Dr. Maynard's outline on neuromuscular disorders (presented on 9/23/10).

1. Neuromuscular Diseases
Roy Maynard, M.D.
September 23, 2010

2. 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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3. Classification
• Muscular Dystrophies
• Congenital and Metabolic Myopathies
• Anterior Horn Cell Disorders
• Neuromuscular Junction Diseases
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4. Epidemiology of Neuromuscular Diseases
http://www.mfm-nmd.org/history.aspx
Accessed on September 14, 2010
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5. 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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6. 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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7. Clinical Symptoms of
Impending Respiratory Failure
• Infants
– Paradoxical breathing
– Tachypnea
– Head bobbing
– Poor feeding
– Increasing muscle weakness and hypotonia
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8. 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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9. 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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10. 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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11. Duchenne Muscular Dystrophy
http://upload.wikimedia.org/wikipedia/commons/4/49/Duchenne-muscular-dystrophy.jpg
Accessed on September 20, 2010
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12. Duchenne Muscular Dystrophy
http://www.humgen.nl/lab-vdeutekom/pictures/DGC.jpg
Accessed 9/20/10
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13. Classification: Congenital Myopathies
• Nemaline myopathy
• Myotubular/Centronuclear myopathy
• Central core disease
• Multiminicore disease
• Congenital fiber-type disproportion
myopathy
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14. 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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15. Nemaline Myopathy
http://www.childrenshospital.org/cfapps/research/data_admin/Site1694/Images/S93-1497EM25039_490px.jpg
Accessed 9/20/10
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16. 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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17. Myotubular Myopathy
http://www.mtmrg.org/MTM%20Article%20by%20CR.PDF
Accessed 9/20/10
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18. Myotubular Myopathy
http://www.mtmrg.org/MTM%20Article%20by%20CR.PDF
Accessed 9/20/10
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19. 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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20. 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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21. 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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22. 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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23. Newborn with Hypotonia
http://neuromuscular.wustl.edu/pics/people/patients/cmdl.jpg
Accessed 9/20/10
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24. Multiminicore Disease Myopathy
http://www.scielo.br/img/revistas/anp/v62n4/a02fig04.gif
Accessed 9/20/10
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25. 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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26. Congenital Fiber-Type Disproportion
http://brain.oxfordjournals.org/content/vol128/issue7/images/large/awh511f5.jpeg
Accessed 9/20/10
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27. 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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28. Classification: Anterior Horn Cell Disorders
• Infectious - poliomyelitis
• Motor neuron disease - amyotrophic
lateral sclerosis
• Spinal muscular atrophy (SMA)
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29. 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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30. SMA Types
• Type 1
• Type 2
• Type 3
• Type 4
• Non-5q-SMA’s
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31. Incidence SMA at Birth
12%
Type 1
27% 60% Type 2
Type 3
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32. Prevalence SMA in Population
14%
35%
Type 1
Type 2
Type 3
51%
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33. 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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34. SMA Type 1
http://www.kierahenry.com/i//tn2_1.jpg
Accessed 9/20/10
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35. SMA Type 2
• Intermediate severity
• Age of onset 7-18 months
• Sits but never stands
• Life expectancy > 2 years
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36. 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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37. Anterior Horn Cell Disease
http://www.alsont.ca/_media/Image/about-als/als-diagram.jpg
Accessed 9/20/10
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38. 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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39. 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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40. Classification:
Diseases of the Neuromuscular Junction
• Congenital myasthenic syndromes
• Myasthenia gravis
– Acetylcholine junction
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41. Pathophysiology of Myasthenia Gravis
http://jama.ama-assn.org/content/vol293/issue15/images/medium/jpg0420f1.jpg
Accessed 9/20/10
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42. 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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43. Complications of Neuromuscular Disease
• Scoliosis
• Bulbar Dysfunction
– Swallowing dysfunction, speech
• Osteoporosis
• Respiratory Failure
• Cardiomyopathy/Congestive Heart
Failure
• Early Death
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44. 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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45. Diagnostic Studies
• Polysomnography
– Upper airway obstruction
• Blood gases
• Cardiac Echo
• Serial pulmonary function tests
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46. 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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47. 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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48. 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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49. Negative Pressure Ventilation
http://nivusers.tripod.com/Equipic/Negvent.html
Accessed 9/20/10
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50. 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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51. 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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52. 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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53. Non-Invasive Ventilation
http://thevibe.socialvibe.com/wp-content/uploads/2008/07/photo-764404.jpg
Accessed 9/20/10
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54. Non-Invasive Ventilation
http://www.mda.org/publications/images/q11-3_Taleah_English-SMA.jpg
Accessed 9/20/10
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55. 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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56. Q&A
Thank you for attending!
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