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Myasthenia gravis

Nature Reviews Disease Primers volume 5, Article number: 30 (2019) Cite this article

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Abstract

Myasthenia gravis (MG) is an autoimmune disease caused by antibodies against the acetylcholine receptor (AChR), muscle-specific kinase (MuSK) or other AChR-related proteins in the postsynaptic muscle membrane. Localized or general muscle weakness is the predominant symptom and is induced by the antibodies. Patients are grouped according to the presence of antibodies, symptoms, age at onset and thymus pathology. Diagnosis is straightforward in most patients with typical symptoms and a positive antibody test, although a detailed clinical and neurophysiological examination is important in antibody-negative patients. MG therapy should be ambitious and aim for clinical remission or only mild symptoms with near-normal function and quality of life. Treatment should be based on MG subgroup and includes symptomatic treatment using acetylcholinesterase inhibitors, thymectomy and immunotherapy. Intravenous immunoglobulin and plasma exchange are fast-acting treatments used for disease exacerbations, and intensive care is necessary during exacerbations with respiratory failure. Comorbidity is frequent, particularly in elderly patients. Active physical training should be encouraged.

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Fig. 1: Structure of the neuromuscular junction.
Fig. 2: Structures of the main autoantigens in MG.
Fig. 3: Pathophysiology of MG at the neuromuscular junction.
Fig. 4: The process of normal immune tolerance.
Fig. 5: A simplified diagnostic algorithm for MG.
Fig. 6: Typical asymmetrical bilateral ptosis in a patient with MG.
Fig. 7: Treatment algorithms for chronic MG and acute MG exacerbations.

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References

  1. Gilhus, N. E. Myasthenia gravis. N. Engl. J. Med. 375, 2570–2581 (2016).

    Article  CAS  PubMed  Google Scholar 

  2. Gilhus, N. E. & Verschuuren, J. J. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 14, 1023–1036 (2015). This review article covers most MG aspects.

    Article  CAS  PubMed  Google Scholar 

  3. Kerty, E., Elsais, A., Argov, Z., Evoli, A. & Gilhus, N. E. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur. J. Neurol. 21, 687–693 (2014).

    Article  CAS  PubMed  Google Scholar 

  4. Al-bassam, W. et al. Characteristics, incidence, and outcome of patients admitted to the intensive care unit with myasthenia gravis. J. Crit. Care 45, 90–94 (2018).

    Article  PubMed  Google Scholar 

  5. Andersen, J. B., Gilhus, N. E. & Sanders, D. B. Factors affecting outcome in myasthenia gravis. Muscle Nerve 54, 1041–1049 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Hong, Y. et al. Multiple antibody detection in ‘seronegative’ myasthenia gravis patients. Eur. J. Neurol. 24, 844–850 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Marx, A. et al. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun. Rev. 12, 875–884 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Carr, A. S., Cardwell, C. R., McCarron, P. O. & McConville, J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 10, 46 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Park, S. Y., Lee, J. Y., Lim, N. G. & Hong, Y. H. Incidence and prevalence of myasthenia gravis in Korea: a population-based study using the National Health Insurance Claims Database. J. Clin. Neurol. 12, 340–344 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Heldal, A. T., Owe, J. F., Gilhus, N. E. & Romi, F. Seropositive myasthenia gravis: a nationwide epidemiologic study. Neurology 73, 150–151 (2009).

    Article  PubMed  Google Scholar 

  11. Zieda, A. et al. A nationwide epidemiological study of myasthenia gravis in Latvia. Eur. J. Neurol. 25, 519–526 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Andersen, J. B., Heldal, A. T., Engeland, A. & Gilhus, N. E. Myasthenia gravis epidemiology in a national cohort; combining multiple disease registries. Acta Neurol. Scand. 129, 26–31 (2014).

    Article  CAS  Google Scholar 

  13. Hong, Y. et al. Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms. J. Neurol. 264, 955–962 (2017).

    Article  CAS  PubMed  Google Scholar 

  14. Matsuki, K. et al. HLA antigens in Japanese patients with myasthenia-gravis. J. Clin. Invest. 86, 392–399 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Matsuki, K., Maeda, H., Nomura, Y. & Segawa, M. Distortion of HLA gene transmission in childhood-onset myasthenia-gravis. Lancet 340, 796–796 (1992).

    Article  CAS  PubMed  Google Scholar 

  16. Popperud, T. H., Boldingh, M. I., Rasmussen, M. & Kerty, E. Juvenile myasthenia gravis in Norway: clinical characteristics, treatment, and long-term outcome in a nationwide population-based cohort. Eur. J. Paediatr. Neurol. 21, 707–714 (2017).

    Article  CAS  PubMed  Google Scholar 

  17. Evoli, A. et al. Myasthenia gravis with antibodies to MuSK: an update. Ann. NY Acad. Sci. 1412, 82–89 (2018). This article represents a comprehensive review of an important MG subgroup.

    Article  CAS  PubMed  Google Scholar 

  18. Hong, Y. et al. Autoantibody profile and clinical characteristics in a cohort of Chinese adult myasthenia gravis patients. J. Neuroimmunol. 298, 51–57 (2016).

    Article  CAS  PubMed  Google Scholar 

  19. Hong, Y., Li, H. F., Romi, F., Skeie, G. O. & Gilhus, N. E. HLA and MuSK-positive myasthenia gravis: a systemic review and meta-analysis. Acta Neurol. Scand. 138, 219–226 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Huda, S., Woodhall, M. R., Vincent, A. & Heckmann, J. M. Characteristics of acetylcholine-receptor-antibody-negative myasthenia gravis in a South African cohort. Muscle Nerve 54, 1023–1029 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Zisimopoulou, P. et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J. Autoimmun. 52, 139–145 (2014). This large, multinational study establishes the presence, frequency and some clinical characteristics of anti-LRP4 MG.

    Article  CAS  PubMed  Google Scholar 

  22. Yan, M., Xing, G. L., Xiong, W. C. & Mei, L. Agrin and LRP4 antibodies as new biomarkers of myasthenia gravis. Ann. NY Acad. Sci. 1413, 126–135 (2018).

    Article  CAS  PubMed  Google Scholar 

  23. Zhang, B. et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch. Neurol. 69, 445–451 (2012).

    Article  PubMed  Google Scholar 

  24. Boldingh, M. I. et al. Prevalence and clinical aspects of immigrants with myasthenia gravis in Northern Europe. Muscle Nerve 55, 819–827 (2017).

    Article  PubMed  Google Scholar 

  25. Owe, J. F., Daltveit, A. K. & Gilhus, N. E. Causes of death among patients with myasthenia gravis in Norway between 1951 and 2001. J. Neurol. Neurosurg. Psychiatry 77, 203–207 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hansen, J. S. et al. Mortality in myasthenia gravis: a nationwide population-based follow-up study in Denmark. Muscle Nerve 53, 73–77 (2016). This population-based registry study proves the excellent prognosis of MG with modern treatment.

    Article  CAS  PubMed  Google Scholar 

  27. Gilhus, N. E., Nacu, A., Andersen, J. B. & Owe, J. F. Myasthenia gravis and risks for comorbidity. Eur. J. Neurol. 22, 17–23 (2015).

    Article  CAS  PubMed  Google Scholar 

  28. Ogawa, Y. et al. Survey of epidemiology, clinical picture and current treatments for elderly-onset (>=65 years) patients with myasthenia gravis in Nagano Prefecture. Japan. Neurol. Clin. Neurosci. 5, 107–112 (2017).

    Article  CAS  Google Scholar 

  29. Pedersen, E. G., Hallas, J., Hansen, K., Jensen, P. E. H. & Gaist, D. Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996–2009. Eur. J. Neurol. 20, 309–314 (2013).

    Article  CAS  PubMed  Google Scholar 

  30. Boldingh, M. I. et al. Geographical distribution of myasthenia gravis in Northern Europe - results from a population-based study from two countries. Neuroepidemiology 44, 221–231 (2015).

    Article  PubMed  Google Scholar 

  31. Cea, G. et al. Clinical and epidemiological features of myasthenia gravis in Chilean population. Acta Neurol. Scand. 138, 338–343 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Ramanujam, R., Pirskanen, R., Ramanujam, S. & Hammarstrom, L. Utilizing twins concordance rates to infer the predisposition to myasthenia gravis. Twin Res. Hum. Genet. 14, 129–136 (2011).

    Article  PubMed  Google Scholar 

  33. Li, F., Yuan, W. Z. & Wu, X. S. Association of CTLA-4 polymorphisms with increased risks of myasthenia gravis. Ann. Hum. Genet. 82, 358–369 (2018).

    Article  CAS  PubMed  Google Scholar 

  34. Giraud, M. et al. An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448, 934–937 (2007).

    Article  CAS  PubMed  Google Scholar 

  35. Punga, A. R. & Punga, T. Circulating microRNAs as potential biomarkers in myasthenia gravis patients. Ann. NY Acad. Sci. 1412, 33–40 (2018).

    Article  CAS  PubMed  Google Scholar 

  36. Boldingh, M. I. et al. Increased risk for clinical onset of myasthenia gravis during the postpartum period. Neurology 87, 2139–2145 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  37. Berrih-Aknin, S. & Le Panse, R. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J. Autoimmun. 52, 90–100 (2014). This article explains the major immunological mechanisms in MG.

    Article  CAS  PubMed  Google Scholar 

  38. Dragin, N. et al. Estrogen-mediated downregulation of AIRE influences sexual dimorphism in autoimmune diseases. J. Clin. Invest. 126, 1525–1537 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Cavalcante, P. et al. Epstein-barr virus persistence and reactivation in myasthenia gravis thymus. Ann. Neurol. 67, 726–738 (2010).

    PubMed  Google Scholar 

  40. Meyer, M. et al. Lack of evidence for epstein-barr virus infection in myasthenia gravis thymus. Ann. Neurol. 70, 515–518 (2011).

    Article  PubMed  Google Scholar 

  41. Gilhus, N. E., Romi, F., Hong, Y. & Skeie, G. O. Myasthenia gravis and infectious disease. J. Neurol. 265, 1251–1258 (2018).

    Article  CAS  PubMed  Google Scholar 

  42. Kao, J. C., Brickshawana, A. & Liewluck, T. Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors. Curr. Neurol. Neurosci. Rep. 18, 63 (2018).

    Article  CAS  PubMed  Google Scholar 

  43. Benfaremo, D., Manfredi, L., Luchetti, M. M. & Gabrielli, A. Musculoskeletal and rheumatic diseases induced by immune checkpoint inhibitors: a review of the literature. Curr. Drug Safety 13, 150–164 (2018).

    Article  CAS  Google Scholar 

  44. Patrick, J. & Lindstrom, J. Autoimmune response to acetylcholine receptor. Science 180, 871–872 (1973).

    Article  CAS  PubMed  Google Scholar 

  45. Lindstrom, J. M., Seybold, M. E., Lennon, V. A., Whittingham, S. & Duane, D. D. Antibody to acetylcholine-receptor in myasthenia-gravis - prevalence, clinical correlates, and diagnostic value. Neurology 26, 1054–1059 (1976).

    Article  CAS  PubMed  Google Scholar 

  46. Toyka, K. V., Drachman, D. B., Pestronk, A. & Kao, I. Myasthenia-gravis - passive transfer from man to mouse. Science 190, 397–399 (1975).

    Article  CAS  PubMed  Google Scholar 

  47. Zisimopoulou, P., Brenner, T., Trakas, N. & Tzartos, S. J. Serological diagnostics in myasthenia gravis based on novel assays and recently identified antigens. Autoimmun. Rev. 12, 924–930 (2013).

    Article  CAS  PubMed  Google Scholar 

  48. Changeux, J. P. The nicotinic acetylcholine receptor: the founding father of the pentameric ligand-gated ion channel superfamily. J. Biol. Chem. 287, 40207–40215 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Luo, J. et al. Main immunogenic region structure promotes binding of conformation-dependent myasthenia gravis autoantibodies, nicotinic acetylcholine receptor conformation maturation, and agonist sensitivity. J. Neurosci. 29, 13898–13908 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tzartos, S. J. et al. Anatomy of the antigenic structure of a large membrane autoantigen, the muscle-type nicotinic acetylcholine receptor. Immunol. Rev. 163, 89–120 (1998).

    Article  CAS  PubMed  Google Scholar 

  51. Noridomi, K., Watanabe, G., Hansen, M. N., Han, G. W. & Chen, L. Structural insights into the molecular mechanisms of myasthenia gravis and their therapeutic implications. eLife 6, e23043 (2017). This study clarifies the pathogenetic effect of anti-AChR antibodies.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Tuzun, E. & Christadoss, P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun. Rev. 12, 904–911 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Kordas, G., Lagoumintzis, G., Sideris, S., Poulas, K. & Tzartos, S. J. Direct proof of the in vivo pathogenic role of the AChR autoantibodies from myasthenia gravis patients. PLOS ONE 10, e0117673 (2015).

    Article  Google Scholar 

  54. Gilhus, N. E. et al. Myasthenia gravis - autoantibody characteristics and their implications for therapy. Nat. Rev. Neurol. 12, 259–268 (2016).

    Article  CAS  PubMed  Google Scholar 

  55. Hara, H. et al. Detection and characterization of blocking-type antiacetylcholine receptor antibodies in sera from patients with myasthenia-gravis. Clin. Chem. 39, 2053–2057 (1993).

    CAS  PubMed  Google Scholar 

  56. Messeant, J. et al. MuSK frizzled-like domain is critical for mammalian neuromuscular junction formation and maintenance. J. Neurosci. 35, 4926–4941 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Li, L. et al. Enzymatic activity of the scaffold protein rapsyn for synapse formation. Neuron 92, 1007–1019 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Hoch, W. et al. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat. Med. 7, 365–368 (2001).

    Article  CAS  PubMed  Google Scholar 

  59. Koneczny, I. et al. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. J. Autoimmun. 77, 104–115 (2017).

    Article  CAS  PubMed  Google Scholar 

  60. Huijbers, M. G. et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc. Natl Acad. Sci. USA 110, 20783–20788 (2013). This study represents an achievement in understanding the role of anti-MuSK antibodies in disease development.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Huijbers, M. G. et al. Longitudinal epitope mapping in MuSK myasthenia gravis: implications for disease severity. J. Neuroimmunol. 291, 82–88 (2016).

    Article  CAS  PubMed  Google Scholar 

  62. Poulas, K., Koutsouraki, E., Kordas, G., Kokla, A. & Tzartos, S. J. Anti-MuSK- and anti-AChR-positive myasthenia gravis induced by d-penicillamine. J. Neuroimmunol. 250, 94–98 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Kim, N. et al. Lrp4 is a receptor for agrin and forms a complex with MuSK. Cell 135, 334–342 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Higuchi, O., Hamuro, J., Motomura, M. & Yamanashi, Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann. Neurol. 69, 418–422 (2011).

    Article  CAS  PubMed  Google Scholar 

  65. Tzartos, J. S. et al. LRP4 antibodies in serum and CSF from amyotrophic lateral sclerosis patients. Ann. Clin. Transl Neurol. 1, 80–87 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Shen, C. Y. et al. Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J. Clin. Invest. 123, 5190–5202 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Ulusoy, C., Cavus, F., Yilmaz, V. & Tuzun, E. Immunization with recombinantly expressed LRP4 induces experimental autoimmune myasthenia gravis in C57BL/6 mice. Immunol. Invest. 46, 490–499 (2017).

    Article  CAS  PubMed  Google Scholar 

  68. Mori, S. et al. Immunization of mice with LRP4 induces myasthenia similar to MuSK-associated myasthenia gravis. Exp. Neurol. 297, 158–167 (2017).

    Article  CAS  PubMed  Google Scholar 

  69. Witzemann, V., Chevessier, F., Pacifici, P. G. & Yampolsky, P. The neuromuscular junction: selective remodeling of synaptic regulators at the nerve/muscle interface. Mech. Dev. 130, 402–411 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Gasperi, C. et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology 82, 1976–1983 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Yan, M. et al. Induction of anti-agrin antibodies causes myasthenia gravis in mice. Neuroscience 373, 113–121 (2018).

    Article  CAS  PubMed  Google Scholar 

  72. Cossins, J. et al. in Myasthenia Gravis and Related Disorders II: 12th International Conference Vol. 1275 (eds Wolfe, G. I., Meriggioli, M. N., Ciafaloni, E. & Ruff, R. L.) 123–128 (Wiley, 2012).

  73. Romi, F. et al. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. J. Neurol. 259, 1312–1316 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Suzuki, S. et al. Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. Eur. J. Neurol. 21, 223–230 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. O’Connell, K. M. S., Whitesell, J. D. & Tamkun, M. M. Localization and mobility of the delayed-rectifer K+ channel Kv2.1 in adult cardiomyocytes. Am. J. Physiol. Heart Circ. Physiol. 294, H229–H237 (2008).

    Article  CAS  PubMed  Google Scholar 

  76. Powers, K. et al. Titin force enhancement following active stretch of skinned skeletal muscle fibres. J. Exp. Biol. 220, 3110–3118 (2017).

    Article  PubMed  Google Scholar 

  77. Romi, F., Hong, Y. & Gilhus, N. E. Pathophysiology and immunological profile of myasthenia gravis and its subgroups. Curr. Opin. Immunol. 49, 9–13 (2017).

    Article  CAS  PubMed  Google Scholar 

  78. Szczudlik, P. et al. Antititin antibody in early- and late-onset myasthenia gravis. Acta Neurol. Scand. 130, 229–233 (2014).

    Article  CAS  PubMed  Google Scholar 

  79. Gautel, M. et al. Titin antibodies in myasthenia-gravis - identification of a major immunogenic region of titin. Neurology 43, 1581–1585 (1993).

    Article  CAS  PubMed  Google Scholar 

  80. Santulli, G., Nakashima, R., Yuan, Q. & Marks, A. R. Intracellular calcium release channels: an update. J. Physiol. 595, 3041–3051 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Mygland, A. et al. Ryanodine receptor autoantibodies in myasthenia-gravis patients with a thymoma. Ann. Neurol. 32, 589–591 (1992).

    Article  CAS  PubMed  Google Scholar 

  82. Romi, F., Skeie, G. O., Gilhus, N. E. & Aarli, J. A. Striational antibodies in myasthenia gravis - Reactivity and possible clinical significance. Arch. Neurol. 62, 442–446 (2005).

    Article  PubMed  Google Scholar 

  83. Gallardo, E. et al. Cortactin autoantibodies in myasthenia gravis. Autoimmun. Rev. 13, 1003–1007 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Illa, I., Cortes-Vicente, E., Martinez, M. A. & Gallardo, E. Diagnostic utility of cortactin antibodies in myasthenia gravis. Ann. NY Acad. Sci. 1412, 90–94 (2018).

    Article  CAS  PubMed  Google Scholar 

  85. Labrador-Horrillo, M. et al. Identification of a novel myositis-associated antibody directed against cortactin. Autoimmun. Rev. 13, 1008–1012 (2014).

    Article  CAS  PubMed  Google Scholar 

  86. Strobel, P. et al. The ageing and myasthenic thymus: a morphometric study validating a standard procedure in the histological workup of thymic specimens. J. Neuroimmunol. 201, 64–73 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Wolfe, G. I. et al. Randomized trial of thymectomy in myasthenia gravis. N. Engl. J. Med. 375, 511–522 (2016). This randomized trial confirms the efficacy of thymectomy in some MG subgroups with anti-AChR antibodies.

    Article  PubMed  PubMed Central  Google Scholar 

  88. Cron, M. A. et al. Thymus involvement in early-onset myasthenia gravis. Ann. NY Acad. Sci. 1412, 137–145 (2018).

    Article  CAS  PubMed  Google Scholar 

  89. Valencia, X. & Lipsky, P. E. CD4+ CD25+ FoxP3+ regulatory T cells in autoimmune diseases. Nat. Clin. Pract. Rheumatol. 3, 619–626 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Cheng, M. & Anderson, M. S. Thymic tolerance as a key brake on autoimmunity. Nat. Immunol. 19, 659–664 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Weis, C. A., Schalke, B., Strobel, P. & Marx, A. Challenging the current model of early-onset myasthenia gravis pathogenesis in the light of the MGTX trial and histological heterogeneity of thymectomy specimens. Ann. NY Acad. Sci. 1413, 82–91 (2018).

    Article  CAS  PubMed  Google Scholar 

  92. Yi, J. S. et al. Characterization of CD4 and CD8 T cell responses in MuSK myasthenia gravis. J. Autoimmun. 52, 130–138 (2014).

    Article  CAS  PubMed  Google Scholar 

  93. Buckner, J. H. Mechanisms of impaired regulation by CD4+CD25+FOXP3+ regulatory T cells in human autoimmune diseases. Nat. Rev. Immunol. 10, 849–859 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Luther, C. et al. Prednisolone treatment induces tolerogenic dendritic cells and a regulatory milieu in myasthenia gravis patients. J. Immunol. 183, 841–848 (2009).

    Article  CAS  PubMed  Google Scholar 

  95. Gradolatto, A. et al. Both Treg cells and Tconv cells are defective in the myasthenia gravis thymus: roles of IL-17 and TNF-alpha. J. Autoimmun. 52, 53–63 (2014).

    Article  CAS  PubMed  Google Scholar 

  96. Marx, A. et al. Thymoma related myasthenia gravis in humans and potential animal models. Exp. Neurol. 270, 55–65 (2015).

    Article  PubMed  Google Scholar 

  97. Leite, M. I. et al. Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann. Neurol. 57, 444–448 (2005).

    Article  PubMed  Google Scholar 

  98. Singman, E. L., Matta, N. S. & Silbert, D. I. Use of the Cogan lid twitch to identify myasthenia gravis. J. Neuroophthalmol. 31, 239–240 (2011).

    Article  PubMed  Google Scholar 

  99. Van Stavern, G. P., Bhatt, A., Haviland, J. & Black, E. H. A prospective study assessing the utility of Cogan’s lid twitch sign in patients with isolated unilateral or bilateral ptosis. J. Neurol. Sci. 256, 84–85 (2007).

    Article  PubMed  Google Scholar 

  100. Chatzistefanou, K. I. et al. The ice pack test in the differential diagnosis of myasthenic diplopia. Ophthalmology 116, 2236–2243 (2009).

    Article  PubMed  Google Scholar 

  101. Yamamoto, D. et al. Effect of local cooling on excitation-contraction coupling in myasthenic muscle: another mechanism of ice-pack test in myasthenia gravis. Clin. Neurophysiol. 128, 2309–2317 (2017).

    Article  PubMed  Google Scholar 

  102. Richards, J. & Howard, J. F. Seronegative myasthenia gravis associated with malignant thymoma. Neuromuscul. Disord. 27, 417–418 (2017).

    Article  PubMed  Google Scholar 

  103. Stergiou, C. et al. Titin antibodies in “seronegative” myasthenia gravis - a new role for an old antigen. J. Neuroimmunol. 292, 108–115 (2016).

    Article  CAS  PubMed  Google Scholar 

  104. Leite, M. I. et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 131, 1940–1952 (2008). This study discovers that some MG autoantibodies are undetectable by the classical methods and introduces cell-based assays.

    Article  PubMed  PubMed Central  Google Scholar 

  105. Cruz, P. M. R. et al. Clinical features and diagnostic usefulness of antibodies to clustered acetylcholine receptors in the diagnosis of seronegative myasthenia gravis. JAMA Neurol. 72, 642–649 (2015). This study reports the characteristics of all patients with anti-AChR antibodies exclusively identified by the cell-based assay.

    Article  Google Scholar 

  106. Vincent, A. et al. in Myasthenia Gravis and Related Disorders: 11th International Conference Vol. 1132 (eds Kaminski, H. J. & Barohn, R. J.) 84–92 (The New York Academy of Sciences, 2008).

  107. Tsonis, A. I. et al. MuSK autoantibodies in myasthenia gravis detected by cell based assay - a multinational study. J. Neuroimmunol. 284, 10–17 (2015).

    Article  CAS  PubMed  Google Scholar 

  108. Huda, S. et al. IgG-specific cell-based assay detects potentially pathogenic MuSK-Abs in seronegative MG. Neurol. Neuroimmunol. Neuroinflamm. 4, e357 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  109. Liik, M. & Punga, A. R. Repetitive nerve stimulation often fails to detect abnormal decrement in acute severe generalized myasthenia gravis. Clin. Neurophysiol. 127, 3480–3484 (2016).

    Article  PubMed  Google Scholar 

  110. Nikolic, A., Basta, I., Stojanovic, V. R., Stevic, Z. & Lavrnic, D. Electrophysiological profile of the patients with MuSK positive myasthenia gravis. Neurol. Res. 36, 945–949 (2014).

    Article  CAS  PubMed  Google Scholar 

  111. Nikolic, A. V., Bojic, S. D., Stojanovic, V. M. R., Basta, I. Z. & Lavrnic, D. V. Electrophysiological findings in patients with low density lipoprotein receptor related protein 4 positive myasthenia gravis. Eur. J. Neurol. 23, 1635–1641 (2016).

    Article  CAS  PubMed  Google Scholar 

  112. Stalberg, E., Sanders, D. B. & Kouyoumdjian, J. A. Pitfalls and errors in measuring jitter. Clin. Neurophysiol. 128, 2233–2241 (2017). This article informs about how to interpret key neurophysiological findings in MG.

    Article  PubMed  Google Scholar 

  113. Thornton, R. C. & Michell, A. W. Techniques and applications of EMG: measuring motor units from structure to function. J. Neurol. 259, 585–594 (2012).

    Article  PubMed  Google Scholar 

  114. Cruz, P. M. R., Palace, J. & Beeson, D. The neuromuscular junction and wide heterogeneity of congenital myasthenic syndromes. Int. J. Mol. Sci. 19, E1677 (2018).

    Article  CAS  Google Scholar 

  115. Lee, M., Beeson, D. & Palace, J. Therapeutic strategies for congenital myasthenic syndromes. Ann. NY Acad. Sci. 1412, 129–136 (2018).

    Article  CAS  PubMed  Google Scholar 

  116. Titulaer, M. J., Lang, B. & Verschuuren, J. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 10, 1098–1107 (2011).

    Article  PubMed  Google Scholar 

  117. Verschuuren, J., Strijbos, E. & Vincent, A. Neuromuscular junction disorders. Handb. Clin. Neurol. 133, 447–466 (2016).

    Article  PubMed  Google Scholar 

  118. Sanders, D. B. et al. Is the decremental pattern in Lambert-Eaton syndrome different from that in myasthenia gravis? Clin. Neurophysiol. 125, 1274–1277 (2014).

    Article  CAS  PubMed  Google Scholar 

  119. Di Lorenzo, R. et al. Low specificity of voltage-gated calcium channel antibodies in Lambert-Eaton myasthenic syndrome: a call for caution. J. Neurol. 265, 2114–2119 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Lacey, B., Chang, W. & Rootman, J. Nonthyroid causes of extraocular muscle disease. Surv. Ophthalmol. 44, 187–213 (1999).

    Article  CAS  PubMed  Google Scholar 

  121. Skeie, G. O. et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur. J. Neurol. 17, 893–902 (2010).

    Article  CAS  PubMed  Google Scholar 

  122. Sanders, D. B. et al. International consensus guidance for management of myasthenia gravis: executive summary. Neurology 87, 419–425 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  123. Sussman, J. et al. The Association of British Neurologists’ myasthenia gravis guidelines. Ann. NY Acad. Sci. 1412, 166–169 (2018).

    Article  PubMed  Google Scholar 

  124. Murai, H. et al. Rationale for the clinical guidelines for myasthenia gravis in Japan. Ann. NY Acad. Sci. 1413, 35–40 (2018).

    Article  PubMed  Google Scholar 

  125. Pitha, J. et al. Guideline for the diagnosis and therapy of myasthenia gravis. Cesk. Neurol. Neurochir. 75, 244–252 (2012).

    Google Scholar 

  126. Gilhus, N. E., Kerty, E., Loseth, S., Mygland, A. & Tallaksen, C. Myasthenia gravis - diagnosis and treatment [Norwegian]. Tidsskr. Nor. Laegeforen. 136, 1089–1094 (2016).

    Article  PubMed  Google Scholar 

  127. Evoli, A. & Padua, L. Diagnosis and therapy of myasthenia gravis with antibodies to muscle-specific kinase. Autoimmun. Rev. 12, 931–935 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Bonanno, S. et al. Amifampridine phosphate in the treatment of muscle-specific kinase myasthenia gravis: a phase IIb, randomized, double-blind, placebo-controlled, double crossover study. Sage Open Med. 6, 2050312118819013 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Mantegazza, R., Bonanno, S., Camera, G. & Antozzi, C. Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatr. Dis. Treat 7, 151–160 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Meriggioli, M. N. & Sanders, D. B. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 8, 475–490 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Sieb, J. P. Myasthenia gravis: an update for the clinician. Clin. Exp. Immunol. 175, 408–418 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Sanders, D. B. & Evoli, A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity 43, 428–435 (2010).

    Article  CAS  PubMed  Google Scholar 

  133. Utsugisawa, K. et al. Health-related quality-of-life and treatment targets in myasthenia gravis. Muscle Nerve 50, 493–500 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Gotterer, L. & Li, Y. B. Maintenance immunosuppression in myasthenia gravis. J. Neurol. Sci. 369, 294–302 (2016).

    Article  PubMed  Google Scholar 

  135. Benatar, M. et al. Efficacy of prednisone for the treatment of ocular myasthenia (epitome): a randomized, controlled trial. Muscle Nerve 53, 363–369 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. El-Salem, K. et al. Treatment of MuSK-associated myasthenia gravis. Curr. Treat Options Neurol. 16, 283 (2014).

    Article  PubMed  Google Scholar 

  137. Hobson-Webb, L. D. et al. Can mycophenolate mofetil be tapered safely in myasthenia gravis? A retrospective, multicenter analysis. Muscle Nerve 52, 211–215 (2015).

    Article  PubMed  Google Scholar 

  138. Sathasivam, S. Current and emerging treatments for the management of myasthenia gravis. Ther. Clin. Risk Manag. 7, 313–323 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Hehir, M. K. et al. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 41, 593–598 (2010).

    Article  CAS  PubMed  Google Scholar 

  140. Cruz, J. L., Wolff, M. L., Vanderman, A. J. & Brown, J. N. The emerging role of tacrolimus in myasthenia gravis. Ther. Adv. Neurol. Disord. 8, 92–103 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Tindall, R. S. A., Phillips, J. T., Rollins, J. A., Wells, L. & Hall, K. A. Clinical therapeutic trial of cyclosporine in myasthenia-gravis. Ann. NY Acad. Sci. 681, 539–551 (1993).

    Article  CAS  PubMed  Google Scholar 

  142. Palace, J., Newsom-Davis, J. & Lecky, B. A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Neurology 50, 1778–1783 (1998). This study still represents the scientific proof for the effect of combination immunosuppressive therapy in MG.

    Article  CAS  PubMed  Google Scholar 

  143. Sanders, D. B. et al. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 71, 394–399 (2008).

    Article  CAS  Google Scholar 

  144. Sanders, D. B. et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 71, 400–406 (2008).

    Article  CAS  PubMed  Google Scholar 

  145. Nagane, Y., Utsugisawa, K., Obara, D., Kondoh, R. & Terayama, Y. Efficacy of low-dose FK506 in the treatment of myasthenia gravis - a randomized pilot study. Eur. Neurol. 53, 146–150 (2005).

    Article  CAS  PubMed  Google Scholar 

  146. Yoshikawa, H., Kiuchi, T., Saida, T. & Takamori, M. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J. Neurol. Neurosurg. Psychiatry 82, 970–977 (2011).

    Article  PubMed  Google Scholar 

  147. Pasnoor, M. et al. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology 87, 57–64 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Heckmann, J. M., 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. 11, 97 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Tandan, R., Hehir, M. K., Waheed, W. & Howard, D. B. Rituximab treatment of myasthenia gravis: a systematic review. Muscle Nerve 56, 185–196 (2017). This article reviews the evidence thus far for rituximab as a promising therapy in MG.

    Article  CAS  PubMed  Google Scholar 

  150. Robeson, K. R. et al. Durability of the rituximab response in acetylcholine receptor autoantibody-positive myasthenia gravis. JAMA Neurol. 74, 60–66 (2017).

    Article  PubMed  Google Scholar 

  151. Anderson, D., Phan, C., Johnston, W. S. & Siddiqi, Z. A. Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up. Ann. Clin. Transl Neurol. 3, 552–555 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kanth, K. M., Solorzano, G. E. & Goldman, M. D. PML in a patient with myasthenia gravis treated with multiple immunosuppressing agents. Neurol. Clin. Pract. 6, E17–E19 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Afanasiev, V. et al. Resistant myasthenia gravis and rituximab: a monocentric retrospective study of 28 patients. Neuromuscul. Disord. 27, 251–258 (2017).

    Article  PubMed  Google Scholar 

  154. Howard, J. F. et al. 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. 16, 976–986 (2017). This article reports the promising results regarding the effect of a complement inhibitory drug in MG.

    Article  CAS  PubMed  Google Scholar 

  155. Gilhus, N. E. Eculizumab: a treatment option for mysthenia gravis? Lancet Neurol. 16, 947–948 (2017).

    Article  PubMed  Google Scholar 

  156. Hewett, K. et al. Randomized study of adjunctive belimumab in participants with generalized myasthenia gravis. Neurology 90, E1425–E1434 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. De Feo, L. G., Schottlender, J., Martelli, N. A. & Molfino, N. A. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle Nerve 26, 31–36 (2002).

    Article  CAS  PubMed  Google Scholar 

  158. Drachman, D. B., Adams, R. N., Hu, R., Jones, R. J. & Brodsky, R. A. in Myasthenia Gravis and Related Disorders: 11th International Conference Vol. 1132 (eds Kaminski, H. J. & Barohn, R. J.) 305–314 (The New York Academy of Sciences, 2008).

  159. Bryant, A. et al. Myasthenia gravis treated with autologous hematopoietic stem cell transplantation. JAMA Neurol. 73, 652–658 (2016).

    Article  PubMed  Google Scholar 

  160. Gelfand, E. W. Mechanisms of disease intravenous immune globulin in autoimmune and inflammatory diseases. N. Engl. J. Med. 367, 2015–2025 (2012).

    Article  CAS  PubMed  Google Scholar 

  161. Gajdos, P., Chevret, S., Clair, B., Tranchant, C. & Chastang, C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann. Neurol. 41, 789–796 (1997).

    Article  CAS  PubMed  Google Scholar 

  162. Gajdos, P., Chevret, S. & Toyka, K. V. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst. Rev. 12, CD002277 (2012).

    PubMed  Google Scholar 

  163. Bourque, P. R., Pringle, C. E., Cameron, W., Cowan, J. & Chardon, J. W. Subcutaneous immunoglobulin therapy in the chronic management of myasthenia gravis: a retrospective cohort study. PLOS ONE 11, e0159993 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Beecher, G., Anderson, D. & Siddiqi, Z. A. Subcutaneous immunoglobulin in myasthenia gravis exacerbation: A prospective, open-label trial. Neurology 89, 1135–1141 (2017).

    Article  CAS  PubMed  Google Scholar 

  165. Meyer, D. M. et al. Comparative clinical outcomes of thymectomy for myasthenia gravis performed by extended transsternal and minimally invasive approaches. Ann. Thorac Surg. 87, 385–391 (2009).

    Article  PubMed  Google Scholar 

  166. Keijzers, M. et al. Robotic thymectomy in patients with myasthenia gravis: neurological and surgical outcomes. Eur. J. Cardiothorac Surg. 48, 40–45 (2015).

    Article  PubMed  Google Scholar 

  167. Gronseth, G. S. & Barohn, R. J. Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review) - report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 55, 7–15 (2000).

    Article  CAS  PubMed  Google Scholar 

  168. Rahbek, M. A. et al. Exercise in myasthenia gravis: a feasibility study of aerobic and resistance training. Muscle Nerve 56, 700–709 (2017).

    Article  PubMed  Google Scholar 

  169. Westerberg, E., Molin, C. J., Lindblad, I., Emtner, M. & Punga, A. R. Physical exercise in myasthenia gravis is safe and improves neuromuscular parameters and physical performance-based measures: a pilot study. Muscle Nerve 56, 207–214 (2017).

    Article  CAS  PubMed  Google Scholar 

  170. Nicolle, M. W. et al. Sleep apnea in patients with myasthenia gravis. Neurology 67, 140–142 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Pedersen, E. G. et al. Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine. Eur. J. Neurol. 21, 454–458 (2014).

    Article  CAS  PubMed  Google Scholar 

  172. Pedersen, E. G. et al. Myasthenia and risk of cancer: a population-based case-control study. Eur. J. Neurol. 21, 773–778 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. Owe, J. F., Cvancarova, M., Romi, F. & Gilhus, N. E. Extrathymic malignancies in thymoma patients with and without myasthenia gravis. J. Neurol. Sci. 290, 66–69 (2010).

    Article  PubMed  Google Scholar 

  174. Norwood, F. et al. Myasthenia in pregnancy: best practice guidelines from a UK multispecialty working group. J. Neurol. Neurosurg. Psychiatry 85, 538–543 (2014). This article is a useful consensus document regarding treatment for MG for women of child-bearing potential and during pregnancy.

    Article  PubMed  Google Scholar 

  175. Gilhus, N. E. & Hong, Y. Maternal myasthenia gravis represents a risk for the child through autoantibody transfer, immunosuppressive therapy and genetic influence. Eur. J. Neurol. 25, 1402–1409 (2018).

    Article  CAS  PubMed  Google Scholar 

  176. Wolfe, G. I. et al. Myasthenia gravis activities of daily living profile. Neurology 52, 1487–1489 (1999).

    Article  CAS  PubMed  Google Scholar 

  177. Barnett, C., Bril, V., Kapral, M., Kulkarni, A. & Davis, A. M. Development and validation of the Myasthenia Gravis Impairment Index. Neurology 87, 879–886 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Burns, T. M., Grouse, C. K., Conaway, M. R. & Sanders, D. B. Construct and concurrent validation of the MG-QOL15 in the practice setting. Muscle Nerve 41, 219–226 (2010).

    PubMed  Google Scholar 

  179. Burns, T. M. et al. The MG-QOL15 for following the health-related quality of life of patients with myasthenia gravis. Muscle Nerve 43, 14–18 (2011).

    Article  PubMed  Google Scholar 

  180. Burns, T. M. et al. International clinimetric evaluation of the MG-QOL15, resulting in slight revision and subsequent validation of the MG-QOL15R. Muscle Nerve 54, 1015–1022 (2016).

    Article  PubMed  Google Scholar 

  181. Padua, L. et al. Myasthenia gravis outcome measure: development and validation of a disease-specific self-administered questionnaire. Neurol. Sci. 23, 59–68 (2002).

    Article  CAS  PubMed  Google Scholar 

  182. Mullins, L. L., Carpentier, M. Y., Paul, R. H. & Sanders, D. B. Disease-specific measure of quality of life for myasthenia gravis. Muscle Nerve 38, 947–956 (2008).

    Article  PubMed  Google Scholar 

  183. Koopman, W. J., LeBlanc, N., Fowler, S., Hulley, D. & Nicolle, M. W. Hope, well-being, coping, and quality of life in adults with myasthenia gravis [abstract]. Muscle Nerve 52, S141 (2015).

    Google Scholar 

  184. Jaretzki, A. et al. Myasthenia gravis - recommendations for clinical research standards. Neurology 55, 16–23 (2000).

    Article  PubMed  Google Scholar 

  185. Burns, T. M., Conaway, M. & Sanders, D. B. The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 74, 1434–1440 (2010). This article illustrates the importance of systematic testing and follow-up of patients with MG.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Behin, A. & Le Panse, R. New pathways and therapeutic targets in autoimmune myasthenia gravis. J. Neuromuscul. Dis. 5, 265–277 (2018). This article provides a nice overview of potential, new treatment targets in MG.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Mantegazza, R., Bernasconi, P. & Cavalcante, P. Myasthenia gravis: from autoantibodies to therapy. Curr. Opin. Neurol. 31, 517–525 (2018).

    CAS  PubMed  Google Scholar 

  188. Molina, V. et al. Immunomodulation of experimental pulmonary fibrosis by intravenous immunoglobulin (IVIG). Autoimmunity 39, 711–717 (2006).

    Article  CAS  PubMed  Google Scholar 

  189. He, D. et al. Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis. Ann. Neurol. 84, 386–400 (2018). This article describes how specific vaccination may be involved in the onset of MG.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Makino, T. et al. Analysis of peripheral B cells and autoantibodies against the anti-nicotinic acetylcholine receptor derived from patients with myasthenia gravis using single-cell manipulation tools. PLOS ONE 12, e0185976 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Cron, M. A. et al. Analysis of microRNA expression in the thymus of myasthenia gravis patients opens new research avenues. Autoimmun. Rev. 17, 588–600 (2018).

    Article  CAS  PubMed  Google Scholar 

  192. Sabre, L., Maddison, P., Sadalage, G., Ambrose, P. A. & Punga, A. R. Circulating microRNA miR-21-5p, miR-150-5p and miR-30e-5p correlate with clinical status in late onset myasthenia gravis. J. Neuroimmunol. 321, 164–170 (2018).

    Article  CAS  PubMed  Google Scholar 

  193. Cruz, P. M. R., Huda, S., Lopez-Ruiz, P. & Vincent, A. Use of cell-based assays in myasthenia gravis and other antibody-mediated diseases. Exp. Neurol. 270, 66–71 (2015).

    Article  CAS  Google Scholar 

  194. Trakas, N. & Tzartos, S. J. Immunostick ELISA for rapid and easy diagnosis of myasthenia gravis. J. Immunol. Methods 460, 107–112 (2018).

    Article  CAS  PubMed  Google Scholar 

  195. Valko, Y. et al. Ocular vestibular evoked myogenic potentials as a test for myasthenia gravis. Neurology 86, 660–668 (2016).

    Article  PubMed  Google Scholar 

  196. Chan, J. W. & Orrison, W. W. Ocular myasthenia: a rare presentation with MuSK antibody and bilateral extraocular muscle atrophy. Br. J. Ophthalmol. 91, 842–843 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  197. Priola, A. M. et al. Comparison of CT and chemical-shift MRI for differentiating thymoma from non-thymomatous conditions in myasthenia gravis: value of qualitative and quantitative assessment. Clin. Radiol. 71, E157–E169 (2016).

    Article  CAS  PubMed  Google Scholar 

  198. Sala, T. P. et al. Efficacy and patient satisfaction in the use of subcutaneous immunoglobulin immunotherapy for the treatment of auto-immune neuromuscular diseases. Autoimmun. Rev. 17, 873–881 (2018).

    Article  CAS  PubMed  Google Scholar 

  199. Lazaridis, K., Dalianoudis, I., Baltatzidi, V. & Tzartos, S. J. Specific removal of autoantibodies by extracorporeal immunoadsorption ameliorates experimental autoimmune myasthenia gravis. J. Neuroimmunol. 312, 24–30 (2017).

    Article  CAS  PubMed  Google Scholar 

  200. Ulrichts, P. et al. Neonatal Fc receptor antagonist efgartigimod safely and sustainably reduces IgGs in humans. J. Clin. Invest. 128, 4372–4386 (2018). This article describes a class of drugs that may offer a new therapeutic approach in IgG-driven autoimmune disease.

    Article  PubMed  PubMed Central  Google Scholar 

  201. Devanaboyina, S. C., Khare, P., Challa, D. K., Ober, R. J. & Ward, E. S. Engineered clearing agents for the selective depletion of antigen-specific antibodies. Nat. Commun. 8, 15314 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Lonze, B. E. et al. IdeS (Imlifidase): a novel agent that cleaves human IgG and permits successful kidney transplantation across high-strength donor-specific antibody. Ann. Surg. 268, 488–496 (2018).

    Article  PubMed  Google Scholar 

  203. Lipka, A. F. et al. Ephedrine treatment for autoimmune myasthenia gravis. Neuromuscul. Disord. 27, 259–265 (2017).

    Article  PubMed  Google Scholar 

  204. Sanders, D. B. et al. A double-blinded, randomized, placebo-controlled trial to evaluate efficacy, safety, and tolerability of single doses of tirasemtiv in patients with acetylcholine receptor-binding antibody-positive myasthenia gravis. Neurotherapeutics 12, 455–460 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Unwin, N. Nicotinic acetylcholine receptor and the structural basis of neuromuscular transmission: insights from Torpedo postsynapticmembranes. Q. Rev. Biophys. 46, 283–322 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Stiegler, A. L., Burden, S. J. & Hubbard, S. R. Crystal structure of the frizzled-like cysteine-rich domain of the receptor tyrosine kinase MuSK. J. Mol. Biol. 393, 1–9 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Zong, Y. N. et al. Structural basis of agrin-LRP4-MuSK signaling. Genes Dev. 26, 247–258 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Nils Erik Gilhus

  2. Department of Neurology, Haukeland University Hospital, Bergen, Norway

    Nils Erik Gilhus

  3. Department of Neurobiology, Hellenic Pasteur Institute and Tzartos NeuroDiagnostics, Athens, Greece

    Socrates Tzartos

  4. Istituto di Neurologia, Fondazione Policlinico A. Gemelli, IRCCS, Rome, Italy

    Amelia Evoli

  5. Università Cattolica del Sacro Cuore, Rome, Italy

    Amelia Evoli

  6. Nuffield Department of Clinical Neurosciences, University of Oxford, Hospitals Trust, Oxford, UK

    Jacqueline Palace

  7. Department of Neurology, University of Virginia, Charlottesville, VA, USA

    Ted M. Burns

  8. Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands

    Jan J. G. M. Verschuuren

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Contributions

All authors have contributed to and are responsible for all parts of the Review. The first draft was written by N.E.G. (Introduction, Epidemiology and Overview of Primer); S.T. (Mechanisms/pathophysiology); J.P. (Diagnosis, screening and prevention); A.E. (Management); T.M.B. (Quality of life); and J.J.G.M.V. (Outlook).

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Correspondence to Nils Erik Gilhus.

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Competing interests

N.E.G. has received speaker’s honoraria from Octapharma and Alexion and consulting honoraria from Argenx and Ra Pharma. S.T. has shares in the research and diagnostic laboratory Tzartos NeuroDiagnostics. A.E. was a member of the advisory board for Alexion and is a scientific award jury member for Grifols and a safety data monitor for UCB. J.P. has received travel support or honoraria from MerckSerono, Biogen Idec, Novartis, Teva, Chugai Pharma, Bayer Schering, Alexion, Roche, Genzyme, Medimmune, Eurimmune, MedDay, Abide and Argenx and grants from MerckSerono, Novartis, Biogen Idec, Teva, Abide and Bayer Schering. T.M.B. was a member of the steering committee for Argenx. The institution of J.J.G.M.V. (Leiden University Medical Centre) has received fees from Alexion, Argenx and Ra Pharma owing to consultations by J.J.G.M.V. and has received royalties for antibody tests.

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Gilhus, N.E., Tzartos, S., Evoli, A. et al. Myasthenia gravis. Nat Rev Dis Primers 5, 30 (2019). https://doi.org/10.1038/s41572-019-0079-y

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