX2B mutations . Chest CT . PSG . Abdominal imaging . Blood gas- awake and asleep . Urinalysis . Ventilatory response to . Opthamology assessment hypercapnia and hypoxia . Echocardiogram . MRI brain/brainstem/spine . EKG and Holter monitor . EEG . Metabolic screen . Manometry and rectal biopsy . Haemoglobin and . Fluroscopy of the diaphragm haematocrit levels

Ventilatory Management of CCHS

Strategies include:

. Tracheostomy and ventilator 24 hours per day . Tracheostomy and ventilator nocturnally only . Bi-level PAP nocturnally . Negative pressure ventilation . Diaphragmatic pacing

. 18 children, 14 with trach . 10/18 had PARMS 20/25 . DP at mean age of 9.6 years . Post DP, 13/18 ventilated without trach at night . Decannulated 12 months post DP . 2 obese kids not decannulated . Complicated by snoring and OSA

Surveillance after CCHS Diagnosis

Weese-Mayer D, ARJCCM 2010 Monitoring and Home Care

. Needs to be very comprehensive . Continued vigilance in all aspects of medical and home care

. Continuous pulse oximetry /CO2 . Trained carers at all times . Extra equipment etc etc . Guidance regarding . Illness . Swimming . Anesthesia . , - avoid at all costs Psychosocial Outcomes in CCHS

. Retrospective study in Variable Result preschool CCHS children Age (months) 25 ± 8.51 . 31 children F : M 14 : 17 . Mean age 25 months PARMS : NPARMS 26 : 5 Breath-holding, no. (%) 19 (61) . NC testing using Bayley 24 hr vent, no. (%) 17 (55) Scales of infant Seizures, no. (%) 15 (48) development (normal = Diaphragmatic Pacing, no. (%) 12 (39) 100) Cardiac Pacemaker, no. (%) 9 (29) . Evidence for delayed Cor Pulmonale, no. (%) 7 (23) neurocognition in pre- Bayley Mental Score 83.3 ± 24 school Motor Development Score 73.3

CCHS and HRQOL

Subjects Results . 12 patients with CCHS, 11 PARMS . HRQOL at first adult visit- . Age, 24 years, range 15-33 only moderate alterations in . All trach and vent < 1 year HRQOL . . 5/12 still had trach and vent Anxiety common . . All attended school Depression not common . 6/12 still lived at home with parent, 5 away from home, one in an institution

Summary

. CCHS is a rare, complex disorder with failure of central control of ventilation across the lifespan . Genotype can help predict prognosis, guide investigations and management . Intensive surveillance and timely interventions mandatory to limit long- term morbidity . Understanding the molecular mechanisms underlying control of ventilation may provide a target for future therapies for CCHS