Neuromuscular Disorders:disorders of neuromuscular junction, motor neuron, and muscleKasia PetelenzGreg Gordon (and others)November 15, 2005

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

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.

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

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

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

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

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

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

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.

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

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

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

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.

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

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

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

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

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

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

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

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

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

Disorders of Muscle Congenital Muscular

Dystrophies Myotonic Duchenne, Becker

Acquired Myopathies Cushing’s Syndrome Dermatomyositis Polymyositis

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

Characteristic Appearance - MD

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

Coexisting Organ Dysfunction - MD Cataracts very common GI abnormalities

Gastric atony Intestinal hyper-

motility Pharyngeal muscle

weakness with impaired airway protection

Cholelithiasis

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

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

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

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

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”

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

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

Progressive disease course

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

Gowers’ Maneuver

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

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

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

Case Report: DMD, PEG, and LMA CHF

LVEF 20% Physical Exam:

hypertrophied tongue MP III muscle strength 1-2/5 upper and lower

extremities

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

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

Why this type of anesthetic?

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

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

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

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