1. Kasia Petelenz Greg Gordon (and others) November 15, 2005
Neuromuscular Disorders: disorders of neuromuscular junction, motor neuron, and muscle
Kasia Petelenz
Greg Gordon (and others)
November 15, 2005

2. Myasthenia Gravis Incidence 1:10,000 to 1:30,000
Women 20 – 30 years of age are most often affected; men older than 60 display symptoms
Acquired chronic autoimmune disorder
Hallmarks are weakness and rapid exhaustion of voluntary skeletal muscles
The neonatal form of disease occurs in 20% of newborns.
Neonatal Persistent has an onset at apprximately 2 to 3 months of age. This is a rare form of disease. Patients have not antibodies to AChRs and some may have a totally unrelated diease. More care may be needed in diagnosis.

3. Myasthenia Gravis
Muscle strength characteristically improves with rest, deteriorates rapidly with exertion
Skeletal muscle atrophy is unlikely
Laryngeal and pharyngeal muscle weakness may lead to aspiration, problems clearing secretions, difficulty chewing.

4. Myasthenia Gravis Presentations
Clinical Classification
Class 1: ocular symptoms only
Class 1A: ocular symptoms with EMG evidence of peripheral muscle involvement
Class 2A: mild generalized symptoms
Class 2B: more severe and rapidly progressive symptoms
Class 3: acute and presenting in weeks to months with severe bulbar symptoms
Class 4: late in the course of disease with severe bulbar symptoms and marked generalized weakness

5. Myasthenia Gravis
Disease course marked by exacerbations and remissions
Infection, stress, surgery, pregnancy have unpredictable effects, but often cause exacerbations
Antibiotics can aggravate weakness
Diseases considered AI in origin often coexist
Decreased thyroid function RA
SLE
Pernicious Anemia

6. Mechanism - MG
Decrease in functional Acetylcholine receptors at the nicotinic neuromuscular junction
70% - 90% have circulating antibodies to AChR’s
Neonatal
Transient born to mothers with MG – Ab’s cross placenta
Only 12% symptomatic

7. Normal transmission:
Nerve action potentials cause the release of Ach from nerve terminals.
Ach crosses the cynaptic cleft, attaches to the receptor site on the sarcolemma, causing dpeolarization -> endplate potential
If the threshold for excitation is exceeded by the summation of many EPPs and action potential invades the muscle cell membrane and spreads along its surface, causing muscle contraction
In myasthenia, amount of Ach released is normal, or even increased, but, alterations found at the NM junctions cause alterations in transmission of impulses
Widening of synaptic space at NMJ
Degeneration of Junctional folds
3) Concentration of functional AChRs on postsynptic membrane reduced by more than 60% -> secondary to antiboies to the AChR
4) AChR ab’s decrease amount of function Ach via direct blockade, complement-mediated lysis, and increased receptor degradation rate

8. Therapy - Myasthenia Gravis
Immunosuppressants:
Steroids - Commonly cause dose dependent weakness
Azathioprine,Cyclosporine
Plasmapheresis, iv immunoglobulin
Acute exacerbations, i.e. in immediate post-operative period if anticholinesterases have been withheld and symptoms are severe
Plasmapheresis + IVIG for 5 days -> rapid improvement, may last for weeks
Thymectomy

9. Important part of Rx Anticholinesterase drugs
Pyridostigmine, po duration of 2-4 hours
Excessive administration -> Cholinergic Crisis
SLUDGE: Salivation, lacrimation, urination, defecation, + miosis + bradycardia + bronchospasm
Profound weakness: due to excess Ach at NMJ -> persistent depolarization
Treatment of Cholinergic Crisis: Atropine, Mechanical Ventilation if needed

10. Anesthetic Concerns - MG
Pre-op Predictors of Need for Post-Operative Ventilatory Support
Disease duration > 6 years
Concomitant pulmonary disease
Maximum inspiratory force (MIF) <-25cm H2O
VC < 4 mL/kg
Pyridostigmine dose >750 mg/day

11. Anesthetic Considerations
Old School: Recommended to d/c anticholinesterase if pt has only mild weakness
Theory: Potentiates Sux, inhibit effect of NDMR’s
Pts more susceptible to vagal arrhythmias
Slows metabolism of ester LA’s, Sux, Mivacron
New School: No experimental evidence to suggest that altering a pt’s anticholinesterase regimen has any clinically significant effect on NMB or duration of mechanical ventilation post-op.

12. Anesthetic Considerations
Increased risk for aspiration
Premed with Reglan/Ranitidine
Reduced respiratory reserve
Avoid premeds with opioids, benzo’s
Pts are very sensitive to respiratory depressant effects

13. Anesthetic Considerations - MG
Response to Sux is unpredictable
Relative resistance usually seen
ED95 approximately 2.6 x normal
Exquisitely sensitive to NDMRs!!
All NDMRs have been used successfully and uneventfully if twitches are monitored
Should be titrated in 1/10 to 1/20 normal dose
Sensitivity to NMDRs is increased during co-administration of potent inhaled anesthetic
Reverse with standard doses of anticholinesterase and anti-cholinergic

14. Post-Op Considerations – MG
Case Scenario: Pt extubated in OR, 40 minutes later c/o feeling weak and unable to breathe
Myasthenic crisis: decreased response to anticholinesterases
Cholinergic crisis: overdose of anticholinesterases
Both: increases in muscle weakness, salivation, and sweat occur

15. Post-Op Anesthetic Considerations – Myasthenia Gravis
Differentiate with response to 10mg iv Edrophonium:
Myasthenic crisis shows some improvement in muscle strength
Cholinergic crisis shows no increase in muscle strength and worsening of respiratory distress.

16. MG upstairs Epidural Analgesia preferred
Maintains SV and LA dose can be easily titrated
No evidence that MG pts are more sensitive to LA used for conduction anesthesia, but MG predisposes to increased weakness
Amide LAs probably better:
Hepatic Metabolism
Not hydrolyzed by serum cholinesterases
Emergent C/S
Sux to allow rapid control and protection of airway
30% chance of getting worse during the purperium and then returns to the prepregnant state of weakness immediately postpartum
Maternal and fetal mortality rates are increased approximately 5 fold by the disease.

17. Lambert-Eaton Syndrome
Mimics Myasthenia Gravis
Most often affects older males
Usually associated with Small Cell CA (lung)
Voltage increment to repeated stimulation and a poor response to anticholinesterases
Sensitive to NMDR’s, normal/increased response to Sux
Antibodies to Ca channel associated protein synaptogamin present

18. Motor Neuron Diseases Degeneration of upper and/or lower motor neurons
i.e. Amyotrophic Lateral Sclerosis
Muscular weakness and atrophy
Steady, asymmetric progression
Sensory systems, voluntary eye movements, and urinary sphincters are spared
Spinal msucular atrophy is another montor neuron degenerative disease, but the peripheral motor neurons are afffected without involvement of the upper motor neurons. Anesthesia management is basicially the same.

19. Amyotrophic Lateral Sclerosis
Progressive neuromuscular disorder
Characterized by degeneration of spinal motor neurons, leading to:
Denervation
Muscle wasting
Paralysis
Eventually death, most often secondary to respiratory failure

20. ALS – Anesthetic Concerns
Increased Sensitivity to NDMRs
Reduction in choline acetyltransferase (involved in synthesis of ACh) occurs secondary to degeneration of anterior horn cells
Avoid Sux
Hyperkalemic response in degenerating muscles
Main cause of concern is

21. ALS – Anesthetic Concerns
GA documented to cause ventilatory depression post-operatively, even without use of muscle relaxants
Respiratory complications are common and a major cause for concern
Regional relatively contraindicated in pts with motor neuron disease, including ALS, for the fear of exacerbating the disease

22. ALS – Case Description
76 y/o with rapidly progressing ALS, s/p femoral head fx
PE: siallorrhea, dysarthria, dysphonia, cachexia
Recent PFT’s reveal 20% nL lung function
Refused to withdraw “Do not intubate” orders for the intra and post-op time frames

23. Intra-Op Course Intrathecal Catheter placed at L3/4
0.25 mL of Bupivicaine 0.75% (1.9 mg) injected through catheter
T8 level
Catheter was discontinued upon completion of case
POD #1: minor desats, resolved with O2 therapy
No c/o HA during post-op course

24. Choice of most minimally invasive anesthetic method
Case reports have documented successful use of epidural anesthesia
Gradual onset of block
Less hemodynamic instability
But inadequate epidural anesthesia may result
Incremental Intrathecal technique allowed adequate anesthesia without adverse hemodynamic consequences, and enabled extension of block as needed

25. Disorders of Muscle Congenital Muscular Dystrophies
Myotonic
Duchenne, Becker
Acquired Myopathies
Cushing’s Syndrome
Dermatomyositis
Polymyositis

26. Myotonic Dystrophy
Characterized by persistent contractures of skeletal muscles after voluntary contraction or following electrical stimulation
Peripheral nerves and NMJ are not affected.
Abnormality in the intracellular ATP system that fails to return calcium to the sarcoplasmic reticulum
Contractures are not relieved by NDMRs, regional or deep anesthesia
Infiltration of LA into skeletal muscle may induce relaxation
Depression of rapid sodium flux into muscle cells by phenytoin, procainamide, quinidine, may alleviate contracture by delaying membrane excitability
2.4 to 5.5 per 100,000 population
Inherited Autosomal Dominant
Treatment is symptomatic

27. Characteristic Appearance - MD
Characteristic triad of mental retardation, frontal baldness, cataract fomration.
Also see expressionless facies secondary to facial weakness
Wasting and weakness of sternocleidomastoid muscles
ptosis

28. Coexisting Organ Dysfunction - MD
Cardiac Involvement
Mitral valve prolapse – 20% of individuals
Deterioration of the His-Purkinje system lead to arrhythmias
1st degree AV block very common
Pulmonary Pathology
Restrictive lung disease
Impaired responses to hypoxia and hypercarbia
High perioperative morbidity and mortality are caused pricipally by cardiopulmonary complications

29. Coexisting Organ Dysfunction - MD
Cataracts very common
GI abnormalities
Gastric atony
Intestinal hyper-motility
Pharyngeal muscle weakness with impaired airway protection
Cholelithiasis

30. Anesthetic Pre-Op Concerns
Eventually develop extremely compromised respiratory function
Pulmonary Aspiration, Pneumonia
Chronic Alveolar hypoventilation because of impaired neuromuscular function -> chronic hypercapnea
Decreased FRC, VC, MIP
Avoid premeds – very sensitive to respiratory depressant effects of narcotics and benzos

31. Anesthetic Concerns MD
Avoid Etomidate
May cause myoclonus and precipitate contractures
Avoid Sux
Produces an exaggerated contracture
Susceptible to MH
Avoid Anticholinesterases – may precipitate contracture by increasing ACh available at NMJ
Keep room warm – shivering may lead to contractures
because of Ach facilitated depolarization at NMJ

32. Anesthetic Concerns MD
Exaggerated effects of myocardial depression from inhaled agents- even Asymptomatic pts have some degree of cardiomyopathy
Anesthesia and surgery could theoretically aggravate co-existing cardiac conduction blockade by increasing vagal tone or causing transient hypoxia of the conduction system
Pregnancy:
Exacerbation of symptoms is likely
Uterine atony and retained placental often complicate vaginal delivery
because of Ach facilitated depolarization at NMJ

33. Guillaume Benjamin Amand Duchenne
The French neurologist, who studied and defined many neuromuscular diseases, in the mid 1900’s, including the one named for him

34. Completely irrelevant side note
Duchenne investigated facial expression in a crude but effective manner of ‘shocking’ the facial muscles using galvanic current – defined “facial expressions”

35. Duchenne Muscular Dystrophy
Most common muscular dystrophy encountered by anesthesiology
Incidence 1:3,500 live male births
Characterized by painless degeneration and atrophy of skeletal muscles
X-linked disorder
DMD gene isolated to short arm of the X chromosome at position 21
Estimated mutation rate is one of the highest for any human disease

36. Duchenne Muscular Dystrophy
DMD gene product: dystrophin
Absent or nonfunctional in DMD patients
Associated with muscle cell membranes
In its absence, a sequence of events occurs that leads to calcium influx into the muscle cells -> cell degeneration and death
Affects Skeletal, Cardiac, and Smooth muscle

37. Progressive disease course

38. DMD: Disease Progression
Under 2 yrs old
Behave like healthy toddlers
2-5 yrs old
First outward signs of muscular weakness
Clumsiness, frequent falling, waddling gait, difficulty climbing stairs
Calf muscles begin to look enlarged
6-12 yrs old
Child walks on toes secondary to Achilles tendon tightening and to compensate for weak quads
Weakening pelvic and shoulder girdles -> compensatory lordosis

39. Gowers’ Maneuver

40. DMD: Disease Progression
8-14 yrs old
Lose ability to walk
Decrease in caloric requirements -> even normal diet leads to obesity
95% develop scoliosis
Adult phase
Scoliosis + weakened respiratory muscles, inactivity, obesity -> compromised lung expansion and function
Vital capacity decreased approximately 50%
Weak cough -> vulnerable to pneumonia
Late 20’s
90% die of respiratory complications, 10% cardiac

41. Cardiopulmonary Dysfunction
Degeneration of cardiac muscle inevitable
Tall R waves in V1; deep Q waves in limb leads; short PR intervals; sinus tach
MR due to papillary muscle dysfunction
Decreased cardiac contractility
Pulmonary difficulties
Chronic weakness predisposes to decreased ability to cough, leads to accumulation of secretions -> pneumonia
Sleep apnea common -> pulmonary hypertension

42. Case Report: DMD, PEG, and LMA
20 yr old with DMD
Chronic Respiratory Failure
Vital Capacity 450 mL (9% predicted)
Maximum inspiratory and expiratory pressures: -20 and +5 cm H2O
To generate effective cough: MEP >60
Cough peak flow of 40 L/min
Cough <160 L/min associated with ineffective airway clearance
On 24 hr nasal BiPAP, settings 20/7, rate 16

43. Case Report: DMD, PEG, and LMA
CHF
LVEF 20%
Physical Exam:
hypertrophied tongue
MP III
muscle strength 1-2/5 upper and lower extremities

44. Case Report: DMD, PEG, and LMA
Procedure performed in PACU
Standard monitors
Premed: 1mg Midazolam, just prior to induction
Induction:
300mcg/kg/min Propofol, adj for maintenance as needed
30 mg Ketamine
SV with NPPV until eyelash reflex abolished

45. Case Report: DMD, PEG, and LMA
Appropriate LMA inserted
Well lubricated gastroscope passed through the mouth, behind LMA
LMA deflated as necessary to allow better scope navigation
Ventilation assisted as needed to maintain PaCO
LMA removed after procedure under deep sedation with spontaneous ventilation, and NPPV replaced
PICU monitoring overnight, d/c home < 24 hours

47. Why this type of anesthetic?

48. Anesthesia Concerns with DMD
Lingular hypertrophy: difficult intubation
Association with MH has been suggested but not validated
But, avoid volatile agents if possible, and keep Dantrolene available

49. Anesthesia Concerns with DMD
NDMR’s ok, but action is prolonged
SUX IS CONTRAINDICATED
Regenerating muscle fibers, common in DMD until at least 8 years of age, are considered to be more vulnerable to the effects of SUX
Difficult Extubation:
Endotracheal edema
Mucosal congestion
Inability to clear retained secretions
Acute respiratory failure

50. Review Questions (Hall)
173. Which of the following diseases is associated with increased resistance to neuromuscular blockade?
A. Myasthenia Gravis
B. Myasthenic Syndrome
C. Huntington’s chorea
D. Duchenne muscular dystrophy

51. Answer: A Myasthenia Gravis Myasthenic Syndrome (Eaton Lambert)
Fewer AChRs.
Resistant to Sux.
Sensitive to NMDR’s.
Myasthenic Syndrome (Eaton Lambert)
Decreased release of Ach but normal number of AChRs
Sensitive to Sux and NMDRs
Huntington’s chorea
Decreased plasma cholinesterase activity
Prolonged response to Sux
Duchenne Muscular Dystrophy
Sux is relatively contraindicated
NMDR’s have a normal response, although patients have prominent skeletal muscle weakness.

52. Review Questions (Hall)
y/o male with myasthenia gravis, to ED, confused, agitated, 2 day h/o weakness, SOB. RR 30 breaths/min, TV 4mL/kg.
ABG: PaO2 60; PaCO2 51; HCO3 -25; pH 7.3; SaO2 90%
Edrophonium 5mg iv -> TV 2mL/kg
A. Tracheal Intubation and Mechanical Ventilation
B. Repeat Edrophonium
C. Neostigmine 1 mg IV
D. Emergency Trach
E. Atropine 0.4 mg IV

53. Answer: A Cholinergic crisis vs. myasthenic crisis
Cholinergic crisis worsens with administration of anticholinesterase
Pt should be electively intubated until strength returns.
Again, to review:
If muscle strength improves, the patient is undertreated with anticholinsterase therpay. If no increase in muscle strength occurs, or if repiratory distress becomes worse, the patient is probably in a cholinergic crisis.
However, respiratory support, if needed, should not await the anitcholinesterase test.

54. Review Questions (Hall)
669. A lumbar epidural is placed in a 24 y/o G1P0 with myasthenia gravis. Select the true statement regarding neonatal MG.
A. The newborn is usually affected.
B. The newborn is affected by maternal IgM
C. The newborn may require anticholinesterase therapy for up to 3 weeks
D. The newborn will need lifelong treatment
E. Only female newborns are affected

55. Answer: C IgG antibodies are directed against AChRs
IgG can cross placenta
Neonatal MG is characterized by muscle weakness (hypotonia, respiratory difficulty)
Presents within the first 4 days of life (80% within first 24 hours)
Anticholinesterase therapy may be required until the maternal IgG is metabolized

56. References
Bach JR, Ishikawa Y, Kim H. Prevention of Pulmonary Morbidity for patients with Duchenne Muscular Dystrophy. Chest 1997;112:
Benumoff JL, ed. Anesthesia & Uncommon Diseases, 4th Ed. Philadelphia: WB Saunders. 9, 373-4
Brimacombe J, Newell S, Bergin A, et al. The Laryngeal Mask for Percuatneous Endoscopic Gastrostomy. Anesth Analg 2000;91:635-6
Dillon FX. Anesthesia issues in the perioperative management of myasthenia gravis. Semin Neurol Mar;24(1):83-94.
Faust RJ, ed. Anesthesiology Review, 3rd Ed. Philadelphia: Churchill Livingstone
Hara K, Sakura S, Saito Y, et al. Epidural Anesthesia and Pulmonary Function in a Patient with Amyotrophic Lateral Sclerosis. Anesth Analg 1996;83:878-9

57. References
Morris P. Duchenne Muscular Dystrophy: a challenge for the anaesthetist. Paediatric Anaesthesia 1997;6:1-4
Moser B, Lirk P, Lechner M, et al. General anaesthesia in a patient with motor neuron disease. Eur J Anesthes 2004;21:
Otsuka N, Igarashi M, Shmiodate, et al. Anesthetic management of two patients with amyotrophic lateral sclerosis. Masui Nov;53(11):
Pope JF, BirnKrant DJ, et al. Noninvasive Ventilation during percuatneous gastrostomy placement in Duchenne Muscular Dystrophy. Pediatr Pulmonol 1997;23:
Stoelting RK, Dierdor SF, ed. Anesthesia and Co-Existing Disease, 4th Ed. Philadelphia: Churchill Livingstone. 217, ,
Yao FS, ed. Anesthesiology: Problem-Oriented Patient Management, 5th Ed. Philadelphia: Lippincott Williams & Wilkins