clinical

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

2. Objectives
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• Identify clinical signs of impending
respiratory failure
• List 3lung function testsusedto
monitor patients with neuromuscular
disease for respiratory failure
• Define Non-Invasive Ventilation

3. Classification
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• Muscular Dystrophies
• Congenital and Metabolic Myopathies
• Anterior Horn Cell Disorders
• Neuromuscular Junction Diseases

4. Epidemiology of Neuromuscular Diseases
http://www.mfm-nmd.org/history.aspx
Accessed on S
eptember 14, 2010
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5. Clinical Signs of Neuromuscular Disease
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• 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

6. Work-Up Hypotonia and Weakness
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• CK - creatinine kinase
• EMG - electromyogram
• NCS - nerve conduction study
• ECG - cardiac muscle involvement
• Muscle Biopsy - electron microscopy
• Nerve Biopsy
• Gene testing
• Others

7. Clinical Symptoms of
Impending Respiratory Failure
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• Infants
– Paradoxical breathing
– Tachypnea
– Head bobbing
– Poor feeding
– Increasing muscle weakness and hypotonia

8. Clinical Symptoms of
Impending Respiratory Failure
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• Older children
– Sleep disordered breathing (SDB)
• Daytime behavioral and neurocognitive
problems
• Hyperactivity
• Tiredness
• Morning headaches
• Nocturnal arousals
• Daytime sleepiness
• Anorexia

9. Classification: Muscular Dystrophies
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– Duchenne muscular dystrophy
– Becker muscular dystrophy
– Myotonic muscular dystrophy
– Congenital muscular dystrophy (8)
– Distal muscular dystrophy (8)
– Others

10. Duchenne Muscular Dystrophy
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• Genetics
– X-linked recessive (males)
– Chromosome X, DMD gene
• Cause
– Dystrophin protein needed for muscle cell interaction
• Onset
– 2-6years of age degenerative disease
• Symptoms
– Proximal muscleweakness,affects respiratory and
cardiac muscle

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
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• Nemaline myopathy
• Myotubular/Centronuclear myopathy
• Central core disease
• Multiminicore disease
• Congenital fiber-type disproportion
myopathy

14. Nemaline Myopathy
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• Genetics
– Autosomal recessive and dominant forms
– First discovered in 1956by Dr. Reyes
– 1/50,000 births
– 6different mutations identified
• Onset
– Infancy and early childhood
• Clinical presentation
– Face, neck and proximal muscle weakness
– Absent deep tendon reflexes (DTR), normal creatinine
kinase

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
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• 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

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
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• Proximal skeletal muscles
• Variable clinical picture
• Malignant hyperthermia
• Rare
• Mutations RYR1 gene
• Genetics autosomal dominant (some
autosomal recessive)

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
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• Genetics autosomal recessive
– SEPPN1 mutation
– Rare disease
• C linical
– 4 types
• Rigid spine (classic)
• Progressive with hand involvement
• Arthrogryposis multiplex
• opththalmoplegic

22. Multiminicore Disease
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• 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

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
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• Genetics
– 3different mutations, usually present first year of
life
• Clinical
– Hypotonia, weakness,delayedmotor development
first year of life
– 90%static or slow improvement over time
– Contractures at birth
– Scoliosis
– Dislocated hips

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
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• Pompe disease
• Phosphorylase deficiency
• Phosphofructokinase deficiency
• Debrancher enzyme deficiency
• Mitochondrial myopathy
• Carnitine deficiency
• Carnitine palmityl transferase deficiency
• Lactate dehydrogenase deficiency
• Others

28. Classification: Anterior Horn Cell Disorders
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• Infectious - poliomyelitis
• Motor neuron disease - amyotrophic
lateral sclerosis
• Spinal muscular atrophy (SMA)

29. SMA
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• Genetics
– Autosomal recessive
– 1/6000births
– 1/40 carriers
– SMA1 and SMA2 identified to chromosome 5q
in 1995
– Variable based on specific genetic defect

30. SMA Types
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• Type 1
• Type 2
• Type 3
• Type 4
• Non-5q-SMA’s

31. Incidence SMA at Birth
Type 1
Type 2
Type 3
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60%
12%
27%

32. Prevalence SMA in Population
Type 1
Type 2
Type 3
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14%
35%
51%

33. SMA Type 1
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• Werdnig-Hoffman Disease
• Severe
• Age of onset 0-6months
• Never sits, flaccid paralysis, absent deep
tendon reflexes, tongue fasiculations
• Life expectancy < 2years

34. SMA Type 1
http://www.kierahenry.com/i//tn2_1.jpg
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35. SMA Type 2
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• Intermediate severity
• Age of onset 7-18months
• Sits but never stands
• Life expectancy > 2 years

36. SMA Types 3 and 4
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• SMA 3
– Kugelberg-Welander Disease
– Mild severity
– Age of onset > 18months
– Function stands and walks
– Life expectancy - adult
• SMA 4(adult form – rare)
– Very mild severity
– Presents 2nd and 3rd decade
– Ambulatory

37. Anterior Horn Cell Disease
http://www.alsont.ca/_media/Image/about-als/als-diagram.jpg
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38. Anterior Horn Cell Disease
http://www.ott.zynet.co.uk/polio/lincolnshire/library/gawne/images/pandcmfig3.gif
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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
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• Congenital myasthenic syndromes
• Myasthenia gravis
– Acetylcholine junction

41. http://jama.ama-assn.org/content/vol293/issue15/images/medium/jpg0420f1.jpg
Accessed 9/20/10
Pathophysiology of Myasthenia Gravis
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42. Congenital Myastheinic Syndromes
• Presynaptic insufficient acetylcholine
• Postsynaptic receptor problem
• Synapticacetylcholinesterase 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
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• Scoliosis
• Bulbar Dysfunction
– Swallowing dysfunction, speech
• Osteoporosis
• Respiratory Failure
• Cardiomyopathy/Congestive Heart
Failure
• Early Death

44. Monitoring for Respiratory Failure
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• Serial monitoring of lung function whenableto
be performed ( > 5years of age)
– FVC < 1liter
• Close monitoring, consider NIV
– FVC < 40%of predicted (nocturnal hypoventilation)
• Refer for polysomnography
– MIP < 40 cm H2O MEP < 45cm H2O
• Polysomnography, consider day/night CO2
– Peak Cough Flows < 270L/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

45. Diagnostic Studies
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• Polysomnography
– Upper airway obstruction
• Blood gases
• Cardiac Echo
• Serial pulmonary function tests

46. Physiology of Respiratory Pump Failure
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• 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

47. Interventions
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• Adenotonsillectomy
• Limited care
• Non-invasive ventilation
– High flow nasal cannula, sipap
– Sip andpuff,
insufflation/exsufflation
– Cpap face or nasal
– Bipap face or nasal
– Negative pressure ventilation
• Invasive ventilation
– Trach

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
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• First used in the 1960’s
• First suggested for use in 1980’sfor NMD
• May reduceincidence of respiratory
infections
• Techniques to improve pulmonary toilet –
breath stacking, cough assist devices
• Possible benefit of high-frequency chest
walloscillation andintrapulmonary
percussive ventilation

52. Non-Invasive Ventilation
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• According to international consensus,
NIV isdefinedasanyform of
ventilatory support appliedwithout
endotrachealintubation andincludes
bipap, cpap and other modes

53. Non-Invasive Ventilation
http://thevibe.socialvibe.com/wp-content/uploads/2008/07/photo-764404.jpg
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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
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• Marked improvementin managementof
respiratory complications of neuromuscular
disease in past 15years
• Serialmonitoring for progressiverespiratory
pump failure necessary to minimize pulmonary
complications
• Early implementation of therapiesto treat
hypoventilation and promote airway clearance
may augment quality and quantity of life

56. Q&A
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Thank you for attending!