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myasthenia gravis

Etiology: 1) autoimmune disorder - association with autoimmune thyroid disease [2] 2) humoral &/or cell mediated activity against nicotinic acetylcholine receptors - checkpoint inhibitor therapy may exacerbate preexisting myastheia or rarely induce de novo myastheia gravis [11] 3) thymoma [2] Epidemiology: - occurs most common in women 20-30 years & men > age 50 years [2] Pathology: 1) 85-95% of patients have antibodies to motor endplate nicotinic receptors 2) since disease occurs in adults, mature nicotinic receptors, especially nicotinic receptor epsilon implicated as antigenic target 3) among patients with antibodies to nicotinic receptors, 50% have antibodies to muscle-specific tyrosine kinase receptors [2] 4) muscle-specific kinase Ab in 1/2 of patients seronegative for nicotinic receptor Ab 5) fluoroquinolones may decrease transmission at the neuromuscular junction & exacerbate myasthenia gravis [2] Clinical manifestations: 1) voluntary muscle weakness a) muscle weakness may initially be transitory - painless & generally without sensory loss - included dysphagia & dsypnea b) exacerbated by: - continuous use (i.e. muscle weakness worsens with repetitive movement) - warmer environment - later in day - physiologic stress - psychosocial stress c) order of muscle group involvement - ocular 90% - ptosis or diplopia (1st manifestation in most patients) [2] - strabismus - pupils are normal [2]* - bulbar 40% - neck - expecially weakness of cervical extension [2] - sensation of heaviness of head [2] - limb-girdle - distal extremities 2) diplopia 3) eating difficulties - jaw weakness while chewing - choking - fluid regurgitation through nose when swallowing - food in mouth after swallowing [4] 4) dysarthria - difficulty maintaining volume of voice - unintelligible speech after prolonged speaking [4] 5) normal deep tendon reflexes 6) normal sensation * distinguishes from botulism Laboratory: 1) nicotinic acetylcholine receptor antibody a) positive in 85-95% of generalized myasthenia b) ocular myasthenia less sensitive 2) antistriational antibody is present in most patients with associated thymoma 3) anti-MUSK Ab - affects therapy 4) autoantibodies to C terminal portion of AKAP12 (gravin) 5) serum TSH may be elevated with autoimmune thyroid disease [2] 6) see ARUP consult [3] Special laboratory: 1) edrophonium (tensilon test): a) Adults & children > 75 pounds: 1] 2 mg of edrophonium IV over 15-30 seconds - positive test: increased muscle strength - negative test: 8 mg additional edrophonium IV; evaluate muscle strength again b) decreased doses for infants & children < 75 pounds c) false negative tests occur especially with ocular myasthenia d) false positive tests have been reported 2) electromyography a) decremental response to repetitive stimulation seen with myasthenia b) repetitive single fiber stimulation c) need to specifically request repetitive stimulation protocol [2] 3) ice-pack test [7] - sustained upward gaze can produce ptosis in patients with myasthenia gravis - placing an ice pack over an eye with unilateral ptosis diminishes ptosis in patients with myasthenia gravis* * acetylcholinesterase activity is inhibited at a lower temperature Radiology: - CT of thorax to rule out thymoma [2] Differential diagnosis: 1) Eaton-Lambert syndrome - muscle weakness improves with repetitive movement 2) botulism: - diplopia, dysphagia - sluggishly reactive or non-reactive pupils (normal in myasthenia gravis) 3) muscular dystrophies 4) brain tumors 5) endocrine myopathies 6) amyotrophic lateral sclerosis 7) D-penicillamine administration may produce acetylcholine receptor Ab Complications: - respiratory failure (myasthenic crisis) - risk increased by: - surgical procedures - infections - corticosteroid therapy - use of aminoglycosides, quinolones - beta-blockers, calcium channel blockers Management: 1) early after onset of generalized myasthenia gravis - rituximab 500 mg single dose increases likelihood of minimal manifestations of myasthenia gravis & reduced need of rescue medications [12] 2) stop exacerbating factors: a) over activity may exacerbate myasthenia b) stress - physiologic - treat infections - psychosocial c) medications - antibiotics: aminoglycosides, polymixins, tetracyclines, erythromycin - cardiac drugs: verapamil, beta blockers - phenytoin - chlorpromazine 3) progressive respiratory failure (mysathenic crisis) with vital capacity < 15 mL/kg a) endotracheal intubation b) plasmapheresis or intravenous immunoglobulin 4) pharmaceutical agents a) acetylcholinesterase inhibitors - pyridostigmine (Mestinon) (treatment of choice [2]) - can worsen respiratory secretions - avoid monotherapy with acute respiratory failure (myasthenic crisis) [2] - neostigmine bromide (Prostigmin) - ambenonium chloride (Mytelase) - titrate to effect; diminish dose for drug adverse effects of cholinesterase inhibitors b) immunosuppressive agents for more severe disease & ocular myasthenia [2,11] - glucocorticoids (prednisone) can initially exacerbate myasthenia gravis - high dose IV methylprednisolone not beneficial for severe exacerbations or mysathenic crisis, but may worsen symptoms [13] - cyclophosphamide (Cytoxan) - cyclosporin (Sandimmune) - rituximab - azathioprine (Imuran) - mycophenolate - similar efficacy to azathioprine but potentially fewer serious side effects - methotrexate may be tried when other immunosuppressants fail [11] c) plasmapheresis or intravenous immunoglobulin for more severe exacerbations or mysathenic crisis [2] d) complement C5 inhibitors - zilucoplan (Zilbrysq) - eculizumab may improve ~50% of refractory AChR-Ab + myasthenia e) efgartigimod alfa-fcab (Vyvgart) FDA-approved f) anti-MUSK Ab (antibodies to muscle-specific tyrosine kinase receptors - immunosuppression & IV IgG effective [2] - rituximab is highly effective g) fluoroquinolones may exacerbate myasthenia gravis [9] 5) sternal-splitting thymectomy [11] a) all patients with thymoma [2] b) need to minimize immunotherapy in patients without thymoma, active disease, + AChR-Ab, < 65 years, with 3 years of diagnosis [2] c) less effective with ocular myasthenia d) not effective if anti-MUSK Ab [11] e) most effective if done early in the course of the disease f) over 90% improve; many achieve clinical remission 6) diet a) calorie restriction b) K+ supplementation may be necessary 7) follow-up: a) progression of weakness b) thyroid function studies c) screen for other autoimmune diseases

Interactions

disease interactions

Related

acetylcholine (nicotinic) receptor antibody anti-striational antibody (anti-striated muscle antibody) Lambert-Eaton myasthenic syndrome (LEMS) myasthenic syndrome (congenital myasthenic syndrome, CMS) thymoma

Specific

familial myasthenia gravis

General

autoimmune disease neuromuscular junction disorder thymic disease

Database Correlations

OMIM 254200

References

  1. Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996 pg 1056-57
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 1998, 2006, 2009, 2012, 2015, 2018, 2021. - Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022
  3. ARUP Consult: Myasthenia Gravis - MG The Physician's Guide to Laboratory Test Selection &vInterpretation https://www.arupconsult.com/content/myasthenia-gravis - ARUP Consult: Myasthenia Gravis Testing https://arupconsult.com/ati/myasthenia-gravis-testing
  4. The NNT: Myasthenia Gravis Diagnostics and Likelihood Ratios, Explained http://www.thennt.com/lr/myasthenia-gravis/ - Scherer K, Bedlack RS, Simel DL. Does this patient have myasthenia gravis? JAMA. 2005 Apr 20;293(15):1906-14. PMID: 15840866
  5. Kumar V1, Kaminski HJ. Treatment of myasthenia gravis. Curr Neurol Neurosci Rep. 2011 Feb;11(1):89-96. PMID: 20927659
  6. Silvestri NJ, Wolfe GI. Myasthenia gravis. Semin Neurol. 2012 Jul;32(3):215-26 PMID: 23117946
  7. Liu WW, Chen A Diagnosing Myasthenia Gravis with an Ice Pack. N Engl J Med 2016; 375:e39. November 10, 2016 PMID: 27959645 http://www.nejm.org/doi/full/10.1056/NEJMicm1509523
  8. Gilhus NE Myasthenia Gravis N Engl J Med 2016; 375:2570-2581. December 29, 2016 PMID: 28029925 http://www.nejm.org/doi/full/10.1056/NEJMra1602678
  9. Lowes R FDA Approves Delafloxacin (Baxdela) for Skin Infections Medscape - Jun 19, 2017. http://www.medscape.com/viewarticle/881827
  10. Sanders DB, Guptill JT. Myasthenia gravis and Lambert-Eaton myasthenic syndrome. Continuum (Minneap Minn). 2014 Oct;20 (5 Peripheral Nervous System Disorders):1413-25. Review. PMID: 2529929
  11. Narayanaswami P et al. International consensus guidance for management of myasthenia gravis: 2020 update. Neurology 2020 Nov 3 PMID: 33144515 Review. https://n.neurology.org/content/96/3/114
  12. Piehl F, Eriksson-Dufva A, Budzianowska A et al Efficacy and Safety of Rituximab for New-Onset Generalized Myasthenia Gravis. The RINOMAX Randomized Clinical Trial. JAMA Neurol. 2022;79(11):1105-1112 PMID: 36121672 PMCID: PMC9486640 Free PMC article https://jamanetwork.com/journals/jamaneurology/fullarticle/2796552
  13. NEJM Knowledge+ - Alhaidar MK, Abumurad S, Soliven B, Rezania K Current Treatment of Myasthenia Gravis. J Clin Med. 2022 Mar 14;11(6):1597. PMID: 35329925 PMCID: PMC8950430 Free PMC article. Review.
  14. Narayanaswami P, Sanders DB, Thomas L et al. Comparative effectiveness of azathioprine and mycophenolate mofetil for myasthenia gravis (PROMISE-MG): A prospective cohort study. Lancet Neurol 2024 Mar; 23:267-276. PMID: 38365379 https://www.thelancet.com/journals/laneur/article/PIIS1474-4422(24)00028-0/abstract
  15. National Institute of Neurological Disorders and Stroke (NINDS) - NINDS Myasthenia Gravis Information Page https://www.ninds.nih.gov/Disorders/All-Disorders/Myasthenia-Gravis-Information-Page - Myasthenia Gravis Fact Sheet https://www.ninds.nih.gov/disorders/patient-caregiver-education/fact-sheets/myasthenia-gravis-fact-sheet