ANLS 2008

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

Fritz Sumantri UsmanNeurologist & 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 AChR’s

• Neonatal – Transient born to mothers with MG – Ab’s 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 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

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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 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.

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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

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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 co-

administration 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 NMDR’s, 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 PFT’s 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– Cushing’s 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 hyper-motility– 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 1900’s, 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 20’s– 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• 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

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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. Huntington’s chorea– D. Duchenne muscular dystrophy

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Answer: A• Myasthenia Gravis

– 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.

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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;112:1024-28• 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. 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