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

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.

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

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

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 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.

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 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.

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 Main cause of concern is

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 2.4 to 5.5 per 100,000 population Inherited Autosomal Dominant Treatment is symptomatic

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

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

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 because of Ach facilitated depolarization at NMJ

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

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

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

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

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.

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

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.

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

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

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