Advertisement

Myasthenia Gravis and Other Immune-Mediated Disorders of the Neuromuscular Junction

  • Nils Erik GilhusEmail author
Chapter
Part of the Contemporary Clinical Neuroscience book series (CCNE)

Abstract

Myasthenia gravis (MG), Lambert-Eaton myasthenic syndrome (LEMS) and neuromyotonia represent the three autoantibody-mediated disorders at the neuromuscular junction. They give muscle weakness and fatigability as their dominating symptoms. The weakness has usually a preferred localization to some but not all muscles. MG subgroups reflect pathogenesis and direct therapy. Patients should always be classified according to type of antibody, thymus pathology, age at symptom onset and generalized versus pure ocular symptoms. LEMS and neuromyotonia are subgrouped according to paraneoplasia or not. All conditions have well-defined autoantibodies that bind in vivo and directly induce the muscle weakness. Therapy includes symptomatic drugs influencing the acetylcholine receptor activity in the postsynaptic membrane and immunosuppressive treatment influencing the pathogenic autoantibodies. This immunoactive treatment is not yet specific for the disease-inducing antigen-antibody interaction. Treatment is usually effective, and most patients obtain mild symptoms only or a full clinical remission. Comorbidities need to be treated, especially a thymoma in paraneoplastic MG or neuromyotonia and a lung cancer in paraneoplastic LEMS. Supportive therapy is important, and a well-adapted daily training program is recommended. Severe exacerbations (myasthenic crisis) with the need for respiratory support are rare, occur mainly together with infections, and need immediate intensive care.

Keywords

Myasthenia gravis Lambert-Eaton myasthenic syndrome Neuromyotonia Neuromuscular junction Autoimmunity 

References

  1. 1.
    Beeson D. Congenital myasthenic syndromes: recent advances. Curr Opin Neurol. 2016;29:565–71.CrossRefGoogle Scholar
  2. 2.
    Gilhus NE. Myasthenia Gravis. N Engl J Med. 2016;375:2570–81.CrossRefGoogle Scholar
  3. 3.
    Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis – autoantibody characteristics and their implications for therapy. Nat Rev Neurol. 2016;12:259–U291.CrossRefGoogle Scholar
  4. 4.
    Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol. 2015;14:1023–36.CrossRefGoogle Scholar
  5. 5.
    Titulaer MJ, Lang B, Verschuuren J. Lambert-Eaton myasthenic syndrome: from clinical characteristics to therapeutic strategies. Lancet Neurol. 2011;10:1098–107.CrossRefGoogle Scholar
  6. 6.
    Lang B, Makuch M, Moloney T, et al. Intracellular and non-neuronal targets of voltage-gated potassium channel complex antibodies. J Neurol Neurosurg Psychiatry. 2017;88:353–61.CrossRefGoogle Scholar
  7. 7.
    Hong Y, Zisimopoulou P, Trakas N, et al. Multiple antibody detection in ’seronegative’ myasthenia gravis patients. Eur J Neurol. 2017;24:844–50.CrossRefGoogle Scholar
  8. 8.
    Kerty E, Elsais A, Argov Z, Evoli A, Gilhus NE. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur J Neurol. 2014;21:687–93.CrossRefGoogle Scholar
  9. 9.
    Heldal AT, Owe JF, Gilhus NE, Romi F. SEROPOSITIVE MYASTHENIA GRAVIS: A NATIONWIDE EPIDEMIOLOGIC STUDY. Neurology. 2009;73:150–1.CrossRefGoogle Scholar
  10. 10.
    Carr AS, Cardwell CR, McCarron PO, McConville J. A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol. 2010;10:46.CrossRefGoogle Scholar
  11. 11.
    Hong Y, Skeie GO, Zisimopoulou P, et al. Juvenile-onset myasthenia gravis: autoantibody status, clinical characteristics and genetic polymorphisms. J Neurol. 2017;264:955–62.CrossRefGoogle Scholar
  12. 12.
    Pedersen EG, Hallas J, Hansen K, Jensen PEH, Gaist D. Late-onset myasthenia not on the increase: a nationwide register study in Denmark, 1996-2009. Eur J Neurol. 2013;20:309–14.CrossRefGoogle Scholar
  13. 13.
    Guptill JT, Sanders DB, Evoli A. ANTI-MuSK Antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve. 2011;44:36–40.CrossRefGoogle Scholar
  14. 14.
    Hong Y, Li HF, Skeie GO, et al. Autoantibody profile and clinical characteristics in a cohort of Chinese adult myasthenia gravis patients. J Neuroimmunol. 2016;298:51–7.CrossRefGoogle Scholar
  15. 15.
    Boldingh MI, Maniaol A, Brunborg C, et al. Prevalence and clinical aspects of immigrants with myasthenia gravis in northern europe. Muscle Nerve. 2017;55:819–27.CrossRefGoogle Scholar
  16. 16.
    Romi F, Hong Y, Gilhus NE. Pathophysiology and immunological profile of myasthenia gravis and its subgroups. Curr Opin Immunol. 2017;49:9–13.CrossRefGoogle Scholar
  17. 17.
    Wirtz PW, Nijnuis MG, Sotodeh M, et al. The epidemiology of myasthenia gravis, Lambert-Eaton myasthenic syndrome and their associated tumours in the northern part of the province of South Holland. J Neurol. 2003;250:698–701.CrossRefGoogle Scholar
  18. 18.
    Titulaer MJ, Wirtz PW, Kuks JBM, et al. The Lambert-Eaton myasthenic syndrome 1988-2008: A clinical picture in 97 patients. J Neuroimmunol. 2008;201:153–8.CrossRefGoogle Scholar
  19. 19.
    Titulaer MJ, Maddison P, Sont JK, et al. Clinical Dutch-English Lambert-Eaton Myasthenic Syndrome (LEMS) Tumor Association Prediction Score Accurately Predicts Small-Cell Lung Cancer in the LEMS. J Clin Oncol. 2011;29:902–8.CrossRefGoogle Scholar
  20. 20.
    Vinge L, Andersen H. Muscle strength and fatigue in newly diagnosed patients with myasthenia gravis. Muscle Nerve. 2016;54:709–14.CrossRefGoogle Scholar
  21. 21.
    Andersen JB, Gilhus NE, Sanders DB. Factors affecting outcome in myasthenia gravis. Muscle Nerve. 2016;54:1041–9.CrossRefGoogle Scholar
  22. 22.
    Popperud TH, Boldingh MI, 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. 2017;21:707–14.CrossRefGoogle Scholar
  23. 23.
    Antoine JC, Camdessanche JP. Paraneoplastic neuropathies. Curr Opin Neurol. 2017;30:513–20.CrossRefGoogle Scholar
  24. 24.
    Zisimopoulou P, Evangelakou P, Tzartos J, et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun. 2014;52:139–45.CrossRefGoogle Scholar
  25. 25.
    Tsonis AI, Zisimopoulou P, Lazaridis K, et al. MuSK autoantibodies in myasthenia gravis detected by cell based assay - A multinational study. J Neuroimmunol. 2015;284:10–7.CrossRefGoogle Scholar
  26. 26.
    Keogh M, Sedehizadeh S, Maddison P. Treatment for Lambert-Eaton myasthenic syndrome. Cochrane Database of Syst Rev. 2011.Google Scholar
  27. 27.
    Kucukali CI, Kurtuncu M, Akcay HI, Tuzun E, Oge AE. Peripheral nerve hyperexcitability syndromes. Rev Neurosci. 2015;26:239–51.CrossRefGoogle Scholar
  28. 28.
    Maddison P. Neuromyotonia. Clin Neurophysiol. 2006;117:2118–27.CrossRefGoogle Scholar
  29. 29.
    Binks S, Vincent A, Palace J. Myasthenia gravis: a clinical-immunological update. J Neurol. 2016;263:826–34.CrossRefGoogle Scholar
  30. 30.
    Koneczny I, Stevens JAA, De Rosa A, et al. IgG4 autoantibodies against muscle-specific kinase undergo Fab-arm exchange in myasthenia gravis patients. J Autoimmun. 2017;77:104–15.CrossRefGoogle Scholar
  31. 31.
    Zhang B, Tzartos JS, Belimezi M, et al. Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol. 2012;69:445–51.CrossRefGoogle Scholar
  32. 32.
    Romi F, Skeie GO, Gilhus NE, Aarli JA. Striational antibodies in myasthenia gravis - Reactivity and possible clinical significance. Arch Neurol. 2005;62:442–6.CrossRefGoogle Scholar
  33. 33.
    Skeie GO, Mygland A, Treves S, Gilhus NE, Aarli JA, Zorzato F. Ryanodine receptor antibodies in myasthenia gravis: Epitope mapping and effect on calcium release in vitro. Muscle Nerve. 2003;27:81–9.CrossRefGoogle Scholar
  34. 34.
    Gasperi C, Melms A, Schoser B, et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology. 2014;82:1976–83.CrossRefGoogle Scholar
  35. 35.
    Suzuki S, Baba A, Kaida K, et al. Cardiac involvements in myasthenia gravis associated with anti-Kv1.4 antibodies. Eur J Neurol. 2014;21:223–30.CrossRefGoogle Scholar
  36. 36.
    Romi F, Suzuki S, Suzuki N, Petzold A, Plant GT, Gilhus NE. Anti-voltage-gated potassium channel Kv1.4 antibodies in myasthenia gravis. J Neurol. 2012;259:1312–6.CrossRefGoogle Scholar
  37. 37.
    Gilhus NE, Willcox N, Harcourt G, et al. Antigen presentation by thymoma epithelial-cells from myasthenia-gravis patients to potentially pathogenic t-cells. J Neuroimmunol. 1995;56:65–76.CrossRefGoogle Scholar
  38. 38.
    Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Strobel P. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev. 2013;12:875–84.CrossRefGoogle Scholar
  39. 39.
    Myking AO, Skeie GO, Varhaug JE, Andersen KS, Gilhus NE, Aarli JA. The histomorphology of the thymus in late onset, non-thymoma myasthenia gravis. Eur J Neurol. 1998;5:401–5.CrossRefGoogle Scholar
  40. 40.
    Cavalcante P, Serafini B, Rosicarelli B, et al. Epstein-Barr Virus persistence and reactivation in myasthenia gravis thymus. Ann Neurol. 2010;67:726–38.PubMedGoogle Scholar
  41. 41.
    Gilhus NE. Myasthenia and the neuromuscular junction. Curr Opin Neurol. 2012;25:523–9.CrossRefGoogle Scholar
  42. 42.
    Avidan N, Le Panse R, Berrih-Aknin S, Miller A. Genetic basis of myasthenia gravis - A comprehensive review. J Autoimmun. 2014;52:146–53.CrossRefGoogle Scholar
  43. 43.
    Pirskanen R. Genetic aspects in myasthenia-gravis - family study of 264 finnish patients. Acta Neurol Scand. 1977;56:365–88.CrossRefGoogle Scholar
  44. 44.
    Salvado M, Canela M, Maria J, et al. Study of the prevalence of familial autoimmune myasthenia gravis in a Spanish cohort. J Neurol Sci. 2016;360:110–4.CrossRefGoogle Scholar
  45. 45.
    Lisak RP, Barcellos L. New Insights Into the Genetics of Autoimmune Myasthenia Gravis An Evolving Story. JAMA Neurol. 2015;72:386–7.CrossRefGoogle Scholar
  46. 46.
    Renton AE, Pliner HA, Provenzano C, et al. A Genome-Wide Association Study of Myasthenia Gravis. JAMA Neurol. 2015;72:396–404.CrossRefGoogle Scholar
  47. 47.
    Bach JF. The etiology of autoimmune diseases: the case of myasthenia gravis. In: Wolfe GI, Meriggioli MN, Ciafaloni E, Ruff RL, editors. Myasthenia Gravis and Related Disorders I. Boston: Wiley Periodicals; 2012. p. 33–9.Google Scholar
  48. 48.
    Verschuuren J, Strijbos E, Vincent A. Neuromuscular junction disorders. Handbook of clinical neurology. Amsterdam: Elsevier; 2016;133:447–466..Google Scholar
  49. 49.
    Takamori M. Lambert-Eaton myasthenic syndrome: Search for alternative autoimmune targets and possible compensatory mechanisms based on presynaptic calcium homeostasis. J Neuroimmunol. 2008;201:145–52.CrossRefGoogle Scholar
  50. 50.
    Titulaer MJ, Verschuuren J. Lambert-Eaton myasthenic syndrome - Tumor versus nontumor forms. In: Kaminski HJ, Barohn RJ, editors. Myasthenia gravis and related disorders: 11th international conference; 2008. p. 129–34.Google Scholar
  51. 51.
    Fleisher J, Richie M, Price R, Scherer S, Dalmau J, Lancaster E. Acquired neuromyotonia heralding recurrent thymoma in myasthenia gravis. JAMA Neurol. 2013;70:1311–4.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Song J, Jing SS, Quan C, et al. Isaacs syndrome with CASPR2 antibody: A series of three cases. J Clin Neurosci. 2017;41:63–6.CrossRefGoogle Scholar
  53. 53.
    Irani SR, Pettingill P, Kleopa KA, et al. Morvan syndrome: clinical and serological observations in 29 cases. Ann Neurol. 2012;72:241–55.CrossRefGoogle Scholar
  54. 54.
    Heldal AT, Eide GE, Romi F, Owe JF, Gilhus NE. Repeated acetylcholine receptor antibody-concentrations and association to clinical myasthenia gravis development. PLoS One. 2014;9:e114060.CrossRefGoogle Scholar
  55. 55.
    Stergiou C, Lazaridis K, Zouvelou V, et al. Titin antibodies in "seronegative" myasthenia gravis - A new role for an old antigen. J Neuroimmunol. 2016;292:108–15.CrossRefGoogle Scholar
  56. 56.
    Priola AM, Priola SM, Giraudo MT, et al. Chemical-shift and diffusion-weighted magnetic resonance imaging of thymus in myasthenia gravis usefulness of quantitative assessment. Investig Radiol. 2015;50:228–38.CrossRefGoogle Scholar
  57. 57.
    Priola AM, Priola SM, Gned D, Giraudo MT, Fornari A, Veltri A. 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. 2016;71:E157–69.CrossRefGoogle Scholar
  58. 58.
    Gilhus NE, Nacu A, Andersen JB, Owe JF. Myasthenia gravis and risks for comorbidity. Eur J Neurol. 2015;22:17–23.CrossRefGoogle Scholar
  59. 59.
    Nacu A, Andersen JB, Lisnic V, Owe JF, Gilhus NE. Complicating autoimmune diseases in myasthenia gravis: a review. Autoimmunity. 2015;48:362–8.CrossRefGoogle Scholar
  60. 60.
    Sanders DB, Wolfe GI, Benatar M, et al. International consensus guidance for management of myasthenia gravis: Executive summary. Neurology. 2016;87:419–25.CrossRefGoogle Scholar
  61. 61.
    Skeie GO, Apostolski S, Evoli A, et al. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol. 2010;17:893–902.CrossRefGoogle Scholar
  62. 62.
    Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol. 2015;262:1115–9.CrossRefGoogle Scholar
  63. 63.
    Randall KL. Rituximab in autoimmune diseases. Aust Prescr. 2016;39:131–4.CrossRefGoogle Scholar
  64. 64.
    Sanders DB, McDermott M, Thornton C, et al. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology. 2008;71:394–9.CrossRefGoogle Scholar
  65. 65.
    Sanders DB, Hart IK, Mantegazza R, et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology. 2008;71:400–6.CrossRefGoogle Scholar
  66. 66.
    Evoli A, Alboini PE, Damato V, et al. Myasthenia gravis with antibodies to MuSK: an update. Ann N Y Acad Sci. 2018;1412:82–9.CrossRefGoogle Scholar
  67. 67.
    Wolfe GIKH, Aban IB, Minisman G, et al. Randomized trial of thymectomy in myasthenia gravis. N Engl J Med. 2016;375:511–22.CrossRefGoogle Scholar
  68. 68.
    Howard JF, Barohn RJ, Cutter GR, et al. A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve. 2013;48:76–84.CrossRefGoogle Scholar
  69. 69.
    Gilhus NE. Eculizumab: a treatment option for mysthenia gravis? Lancet Neurol. 2017;16:947–8.CrossRefGoogle Scholar
  70. 70.
    Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database of Systematic Reviews. 2012.Google Scholar
  71. 71.
    Beecher G, Anderson D, Siddiqi ZA. Subcutaneous immunoglobulin in myasthenia gravis exacerbation A prospective, open-label trial. Neurology. 2017;89:1135–41.CrossRefGoogle Scholar
  72. 72.
    Kiessling P, Lledo-Garcia R, Watanabe S, et al. The FcRn inhibitor rozanolixizumab reduces human serum IgG concentration: A randomized phase 1 study. Sci Transl Med. 2017;9:eaan1208.CrossRefGoogle Scholar
  73. 73.
    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;56:700–9.CrossRefGoogle Scholar
  74. 74.
    Andersen JB, Owe JF, Engeland A, Gilhus NE. Total drug treatment and comorbidity in myasthenia gravis: a population-based cohort study. Eur J Neurol. 2014;21:948–55.CrossRefGoogle Scholar
  75. 75.
    Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis in pregnancy and birth: identifying risk factors, optimising care. Eur J Neurol. 2007;14:38–43.CrossRefGoogle Scholar
  76. 76.
    Norwood F, Dhanjal M, Hill M, et al. Myasthenia in pregnancy: best practice guidelines from a UK multispecialty working group. J Neurol Neurosurg Psychiatry. 2014;85:538–43.CrossRefGoogle Scholar
  77. 77.
    Hoff JM, Daltveit AK, Gilhus NE. Myasthenia gravis - Consequences for pregnancy, delivery, and the newborn. Neurology. 2003;61:1362–6.CrossRefGoogle Scholar
  78. 78.
    Hacohen Y, Jacobson LW, Byrne S, et al. Fetal acetylcholine receptor inactivation syndrome A myopathy due to maternal antibodies. Neurol Neuroimmunol Neuroinflammation. 2015;2:e57.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Clinical MedicineUniversity of BergenBergenNorway
  2. 2.Department of NeurologyHaukeland University HospitalBergenNorway

Personalised recommendations