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Disorders of Neuromuscular Transmission

  • Nages Nagaratnam
  • Kujan Nagaratnam
  • Gary Cheuk
Reference work entry

Abstract

Myasthenia gravis (MG) is an autoimmune disorder characterized by fluctuating muscle weakness and fatigue caused by antibodies directed against the nicotine acetylcholine (ACh) receptor (AChR) or against the muscle-specific tyrosine kinase (MuSK) receptor. The prevalence has increased over the past four to five decades, and the increase is mainly found in patients over the age of 50 years. Clinically and epidemiologically, it is possible to recognize two subtypes, the early-onset myasthenia gravis (EOMG) and the late-onset myasthenia gravis (LOMG). In MG, antibodies to the AChR cause a functional blockade of the binding site for ACh. Some MG patients do not have detectable AChR antibodies and are termed seronegative MG. In 2–3% of AChR-seronegative patients, there was seropositivity of anti-MuSK antibody. It had been reported that anti-AChR antibodies were seen in 65% with early-onset MG compared to 85% in the late-onset MG and elevated titers of anti-MuSK antibodies were similar. Ocular MG is more common in LOMG compared to EOMG so is myopathy. About 30% of late-onset MG patients without thymoma have antibodies to titin, whereas titin antibodies are uncommon in the early-onset MG. Significant therapeutic progress has been made in the treatment of MG and introduction of new modalities especially immunosuppressive, immunomodulating drugs, plasma exchange, and thymectomy. In Eaton-Lambert syndrome (E-LS), there is a reduction in the release of acetylcholine from the motor nerve terminals. There are substantial differences between E-LS and MG in the pathophysiology, clinical features, electromyographic changes, and treatment. More than half the patients with E-LS are associated with malignancies such as small cell lung cancer (SCLC) non-small cell lung cancer, and lymphoma, among others. The antibodies in E-LS prevent the opening of the calcium channels, and hence the release of ACh and voltage-gated calcium channels (VGCC) antibodies has been reported in 75–100% of patients with L-ES. Guanidine increases the release of ACh.

Keywords

Myasthenia gravis Late-onset myasthenia gravis Early-onset myasthenia gravis Muscle- specific tyrosine kinase (MuSK) receptor Eaton-Lambert syndrome 

References

  1. 1.
    Montero-Odasso M. Dysphonia as first symptom of late onset myasthenia gravis. J Gen Intern Med. 2006;21:C4–C6.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Aarli JA. Late-onset myasthenia gravis: changing scene Arch Neurol. 1999;56:25–27.CrossRefPubMedGoogle Scholar
  3. 3.
    Vincent A, Clover L, Buckley C, Evans JG, Rothwell PM. Evidence of underdiagnosis of myasthenia gravis in older people. J Neurol Neurosurg Psychiatry. 2003;74(8):1105–1108.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Aarli JA. Myasthenia gravis in the elderly: Is it different. Ann NY Acad Sci. 2008;1132:238–243.CrossRefPubMedGoogle Scholar
  5. 5.
    Aragones JM, Bolibar I, Bonfill X, Bufill E, Mummany A Alousef et al., Myasthenia, gravis: a higher than expected incidence in the elderly. Neurology. 2003;60(6):1024–1026.CrossRefPubMedGoogle Scholar
  6. 6.
    Simpson JF, Westerberg MR, Magee KR. Myasthenia gravis : an analysis of 295 cases. Acta Neurol Scand. 1996;42(suppl 23):1–27.Google Scholar
  7. 7.
    Zivkovic SA, Clemens PR, Lacomis D. Characteristics of late-onset myasthenia gravis. J Neurol. 2012;259(10):2167–71.CrossRefPubMedGoogle Scholar
  8. 8.
    Pourmand R. Myasthenia gravis. Dis Mon. 1997;43:65–109.CrossRefPubMedGoogle Scholar
  9. 9.
    Somnier F, Trojaburg W. Neurophysiological evaluation in myasthenia gravis: a comprehensive study of a complete patient population. Electroencephhalogr Clin Neurophysiol. 1993;89:73–87.CrossRefGoogle Scholar
  10. 10.
    Chaudhuri A. Myasthenic crises. QJM 2014;102(2):97–107.CrossRefGoogle Scholar
  11. 11.
    Koneczay I, Cossins J, Vincent A. The role of muscle specific tyrosine kinase (MuSK) and mystery of MuSK myasthenia gravis. J Anatomy. 2014;224:21–35.Google Scholar
  12. 12.
    Lee JY, Sung JJ, Cho JY, Oh DH, Kim HJ, Park JH, et al. MuSK antibody positive, seronegative Myasthenia gravis in Korea J Clin Neurosci. 2006;13:353–355.CrossRefPubMedGoogle Scholar
  13. 13.
    Evoli A, Blanchi MR, Riso R, Minicuci GM, Batocchi AP, Servidel S, et al. response to therapy in myasthenia gravis with antiMuSK antibodies. Ann NY Acad Sci. 2008;1132:76–83.CrossRefPubMedGoogle Scholar
  14. 14.
    Chang T, Gunaratne P, Gamage R, Riffsy MTM, Vincent V. MuSK antoibody positive myasthenia gravis in South Asian population. J Neurol Sci. 2009;33:35.Google Scholar
  15. 15.
    Suzuki S, Utsugisawa K, Nagane Y, Satoh T, Kuwna M, Suzuki N, et al. Clinical and immunological differences between early and late-onset myasthenia gravis in Japan. Neuroimmunol. 2011;230(1–2):148–52.CrossRefGoogle Scholar
  16. 16.
    Romi F. Thymoma in myasthenia gravis: from diagnosis to treatment. Autoimmune Dis 2011;2011:474–512.  https://doi.org/10.4061/2011/474512. Epub2011 Aug 10.Google Scholar
  17. 17.
    Gunji K, Skolnick C, Bednarczuk T, Benes S, Ackrell BHC, Cochran P, et al. Eye muscle antibodies in patients with ocular myasthenia gravis: possible mechanism for eye muscle inflammation in acetylcholine receptor antibody-negative patients. Clin Immunol Immunopathol. 1998;87(3):276–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Wang W, Hen YP, Wei DN. The clinical characteristics of early-oset versus late-onset types of myasthenia gravis. Zhonghua Nei Ke Za Zhi. 2011;50(6):496–8.PubMedGoogle Scholar
  19. 19.
    Somnier FE. Myasthenia gravis. Dan Med Bull. 1996;43(1):1–10.PubMedGoogle Scholar
  20. 20.
    Schon F, Drayson M,Thompson RA. Myasthenia gravis in elderly people. Age Ageing. 1996;25:56–58.CrossRefPubMedGoogle Scholar
  21. 21.
    Maniaol AH, Elsais A, Lorentzen AR, Owe JK, Viken MH, Seether H, et al. Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLOS ONE 2012 May 09.  https://doi.org/10.1371/journal pone.0036603.
  22. 22.
    Aarli JA. Late-onset myasthenia gravis. Eur J Neurol. 1997;4:203–209.CrossRefGoogle Scholar
  23. 23.
    Barbaud A, Carlander B, Pages M. Late onset forms of myasthenia gravis. Comparison with early-onset myasthenia gravis. Rev Neurol (Paris). 2006;162(10):990–6.CrossRefPubMedGoogle Scholar
  24. 24.
    Meriggioli MN, Sanders DB. Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol. 2009;8(5):475=490.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Howard JJ, Jr Clinical overview of myasthenia gravis. http://www.myasthenia.org/healthprofessionals/clinicaloverviewofmg-aspx retrieved on 1 July 2014.
  26. 26.
    Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. 2004;29:484–505.CrossRefPubMedGoogle Scholar
  27. 27.
    Chaudhry V, Cornblath DR, Griffin KW, O’Brien R, Drachman DB. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular disorders. Neurology. 2001;56:94–96.CrossRefPubMedGoogle Scholar
  28. 28.
    Donaldson DH, Ansker M, Horan S, Rutherford RP, Ringle SP. The relationship of age to outcome of myasthenia gravis. Neurology. 1990; 40:786–790.CrossRefPubMedGoogle Scholar
  29. 29.
    Antonini G, Morino S, Gragnani F, Fiorelli M. Myasthenia gravis in the elderly. Acta Neurol Sci. 1996; 93:260–263.Google Scholar
  30. 30.
    Kuks JBM, Linsburg PG, Horst G, Oosterhuis HJGH. Antibodies to skeletal muscle in MG part 2. Prevalence in non-thymoma patients. J Neuro Sci. 1993;120:78.CrossRefGoogle Scholar
  31. 31.
    Szczudlik P, Szyluk B, Lipowska M, Ryniewicz B, Kubiszewska J, Dutkiewicz M, et al. Antititin antibody in early –and late-onset myasthenia gravis. Acta Neurol Scand. 2014;130(4):229–33.CrossRefPubMedGoogle Scholar
  32. 32.
    Diagnosis-How is myasthenis gravis confirmed? www.myasthenia.org.au/background/diagnosis/ accessed 25 Aug 2016.
  33. 33.
    Mantegazza R, Bonanno S, Camera G, Antozzi A. Current and emerging therapies for the treatment of myasthenia gravis. Neuropsychiatr Dis Treat. 2011;7:151–160.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Kawaguchi N. Immunosuppressive/immunomodulating therapies in myasthenia gravis-at present and in the near future. Brain Nerve. 2–11;63(7):737–43.Google Scholar
  35. 35.
    Sanders DB, Evoli, Immunosuppressive therapies in myasthenia gravis. Autoimmunity. 2010;43(5–6)428–35.CrossRefPubMedGoogle Scholar
  36. 36.
    Newsom-Davis J. Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome. Semin Neurol. 2003;23(2):191–8.CrossRefPubMedGoogle Scholar
  37. 37.
    Kaminski HJ. Treatment of myasthenia gravis. In: Kaminski HHJ, editor. Myasthenia and related disorders. Totowa: Humana Press; 2003 p 197–221.Google Scholar
  38. 38.
    Ciafaloni E, Nikhar NK, Massey JM, Sanders DM. Retrospective analysis of the use of cyclosporine in myasthenia gravis. Neurology. 2000;448–450.Google Scholar
  39. 39.
    Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand. Suppl 2006;183:19–23.CrossRefPubMedGoogle Scholar
  40. 40.
    Shah AK. Excerpt from myasthenia gravis. e medicine –Myasthenia gravis http://www.emediine.com/neuro/byname/myasthenia-gravis.htm.
  41. 41.
    Suzuki S. Lambert-Eaton myasthenia syndrome (LEMS). Brain Nerve. 2010;62(4):419–26.PubMedGoogle Scholar
  42. 42.
    Bekircan-Kurt CE, DerleCiftci E, Kurne AT, Anlar B. Voltage gated calcium antibody-related neurological diseases. World J Clin Cases. 2015;3(3):293–300.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Motomura M, Fukuda T. Lambert-Eaton myasthenic syndrome. Brain Nerve. 2011;63(7):745–54.PubMedGoogle Scholar
  44. 44.
    Sakai W, Nakane S, Matsuo H. Autoantibody against the presynaptic P/Q- type voltage-gated calcium channel in Lambert-Eaton myasthenic syndrome. Brain Nerve. 2013;65(4):441–8.PubMedGoogle Scholar
  45. 45.
    Writz PN, Nijnuis MG, Sotodeh M, Willems LN, Brahim JJ, Putter H, et al. The epidemiology of myasthenia gravis. Lambert-Eaton myasthenia gravis and their associated tumours in the northern part of the province of South Holland. J Neurol. 2003;250(6):698–7.CrossRefGoogle Scholar
  46. 46.
    Newsom-Davis J. Therapy in myasthenia gravis and Lambert-Eaton myasthenic syndrome. Semin Neurol. 2003;2(2):191–8.Google Scholar
  47. 47.
    Lorenzoni PJ, Scola RH, Kay CSK. Non-neoplastic Lambert-Eaton myasthenia gravis. Arq Neuropsyquiatr. 2010;68(6):849–854.CrossRefGoogle Scholar
  48. 48.
    Titulaer MJ, Wirtz PW, Kuks JB, Schelhs HJ, van der Kooi AJ, Faber EG, et al. The Lambert-Eaton myasthenia gravis 1988–2008: a clinical picture of 97 patients. J Neurol immunol. 2008;201–202:153–58.Google Scholar
  49. 49.
    Gilhus NE, Lambert-Eaton myasthenia gravis. Pathophysiology diagnosis and therapy. Autoimmun Dis. vol 2011.  https://doi.org/10.4061/2011/973808.
  50. 50.
    Strikler DE, Sanders DB. Lambert-Eaton Myasthenic Syndrome. e-medicine Updated Jan 10, 2007.Google Scholar
  51. 51.
    Sanders DB. Lambert-Eaton Myasthenic syndrome. Clinical diagnosis, immune –mediated mechanisms and update therapies. Ann Neurol. 1995;37(S1):S63.CrossRefPubMedGoogle Scholar
  52. 52.
    Keogh M, Sedehizadehs S, Maddison P. Treatment for lambert-Eaton myasthenia gravis. Cochrane summaries  https://doi.org/10.1002/14651858:CD003279pub3.
  53. 53.
    Sanders DB, Kim YI, Howard JF, Jr, Goetsch A. Eaton-Lambert syndrome: clinical and electrophysiological study of a patient with 4-aminopyridine. J Neurol Neurosurg Psychiatry. 1980;43:978–985.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Trouth JA, Dabi A, Solieman N, Kurukumbi M, Klyanam J. Myasthenia gravis: a review. Autoimmune Dis 2012;2012:874680.  https://doi.org/10.1155/2012/874680. Epub2012 Oct 31.
  55. 55.
    Paul RH, Cohen RA, Goldstein JM, Gilchrist JM. Fatigue and its impact on patients with myasthenia gravis. Muscle Nerve. 23(9):1402–6.Google Scholar
  56. 56.
    Aarli JA. Late-onset myasthenia gravis. Neurol Rev. 1999;56(2):25–27.Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  • Nages Nagaratnam
    • 1
  • Kujan Nagaratnam
    • 1
  • Gary Cheuk
    • 2
  1. 1.The University of SydneyWestmead Clinical SchoolWestmeadAustralia
  2. 2.Rehabilitation and Aged Care ServiceBlacktown-Mt Druitt HospitalMount DruittAustralia

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