Neuromuscular Disorders : Disorders of Neuromuscular Junction, Motor Neuron, and Muscle

Fritz Sumantri Usman

Neurologist & Interventional Neurologist

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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
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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.
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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
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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

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Mechanism - MG
Decrease in functional Acetylcholine receptors at the nicotinic neuromuscular junction 70% - 90% have circulating antibodies to AChRs
Neonatal
Transient born to mothers with MG Abs cross placenta Only 12% symptomatic
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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
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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

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

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Anesthetic Considerations
Old School: Recommended to d/c anticholinesterase if pt has only mild weakness
Theory: Potentiates Sux, inhibit effect of NDMRs Pts more susceptible to vagal arrhythmias Slows metabolism of ester LAs, Sux, Mivacron

New School: No experimental evidence to suggest that altering a pts anticholinesterase regimen has any clinically significant effect on NMB or duration of mechanical ventilation postop.
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Anesthetic Considerations
Increased risk for aspiration
Premed with Reglan/Ranitidine

Reduced respiratory reserve

Avoid premeds with opioids, benzos Pts are very sensitive to respiratory depressant effects

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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 coadministration of potent inhaled anesthetic

Reverse with standard doses of anticholinesterase and anti-cholinergic

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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

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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.

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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
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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 NMDRs, normal/increased response to Sux Antibodies to Ca channel associated protein synaptogamin present
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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
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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
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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

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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
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ALS Case Description

76 y/o with rapidly progressing ALS, s/p femoral head fx PE: siallorrhea, dysarthria, dysphonia, cachexia Recent PFTs reveal 20% nL lung function Refused to withdraw Do not intubate orders for the intra and post-op time frames
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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
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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
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Disorders of Muscle
Congenital Muscular Dystrophies
Myotonic Duchenne, Becker

Acquired Myopathies
Cushings Syndrome Dermatomyositis Polymyositis

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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
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Characteristic Appearance - MD

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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

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Coexisting Organ Dysfunction - MD

Cataracts very common GI abnormalities
Gastric atony Intestinal hypermotility Pharyngeal muscle weakness with impaired airway protection Cholelithiasis
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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
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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
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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
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Guillaume Benjamin Amand Duchenne

The French neurologist, who studied and defined many neuromuscular diseases, in the mid 1900s, including the one named for him
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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
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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
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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

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Progressive disease course

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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
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Gowers Maneuver

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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 20s
90% die of respiratory complications, 10% cardiac
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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
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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

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Case Report: DMD, PEG, and LMA

CHF
LVEF 20%

Physical Exam:
hypertrophied tongue MP III muscle strength 1-2/5 upper and lower extremities

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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

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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
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Why this type of anesthetic?

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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

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Anesthesia Concerns with DMD

NDMRs 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
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Review Questions (Hall)

173. Which of the following diseases is associated with increased resistance to neuromuscular blockade?
A. Myasthenia Gravis B. Myasthenic Syndrome C. Huntingtons chorea D. Duchenne muscular dystrophy

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Answer: A
Myasthenia Gravis
Fewer AChRs. Resistant to Sux. Sensitive to NMDRs.

Myasthenic Syndrome (Eaton Lambert)

Decreased release of Ach but normal number of AChRs Sensitive to Sux and NMDRs

Huntingtons chorea
Decreased plasma cholinesterase activity Prolonged response to Sux

Duchenne Muscular Dystrophy

Sux is relatively contraindicated NMDRs have a normal response, although patients have prominent skeletal muscle weakness.

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Review Questions (Hall)

489. 37 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
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Answer: A
Cholinergic crisis vs. myasthenic crisis Cholinergic crisis worsens with administration of anticholinesterase Pt should be electively intubated until strength returns.

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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
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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
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References
Bach JR, Ishikawa Y, Kim H. Prevention of Pulmonary Morbidity for patients with Duchenne Muscular Dystrophy. Chest 1997;112:102428 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;91:6356 Dillon FX. Anesthesia issues in the perioperative management of myasthenia gravis. Semin Neurol. 2004 Mar;24(1):83-94. Faust RJ, ed. Anesthesiology Review, 3rd Ed. Philadelphia: Churchill Livingstone. 490-494 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
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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;21:921-922 Otsuka N, Igarashi M, Shmiodate, et al. Anesthetic management of two patients with amyotrophic lateral sclerosis. Masui. 2004 Nov;53(11):1279-81 Pope JF, BirnKrant DJ, et al. Noninvasive Ventilation during percuatneous gastrostomy placement in Duchenne Muscular Dystrophy. Pediatr Pulmonol 1997;23:468-471 Stoelting RK, Dierdor SF, ed. Anesthesia and Co-Existing Disease, 4th Ed. Philadelphia: Churchill Livingstone. 217,517-519,522-528 Yao FS, ed. Anesthesiology: Problem-Oriented Patient Management, 5th Ed. Philadelphia: Lippincott Williams & Wilkins.1019-1032

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