Myasthenia Gravis

Myasthenia Gravis NMJ / Endplate Chemical synapse Presynaptic membrane Synaptic cleft Postsynaptic membrane

Arrival of AP to Nerve terminal Ca++ enters presynaptic terminal thru VGCCs. Vesicle fuses to presynaptic membrane Ach released to synaptic cleft within 50-200msec. Ach bind to AchR, open pores, cations enter, resulting in an EPP EPP reaches threshold, muscle AP is propagated.

Nicotinic Acetylcholine Receptor Glycoprotein:5 subunits Alpha ( 2 ) Beta ( 1 ) Epsilon ( 1 ) Gamma ( 1 ) Binding site of Ach Alpha subunits Codon 192-193 Opens channel to cations Half-life of AchR is 8.5 days

Myasthenia Gravis Autoimmune disorder Caused by antibody-mediated attack on the postsynaptic nicotinic Ach of the NMJ Destruction of the AchR and postjunctional folds Widening of the Synapse Interferes with Ach binding

Myasthenia Gravis Prevalence (US) Annual Incidence Bimodal incidence 1/10,000 persons Annual Incidence 2-5 per year/million Bimodal incidence Younger females 10-40 y/o Older males 50-70 yrs Genetics Higher freq HLA-B8, DR3

Clinical Features Fluctuating Weakness Ocular muscles Ptosis, Diplopia Oropharyngeal Muscles Dysphagia, dysphonia, jaw fatigue Proximal Muscles No sensory symptoms No cognitive abnormalities No incoordination Normal reflexes

Pathophysiology Immune-mediated attack against postsynaptic nicotinic receptors Myoid cells/ other stem cells in thymus Hyperplastic in 2/3 of patients with MG Thymoma in 12% May serve as autoantigens Express surface AchR or one of its protein components

MGFA Clinical Classification Grade I: Ocular MG Ptosis and diplopia 15% never spread beyond ocular area Grade II: Mild Generalized Dysphonia, dysphagia, dysarthria, limb weakness IIa extremity; IIb bulbar Grade III: Moderate IIIa extremity; IIIb bulbar Grade IV: Severe Grade V: Crisis Respiratory failure

Work-up History compatible with physical examination Tensilon test ( edrophonium ) Short acting anti-cholinesterase Onset 30 sec, duration 5 minutes Initial 2 mg IV Watch for bradycardia, hypotension, arrhythmias If no SE give 8 mg IV and observe for improvement. Give atropine 0.5 to 1 mg IV if with SE Ice-pack test for ptosis. 80-90% sensitive.

Confirmatory Diagnosis Repetitive nerve stimulation ( Jolly test ) 75% sensitive May be normal in ocular MG. AchR antibody assay (+) in 80-90% with generalized MG (+) in 50% of Ocular MG Anti-MuSK ( muscle specific tyrosine kinase ) Titers do not correlate with severity of disease. Anti-skeletal muscle AB: +30% gen MG, +85% MG+thymoma SFEMG Increased jitter Time variation in NMJ transmission (+) in 80% of Ocular, in 100% of generalized MG. In 9% of MG, this may be the only abnormal Test.

Work-up Laboratory CXR, Chest CT r/o thymoma ( 15% MG ) ESR, ANA, RF TSH, T4 ( hypo or hyper-T can exacerbate MG ) CBC with diff, UA, Electrolytes, Blood glucose, Renal profile. CXR, Chest CT r/o thymoma ( 15% MG ) PPD skin test (if considering immunosuppressive trx) PFT Medication list review D-penicillamine, interferon-alfa, antibiotics (aminoglycosides), Antiarrhythmics ( quinidine, procainamide ), Beta-blockers, Ca channel blockers, Phenytoin, Thyroid hormones, lithium, chlorpromazine, estrogen

5-hertz Repetitive Nerve stimulation Normal sF Threshold 15mV

5-hertz RNS Abnormal 20 mV sF 16 mV 15 mV Threshold 13 mV 10mV

SFEMG

SFEMG

Management Symptomatic trx: anticholinesterase Pyridostigmine (Mestinon) Onset 30 min. Peak 2 hrs. Lasts 3-6 hrs. Dose: 30-90 mg q 3-6 hrs. Max 120 mg q3h IV dose is 1 per 30mg of po dose. SE: Cholinergic Diarrhea, N&V, sweating, hypersalivation/ secretions, Miosis, bradycardia, hypotension.

Management Immunotherapy: Often required Surgical treatment Prednisone: mainstay for MG immunotherapy 15-20 mg/day, titrate up to 1mg/kg/day Azathioprine initiated at 50 mg QD titrated to 2mg/kg/day (Mycophenolate: 500mg BID titrated to 2-3g/day) Cyclosporine: 5 mg/kg/day with clinical effect in 1-2 mos. TPE IVIG Surgical treatment Thymectomy indicated in thymomatous MG Non-thymomatous MG: thymectomy is an option

Differential Diagnosis Lambert-Eaton Myasthenic syndrome Botulism Chronic fatigue syndrome Intracranial mass A diagnosis of MG may give clues to other maladies Hyperthyroidism seen in 3-8% Autoimmune disorders SLE, Rheumatoid arthritis

Questions?

Sir Charles Bell’s portrait of dying soldier with tetanus. Opisthotonus and risus sardonicus

Cholinergic vs. Myasthenic crisis Cholinergic crisis Overmedication Cholinergic Effects Miosis Increased salivation and secretion Diarrhea Cramps Fasciculations Myasthenic crisis Generalized weakness Respiratory failure