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Dr. Maynard's outline on neuromuscular disorders (presented on 9/23/10).
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Neuromuscular Diseases Roy Maynard, M.D. September 23, 2010
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Objectives
• Identify clinical signs of impending respiratory failure
• List 3 lung function tests used to monitor patients with neuromuscular disease for respiratory failure
• Define Non-Invasive Ventilation
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Classification
• Muscular Dystrophies • Congenital and Metabolic Myopathies • Anterior Horn Cell Disorders • Neuromuscular Junction Diseases
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Epidemiology of Neuromuscular Diseases
http://www.mfm-nmd.org/history.aspx Accessed on September 14, 2010
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Clinical Signs of Neuromuscular Disease
• Weakness, poor cough, retained airway secretions • Inability to lift extremities against gravity • Muscle wasting • Low muscle tone (hypotonia) • Poor feeding, swallowing dysfunction • Failure to thrive • Increased respiratory rate • Use of accessory muscles of respiration • Recurrent infections • Night sweats
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Work-Up Hypotonia and Weakness
• CK - creatinine kinase • EMG - electromyogram • NCS - nerve conduction study • ECG - cardiac muscle involvement • Muscle Biopsy - electron microscopy • Nerve Biopsy • Gene testing • Others
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Clinical Symptoms of Impending Respiratory Failure
• Infants – Paradoxical breathing – Tachypnea – Head bobbing – Poor feeding – Increasing muscle weakness and hypotonia
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Clinical Symptoms of Impending Respiratory Failure
• Older children – Sleep disordered breathing (SDB)
• Daytime behavioral and neurocognitive problems
• Hyperactivity • Tiredness • Morning headaches • Nocturnal arousals • Daytime sleepiness • Anorexia
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Classification: Muscular Dystrophies
– Duchenne muscular dystrophy – Becker muscular dystrophy – Myotonic muscular dystrophy – Congenital muscular dystrophy (8) – Distal muscular dystrophy (8) – Others
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Duchenne Muscular Dystrophy
• Genetics – X-linked recessive (males) – Chromosome X, DMD gene
• Cause – Dystrophin protein needed for muscle cell interaction
• Onset – 2-6 years of age degenerative disease
• Symptoms – Proximal muscle weakness, affects respiratory and
cardiac muscle
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Duchenne Muscular Dystrophy
http://upload.wikimedia.org/wikipedia/commons/4/49/Duchenne-muscular-dystrophy.jpg Accessed on September 20, 2010
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Duchenne Muscular Dystrophy
http://www.humgen.nl/lab-vdeutekom/pictures/DGC.jpg Accessed 9/20/10
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Classification: Congenital Myopathies
• Nemaline myopathy • Myotubular/Centronuclear myopathy • Central core disease • Multiminicore disease • Congenital fiber-type disproportion
myopathy
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Nemaline Myopathy • Genetics
– Autosomal recessive and dominant forms – First discovered in 1956 by Dr. Reyes – 1/50,000 births – 6 different mutations identified
• Onset – Infancy and early childhood
• Clinical presentation – Face, neck and proximal muscle weakness – Absent deep tendon reflexes (DTR), normal creatinine
kinase
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Nemaline Myopathy
http://www.childrenshospital.org/cfapps/research/data_admin/Site1694/Images/S93-1497EM25039_490px.jpg Accessed 9/20/10
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Myotubular Myopathy
• A form of centronuclear myopathy • Genetics
– X-linked recessive – Autosomal recessive and dominant
• Onset – Birth for X-linked recessive – Infancy and childhood for autosomal recessive – Adult for autosomal dominant
• X-linked is most common form and most severe • Clinical
– Hypotonia, respiratory pump failure, scaphocephaly
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Myotubular Myopathy
http://www.mtmrg.org/MTM%20Article%20by%20CR.PDF Accessed 9/20/10
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Myotubular Myopathy
http://www.mtmrg.org/MTM%20Article%20by%20CR.PDF Accessed 9/20/10
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Central Core Disease
• Proximal skeletal muscles • Variable clinical picture • Malignant hyperthermia • Rare • Mutations RYR1 gene • Genetics autosomal dominant (some
autosomal recessive)
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Central Core Disease
http://www.neurologyindia.com/articles/2008/56/3/images/ni_2008_56_3_325_43451_u1.jpg Accessed 9/20/10
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Multiminicore Disease
• Genetics autosomal recessive – SEPPN1 mutation – Rare disease
• Clinical – 4 types
• Rigid spine (classic) • Progressive with hand involvement • Arthrogryposis multiplex • opththalmoplegic
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Multiminicore Disease
• Symptoms – Muscle weakness and wasting – Scoliosis – Impaired respiratory function – Delayed motor development – Feeding problems in infants – Contractures – Weak eye movements – Low set ears
• Management – Supportive
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Newborn with Hypotonia
http://neuromuscular.wustl.edu/pics/people/patients/cmdl.jpg Accessed 9/20/10
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Multiminicore Disease Myopathy
http://www.scielo.br/img/revistas/anp/v62n4/a02fig04.gif Accessed 9/20/10
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Congenital Fiber-Type Disproportion
• Genetics – 3 different mutations, usually present first year of
life
• Clinical – Hypotonia, weakness, delayed motor development
first year of life – 90% static or slow improvement over time – Contractures at birth – Scoliosis – Dislocated hips
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Congenital Fiber-Type Disproportion
http://brain.oxfordjournals.org/content/vol128/issue7/images/large/awh511f5.jpeg Accessed 9/20/10
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Metabolic Myopathies
• Pompe disease • Phosphorylase deficiency • Phosphofructokinase deficiency • Debrancher enzyme deficiency • Mitochondrial myopathy • Carnitine deficiency • Carnitine palmityl transferase deficiency • Lactate dehydrogenase deficiency • Others
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Classification: Anterior Horn Cell Disorders
• Infectious - poliomyelitis • Motor neuron disease - amyotrophic
lateral sclerosis • Spinal muscular atrophy (SMA)
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SMA
• Genetics – Autosomal recessive – 1/6000 births – 1/40 carriers – SMA1 and SMA2 identified to chromosome 5q
in 1995 – Variable based on specific genetic defect
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SMA Types
• Type 1 • Type 2 • Type 3 • Type 4 • Non-5q-SMA’s
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Incidence SMA at Birth
Type 1Type 2Type 3
60%
12%
27%
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Prevalence SMA in Population
Type 1Type 2Type 3
51%
14%
35%
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SMA Type 1
• Werdnig-Hoffman Disease • Severe • Age of onset 0-6 months • Never sits, flaccid paralysis, absent deep
tendon reflexes, tongue fasiculations • Life expectancy < 2 years
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SMA Type 1
http://www.kierahenry.com/i//tn2_1.jpg Accessed 9/20/10
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SMA Type 2
• Intermediate severity • Age of onset 7-18 months • Sits but never stands • Life expectancy > 2 years
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SMA Types 3 and 4
• SMA 3 – Kugelberg-Welander Disease – Mild severity – Age of onset > 18 months – Function stands and walks – Life expectancy - adult
• SMA 4 (adult form – rare) – Very mild severity – Presents 2nd and 3rd decade – Ambulatory
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Anterior Horn Cell Disease
http://www.alsont.ca/_media/Image/about-als/als-diagram.jpg Accessed 9/20/10
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Anterior Horn Cell Disease
http://www.ott.zynet.co.uk/polio/lincolnshire/library/gawne/images/pandcmfig3.gif Accessed 9/20/10
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Anterior Horn Cell Disease
http://www.anatomyatlases.org/MicroscopicAnatomy/Images/Plate89.jpg and www.anatomyatlases.org/MicroscopicAnatomy/Section06/Plate0689.shtml
Accessed both websites 9/20/10
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Classification: Diseases of the Neuromuscular Junction
• Congenital myasthenic syndromes • Myasthenia gravis
– Acetylcholine junction
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http://jama.ama-assn.org/content/vol293/issue15/images/medium/jpg0420f1.jpg Accessed 9/20/10
Pathophysiology of Myasthenia Gravis
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Congenital Myastheinic Syndromes
• Presynaptic insufficient acetylcholine • Postsynaptic receptor problem • Synaptic acetylcholinesterase deficiency
http://www.med.nagoya-u.ac.jp/imgs04/i4l02m11mp1d310007_3.jpg Accessed 9/20/10
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Complications of Neuromuscular Disease
• Scoliosis • Bulbar Dysfunction
– Swallowing dysfunction, speech
• Osteoporosis • Respiratory Failure • Cardiomyopathy/Congestive Heart
Failure • Early Death
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Monitoring for Respiratory Failure
• Serial monitoring of lung function when able to be performed (> 5 years of age) – FVC < 1 liter
• Close monitoring, consider NIV – FVC < 40% of predicted (nocturnal hypoventilation)
• Refer for polysomnography – MIP < 40 cm H2O MEP < 45 cm H2O
• Polysomnography, consider day/night CO2 – Peak Cough Flows < 270 L/min in older children
• Monitor closely for respiratory failure – Wheelchair bound
• Consider overnight sleep monitoring – Upper airway obstruction
• Adenotonsillectomy (CPAP if no hypertrophy) – Chronic hypercarbia or acute respiratory failure
• NIV
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Diagnostic Studies
• Polysomnography – Upper airway obstruction
• Blood gases • Cardiac Echo • Serial pulmonary function tests
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Physiology of Respiratory Pump Failure
• Infants highly compliant chest • Hypopnea • Low tidal volumes (scoliosis impairs) • Decreased FRC • Early airway closure and atelectasis • Mechanical disadvantage • Poor collateral ventilation • Respiratory muscles change with time • Decreased chest wall movement • Impaired cough
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Interventions • Adenotonsillectomy • Limited care • Non-invasive ventilation
– High flow nasal cannula, sipap – Sip and puff,
insufflation/exsufflation – Cpap face or nasal – Bipap face or nasal – Negative pressure ventilation
• Invasive ventilation – Trach
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Negative Pressure Ventilation
http://www.ispub.com/ispub/ijh/volume_3_number_2_21/intensive_care_unit/icu-fig2a.jpg Accessed 9/20/10
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Negative Pressure Ventilation
http://nivusers.tripod.com/Equipic/Negvent.html Accessed 9/20/10
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Invasive Respiratory Support
http://upload.wikimedia.org/wikipedia/commons/thumb/9/94/VIP_Bird2.jpg/300px-VIP_Bird2.jpg Accessed 9/20/10
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NIV and Airway Clearance
• First used in the 1960’s • First suggested for use in 1980’s for NMD • May reduce incidence of respiratory
infections • Techniques to improve pulmonary toilet –
breath stacking, cough assist devices • Possible benefit of high-frequency chest
wall oscillation and intrapulmonary percussive ventilation
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Non-Invasive Ventilation
• According to international consensus, NIV is defined as any form of ventilatory support applied without endotracheal intubation and includes bipap, cpap and other modes
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Non-Invasive Ventilation
http://thevibe.socialvibe.com/wp-content/uploads/2008/07/photo-764404.jpg Accessed 9/20/10
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Non-Invasive Ventilation
http://www.mda.org/publications/images/q11-3_Taleah_English-SMA.jpg Accessed 9/20/10
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Conclusions
• Marked improvement in management of respiratory complications of neuromuscular disease in past 15 years
• Serial monitoring for progressive respiratory pump failure necessary to minimize pulmonary complications
• Early implementation of therapies to treat hypoventilation and promote airway clearance may augment quality and quantity of life
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Q&A
Thank you for attending!