An approach to children with neuromuscular disease Narong Simakajornboon, MD Associate Professor of Pediatrics Director, Sleep Disorders Center, Cincinnati Children Hospital Medical Center, Cincinnati, Ohio, USA

Topics Prototypic diseases Clinical assessment Management

Prototypic diseases Cerebral palsy Predisposing factors Muscle spasticity (upper airway, tongue, soft palate, pharynx) during awake and sleep Seizure [Strores 2001] Visual impairment [Palm et al 1997] Obstructive apnea, hypoventilation [Cohen et al 1997]

Difficulty initiating and maintaining sleep, sleep-wake transition [Newman et al 2006] Athetoid CP- abnormal movements during REM sleep [Hayashi et al 1990] Prototypic diseases

Myelomeningocele & Arnold-Chiari Malformation Incomplete closure of the spinal cord at the occipital level or lower Incidence – 1:1000 Impaired arousal to hypoxia and hypercapnia [Ward et al 1986, Gozal et al 1995] SDB in myelomeningocele 62% of patients [Waters et al 1998] Symptoms of snoring, EDS did not predict the presence of SDB Life threatening prolonged apnea during PB [Wealthall et al]

Myelomeningocele & Arnold-Chiari Malformation Severe breath holding spells [Cochrane et al 1991] Neonatal apneic spells [Nishimura et al 1995] Four types : Type I – central apnea and hypersomnolence [Keefover et al 1995] Type II – OSA and hypoventilation

Gozal et al 1995

Spinal muscular atrophy Common genetic cause of child mortality AR: 5q11.2-q13.3 Ant Horn Cell degeneration and proximal muscle weakness Resp muscle paralysis except diaphragm 3 types Type I (Werdnig-Hoffman) 1:20,000 Onset before six months: Floppy infant, Frog-leg Variant form: early diaphragm paralysis

Spinal muscular atrophy Type II& III: 1:24,000 Type II may sit but cannot walk Type III (Kugelberg-Welander disease) presents at 2-3 years of life Unrecognized nocturnal hypoxemia or hypoventilation [Bach and Wang 1995] Central apnea, mixed apnea, hypopnea, REM- related hypoxemia or hypoventilation [Manni et al 1993] Nocturnal ventilation: improve rib-cage development, lung growth, daytime function

Puruckherr, M. et al. Chest 2004;126: Polysomnographic tracings in SMA type III demonstrating severe OSA

X-linked recessive inheritance : 1: 3500 in male DMD and Becker MD (allelic): Mutations in the Xp21 Dystrophin: 5 isoforms SDB can present early in life and can not reliably be predicted from PFT [Smith et al 1988] Obstructive apnea, central apnea, paradoxical breathing, hypoventilation, non-apneic nocturnal hypoxia [Khan and Heckmatt 1994] Duchenne Muscular Dystrophy (DMD)

Suresh et al 2005 Relationship between sleep-related symptoms and Sleep disorders diagnosis

Myotonic Dystrophy Congenital myotonic dystrophy: AD, hypotonia, facial diplegia, limb contracture, sucking & swallowing problem, recurrent aspiration SDB: Central apnea, mixed apnea, obstructive apnea, REM- related hypoxia, hypoventilation [Guilleminault et al 1978] Hypersomnolence 33% of patients, correlate with muscle impairment [Laberge et al 2004] Hypersomnia with REM onset [Park and Radtke 1995] Correction of hypoventilation does not always improve this symptom [Coccagna et al 1982] Response to stimulant meds; methylphenidate [Meche et al 1986], modafinil [Mac Donald et al 2002]

Congenital and other non-progresseive myopathies Emery-Dreifuss MD, limb-girdle MD, Nemaline Rod myopathy, Metabolic myopathies SDB: nocturnal desaturation, hypoventilation

Cerebral PalsyNo data available OA, MA > CA, hypoventilation, Abn REM No data available Spinal muscular atrophy ↓ TLC, FRC ↓ MIP, MEP CA, MA, hypoventilation ↑ occlusion pressure Duchenne muscular dystrophy ↓ TLC, FRC ↓ MIP, MEP OA, MA, CA, hypoventilation, Nonapneic hypoxemia ↓ HVR, Hypercapnic VR N or ↑ occlusion pressure Myotonic dystrophy N or ↓ FRC ↓ MIP, MEP CA>OA, MA, REM-related hypoxemia, hypoventilation, EDS, sleep- onset REM ↓ HVR, Hypercapnic VR N or ↑ occlusion pressure Disease Pulmonary Function Sleep Abnormalites Ventilatory Control

Clinical Manifestation (SDB) Asymptomatic Morning headaches, fatigue, exertional dyspnea, irritability, hyperactivity, impaired learning, vomiting, difficulty tolerating supine position, restless sleep [Heckmatt et al 1989, Labanowski et al 1996] Failure to thrive, nocturnal sweating, developmental delay, cor-pulmonale [Beckerman and Hunt 1992] These symptoms may be erroneously attributed to the NMD rather than SDB [Gozal 2000] Nonrestorative sleep and EDS may be the early sign of SDB

Clinical manifestation PE: Bell shaped chest, tachypnea, use of accessory muscles and paradoxical breathing Even patients with mild symptoms may have significant unrecognized SDB [Labanowski et al 1996] Investigations PFT Ventilatory control Polysomnography Others: Fluoroscopy, CXR, CBC, HCO3

Clinical assessment PFT Spirometry, lung volumes, muscle strength assessment Restrictive physiology Periodic assessment of PFT especially when lung volumes < 60% [Gozal 2000] PFT may not be predictive of SDB [Smith et al 1988, Heckmatt et al 1989, Manni et al 1989, White et al 1995] Other factors contributing to SDB : upper airway, intercostal and diaphragmatic hypotonia, poor airway clearance, pulmonary atelectasis, abdominal distention, GER, pulmonary aspiration, progressive malnutrition or obesity [Givan 2000]

PFT

Critical Pulmonary Function Values in NMD Pulmonary Function FVC < 20 ml/kg ~30% V t < 5 ml/kg FVC < 3 x V t MIP < 30 cm H 2 O MEP < 40 cm H 2 O p a CO 2 > 45 mm Hg Correlation may correlate with elevation of p a CO 2 awake or asleep

Clinical assessment Polysomnography Indication [ATS consensus 1996] : impaired PFT snoring, morning headaches, cor-pulmonale, polycythemia and elevated bicarbonate Planning and implementation of NIPPV Pre and post-operative evaluation DMD: annual PSG starting when wheelchair [ATS consensus statement 2004]

Oximetry vs Full PSG  May be useful as a screening test in DMD [Labonowski et al 1996]  In areas where full PSG is not readily available [ATS consensus 2004]

Management General supportive care : adequate hydration, nutritional support, airway clearance Scoliosis correction and spinal stabilization Specific Rx Elevation of upper body in beds Rocking bed Protryptyline: decrease REM-related respiratory disturbances in DMD [Smith et al 1989]

Management Airway clearance Ineffective airway clearance can accelerate the onset of respiratory failure [Bach et al 1997] Peak cough flows < 160 L/min → ineffective airway clearance [Bach and Saporito 1996] DMD: Peak cough flow < 270 L/min or MEP < 60 cmH 2 O [ATS consensus 2004] 3 types Manual techniques – glossopharyngeal breathing, air stacking [Kang and Bach 2000 ] Mechanical techniques – Insufflator-exsufflators [Bach 1994] Mucus mobilization devices – High frequency chest wall oscillator, intrapulmonary percussive ventilation

Peak cough flow in NMD children Chatwin et al 2003 C C NMD a,c = unassisted cough b,d = insufflation/exsufflation cough

a=ped NMD b=ped control c=adult NMD d=adult control Chatwin et al 2003 UAC = unassisted cough PAC = physiotherapy assisted cough EAC = exsufflation assisted cough IEAC = insufflation-exsufflation assisted cough

Miske, L. J. et al. Chest 2004;125: Patient with SMA using the MI-E via a mouthpiece

Miske, L. J. et al. Chest 2004;125: Left, A: chest radiograph of 22-month-old girl with SMA type I and right upper lobe density

Management Supplemental oxygen REM-related hypoxia May prolong duration of apnea and hypopnea [Smith et al 1989] Mechanical ventilatory support Negative pressure ventilation (NPV) Plexiglass lung, Cuirass shell, Pulmowrap Collapse of upper airway [Levy et al 1989, Hill et al 1992]

Chest cuirass Chest cuirass

Management Positive pressure ventilation Via tracheotomy NIPPV: nasal mask ventilation Normalize blood gas and alleviate symptoms of hypercapnia [Heckmatt et al 1990, Hill et al 1992] Stabilize declining lung function and prolong life expectancy [Vianello et al 1994] Preventive nasal ventilation

Management NIPPV indication Daytime hypercapnia (PCO2>50 mmHg) [ATS consensus 2004, European Consortium 1996] Nocturnal hypoventilation (PCO2>50 mmHg and/or hypoxemia (<92%) Timing of initiation of NIPPV remains controversial One multi-center study found no evidence of lung function preservation in NIPPV patients [Raphael et al 1994] Those with nocturnal hypoventilation are likely to develop daytime hypercapnia within 2 years [Ward et al 2005]

Management Effect of NIPPV in children May stabilize or even improve lung function in non- progressive, slowly progressive diseases [Barois et al 1992& 2005, Canani et al 1997] May stabilize lung function in rapidly progressive diseases [Rideau et al 1995] Mechanism Resting muscles Increased lung compliance Reduced sleep fragmentation [Barbe et al 1996] Resetting of chemoreceptors [Annane et al 1998]

Kirk et al 2000

Mellies et al 2004

Copyright ©2005 BMJ Publishing Group Ltd. Ward, S et al. Thorax 2005;60: Figure 2 Difference between baseline values and those at 6, 12, 18 and 24 months in (A) peak nocturnal TcCO2, (B) mean nocturnal time TcCO2 >6.5 kPa, (C) mean nocturnal SaO2, and (D) mean minimum nocturnal SaO2; p values given at 6 and 24 months. Error bars represent SE.

Simonds, A. K. Chest 2006;130: Impact of NIV therapy on survival time in hypercapnic DMD patients

Management NIPPV in children Two important factors [Panitch 2006] Patient-ventilator synchrony Interface fit and comfort Complications: skin breakdown, sinus and ear pain, eye irritation, gastric distention, excessive leak auto-trigger (nasal prongs) Flattening of facial structures [Li et al 2000, Villa et al 2002, Fauroux et al 2005]

Management Transition to adult care Young adults who started mechanical support in childhood, cont their care in pediatric center Pediatric program may no address adult issues Decision making, daily function, and quality of life [Miller et al 1990, Bach et al 1991, Gibson 2001]

Management Medical-Ethical Decision most difficult even when the prognosis is poor. Physicians underestimate the quality of life perceived by ventilator-dependent NMD patients [Bach et al 1991] Negative perception contribute to failure to offer mechanical ventilatory support option [Gibson 2001] Discussion about mechanical ventilation should occur well before its need is apparent [ATS consensus 2004] End of life care