Download PDF
Nervenheilkunde 2007; 26(07): 587-595
DOI: 10.1055/s-0038-1626902
Original Article
Schattauer GmbH

Myasthenia gravis

Aktuelle Aspekte der Pathogenese, Diagnostik und TherapieMyasthenia graviscurrent aspects of pathogenesis, diagnosis, and therapy
J. Dörr
1   Cecilie-Vogt-Klinik für Molekulare Neurologie, Charité Universitätsmedizin Berlin Neurologische Klinik, HELIOS Klinikum Berlin Buch
,
F. Zipp
1   Cecilie-Vogt-Klinik für Molekulare Neurologie, Charité Universitätsmedizin Berlin Neurologische Klinik, HELIOS Klinikum Berlin Buch
› Author Affiliations
Further Information

Publication History

Eingegangen am: 17 March 2007

angenommen am: 17 March 2007

Publication Date:
20 January 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Die erworbene Myasthenia gravis ist eine seltene autoimmunologische Erkrankung der neuromuskulären Signaltransduktion, die durch Autoantikörper gegen den nikotinischen Azetylcholinrezeptor an der muskulären Endplatte und in seltenen Fällen durch Antikörper gegen die muskelspezifische Rezeptor-Tyrosinkinase (MuSK) hervorgerufen wird. Diese Übersicht fasst den aktuellen Wissensstand zur Pathogenese, Diagnostik und Therapie der Myasthenia gravis zusammen.

Summary

Acquired myasthenia gravis is a rare autoimmune disease of the neuromuscular transmission, resulting from autoantibodies against the nicotinic acetylcholine receptor at the neuromuscular junction or, less frequently, against a muscle-specific receptor tyrosine kinase (MuSK). This review summarizes the current knowledge with respect to pathogenesis, diagnosis, and therapy of myasthenia gravis.

Schlüsselwörter

Myasthenia gravis - Autoantikörper - Azetylcholinrezeptor - Synapse

Keywords

Myasthenia gravis - autoantibodies - acetylcholine receptor - synapse
 

  • Literatur

  • 1 Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis. Muscle Nerve 2000; 23: 551-555.
    CrossrefPubMedSearch in Google Scholar
  • 2 Ahlberg R, Yi Q, Pirskanen R, Matell G, Swerup C, Rieber EP, Riethmuller G, Holm G, Lefvert AK. Treatment of myasthenia gravis with anti-CD4 antibody: improvement correlates to decreased T-cell autoreactivity. Neurology 1994; 44: 1732-1737.
    CrossrefPubMedSearch in Google Scholar
  • 3 Andrews PI, Massey JM, Howard Jr JF, Sanders DB. Race, sex, and puberty influence onset, severity, and outcome in juvenile myasthenia gravis. Neurology 1994; 44: 1208-1214.
    CrossrefPubMedSearch in Google Scholar
  • 4 Aruna BV, Ben David H, Sela M, Mozes E. A dual altered peptide ligand down-regulates myasthenogenicT cell responses and reverses experimental autoimmune myasthenia gravis via up-regulation of Fas-FasL-mediated apoptosis. Immunology 2006; 118: 413-424.
    CrossrefPubMedSearch in Google Scholar
  • 5 Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S. Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 2005; 105: 735-741.
    CrossrefPubMedSearch in Google Scholar
  • 6 Cahoon Jr WD, Kockler DR. Mycophenolate mofetil treatment of myasthenia gravis. Ann Pharmacother 2006; 40: 295-298.
    CrossrefPubMedSearch in Google Scholar
  • 7 Carlsson B, Wallin J, Pirskanen R, Matell G, Smith CI. Different HLA DR-DQ associations in subgroups of idiopathic myasthenia gravis. Immunogenetics 1990; 31: 285-290.
    CrossrefPubMedSearch in Google Scholar
  • 8 Cohen-Kaminsky S, Jambou F. Prospects for a T-cell receptor vaccination against myasthenia gravis. Expert Rev Vaccines 2005; 04: 473-492.
    CrossrefPubMedSearch in Google Scholar
  • 9 Compston DA, Vincent A, Newsom-Davis J, Batchelor JR. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 1980; 103: 579-601.
    CrossrefPubMedSearch in Google Scholar
  • 10 Dayan M, Sthoeger Z, Neiman A, Abarbanel J, Sela M, Mozes E. Immunomodulation by a dual altered peptide ligand of autoreactive responses to the acetylcholine receptor of peripheral blood lymphocytes of patients with myasthenia gravis. Hum Immunol 2004; 65: 571-577.
    CrossrefPubMedSearch in Google Scholar
  • 11 DeChiara TM, Bowen DC, Valenzuela DM, Simmons MV, Poueymirou WT, Thomas S, Kinetz E, Compton DL, Rojas E, Park JS, Smith C, DiStefano PS, Glass DJ, Burden SJ, Yancopoulos GD. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 1996; 85: 501-512.
    CrossrefPubMedSearch in Google Scholar
  • 12 Deitiker P, Ashizawa T, Atassi MZ. Antigen mimicry in autoimmune disease. Can immune responses to microbial antigens that mimic acetylcholine receptor act as initial triggers of Myasthenia gravis? Hum Immunol 2000; 61: 255-265.
    PubMedSearch in Google Scholar
  • 13 Drachman DB. Myasthenia gravis. N Engl J Med 1994; 330: 1797-1810.
    CrossrefPubMedSearch in Google Scholar
  • 14 Engel AG, Lambert EH, Howard FM. Immune complexes (IgG and C3) at the motor end-plate in myasthenia gravis: ultrastructural and light microscopic localization and electrophysiologic correlations. Mayo Clin Proc 1977; 52: 267-280.
    PubMedSearch in Google Scholar
  • 15 Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group. Ann Neurol 1997; 41: 789-796.
    CrossrefPubMedSearch in Google Scholar
  • 16 Gajdos P, Outin H, Elkharrat D, Brunel D, RohanChabot P, Raphael JC, Goulon M, Goulon-Goeau C, Morel E. High-dose intravenous gammaglobulin for myasthenia gravis. Lancet 1984; 01: 406-407.
    Search in Google Scholar
  • 17 Glass DJ, Bowen DC, Stitt TN, Radziejewski C, Bruno J, Ryan TE, Gies DR, Shah S, Mattsson K, Burden SJ, DiStefano PS, Valenzuela DM, DeChiara TM, Yancopoulos GD. Agrin acts via a MuSK receptor complex. Cell 1996; 85: 513-523.
    CrossrefPubMedSearch in Google Scholar
  • 18 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. Neurology 2000; 55: 7-15.
    CrossrefPubMedSearch in Google Scholar
  • 19 Guo CY, Li ZY, Xu MQ, Yuan JM. Preparation of an immunoadsorbent coupled with a recombinant antigen to remove anti-acetylcholine receptor antibodies in abnormal serum. J Immunol Methods 2005; 303: 142-147.
    CrossrefPubMedSearch in Google Scholar
  • 20 Herrlinger U, Weller M, Dichgans J, Melms A. Association of primary central nervous system lymphoma with long-term azathioprine therapy for myasthenia gravis?. Ann Neurol 2000; 47: 682-683.
    PubMedSearch in Google Scholar
  • 21 Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A. Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 2001; 07: 365-368.
    CrossrefPubMedSearch in Google Scholar
  • 22 Hohlfeld R, Engel AG. Induction of HLA-DR expression on human myoblasts with interferongamma. Am J Pathol 1990; 136: 503-508.
    PubMedSearch in Google Scholar
  • 23 Lauriola L, Ranelletti F, Maggiano N, Guerriero M, Punzi C, Marsili F, Bartoccioni E, Evoli A. Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 2005; 64: 536-538.
    CrossrefPubMedSearch in Google Scholar
  • 24 Leker RR, Karni A, Abramsky O. Exacerbation of myasthenia gravis during the menstrual period. J Neurol Sci 1998; 156: 107-111.
    CrossrefPubMedSearch in Google Scholar
  • 25 Liblau R, Gajdos P, Bustarret FA, el Habib R, Bach JF, Morel E. Intravenous gamma-globulin in myasthenia gravis: interaction with anti-acetylcholine receptor autoantibodies. J Clin Immunol 1991; 11: 128-131.
    CrossrefPubMedSearch in Google Scholar
  • 26 Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology 1976; 26: 1054-1059.
    CrossrefPubMedSearch in Google Scholar
  • 27 McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A. Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 2004; 55: 580-584.
    CrossrefPubMedSearch in Google Scholar
  • 28 Meriggioli MN, Sanders DB. Myasthenia gravis: diagnosis. Semin Neurol 2004; 24: 31-39.
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Miller RG, Milner-Brown HS, Mirka A. Prednisone-induced worsening of neuromuscular function in myasthenia gravis. Neurology 1986; 36: 729-732.
    CrossrefPubMedSearch in Google Scholar
  • 30 Mulder DG, Graves M, Herrmann C. Thymectomy for myasthenia gravis: recent observations and comparisons with past experience. Ann Thorac Surg 1989; 48: 551-555.
    CrossrefPubMedSearch in Google Scholar
  • 31 Nath A, Kerman RH, Novak IS, Wolinsky JS. Immune studies in human immunodeficiency virus infection with myasthenia gravis: a case report. Neurology 1990; 40: 581-583.
    CrossrefPubMedSearch in Google Scholar
  • 32 Oh SJ, Kim DE, Kuruoglu R, Bradley RJ, Dwyer D. Diagnostic sensitivity of the laboratory tests in myasthenia gravis. Muscle Nerve 1992; 15: 720-724.
    CrossrefPubMedSearch in Google Scholar
  • 33 Ohta M, Ohta K, Itoh N, Kurobe M, Hayashi K, Nishitani H. Anti-skeletal muscle antibodies in the sera from myasthenic patients with thymoma: identification of anti-myosin, actomyosin, actin, and alpha-actinin antibodies by a solid-phase radioimmunoassay and a western blotting analysis. Clin Chim Acta 1990; 187: 255-264.
    CrossrefPubMedSearch in Google Scholar
  • 34 Ostlie N, Milani M, Wang W, Okita D, Conti-Fine BM. Absence of IL-4 facilitates the development of chronic autoimmune myasthenia gravis in C57BL/6 mice. J Immunol 2003; 170: 604-612.
    CrossrefPubMedSearch in Google Scholar
  • 35 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: 1778-1783.
    CrossrefPubMedSearch in Google Scholar
  • 36 Pascuzzi RM. The history of myasthenia gravis. Neurol Clin 1994; 12: 231-242.
    CrossrefPubMedSearch in Google Scholar
  • 37 Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 1984; 15: 291-298.
    CrossrefPubMedSearch in Google Scholar
  • 38 Patrick J, Lindstrom J. Autoimmune response to acetylcholine receptor. Science 1973; 180: 871-872.
    CrossrefPubMedSearch in Google Scholar
  • 39 Phillips LH. The epidemiology of myasthenia gravis. Semin Neurol 2004; 24: 17-20.
    Thieme ConnectPubMedSearch in Google Scholar
  • 40 Pinching AJ, Peters DK. Remission of myasthenia gravis following plasma-exchange. Lancet 1976; 02: 1373-1376.
    Search in Google Scholar
  • 41 Ponseti JM, Azem J, Fort JM, Codina A, Montoro JB, und MArmengol. Benefits of FK506 (tacrolimus) for residual, cyclosporinand prednisoneresistant myasthenia gravis: one-year follow-up of an open-label study. Clin Neurol Neurosurg 2005; 107: 187-190.
    CrossrefPubMedSearch in Google Scholar
  • 42 Prakash KM, Ratnagopal P, Puvanendran K, Lo YL. Mycophenolate mofetil - as an adjunctive immunosuppressive therapy in refractory myasthenia gravis: The Singapore experience. J Clin Neurosci 2007; 14: 278-281.
    CrossrefPubMedSearch in Google Scholar
  • 43 Psaridi-Linardaki L, Trakas N, Mamalaki A, Tzartos SJ. Specific immunoadsorption of the autoantibodies from myasthenic patients using the extracellular domain of the human muscle acetylcholine receptor alpha-subunit. Development of an antigen-specific therapeutic strategy. J Neuroimmunol 2005; 159: 183-191.
    CrossrefPubMedSearch in Google Scholar
  • 44 Romi F, Gilhus NE, Varhaug JE, Myking A, Aarli JA. Disease severity and outcome in thymoma myasthenia gravis: a long-term observation study. Eur J Neurol 2003; 10: 701-706.
    CrossrefPubMedSearch in Google Scholar
  • 45 Ruegg MA, Bixby JL. Agrin orchestrates synaptic differentiation at the vertebrate neuromuscular junction. Trends Neurosci 1998; 21: 22-27.
    CrossrefPubMedSearch in Google Scholar
  • 46 Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science 2001; 291: 484-486.
    CrossrefPubMedSearch in Google Scholar
  • 47 Saperstein DS, Barohn RJ. Management of myasthenia gravis. Semin Neurol 2004; 24: 41-48.
    Thieme ConnectPubMedSearch in Google Scholar
  • 48 Scherbaum WA, Schumm F, Maisch B, Muller C, Fateh-Moghadam A, Fluchter SH, Seif FJ, Bottazzo GF, Berg PA. Myasthenia gravis: overlap with ‘polyendocrine’ autoimmunity. Klin Wochenschr 1983; 61: 509-515.
    CrossrefPubMedSearch in Google Scholar
  • 49 Schwimmbeck PL, Dyrberg T, Drachman DB, Oldstone MB. Molecular mimicry and myasthenia gravis. An autoantigenic site of the acetylcholine receptor alpha-subunit that has biologic activity and reacts immunochemically with herpes simplex virus. J Clin Invest 1989; 84: 1174-1180.
    CrossrefPubMedSearch in Google Scholar
  • 50 Shigemoto K, Kubo S, Maruyama N, Hato N, Yamada H, Jie C, Kobayashi N, Mominoki K, Abe Y, Ueda N, Matsuda S. Induction of myasthenia by immunization against muscle-specific kinase. J Clin Invest 2006; 116: 1016-1024.
    CrossrefPubMedSearch in Google Scholar
  • 51 Sommer N, Willcox N, Harcourt GC, NewsomDavis J. Myasthenic thymus and thymoma are selectively enriched in acetylcholine receptor-reactive T cells. Ann Neurol 1990; 28: 312-319.
    CrossrefPubMedSearch in Google Scholar
  • 52 Spring PJ, Spies JM. Myasthenia gravis: options and timing of immunomodulatory treatment. BioDrugs 2001; 15: 173-183.
    CrossrefPubMedSearch in Google Scholar
  • 53 Stefansson K, Dieperink ME, Richman DP, Gomez CM, Marton LS. Sharing of antigenic determinants between the nicotinic acetylcholine receptor and proteins in Escherichia coli, Proteus vulgaris, and Klebsiella pneumoniae. Possible role in the pathogenesis of myasthenia gravis. N Engl J Med 1985; 312: 221-225.
    CrossrefPubMedSearch in Google Scholar
  • 54 Sthoeger Z, Neiman A, Elbirt D, Zinger H, Magen E, Burstein R, Eitan S, Abarbanel J, Mozes E. High prevalence of systemic lupus erythematosus in 78 myasthenia gravis patients: a clinical and serologic study. AmJ Med Sci 2006; 331: 4-9.
    Search in Google Scholar
  • 55 Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann NY Acad Sci 1993; 681: 539-551.
    CrossrefPubMedSearch in Google Scholar
  • 56 Tindall RS, Rollins JA, Phillips JT, Greenlee RG, Wells L, Belendiuk G. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N Engl J Med 1987; 316: 719-724.
    CrossrefPubMedSearch in Google Scholar
  • 57 Toyka KV, Drachman DB, Griffin DE, Pestronk A, Winkelstein JA, Fishbeck KH, Kao I. Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N Engl J Med 1977; 296: 125-131.
    CrossrefPubMedSearch in Google Scholar
  • 58 Vernino S, Lennon VA. Autoantibody profiles and neurological correlations of thymoma. Clin Cancer Res 2004; 10: 7270-7275.
    CrossrefPubMedSearch in Google Scholar
  • 59 Vincent A, McConville J, Farrugia ME, NewsomDavis J. Seronegative myasthenia gravis. Semin Neurol 2004; 24: 125-133.
    Thieme ConnectPubMedSearch in Google Scholar
  • 60 Vincent A, Newsom-Davis J. Acetylcholine receptor antibody as a diagnostic test for myasthenia gravis: results in 153 validated cases and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry 1985; 48: 1246-1252.
    CrossrefPubMedSearch in Google Scholar
  • 61 Vincent A, Whiting PJ, Schluep M, Heidenreich F, Lang B, Roberts A, Willcox N, Newsom-Davis J. Antibody heterogeneity and specificity in myasthenia gravis. Ann N Y Acad Sci 1987; 505: 106-120.
    CrossrefPubMedSearch in Google Scholar
  • 62 Voltz RD, Albrich WC, Nagele A, Schumm F, Wick M, Freiburg A, Gautel M, Thaler HT, Aarli J, Kirchner T, Hohlfeld R. Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor. Neurology 1997; 49: 1454-1457.
    CrossrefPubMedSearch in Google Scholar
  • 63 Wang ZY, Karachunski PI, Howard Jr JF, ContiFine BM. Myasthenia in SCID mice grafted with myasthenic patient lymphocytes: role of CD4+ and CD8+ cells. Neurology 1999; 52: 484-497.
    CrossrefPubMedSearch in Google Scholar
  • 64 Wang ZY, Okita DK, Howard Jr J, Conti-Fine BM. T-cell recognition of muscle acetylcholine receptor subunits in generalized and ocular myasthenia gravis. Neurology 1998; 50: 1045-1054.
    CrossrefPubMedSearch in Google Scholar
  • 65 Wilisch A, Gutsche S, Hoffacker V, Schultz A, Tzartos S, Nix W, Schalke B, Schneider C, MullerHermelink HK, Marx A. Association of acetylcholine receptor alpha-subunit gene expression in mixed thymoma with myasthenia gravis. Neurology 1999; 52: 1460-1466.
    CrossrefPubMedSearch in Google Scholar
  • 66 Yamamoto AM, Gajdos P, Eymard B, Tranchant C, Warter JM, Gomez L, Bourquin C, Bach JF, Garchon HJ. Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients. Arch Neurol 2001; 58: 885-890.
    CrossrefPubMedSearch in Google Scholar
  • 67 Yarilin D, Duan R, Huang YM, Xiao BG. Dendritic cells exposed in vitro to TGF-beta1 ameliorate experimental autoimmune myasthenia gravis. Clin Exp Immunol 2002; 127: 214-219.
    CrossrefPubMedSearch in Google Scholar