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Neuromuscular disorders in children; making sense of the muscle, lung and brain Sleep Course-Bristol Anirban Majumdar Consultant Paediatric Neurologist Neuromuscular conditions 1. 2. 3. 4. 5. 6. 7. Overview Diagnosis Pathophysiology Surveillance and Treatments for NMD Trends and Survival in NM disorders Who goes into respiratory failure ? The future 1. 2. 8. 9. What we can do now What we will try to do in the future Clinical vignettes Neuromuscular / respiratory- the interface Brain Brain stem Spinal cord Anterior horn cell Nerve Neuromuscular junction Muscle Multisystem disorders Ataxias Metabolic/ Mitochondrial Chanelopathies/ storage disorders SMA Demylinating/ Axonal Neuropathy Myesthenias Dystrophy Myopathy Tone Hypotonia is a common diagnostic problem Hypotonia = floppiness Weakness MRC evaluation of muscle power 0 – no contraction 1- flicker 2- Active movement with gravity eliminated 3- Active movement against gravity 4 - Active movement against gravity and resistance 5- Normal power + and – denotes through what range of normal movement Recognizable patterns Hypotonia + weakness = neuromuscular disease Hypotonia without weakness may be •CNS • birth asphyxia • CNS malformations •Metabolic • lipidoses/MPS • amino-organic acidurias • peroxisomal •Connective tissue • Ehlers-Danlos/Marfan • OI •Chromosomal • PWS • Downs Neuromuscular disorders • Presents with – floppiness – weakness – delayed motor milestones, – abnormal gait, clumsiness, – speech and swallowing difficulties – Respiratory, cardiac failure • Age : from newborn to adult life • Very wide range of severity and disability • Intelligence : very wide range History Clinical examination Genetic analysis Biochemistry Immunology Muscle imaging EMG/NCV Muscle Biopsy Nerve biopsy Immunohistochemistry Historical Notes 1851: Edward Merynon describes 10 cases in England 1861: Duchenne de Boulogne fils. De la paralysie atrophique graisseuse de l’enfance. Archives Generales de Medicine 1861 Autographed copy of: De la Paralysie Musculaire Pseudo-hypertrophique 1868 Clinical presentation • • • • • • • • Delayed walking Waddling gait Gower sign Pelvic muscle weakness and lumbar lordosis Global developmental delay Pseudo hypertrophy of muscles Learning difficulties Raised CK levels Duchenne (Xp21) MD • The most common muscle disorder in childhood • X-linked, 30 per 100 000 liveborn males (neonatal screening) • Symptoms appear in first 5 years Genetics • X linked with recessive inheritance • 1/3 spontaneous mutations • Affects 1 in 3500 live male births • Absence or deficiency of dystrophin in muscle membrane, smooth muscle and brain Normal Dystrophin Gene dystrophin pre-mRNA dystrophin mRNA DystrophiN protein Duchenne MD DysXrophin Gene dysxrophin pre-mRNA dysxrophin mRNA DysX protein Becker MD Dys-rophin Gene dys-rophin pre-mRNA dys-rophin mRNA DysrophiN protein Surveillance and Treatments in DMD • • • • Heart Respiratory Scoliosis Maintaining ambulation Respiratory - Problems • Respiratory problems are predictable • Correlation with overall muscle strength and ambulation – rarely problems in ambulant boys • Progressive fall in FVC predicts respiratory failure • Nocturnal hypercapnia – subtle symptoms ie headaches, tiredness, poor performance at school, restless sleep Respiratory -Problems • • • • • Increased amount of chest infections FVC <40 % indicates sleep studies Consider flu and pneumococcal vaccination Early antibiotic treatment Physio: Postural drainage / assisted cough What are the symptoms of progressive respiratory failure ? • Subtle – weight loss – reduction in energy levels – poor performance at school. • Sleep disturbance – increased requirement for turning overnight. • Chest infections – frequent and difficult to treat. • Established hypercapnia and not treated – Headaches – general malaise, poor eating – high risk of death from respiratory failure during intercurrent infection. Evolution of respiratory failure in NMD FVC 100% pred Surveillance Normal breathing Monitor REM related sleep disordered breathing FVC < 40% pred NREM and REM sleep disordered breathing FVC < 20% pred Daytime ventilatory failure Simonds A. Chest infection FVC < 60% pred Chest physio NIV Cough assist Respiratory Surveillance: • Forced Vital Capacity (FVC) – absolute values and % predicted for height or arm span – easy way to document the progression of respiratory muscle weakness. • FVC drops to 1.25 l or <40% predicted value – serial measurement of overnight oxymetry and CO2 – allows the recognition of the development of nocturnal respiratory failure. Respiratory- Non-invasive ventilation • Early discussion • Indication: FVC <40 %, nocturnal hypoventilation • Mean age 17 years (Newcastle) • Improvement of daytime symptoms • Less infections • Daytime ventilation later • ? Tolerance Ventilation- the benefits • Patients notice – frequency of chest infections falls – infections that do occur may be effectively managed with the ventilator to assist coughing. – may develop a need to use the ventilator for increasing periods during the day – a portable ventilator may need to be provided that can be transported on the wheelchair. • Nocturnal ventilation – Long-term follow up studies - very effective as a treatment for respiratory failure – often nocturnal use alone provides very good stabilisation for many years. • Ventilation – mean age of death (Newcastle) 19 years to at least 25 years – survival into the fourth decade is now possible ! Current Respiratory guidelines • ATS Consensus Statement: Respiratory Care of the patient with Duchenne Muscular Dystrophy AJRCCM;2004:456-65 • Recommendation for Respiratory care of children with Spinal Muscular Atrophy Type II & III Neuromusc Disord 2003;13:184-89 • Ventilatory support in Congenital Neuromuscular Disorders – congenital myopathies, congenital muscular dystrophies and SMA II Neuromusc Disord 2004;14:56-69 • MDC Recommendations for the Respiratory care of adults with Muscle Disorders (2005-in preparation) • Consensus Conference: Clin indications for NIV in CRF. Chest 1999;116: 521-4 Are we getting it right ? Incidence and mortality rate for DMD (Denmark) Jeppesen J et al Neuromusc Dis 2003; 13:804-2 Management trends in DMD Jeppesen J Neuromusc Dis 2003;13:804-12 When to initiate NIV in NMD • Background: – NIV can be lifesaving in hypercapnic patients. – Mean survival 9.7 months in hypercapnic DMD patients if ventilatory support not provided (Vianello et al, 1997). – Survival extended in other cohorts (Bach, Eagle, Simonds). – Clinical course in other NMD not so predictable • BUT Preventative / prophylactic NIV in asymptomatic normocapnic DMD patients is not beneficial Prophylactic NIPPV in DMD Raphael et al Lancet 1994 Control NIV When to initiate NIV • Initiation of NIV at time of nocturnal hypoventilation before development of daytime hypercapnia will prevent ventilatory decompensation and improve QOL • Initiation of NIV in asymptomatic patients before the onset of sleep disordered breathing or daytime hypercapnia is NOT recommended How do we compare to others ? 100% 80% 60% 40% 20% 0% U K en ed Sw ai n Sp gal r tu Po d l an Po y a rw ds No r lan e th Ne ly It a d lan Ir e e c ee Gr any c r m sso A Ge ce sp an Fr e Ho c an Fr d lan Fin ar k nm D e um l gi Be ia st r Au L AL Lung/airways Thoracic Cage Neuromuscular European use of ventilation by disease categories Lloyd Owen ERJ 2005 Cardiovascular Cardiac- Surveillance • ECG and ECHO at diagnosis, 2-yearly until 10, yearly thereafter (European Neuromuscular Centre, Netherland) • 10% of female carriers develop overt cardiac failure: ECG and ECHO at diagnosis and 5-yearly Cardiac -Treatment • Single study suggests ACE inhibitor use before cardiac abnormalities are detectable as protective in the long term • Currently treatment with ACE inhibitors +/- β-blockers is initiated when echo findings of LV dysfunction • Diuretics etc as required for complications Special case of Emery Dreyfus Muscular Dystrophy • X linked EDMD- arrythmias- pacemaker • AD EDMD- VF-implantable defibrillator Scoliosis surveillance • Factors causing loss of ambulation in Duchenne weakness contractures progressive scoliosis rapid growth spurt falls/injury /fractures fear motivation Marion Main Ways of maintaining ambulation in NM disorders • maintain power – Steroids in DMD – Beta agonists in SMA • control contractures/deformity • prevent injury • Orthoses • maintain motivation – child and parents/carers Marion Main Trends in survival in DMD- secular trends Eagle et al Neuromusc Dis 2002 SS= scoliosis surgery Eagle et al Neuromusc Dis 2002 Duchenne muscular dystrophy - survival in Wales by decade of birth 1955-1995 120 100 percentage alive 80 55-64 60 65-74 75-84 85-94 40 20 0 4 6 8 10 12 14 16 18 20 age / years 22 24 26 28 30 32 34 Duchenne mean survival by 5 year cohort of birth 25 20 age 15 10 5 0 55-59 60-64 65-69 70-74 year of birth 75-79 80-84 Joint neuro respiratory clinics- doing the right thing ? YES When is the right time to refer to the respiratory team ? EARLY Advantages of Joint Clinics • Don’t send patient to …x, y, z • Invite …x, y, z, to be part of your team Who is involved with the care of NM patients? • • • • • • • • • • • • • • • • • • • • • • • • • GP, community paediatrician at district general hospital hospital paediatrician at district general hospital, paediatric neurologist at tertiary hospital, neuromuscular specialist national centre, paediatric respiratory consultant and nurse paediatric cariologist physiotherapist, occupational therapist, speech and language therapist, dietician, social worker, geneticist, orthotist, wheelchair services, orthopaedic surgeon, spinal surgeon, neurophysiologist, Histopathologist, anaesthetist, intensivist, special educational needs teacher. Neuromuscular nurse specialist palliative care team Transitional care team to take over care on reaching adulthood Parents The future 1. 2. What we can do . What we are trying to do. What we can do : Role of steroids • Prednisolone / Deflazacort • Regimes: – Prednisolone 0.75 mg/kg/day – Deflazacort 0.9 mg/kg/day • consider alternate day dose or steroid breaks • How long to give it? • Increase in muscle strength • Prolonged ambulation for up to 2 years • ? Improvement in cardiac function • ? Lessen scoliosis • ? Improves respiratory function Cochrane 2004: Improvement in muscle strength and function for 6 months to 2 years What we can do in 2008 : in the UK Scoliosis surgery Management of nocturnal hypoventilation Maintain ambulation Treatment of cardiomyopathy and arrhythmias Effective transition of care Excellence in palliative care What they can do in 2008 : in Europe All the above AND Provide social opportunities and education Prevent social isolation Have a job Drive a car Have sex / have a relationship PTC124 PTC 124 nonsense mutation allows the cellular machinery to read through premature stop codons in mRNA The future: Nonsense mutation correction The future: Exon skipping Gene therapy progress and prospects: Duchenne muscular dystrophy K Foster, H Foster and J G Dickson http://www.nature.com/gt/journal/v13/n24/full/3302877a.html The future: Use of ACE-I Losartan • angiotensin II receptor antagonist drug used to treat high blood pressure. • positive results in mouse model of Marfan syndrome, • studied in mdx-mice • TGF-β inflammatory pathway is also activated in the muscle of DMD boys and in the mdx mouse. • DMD already use ACE-I for treatment of cardiomyopathy • Why not use Losartan to reduce the inflammation?