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Myasthenia Gravis

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

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Myasthenia Gravis

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  1. Myasthenia Gravis

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

  3. 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.

  4. 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

  5. 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

  6. Myasthenia Gravis • Prevalence (US) • 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

  7. 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

  8. 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

  9. 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

  10. 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.

  11. 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.

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

  13. 5-hertz Repetitive Nerve stimulationNormal sF Threshold 15mV

  14. 5-hertz RNSAbnormal 20 mV sF 16 mV 15 mV Threshold 13 mV 10mV

  15. SFEMG

  16. SFEMG

  17. 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.

  18. Management Immunotherapy: Often required • 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

  19. 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

  20. Questions?

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

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

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