Neuromuscular Disorders: disorders of neuromuscular junction, motor neuron, and muscle

1. 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

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

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

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

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

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

27. Characteristic Appearance - MD

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

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

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

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 PaCO2 35-40 • 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