Treatment of Myasthenia Gravis

Part of the Current Clinical Neurology book series (CCNEU)


Effective therapy for the individual MG patient rests on balancing the risks and benefits of a wide range of therapeutic options. These risks not only include the dangers of severe weakness, limitations on employment, and complications of treatment but access to medications based on insurance company policies or government-set limitations. The typical patient who does not respond to cholinesterase inhibitor treatment will require prednisone and, if poorly responsive or with significant adverse effects, will need immunosuppressive therapy with azathioprine, tacrolimus, or mycophenolate. The treatment-resistant patient who fails corticosteroids and an immunosuppressive may benefit from a switch to another immunosuppressive or eculizumab. Despite the increasing number of excellently performed clinical trials, practice remains compromised by a limited evidence base, but the development of national guidelines for treatment has the promise of guiding clinicians not familiar with this rare disease to care for patients in a logical manner.


Acetylcholine receptor antibodies Azathioprine Eculizumab Methotrexate Myasthenia gravis Mycophenolate Prednisone Pyridostigmine Rituximab Tacrolimus Thymectomy Thymoma Thymus 


  1. 1.
    Walker MB. Treatment of myasthenia gravis with physostigmine. Lancet. 1934;1:1200–1.CrossRefGoogle Scholar
  2. 2.
    Keesey JC. Contemporary opinions about Mary Walker: a shy pioneer of therapeutic neurology. Neurology. 1998;51(5):1433–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Remen L. Zur Pathogenese und Therapie der Myasthenia gravis pseudoparalytica. Dtsch Ztschr f Nervenheilkunde. 1932;128:66–78.CrossRefGoogle Scholar
  4. 4.
    Viets HR. Introductory remarks. In: Ossermann KE, editor. Myasthenia gravis, vol. 135. New York: New York Academy of Sciences; 1966. p. 5–7.Google Scholar
  5. 5.
    Bell ET. Tumors of the thymus in myasthenia gravis. J Nerv Ment Dis. 1917;45:130–43.CrossRefGoogle Scholar
  6. 6.
    Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia gravis and tumors of the thymic region. Report of a case in which the tumor was removed. Ann Surg. 1939;110:544–61.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Kirschner PA. The history of surgery of the thymus gland. Chest Surg Clin N Am. 2000;10(1):153–65.PubMedGoogle Scholar
  8. 8.
    Blalock A. Thymectomy in treatment of myasthenia gravis. J Thorac Surg. 1944;13:316.Google Scholar
  9. 9.
    Blalock A, Harvey AM, Ford FF, Lilienthal JL. The treatment of myasthenia gravis by removal of the thymus gland: preliminary report. JAMA. 1941;117:1529.CrossRefGoogle Scholar
  10. 10.
    Rowland LP. Controversies about the treatment of myasthenia gravis. J Neurol Neurosurg Psychiatry. 1980;43:644–59.PubMedPubMedCentralCrossRefGoogle Scholar
  11. 11.
    Gronseth GS, Barohn RJ. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology [see comments]. Neurology. 2000;55(1):7–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Aban IB, Wolfe GI, Cutter GR, Kaminski HJ, Jaretzki A 3rd, Minisman G, et al. The MGTX experience: challenges in planning and executing an international, multicenter clinical trial. J Neuroimmunol. 2008;201–202:80–4.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Pinching AJ, Peters DK, Newsom-Davis J. Remission of myasthenia gravis following plasma exchange. Lancet. 1976;2:1373–6.PubMedCrossRefGoogle Scholar
  14. 14.
    Benatar M, Sanders DB, Burns TM, Cutter GR, Guptill JT, Baggi F, et al. Recommendations for myasthenia gravis clinical trials. Muscle Nerve. 2012;45(6):909–17.PubMedCrossRefGoogle Scholar
  15. 15.
    Sanders DB, Wolfe GI, Benatar M, Evoli A, Gilhus NE, Illa I, et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology. 2016;87(4):419–25.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Fuhr P, Gold R, Hohlfeld R, Melms A, Melzer N, Tackenberg B, et al. Diagnostik und therapie der myasthenia gravis und des Lambert-Eaton syndroms. In: Diener H, Weimer C, editors. Leitlinien für Diagnostik und Therapie in der Neurologie. 5th ed. Stuttgart: Thieme; 2012. p. 830–56.Google Scholar
  17. 17.
    Murai H. Japanese clinical guidelines for myasthenia gravis: putting into practice. Clin Exp Neuroimmunol. 2015;2015:21–31.CrossRefGoogle Scholar
  18. 18.
    Machado-Alba JE, Calvo-Torres LF, Gaviria-Mendoza A, Augusto Meji AVC. Prescription profile of pyridostigmine use in a population of patients with myasthenia gravis. Muscle Nerve. 2017;56(6):1041–6.PubMedCrossRefGoogle Scholar
  19. 19.
    Makarious D, Horwood K, Coward JIG. Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer. 2017;82:128–36.PubMedCrossRefGoogle Scholar
  20. 20.
    Priola AM, Priola SM. Imaging of thymus in myasthenia gravis: from thymic hyperplasia to thymic tumor. Clin Radiol. 2014;69(5):e230–45.PubMedCrossRefGoogle Scholar
  21. 21.
    de Kraker M, Kluin J, Renken N, Maat AP, Bogers AJ. CT and myasthenia gravis: correlation between mediastinal imaging and histopathological findings. Interact Cardiovasc Thorac Surg. 2005;4(3):267–71.PubMedCrossRefGoogle Scholar
  22. 22.
    Kaminski HJ, Santillan C, Wolfe GI. Autoantibody testing in neuromuscular disorders. Neuromuscular junction and muscle disorders. J Clin Neuromuscul Dis. 2000;2:96–105.PubMedCrossRefGoogle Scholar
  23. 23.
    Meriggioli MN, Sanders DB. Muscle autoantibodies in myasthenia gravis: beyond diagnosis? Expert Rev Clin Immunol. 2012;8(5):427–38.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Dalakas MC. Immunotherapies in the treatment of neuromuscular disorders. In: Katirji B, Kaminski H, Preston D, Ruff R, Shapiro B, editors. Neuromuscular disorders in clinical practice. Boston: Butterworth Heinemann; 2002. p. 364–83.Google Scholar
  25. 25.
    Utsugisawa K, Suzuki S, Nagane Y, Masuda M, Murai H, Imai T, et al. Health-related quality-of-life and treatment targets in myasthenia gravis. Muscle Nerve. 2014;50(4):493–500.PubMedCrossRefGoogle Scholar
  26. 26.
    Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve. 2008;37(2):141–9.PubMedCrossRefGoogle Scholar
  27. 27.
    Phillips LH, Torner JC. Epidemiologic evidence for a changing natural history of myasthenia gravis. Neurology. 1996;47:1233–8.PubMedCrossRefGoogle Scholar
  28. 28.
    Somnier F, Keiding N, Paulson O. Epidemiology of myasthenia gravis in Denmark: a longitudinal and comprehensive study. Arch Neurol. 1991;48:733–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Burns TM, Sanders DB, Kaminski HJ, Wolfe GI, Narayanaswami P, Venitz J. Two steps forward, one step back: mycophenolate mofetil treatment for myasthenia gravis in the United States. Muscle Nerve. 2015;51(5):635–7.PubMedCrossRefGoogle Scholar
  30. 30.
    Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clin Drug Investig. 2011;31(10):691–701.PubMedCrossRefGoogle Scholar
  31. 31.
    Mehndiratta MM, Pandey S, Kuntzer T. Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev. 2014;(10):CD006986.Google Scholar
  32. 32.
    Brenner T, Hamra-Amitay Y, Evron T, Boneva N, Seidman S, Soreq H. The role of readthrough acetylcholinesterase in the pathophysiology of myasthenia gravis. FASEB J. 2003;17(2):214–22.PubMedCrossRefGoogle Scholar
  33. 33.
    Brenner T, Nizri E, Irony-Tur-Sinai M, Hamra-Amitay Y, Wirguin I. Acetylcholinesterase inhibitors and cholinergic modulation in myasthenia gravis and neuroinflammation. J Neuroimmunol. 2008;201–202:121–7.PubMedCrossRefGoogle Scholar
  34. 34.
    Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve. 2011;44(1):36–40.PubMedCrossRefGoogle Scholar
  35. 35.
    Echaniz-Laguna A, Pistea C, Philippi N, Enache I, Oswald-Mammosser M, De Seze J, et al. Asthma as a cause of persistent dyspnea in treated myasthenia gravis patients. Eur Neurol. 2012;68(5):300–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Arsura EL, Brunner NG, Namba T, Grob D. Adverse cardiovascular effects of anticholinesterase medications. Am J Med Sci. 1987;293(1):18–23.PubMedCrossRefGoogle Scholar
  37. 37.
    Said S, Cooper CJ, Alkhateeb H, Elhanafi S, Bizet J, Gosavi S, et al. Pyridostigmine-induced high grade SA-block in a patient with myasthenia gravis. Am J Case Rep. 2013;14:359–61.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Daroff RB. Ocular myasthenia: diagnosis and therapy. In: Glaser J, editor. Neruo-opthalmology. St. Louis: C.V. Mosby; 1980. p. 62–71.Google Scholar
  39. 39.
    Daroff RB. The office tensilon test for ocular myasthenia gravis. Arch Neurol. 1986;43:843–4.PubMedCrossRefGoogle Scholar
  40. 40.
    Juel VC, Massey JM. Autoimmune myasthenia gravis: recommendations for treatment and immunologic modulation. Curr Treat Options Neurol. 2005;7(1):3–14.PubMedCrossRefGoogle Scholar
  41. 41.
    Edgeworth H. A report of progress on the use of ephedrine in a case of myasthenia gravi. JAMA. 1930;94:1136.CrossRefGoogle Scholar
  42. 42.
    Edgeworth H. The effect of ephedrine in the treatment of myasthenia gravis, second report. JAMA. 1933;100:1401.CrossRefGoogle Scholar
  43. 43.
    Lipka AF, Vrinten C, van Zwet EW, Schimmel KJ, Cornel MC, Kuijpers MR, et al. Ephedrine treatment for autoimmune myasthenia gravis. Neuromuscul Disord. 2017;27(3):259–65.PubMedCrossRefGoogle Scholar
  44. 44.
    Evoli A, Alboini PE, Damato V, Iorio R. 3,4-Diaminopyridine may improve myasthenia gravis with MuSK antibodies. Neurology. 2016;86(11):1070–1.PubMedCrossRefGoogle Scholar
  45. 45.
    Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR. Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev. 2005;(2):CD002828.Google Scholar
  46. 46.
    Hoffmann S, Kohler S, Ziegler A, Meisel A. Glucocorticoids in myasthenia gravis—if, when, how, and how much? Acta Neurol Scand. 2014;130(4):211–21.PubMedCrossRefGoogle Scholar
  47. 47.
    Bedlack RS, Sanders DB. Steroids have an important role. Muscle Nerve. 2002;25(1):117–21.PubMedCrossRefGoogle Scholar
  48. 48.
    Rivner MH. Steroids are overutilized. Muscle Nerve. 2002;25(1):115–7.PubMedCrossRefGoogle Scholar
  49. 49.
    Gilhus NE. Myasthenia gravis. N Engl J Med. 2016;375(26):2570–81.PubMedCrossRefGoogle Scholar
  50. 50.
    Evoli A, Batocchi AP, Palmisani MT, Lo Monaco M, Tonali P. Long-term results of corticosteroid therapy in patients with myasthenia gravis. Eur Neurol. 1992;32(1):37–43.PubMedCrossRefGoogle Scholar
  51. 51.
    Xie Y, Li H-F, Sun L, Kusner LL, Wang S, Meng Y, et al. The role of osteopontin and its gene on glucorticoid response in myasthenia gravis. Front Neurol. 2017;8:230.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Xie Y, Meng Y, Li HF, Hong Y, Sun L, Zhu X, et al. GR gene polymorphism is associated with inter-subject variability in response to glucocorticoids in patients with myasthenia gravis. Eur J Neurol. 2016;23(8):1372–9.PubMedCrossRefGoogle Scholar
  53. 53.
    Bae JS, Go SM, Kim BJ. Clinical predictors of steroid-induced exacerbation in myasthenia gravis. J Clin Neurosci. 2006;13(10):1006–10.PubMedCrossRefGoogle Scholar
  54. 54.
    Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol. 1984;15:291–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Beghi E, Antozzi C, Batocchi AP, Cornelio F, Cosi V, Evoli A, et al. Prognosis of myasthenia gravis: a multicenter follow-up study. J Neurol Sci. 1991;106:213–20.PubMedCrossRefGoogle Scholar
  56. 56.
    Seybold M, Drachman D. Gradually increasing doses of prednisone in myasthenia gravis: reducing the hazards of treatment. N Engl J Med. 1974;290:81–4.PubMedCrossRefGoogle Scholar
  57. 57.
    Grob D, Arsura EL, Brunner NG, Namba T. The course of myasthenia gravis and therapies affecting outcome. Ann N Y Acad Sci. 1987;505:472–99.PubMedCrossRefGoogle Scholar
  58. 58.
    Durelli L, Maggi G, Casadio C, Ferri R, Rendine S, Bergamini L. Actuarial analysis of the occurrence of remissions following thymectomy for myasthenia gravis in 400 patients. J Neurol Neurosurg Psychiatry. 1991;54:406–11.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Drachman DB. Myasthenia gravis. N Engl J Med. 1994;330:1797–810.PubMedCrossRefGoogle Scholar
  60. 60.
    Wolfe GI, Kaminski HJ, Aban IB, Minisman G, Kuo HC, Marx A, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375(6):511–22.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Wolfe GI, Kaminski HJ, Jaretzki A 3rd, Swan A, Newsom-Davis J. Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy. Ann N Y Acad Sci. 2003;998:473–80.PubMedCrossRefGoogle Scholar
  62. 62.
    Group MS. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology. 2008;71(6):394–9.CrossRefGoogle Scholar
  63. 63.
    Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn E, Leigh R, et al. A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy. Allergy Asthma Clin Immunol. 2013;9(1):30.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Lewis SJ, Smith PE. Osteoporosis prevention in myasthenia gravis: a reminder. Acta Neurol Scand. 2001;103(5):320–2.PubMedCrossRefGoogle Scholar
  65. 65.
    Narum S, Westergren T, Klemp M. Corticosteroids and risk of gastrointestinal bleeding: a systematic review and meta-analysis. BMJ Open. 2014;4(5):e004587.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Brown ES, Vera E, Frol AB, Woolston DJ, Johnson B. Effects of chronic prednisone therapy on mood and memory. J Affect Disord. 2007;99(1–3):279–83.PubMedCrossRefGoogle Scholar
  67. 67.
    Perantie DC, Brown ES. Corticosteroids, immune suppression, and psychosis. Curr Psychiatry Rep. 2002;4(3):171–6.PubMedCrossRefGoogle Scholar
  68. 68.
    Coutinho AE, Chapman KE. The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights. Mol Cell Endocrinol. 2011;335(1):2–13.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Quax RA, Manenschijn L, Koper JW, Hazes JM, Lamberts SW, van Rossum EF, et al. Glucocorticoid sensitivity in health and disease. Nat Rev Endocrinol. 2013;9(11):670–86.PubMedCrossRefGoogle Scholar
  70. 70.
    Palace J, Newsom-Davis J, Lecky B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology. 1998;50(6):1778–83.PubMedCrossRefGoogle Scholar
  71. 71.
    Heckmann JM, LeePan EB, Eastman RW. High-dose immunosuppressive therapy in generalised myasthenia gravis—a 2-year follow-up study. S Afr Med J. 2001;91(9):765–70.PubMedGoogle Scholar
  72. 72.
    Cosi V, Lombardi M, Erbetta A, Piccolo G. Azathioprine as a single immunosuppressive drug in the treatment of myasthenia gravis. Acta Neurol (Napoli). 1993;15(2):123–31.Google Scholar
  73. 73.
    Mantegazza R, Antozzi C, Peluchetti D, Sghirlanzoni A, Cornelio F. Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis. J Neurol. 1988;235:449–53.PubMedCrossRefGoogle Scholar
  74. 74.
    Gupta A, Goyal V, Srivastava AK, Shukla G, Behari M. Remission and relapse of myasthenia gravis on long-term azathioprine: an ambispective study. Muscle Nerve. 2016;54(3):405–12.PubMedCrossRefGoogle Scholar
  75. 75.
    Witte AS, Cornblath DR, Parry GJ, Lisak RP, Schatz NJ. Azathioprine in the treatment of myasthenia gravis. Ann Neurol. 1984;15:602–5.PubMedCrossRefGoogle Scholar
  76. 76.
    Jack KL, Koopman WJ, Hulley D, Nicolle MW. A review of azathioprine-associated hepatotoxicity and myelosuppression in myasthenia gravis. J Clin Neuromuscul Dis. 2016;18(1):12–20.PubMedCrossRefGoogle Scholar
  77. 77.
    Sanders D, Howard F Jr. Disorders of neuromuscular transmission. In: Bradley W, Daroff R, Fenichel G, Marsden C, editors. Neurology in clinical practice. Boston: Butterworth Heinemann; 2000. p. 2167–85.Google Scholar
  78. 78.
    Pedersen EG, Pottegard A, Hallas J, Friis S, Hansen K, Jensen PE, et al. Use of azathioprine for non-thymoma myasthenia and risk of cancer: a nationwide case-control study in Denmark. Eur J Neurol. 2013;20(6):942–8.PubMedCrossRefGoogle Scholar
  79. 79.
    Machkhas H, Harati Y, Rolak LA. Clinical pharmacology of immunosuppressants: guidelines for neuroimmunotherapy. In: Rolak LA, Harati Y, editors. Neuroimmunology for the clinician. Boston: Butterworth Heinemann; 1997. p. 77–104.Google Scholar
  80. 80.
    Cleary BJ, Kallen B. Early pregnancy azathioprine use and pregnancy outcomes. Birth Defects Res A Clin Mol Teratol. 2009;85(7):647–54.PubMedCrossRefGoogle Scholar
  81. 81.
    Lennard L. Implementation of TPMT testing. Br J Clin Pharmacol. 2014;77(4):704–14.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Maltzman JS, Koretzky GA. Azathioprine: old drug, new actions. J Clin Invest. 2003;111(8):1122–4.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Karran P, Attard N. Thiopurines in current medical practice: molecular mechanisms and contributions to therapy-related cancer. Nat Rev Cancer. 2008;8(1):24–36.PubMedCrossRefGoogle Scholar
  84. 84.
    Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB. Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology. 2001;56(1):97–9.PubMedCrossRefGoogle Scholar
  85. 85.
    Chaudhry V, Cornblath DR, Griffin JW, O’Brien R, Drachman DB. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology. 2001;56(1):94–6.PubMedCrossRefGoogle Scholar
  86. 86.
    Meriggioli MN, Rowin J, Richman JG, Leurgans S. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study. Ann N Y Acad Sci. 2003;998:494–9.PubMedCrossRefGoogle Scholar
  87. 87.
    Chan JW. Mycophenolate mofetil for ocular myasthenia. J Neurol. 2008;255(4):510–3.PubMedCrossRefGoogle Scholar
  88. 88.
    Sanders DB, Hart IK, Mantegazza R, Shukla SS, Siddiqi ZA, De Baets MH, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology. 2008;71(6):400–6.PubMedCrossRefGoogle Scholar
  89. 89.
    Benatar M, Rowland LP. The muddle of mycophenolate mofetil in myasthenia. Neurology. 2008;71(6):390–1.PubMedCrossRefGoogle Scholar
  90. 90.
    Hobson-Webb LD, Hehir M, Crum B, Visser A, Sanders D, Burns TM. Can mycophenolate mofetil be tapered safely in myasthenia gravis? A retrospective, multicenter analysis. Muscle Nerve. 2015;52(2):211–5.PubMedCrossRefGoogle Scholar
  91. 91.
    Coscia LA, Armenti DP, King RW, Sifontis NM, Constantinescu S, Moritz MJ. Update on the teratogenicity of maternal mycophenolate mofetil. J Pediatr Genet. 2015;4(2):42–55.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Buell C, Koo J. Long-term safety of mycophenolate mofetil and cyclosporine: a review. J Drugs Dermatol. 2008;7(8):741–8.PubMedGoogle Scholar
  93. 93.
    O’Neill JO, Edwards LB, Taylor DO. Mycophenolate mofetil and risk of developing malignancy after orthotopic heart transplantation: analysis of the transplant registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant. 2006;25(10):1186–91.PubMedCrossRefGoogle Scholar
  94. 94.
    Vernino S, Salomao DR, Habermann TM, O’Neill BP. Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology. 2005;65(4):639–41.PubMedCrossRefGoogle Scholar
  95. 95.
    Termsarasab P, Katirji B. Opportunistic infections in myasthenia gravis treated with mycophenolate mofetil. J Neuroimmunol. 2012;249(1–2):83–5.PubMedCrossRefGoogle Scholar
  96. 96.
    Villarroel MC, Hidalgo M, Jimeno A. Mycophenolate mofetil: an update. Drugs Today (Barc). 2009;45(7):521–32.Google Scholar
  97. 97.
    Minami N, Fujiki N, Doi S, Shima K, Niino M, Kikuchi S, et al. Five-year follow-up with low-dose tacrolimus in patients with myasthenia gravis. J Neurol Sci. 2011;300(1–2):59–62.PubMedCrossRefGoogle Scholar
  98. 98.
    Zhao CB, Zhang X, Zhang H, Hu XQ, Lu JH, Lu CZ, et al. Clinical efficacy and immunological impact of tacrolimus in Chinese patients with generalized myasthenia gravis. Int Immunopharmacol. 2011;11(4):519–24.PubMedCrossRefGoogle Scholar
  99. 99.
    Cruz JL, Wolff ML, Vanderman AJ, Brown JN. The emerging role of tacrolimus in myasthenia gravis. Ther Adv Neurol Disord. 2015;8(2):92–103.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Yoshikawa H, Kiuchi T, Saida T, Takamori M. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry. 2011;82(9):970–7.PubMedCrossRefGoogle Scholar
  101. 101.
    Benatar M, Sanders D. The importance of studying history: lessons learnt from a trial of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry. 2011;82(9):945.PubMedCrossRefGoogle Scholar
  102. 102.
    Yagi Y, Sanjo N, Yokota T, Mizusawa H. Tacrolimus monotherapy: a promising option for ocular myasthenia gravis. Eur Neurol. 2013;69(6):344–5.PubMedCrossRefGoogle Scholar
  103. 103.
    Kanai T, Uzawa A, Kawaguchi N, Himuro K, Oda F, Ozawa Y, et al. Adequate tacrolimus concentration for myasthenia gravis treatment. Eur J Neurol. 2017;24(2):270–5.PubMedCrossRefGoogle Scholar
  104. 104.
    Azzi JR, Sayegh MH, Mallat SG. Calcineurin inhibitors: 40 years later, can’t live without. J Immunol. 2013;191(12):5785–91.PubMedCrossRefGoogle Scholar
  105. 105.
    MacMillan D. FK506 binding proteins: cellular regulators of intracellular Ca2+ signalling. Eur J Pharmacol. 2013;700(1–3):181–93.PubMedCrossRefGoogle Scholar
  106. 106.
    Furukawa Y, Yoshikawa H, Iwasa K, Yamada M. Clinical efficacy and cytokine network-modulating effects of tacrolimus in myasthenia gravis. J Neuroimmunol. 2008;195(1–2):108–15.PubMedCrossRefGoogle Scholar
  107. 107.
    Imai T, Tsuda E, Hozuki T, Yamauchi R, Saitoh M, Hisahara S, et al. Early effect of tacrolimus in improving excitation-contraction coupling in myasthenia gravis. Clin Neurophysiol. 2012;123(9):1886–90.PubMedCrossRefGoogle Scholar
  108. 108.
    Pasnoor M, He J, Herbelin L, Burns TM, Nations S, Bril V, et al. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology. 2016;87(1):57–64.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Heckmann JM, Rawoot A, Bateman K, Renison R, Badri M. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol. 2011;11:97.PubMedPubMedCentralCrossRefGoogle Scholar
  110. 110.
    Wessels JA, Huizinga TW, Guchelaar HJ. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology (Oxford). 2008;47(3):249–55.CrossRefGoogle Scholar
  111. 111.
    Tindall RSA, Phillips JT, Rollins JA, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci. 1993;681:539–51.PubMedCrossRefGoogle Scholar
  112. 112.
    Ciafaloni E, Nikhar NK, Massey JM, Sanders DB. Retrospective analysis of the use of cyclosporine in myasthenia gravis. Neurology. 2000;55(3):448–50.PubMedCrossRefGoogle Scholar
  113. 113.
    Lavrnic D, Vujic A, Rakocevic-Stojanovic V, Stevic Z, Basta I, Pavlovic S, et al. Cyclosporine in the treatment of myasthenia gravis. Acta Neurol Scand. 2005;111(4):247–52.PubMedCrossRefGoogle Scholar
  114. 114.
    Hart IK, Sathasivam S, Sharshar T. Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev. 2007;(4):CD005224.Google Scholar
  115. 115.
    Tamler R, Epstein S. Nonsteroid immune modulators and bone disease. Ann N Y Acad Sci. 2006;1068:284–96.PubMedCrossRefGoogle Scholar
  116. 116.
    Marder W, McCune WJ. Advances in immunosuppressive therapy. Semin Respir Crit Care Med. 2007;28(4):398–417.PubMedCrossRefGoogle Scholar
  117. 117.
    Nagappa M, Netravathi M, Taly AB, Sinha S, Bindu PS, Mahadevan A. Long-term efficacy and limitations of cyclophosphamide in myasthenia gravis. J Clin Neurosci. 2014;21(11):1909–14.PubMedCrossRefGoogle Scholar
  118. 118.
    Drachman DB, Brodsky RA. High-dose therapy for autoimmune neurologic diseases. Curr Opin Oncol. 2005;17(2):83–8.PubMedCrossRefGoogle Scholar
  119. 119.
    Bryant A, Atkins H, Pringle CE, Allan D, Anstee G, Bence-Bruckler I, et al. Myasthenia gravis treated with autologous hematopoietic stem cell transplantation. JAMA Neurol. 2016;73(6):652–8.PubMedCrossRefGoogle Scholar
  120. 120.
    Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L. Immunomodulatory effects of cyclophosphamide and implementations for vaccine design. Semin Immunopathol. 2011;33(4):369–83.PubMedCrossRefGoogle Scholar
  121. 121.
    Stieglbauer K, Pichler R, Topakian R. 10-year-outcomes after rituximab for myasthenia gravis: efficacy, safety, costs of inhospital care, and impact on childbearing potential. J Neurol Sci. 2017;375:241–4.PubMedCrossRefGoogle Scholar
  122. 122.
    Tandan R, Hehir MK 2nd, Waheed W, Howard DB. Rituximab treatment of myasthenia gravis: a systematic review. Muscle Nerve. 2017;56(2):185–96.PubMedCrossRefGoogle Scholar
  123. 123.
    Anderson D, Phan C, Johnston WS, Siddiqi ZA. Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up. Ann Clin Transl Neurol. 2016;3(7):552–5.PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Robeson KR, Kumar A, Keung B, DiCapua DB, Grodinsky E, Patwa HS, et al. Durability of the rituximab response in acetylcholine receptor autoantibody-positive myasthenia gravis. JAMA Neurol. 2017;74(1):60–6.PubMedCrossRefGoogle Scholar
  125. 125.
    Hehir M, Hobson-Webb L, Benatar M, Barnett C, Silvestri N, Howard J, et al. Rituximab is an effective treatment for anti-MuSK myasthenia gravis. Neurology. 2017;89(10):1069–77.PubMedCrossRefGoogle Scholar
  126. 126.
    Chambers SA, Isenberg D. Anti-B cell therapy (rituximab) in the treatment of autoimmune diseases. Lupus. 2005;14(3):210–4.PubMedCrossRefGoogle Scholar
  127. 127.
    Luu VP, Vazquez MI, Zlotnik A. B cells participate in tolerance and autoimmunity through cytokine production. Autoimmunity. 2014;47(1):1–12.PubMedCrossRefGoogle Scholar
  128. 128.
    Kusner LL, Kaminski HJ. The role of complement in experimental autoimmune myasthenia gravis. Ann N Y Acad Sci. 2012;1274:127–32.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Howard JF Jr, Barohn RJ, Cutter GR, Freimer M, Juel VC, Mozaffar T, et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve. 2013;48(1):76–84.PubMedCrossRefGoogle Scholar
  130. 130.
    Howard JF Jr, Utsugisawa K, Benatar M, Murai M, Barohn RJ, Illa I, Jacob S, Vissing J, Burns TM, Kissel JT, Muppidi S, Nowak RJ, O’Brien F, Wang JJ, Mantegazza R, Regain Study Group. Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study. Lancet Neurol. 2017;16(12):976–86.PubMedCrossRefGoogle Scholar
  131. 131.
    Licht C, Greenbaum LA, Muus P, Babu S, Bedrosian CL, Cohen DJ, et al. Efficacy and safety of eculizumab in atypical hemolytic uremic syndrome from 2-year extensions of phase 2 studies. Kidney Int. 2015;87(5):1061–73.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Ninomiya H, Obara N, Chiba S, Usuki K, Nishiwaki K, Matsumura I, et al. Interim analysis of post-marketing surveillance of eculizumab for paroxysmal nocturnal hemoglobinuria in Japan. Int J Hematol. 2016;104(5):548–58.PubMedCrossRefGoogle Scholar
  133. 133.
    Nishimura J, Yamamoto M, Hayashi S, Ohyashiki K, Ando K, Brodsky AL, et al. Genetic variants in C5 and poor response to eculizumab. N Engl J Med. 2014;370(7):632–9.PubMedCrossRefGoogle Scholar
  134. 134.
    Razzak M. Anaemia: mutations in C5 explain eculizumab resistance. Nat Rev Nephrol. 2014;10(4):182.PubMedCrossRefGoogle Scholar
  135. 135.
    Guptill JT, Oakley D, Kuchibhatla M, Guidon AC, Hobson-Webb LD, Massey JM, et al. A retrospective study of complications of therapeutic plasma exchange in myasthenia. Muscle Nerve. 2013;47(2):170–6.PubMedCrossRefGoogle Scholar
  136. 136.
    Mandawat A, Kaminski HJ, Shaker ZA, Alawi AA, Alshekhlee A. Outcome of plasmapheresis in myasthenia gravis: delayed therapy is not favorable. Muscle Nerve. 2011;43(4):578–84.PubMedCrossRefGoogle Scholar
  137. 137.
    Kohler W, Bucka C, Klingel R. A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apher. 2011;26(6):347–55.PubMedCrossRefGoogle Scholar
  138. 138.
    Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev. 2002;(4):CD002275.Google Scholar
  139. 139.
    Haupt WF, Rosenow F, van der Ven C, Birkmann C. Immunoadsorption in Guillain-Barre syndrome and myasthenia gravis. Ther Apher. 2000;4(3):195–7.PubMedCrossRefGoogle Scholar
  140. 140.
    Grob D, Simpson D, Mitsumoto H, Hoch B, Mokhtarian F, Bender A, et al. Treatment of myasthenia gravis by immunoadsorption of plasma. Neurology. 1995;45(2):338–44.PubMedCrossRefGoogle Scholar
  141. 141.
    Shemin D, Briggs D, Greenan M. Complications of therapeutic plasma exchange: a prospective study of 1,727 procedures. J Clin Apher. 2007;22(5):270–6.PubMedCrossRefGoogle Scholar
  142. 142.
    Vincent A. John Newsom-Davis: clinician-scientist and so much more. Brain. 2011;134(Pt 12):3755–74.PubMedCrossRefGoogle Scholar
  143. 143.
    Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology. 2011;76(23):2017–23.PubMedPubMedCentralCrossRefGoogle Scholar
  144. 144.
    Mandawat A, Kaminski HJ, Cutter G, Katirji B, Alshekhlee A. Comparative analysis of therapeutic options used for myasthenia gravis. Ann Neurol. 2010;68(6):797–805.PubMedCrossRefGoogle Scholar
  145. 145.
    Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology. 2007;68(11):837–41.PubMedCrossRefGoogle Scholar
  146. 146.
    Qureshi AI, Choudhry MA, Akbar MS, Mohammad Y, Chua HC, Yahia AM, et al. Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology. 1999;52(3):629–32.PubMedCrossRefGoogle Scholar
  147. 147.
    Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev. 2008;(1):CD002277.Google Scholar
  148. 148.
    Kazatchkine MD, Kaveri SV. Immunomodulation of autoimmune and inflammatory diseases with intravenous immune globulin. N Engl J Med. 2001;345:747–55.PubMedCrossRefGoogle Scholar
  149. 149.
    Cunningham-Rundles C, Zhou Z, Mankarious S, Courter S. Long-term use of IgA-depleted intravenous immunoglobulin in immunodeficient subjects with anti-IgA antibodies. J Clin Immunol. 1993;13(4):272–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Paran D, Herishanu Y, Elkayam O, Shopin L, Ben-Ami R. Venous and arterial thrombosis following administration of intravenous immunoglobulins. Blood Coagul Fibrinolysis. 2005;16(5):313–8.PubMedCrossRefGoogle Scholar
  151. 151.
    Vucic S, Chong PS, Dawson KT, Cudkowicz M, Cros D. Thromboembolic complications of intravenous immunoglobulin treatment. Eur Neurol. 2004;52(3):141–4.PubMedCrossRefGoogle Scholar
  152. 152.
    Luzi G, Bongiorno F, Paparo Barbaro S, Bruno G. Intravenous IgG: biological modulating molecules. J Biol Regul Homeost Agents. 2009;23(1):1–9.PubMedGoogle Scholar
  153. 153.
    Zhu KY, Feferman T, Maiti PK, Souroujon MC, Fuchs S. Intravenous immunoglobulin suppresses experimental myasthenia gravis: immunological mechanisms. J Neuroimmunol. 2006;176(1–2):187–97.PubMedCrossRefGoogle Scholar
  154. 154.
    Fuchs S, Feferman T, Meidler R, Margalit R, Sicsic C, Wang N, et al. A disease-specific fraction isolated from IVIG is essential for the immunosuppressive effect of IVIG in experimental autoimmune myasthenia gravis. J Neuroimmunol. 2008;194(1–2):89–96.PubMedCrossRefGoogle Scholar
  155. 155.
    Norwood F, Dhanjal M, Hill M, James N, Jungbluth H, Kyle P, et al. Myasthenia in pregnancy: best practice guidelines from a U.K. multispecialty working group. J Neurol Neurosurg Psychiatry. 2014;85(5):538–43.PubMedCrossRefGoogle Scholar
  156. 156.
    Batocchi AP, Majolini L, Evoli A, Lino MM, Minisci C, Tonali P. Course and treatment of myasthenia gravis during pregnancy. Neurology. 1999;52(3):447–52.PubMedCrossRefGoogle Scholar
  157. 157.
    Plauché WC. Myasthenia gravis in mothers and their newborns. Clin Obstet Gynecol. 1991;34:82–99.PubMedCrossRefGoogle Scholar
  158. 158.
    Ducci RD, Lorenzoni PJ, Kay CS, Werneck LC, Scola RH. Clinical follow-up of pregnancy in myasthenia gravis patients. Neuromuscul Disord. 2017;27(4):352–7.PubMedCrossRefGoogle Scholar
  159. 159.
    Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis in pregnancy and birth: identifying risk factors, optimising care. Eur J Neurol. 2007;14(1):38–43.PubMedCrossRefGoogle Scholar
  160. 160.
    Ciafaloni E, Massey JM. The management of myasthenia gravis in pregnancy. Semin Neurol. 2004;24(1):95–100.PubMedCrossRefGoogle Scholar
  161. 161.
    Kalidindi M, Ganpot S, Tahmesebi F, Govind A, Okolo S, Yoong W. Myasthenia gravis and pregnancy. J Obstet Gynaecol. 2007;27(1):30–2.PubMedCrossRefGoogle Scholar
  162. 162.
    Wen JC, Liu TC, Chen YH, Chen SF, Lin HC, Tsai WC. No increased risk of adverse pregnancy outcomes for women with myasthenia gravis: a nationwide population-based study. Eur J Neurol. 2009;16(8):889–94.PubMedCrossRefGoogle Scholar
  163. 163.
    O’Carroll P, Bertorini TE, Jacob G, Mitchell CW, Graff J. Transient neonatal myasthenia gravis in a baby born to a mother with new-onset anti-MuSK-mediated myasthenia gravis. J Clin Neuromuscul Dis. 2009;11(2):69–71.PubMedCrossRefGoogle Scholar
  164. 164.
    Lee JY, Min JH, Han SH, Han J. Transient neonatal myasthenia gravis due to a mother with ocular onset of anti-muscle specific kinase myasthenia gravis. Neuromuscul Disord. 2017;27(7):655–7.PubMedCrossRefGoogle Scholar
  165. 165.
    Townsel C, Keller R, Johnson K, Hussain N, Campbell WA. Seronegative maternal ocular myasthenia gravis and delayed transient neonatal myasthenia gravis. AJP Rep. 2016;6(1):e133–6.PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Gardnerova M, Eymard B, Morel E, Faltin M, Zajac J, Sadovsky O, et al. The fetal/adult acetylcholine receptor antibody ratio in mothers with myasthenia gravis as a marker for transfer of the disease to the newborn. Neurology. 1997;48:50–4.PubMedCrossRefGoogle Scholar
  167. 167.
    Hoff JM, Daltveit AK, Gilhus NE. Artrogryposis multiplex congenita—a rare fetal condition caused by maternal myasthenia gravis. Acta Neurol Scand Suppl. 2006;183:26–7.PubMedCrossRefGoogle Scholar
  168. 168.
    Hacohen Y, Jacobson LW, Byrne S, Norwood F, Lall A, Robb S, et al. Fetal acetylcholine receptor inactivation syndrome: a myopathy due to maternal antibodies. Neurol Neuroimmunol Neuroinflamm. 2015;2(1):e57.PubMedCrossRefGoogle Scholar
  169. 169.
    Midelfart Hoff J, Midelfart A. Maternal myasthenia gravis: a cause for arthrogryposis multiplex congenita. J Child Orthop. 2015;9(6):433–5.PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Riemersma S, Vincent A, Beeson D, Newland C, Hawke S, Vernet-der Garabedian B, et al. Association of arthrogryposis multiplex congenita with maternal antibodies inhibiting fetal acetylcholine receptor function. J Clin Invest. 1996;98(10):2358–63.PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Polizzi A, Huson SM, Vincent A. Teratogen update: maternal myasthenia gravis as a cause of congenital arthrogryposis. Teratology. 2000;62(5):332–41.PubMedCrossRefGoogle Scholar
  172. 172.
    Brueton LA, Huson SM, Cox PM, Shirley I, Thompson EM, Barnes PR, et al. Asymptomatic maternal myasthenia as a cause of the Pena-Shokeir phenotype. Am J Med Genet. 2000;92(1):1–6.PubMedCrossRefGoogle Scholar
  173. 173.
    Mao ZF, Mo XA, Qin C, Lai YR, Hackett ML. Incidence of thymoma in myasthenia gravis: a systematic review. J Clin Neurol. 2012;8(3):161–9.PubMedPubMedCentralCrossRefGoogle Scholar
  174. 174.
    Zielinski M. Management of myasthenic patients with thymoma. Thorac Surg Clin. 2011;21(1):47–57, vi.PubMedCrossRefGoogle Scholar
  175. 175.
    Romi F, Gilhus NE, Aarli JA. Myasthenia gravis: disease severity and prognosis. Acta Neurol Scand Suppl. 2006;183:24–5.PubMedCrossRefGoogle Scholar
  176. 176.
    Bril V, Kojic J, Dhanani A. The long-term clinical outcome of myasthenia gravis in patients with thymoma. Neurology. 1998;51(4):1198–200.PubMedCrossRefGoogle Scholar
  177. 177.
    Evoli A, Minisci C, Di Schino C, Marsili F, Punzi C, Batocchi AP, et al. Thymoma in patients with MG: characteristics and long-term outcome. Neurology. 2002;59(12):1844–50.PubMedCrossRefGoogle Scholar
  178. 178.
    Parr JR, Jayawant S. Childhood myasthenia: clinical subtypes and practical management. Dev Med Child Neurol. 2007;49(8):629–35.PubMedCrossRefGoogle Scholar
  179. 179.
    Andrews PI. Autoimmune myasthenia gravis in childhood. Semin Neurol. 2004;24(1):101–10.PubMedCrossRefGoogle Scholar
  180. 180.
    Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics. 2014;45(2):75–83.PubMedCrossRefGoogle Scholar
  181. 181.
    Matthews HJ, Thambundit A, Allen BR. Anti-MuSK-positive myasthenic crisis in a 7-year-old female. Case Rep Emerg Med. 2017;2017:8762302.PubMedPubMedCentralGoogle Scholar
  182. 182.
    Al-Shekhlee A, Kaminski HJ, Ruff RL. Endocrine myopathies and muscle disorders related to electrolyte disturbance. In: Katirji B, Kaminski HJ, Preston D, Shapiro B, Ruff RL, editors. Neuromuscular disorders in clinical practice. Boston: Butterworth Heinemann; 2002. p. 1187–204.Google Scholar
  183. 183.
    Prudlo J, Koenig J, Ermert S, Juhasz J. Sleep disordered breathing in medically stable patients with myasthenia gravis. Eur J Neurol. 2007;14(3):321–6.PubMedCrossRefGoogle Scholar
  184. 184.
    Nicolle MW, Rask S, Koopman WJ, George CF, Adams J, Wiebe S. Sleep apnea in patients with myasthenia gravis. Neurology. 2006;67(1):140–2.PubMedCrossRefGoogle Scholar
  185. 185.
    Fernandes Oliveira E, Nacif SR, Alves Pereira N, Fonseca NT, Urbano JJ, Perez EA, et al. Sleep disorders in patients with myasthenia gravis: a systematic review. J Phys Ther Sci. 2015;27(6):2013–8.PubMedPubMedCentralCrossRefGoogle Scholar
  186. 186.
    Ambrogi V, Mineo TC. Benefits of comprehensive rehabilitation therapy in thymectomy for myasthenia gravis: a propensity score matching analysis. Am J Phys Med Rehabil. 2017;96(2):77–83.PubMedCrossRefGoogle Scholar
  187. 187.
    Rahbek MA, Mikkelsen EE, Overgaard K, Vinge L, Andersen H, Dalgas U. Exercise in myasthenia gravis: a feasibility study of aerobic and resistance training. Muscle Nerve. 2017;56(4):700–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of NeurologyThe George Washington UniversityWashington, DCUSA

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