Aktuelle Neurologie 2005; 32(1): 3-9
DOI: 10.1055/s-2004-834610
Neues in der Neurologie
© Georg Thieme Verlag KG Stuttgart · New York

Aktuelle Aspekte in der Pathogenese, Diagnostik und Therapie der Myasthenia gravis

Current Aspects in the Pathogenesis, Diagnosis, and Therapy of Myasthenia GravisS.  Jander1 , H.-P.  Hartung1
  • 1Neurologische Klinik, Universitätsklinikum Düsseldorf
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
27. Januar 2005 (online)

Zusammenfassung

In den letzten Jahren ist es bei der Myasthenia gravis zu einer Erweiterung des pathogenetischen Verständnisses und der therapeutischen Möglichkeiten gekommen. Neue klinische und immunologische Befunde legen eine differenzierte Klassifikation der Erkrankung nahe, die wichtige prognostische und therapeutische Implikationen hat. Viele der etablierten Therapien sind trotz unvollständiger Absicherung durch kontrollierte Studien von unbestrittener Wirksamkeit und haben die Prognose der Erkrankung drastisch verbessern können. In der präklinischen Entwicklung haben sich eine Reihe von antigenspezifischen Therapieansätze als wirksam erwiesen und könnten damit zukünftige Alternativen zur derzeit üblichen unspezifischen Immunsuppression darstellen.

Abstract

Recent years have witnessed significant advances in the pathogenetic understanding and therapy of autoimmune myasthenia gravis. New immunological and clinical data suggest a revised classification which has important prognostic and therapeutic implications. Although incompletely tested in controlled trials, immune-directed therapies are of undisputed efficacy and have dramatically improved the prognosis of myasthenic patients. Antigen-specific therapy has proven effective in preclinical animal studies and may offer future alternatives to nonspecific immunosuppression.

Literatur

  • 1 Drachman D B. Myasthenia gravis.  N Engl J Med. 1994;  330 1797-1810
  • 2 Vincent A. Unravelling the pathogenesis of myasthenia gravis.  Nat Rev Immunol. 2002;  2 797-804
  • 3 Richman D P, Agius M A. Treatment of autoimmune myasthenia gravis.  Neurology. 2003;  61 1652-1661
  • 4 Keesey J C. Clinical evaluation and management of myasthenia gravis.  Muscle Nerve. 2004;  29 484-505
  • 5 Lindstrom J M, Seybold M E, Lennon V A. et al . Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value.  Neurology. 1976;  26 1054-1059
  • 6 Toyka K V, Drachman D B, Griffin D E. et al . Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice.  N Engl J Med. 1977;  296 125-131
  • 7 Toyka K V, Heininger K. Acetylcholine receptor antibodies in the diagnosis of myasthenia gravis. Study of 406 confirmed cases.  Dtsch Med Wochenschr. 1986;  111 1435-1439
  • 8 Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets.  Lancet Neurol. 2003;  2 99-106
  • 9 Mossman S, Vincent A, Newsom-Davis J. Myasthenia gravis without acetylcholine-receptor antibody: a distinct disease entity.  Lancet. 1986;  1 116-119
  • 10 Mier A K, Havard C W. Diaphragmatic myasthenia in mother and child.  Postgrad Med J. 1985;  61 725-727
  • 11 Heckmatt J Z, Placzek M, Thompson A H. et al . An unusual case of neonatal myasthenia.  J Child Neurol. 1987;  2 63-66
  • 12 Burges J, Vincent A, Molenaar P C. et al . Passive transfer of seronegative myasthenia gravis to mice.  Muscle Nerve. 1994;  17 1393-1400
  • 13 Hoch W, McConville J, Helms S. et al . Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies.  Nat Med. 2001;  7 365-368
  • 14 Evoli A, Tonali P A, Padua L. et al . Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis.  Brain. 2003;  126 2304-2311
  • 15 McConville J, Farrugia M E, Beeson D. et al . Detection and characterization of MuSK antibodies in seronegative myasthenia gravis.  Ann Neurol. 2004;  55 580-584
  • 16 Zhou L, McConville J, Chaudhry V. et al . Clinical comparison of muscle-specific tyrosine kinase (MuSK) antibody-positive and -negative myasthenic patients.  Muscle Nerve. 2004;  30 55-60
  • 17 Sanders D B, El Salem S, Massey J M. et al . Clinical aspects of MuSK antibody positive seronegative MG.  Neurology. 2003;  60 1978-1980
  • 18 Scuderi F, Marino M, Colonna L. et al . Anti-p110 autoantibodies identify a subtype of „seronegative” myasthenia gravis with prominent oculobulbar involvement.  Lab Invest. 2002;  82 1139-1146
  • 19 Abicht A, Lochmüller H. What's in the serum of seronegative MG and LEMS? MuSK et al.  Neurology. 2002;  59 1672-1673
  • 20 Sahashi K, Engel A G, Lambert E H, Howard Jr F M. Ultrastructural localization of the terminal and lytic ninth complement component (C9) at the motor end-plate in myasthenia gravis.  J Neuropathol Exp Neurol. 1980;  39 160-172
  • 21 Vincent A, McConville J, Farrugia M E. et al . Antibodies in myasthenia gravis and related disorders.  Ann N Y Acad Sci. 2003;  998 324-335
  • 22 Liyanage Y, Hoch W, Beeson D, Vincent A. The agrin/muscle-specific kinase pathway: new targets for autoimmune and genetic disorders at the neuromuscular junction.  Muscle Nerve. 2002;  25 4-16
  • 23 Selcen D, Fukuda T, Shen X M, Engel A G. Are MuSK antibodies the primary cause of myasthenic symptoms?.  Neurology. 2004;  62 1945-1950
  • 24 Lindstrom J. Is „seronegative” MG explained by autoantibodies to MuSK?.  Neurology. 2004;  62 1920-1921
  • 25 Agius M A, Zhu S, Kirvan C A. et al . Rapsyn antibodies in myasthenia gravis.  Ann N Y Acad Sci. 1998;  841 516-521
  • 26 Baets M De, Stassen M, Losen M. et al . Immunoregulation in experimental autoimmune myasthenia gravis - about T cells, antibodies, and endplates.  Ann N Y Acad Sci. 2003;  998 308-317
  • 27 Aarli J A, Stefansson K, Marton L S, Wollmann R L. Patients with myasthenia gravis and thymoma have in their sera IgG autoantibodies against titin.  Clin Exp Immunol. 1990;  82 284-288
  • 28 Romi F, Skeie G O, Aarli J A, Gilhus N E. Muscle autoantibodies in subgroups of myasthenia gravis patients.  J Neurol. 2000;  247 369-375
  • 29 Voltz R D, Albrich W C, Nagele A. et al . Paraneoplastic myasthenia gravis: detection of anti-MGT30 (titin) antibodies predicts thymic epithelial tumor.  Neurology. 1997;  49 1454-1457
  • 30 Buckley C, Newsom-Davis J, Willcox N, Vincent A. Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence?.  Neurology. 2001;  57 1579-1582
  • 31 Yamamoto A M, Gajdos P, Eymard B. et al . Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients.  Arch Neurol. 2001;  58 885-890
  • 32 Compston D A, Vincent A, Newsom-Davis J, Batchelor J R. Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis.  Brain. 1980;  103 579-601
  • 33 Agius M A, Richman D P, Fairclough R H. et al . Three forms of immune myasthenia.  Ann N Y Acad Sci. 2003;  998 453-456
  • 34 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. 2000;  55 7-15
  • 35 Romi F, Gilhus N E, Varhaug J E. et al . Thymectomy and anti-muscle autoantibodies in late-onset myasthenia gravis.  Eur J Neurol. 2002;  9 55-61
  • 36 Graves M, Katz J S. Myasthenia gravis.  Curr Treat Options Neurol. 2004;  6 163-171
  • 37 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
  • 38 Hohlfeld R, Toyka K V, Besinger U A. et al . Myasthenia gravis: reactivation of clinical disease and of autoimmune factors after discontinuation of long-term azathioprine.  Ann Neurol. 1985;  17 238-242
  • 39 Michels M, Hohlfeld R, Hartung H P. et al . Myasthenia gravis: discontinuation of long-term azathioprine.  Ann Neurol. 1988;  24 798
  • 40 Tindall R S, Rollins J A, Phillips J T. et al . Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis.  N Engl J Med. 1987;  316 719-724
  • 41 Behrend M, Lueck R, Pichlmayr R. Long-term experience with mycofenolate mofetil in the prevention of renal allograft rejection.  Transplant Proc. 1997;  29 2927-2929
  • 42 Allison A C, Kowalski W J, Muller C D, Eugui E M. Mechanisms of action of mycophenolic acid.  Ann N Y Acad Sci. 1993;  696 63-87
  • 43 Hauser R A, Malek A R, Rosen R. Successful treatment of a patient with severe refractory myasthenia gravis using mycophenolate mofetil.  Neurology. 1998;  51 912-913
  • 44 Chaudhry V, Cornblath D R, Griffin J W. et al . Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases.  Neurology. 2000;  56 94-96
  • 45 Ciafaloni E, Massey J M, Tucker-Lipscomb B, Sanders D B. Mycophenolate mofetil for myasthenia gravis: an open-label pilot study.  Neurology. 2000;  56 97-99
  • 46 Meriggioli M N, Rowin J. Treatment of myasthenia gravis with mycophenolate mofetil: a case report.  Muscle Nerve. 2000;  23 1287-1289
  • 47 Mowzoon N, Sussman A, Bradley W G. Mycophenolate (CellCept) treatment of myasthenia gravis, chronic inflammatory polyneuropathy and inclusion body myositis.  J Neurol Sci. 2001;  185 119-122
  • 48 Schneider C, Gold R, Reiners K, Toyka K V. Mycophenolate mofetil in the therapy of severe myasthenia gravis.  Eur Neurol. 2001;  46 79-82
  • 49 Meriggioli M N, Ciafaloni E, Al Hayk K A. et al . Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability.  Neurology. 2003;  61 1438-1440
  • 50 Meriggioli M N, Rowin J, Richman J G, Leurgans S. Mycophenolate mofetil for myasthenia gravis: a double-blind, placebo-controlled pilot study.  Ann N Y Acad Sci. 2003;  998 494-499
  • 51 Feo L G de, Schottlender J, Martelli N A, Molfino N A. Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis.  Muscle Nerve. 2002;  26 31-36
  • 52 Drachman D B, Jones R J, Brodsky R A. Treatment of refractory myasthenia: „Rebooting” with high-dose cyclophosphamide.  Ann Neurol. 2003;  53 29-34
  • 53 Gladstone D E, Brannagan III T H, Schwartzman R J. et al . High dose cyclophosphamide for severe refractory myasthenia gravis.  J Neurol Neurosurg Psychiatry. 2004;  75 789-791
  • 54 Zaja F, Russo D, Fuga G. et al . Rituximab for myasthenia gravis developing after bone marrow transplant.  Neurology. 2000;  55 1062-1063
  • 55 Wylam M E, Anderson P M, Kuntz N L, Rodriguez V. Successful treatment of refractory myasthenia gravis using rituximab: a pediatric case report.  J Pediatr. 2003;  143 674-677
  • 56 Gajra A, Vajpayee N, Grethlein S J. Response of myasthenia gravis to rituximab in a patient with non-Hodgkin lymphoma.  Am J Hematol. 2004;  77 196-197
  • 57 Gajdos P, Chevret S, Clair B. et al . Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Myasthenia Gravis Clinical Study Group.  Ann Neurol. 1997;  41 789-796
  • 58 Achiron A, Barak Y, Miron S, Sarova-Pinhas I. Immunoglobulin treatment in refractory Myasthenia gravis.  Muscle Nerve. 2000;  23 551-555
  • 59 Wolfe G I, Barohn R J, Foster B M. et al . Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis.  Muscle Nerve. 2002;  26 549-552
  • 60 Gajdos P, Chevret S, Toyka K. Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev 2002 CD002275
  • 61 Gajdos P, Chevret S, Toyka K. Intravenous immunoglobulin for myasthenia gravis (Cochrane Review). Cochrane Database Syst Rev 2003 CD002277
  • 62 Dalakas M C. Intravenous immunoglobulin in autoimmune neuromuscular diseases.  JAMA. 2004;  291 2367-2375
  • 63 Yeh J H, Chiu H C. Comparison between double-filtration plasmapheresis and immunoadsorption plasmapheresis in the treatment of patients with myasthenia gravis.  J Neurol. 2000;  247 510-513
  • 64 Flachenecker P, Taleghani B M, Gold R. et al . Treatment of severe myasthenia gravis with protein A immunoadsorption and cyclophosphamide.  Transfus Sci. 1998;  19, Suppl 43-46
  • 65 Psaridi-Linardaki L, Mamalaki A, Tzartos S J. Future therapeutic strategies in autoimmune myasthenia gravis.  Ann N Y Acad Sci. 2003;  998 539-548
  • 66 McQuillen M P, Leone M G. A treatment carol: thymectomy revisited.  Neurology. 1977;  27 1103-1106
  • 67 Buckingham J M, Howard Jr F M, Bernatz P E. et al . The value of thymectomy in myasthenia gravis: a computer-assisted matched study.  Ann Surg. 1976;  184 453-458
  • 68 Yim A P, Kay R L, Ho J K. Video-assisted thoracoscopic thymectomy for myasthenia gravis.  Chest. 1995;  108 1440-1443
  • 69 Ruckert J C, Gellert K, Muller J M. Operative technique for thoracoscopic thymectomy.  Surg Endosc. 1999;  13 943-946
  • 70 Wright G M, Barnett S, Clarke C P. Video-assisted thoracoscopic thymectomy for myasthenia gravis.  Intern Med J. 2002;  32 367-371
  • 71 Mantegazza R, Baggi F, Bernasconi P. et al . Video-assisted thoracoscopic extended thymectomy and extended transsternal thymectomy (T-3b) in non-thymomatous myasthenia gravis patients: remission after 6 years of follow-up.  J Neurol Sci. 2003;  212 31-36
  • 72 Ruckert J C, Sobel H K, Gohring S. et al . Matched-pair comparison of three different approaches for thymectomy in myasthenia gravis.  Surg Endosc. 2003;  17 711-715
  • 73 Zielinski M, Kuzdzal J, Szlubowski A, Soja J. Transcervical-subxiphoid-videothoracoscopic „maximal” thymectomy - operative technique and early results.  Ann Thorac Surg. 2004;  78 404-409
  • 74 Zielinski M, Kuzdzal J, Szlubowski A, Soja J. Comparison of late results of basic transsternal and extended transsternal thymectomies in the treatment of myasthenia gravis.  Ann Thorac Surg. 2004;  78 253-258
  • 75 Lanska D J. Indications for thymectomy in myasthenia gravis.  Neurology. 1990;  40 1828-1829
  • 76 Wolfe G I, Kaminski H J, Jaretzki III A. et al . Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy.  Ann N Y Acad Sci. 2003;  998 473-480
  • 77 Abbas A K, Murphy K M, Sher A. Functional diversity of helper T lymphocytes.  Nature. 1996;  383 787-793
  • 78 Balasa B, Sarvetnick N. Is pathogenic humoral autoimmunity a Th1 response? Lessons from (for) myasthenia gravis.  Immunol Today. 2000;  21 19-23
  • 79 Link H, Olsson O, Sun J. et al . Acetylcholine receptor-reactive T and B cells in myasthenia gravis and controls.  J Clin Invest. 1991;  87 2191-2195
  • 80 Balasa B, Deng C, Lee J. et al . Interferon gamma (IFN-gamma) is necessary for the genesis of acetylcholine receptor-induced clinical experimental autoimmune myasthenia gravis in mice.  J Exp Med. 1997;  186 385-391
  • 81 Balasa B, Deng C, Lee J. et al . The Th2 cytokine IL-4 is not required for the progression of antibody-dependent autoimmune myasthenia gravis.  J Immunol. 1998;  161 2856-2862
  • 82 Moiola L, Galbiati F, Martino G. et al . IL-12 is involved in the induction of experimental autoimmune myasthenia gravis, an antibody-mediated disease.  Eur J Immunol. 1998;  28 2487-2497
  • 83 Shi F D, Wang H B, Li H. et al . Natural killer cells determine the outcome of B cell-mediated autoimmunity.  Nat Immunol. 2000;  1 245-251
  • 84 Im S H, Barchan D, Maiti P K. et al . Suppression of experimental myasthenia gravis, a B cell-mediated autoimmune disease, by blockade of IL-18.  FASEB J. 2001;  15 2140-2148
  • 85 Jander S, Stoll G. Increased serum levels of the interferon-gamma-inducing cytokine interleukin-18 in myasthenia gravis.  Neurology. 2002;  59 287-289
  • 86 Pachner A R. Antigen-specific immunotherapy in myasthenia gravis: failed promise and new hope.  J Neuroimmunol. 2004;  152 vii-viii
  • 87 Sela M, Mozes E. Therapeutic vaccines in autoimmunity.  Proc Natl Acad Sci U S A. 2004;  101, Suppl 2 14586-14592
  • 88 Katz-Levy Y, Kirshner S L, Sela M, Mozes E. Inhibition of T-cell reactivity to myasthenogenic epitopes of the human acetylcholine receptor by synthetic analogs.  Proc Natl Acad Sci U S A. 1993;  90 7000-7004
  • 89 Nicolle M W, Nag B, Sharma S D. et al . Specific tolerance to an acetylcholine receptor epitope induced in vitro in myasthenia gravis CD4+ lymphocytes by soluble major histocompatibility complex class II-peptide complexes.  J Clin Invest. 1994;  93 1361-1369
  • 90 Im S H, Barchan D, Fuchs S, Souroujon M C. Suppression of ongoing experimental myasthenia by oral treatment with an acetylcholine receptor recombinant fragment.  J Clin Invest. 1999;  104 1723-1730
  • 91 Paas-Rozner M, Dayan M, Paas Y. et al . Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.  Proc Natl Acad Sci U S A. 2000;  97 2168-2173
  • 92 Souroujon M C, Maiti P K, Feferman T. et al . Suppression of myasthenia gravis by antigen-specific mucosal tolerance and modulation of cytokines and costimulatory factors.  Ann N Y Acad Sci. 2003;  998 533-536
  • 93 Drachman D B, Wu J M, Miagkov A. et al . Specific immunotherapy of experimental myasthenia by genetically engineered APCs: the „guided missile” strategy.  Ann N Y Acad Sci. 2003;  998 520-532
  • 94 Paas-Rozner M, Sela M, Mozes E. The nature of the active suppression of responses associated with experimental autoimmune myasthenia gravis by a dual altered peptide ligand administered by different routes.  Proc Natl Acad Sci U S A. 2001;  98 12642-12647
  • 95 Dayan M, Sthoeger Z, Neiman A. et al . 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

Priv.-Doz. Dr. med. Sebastian Jander

Neurologische Klinik · Universitätsklinikum Düsseldorf · Heinrich-Heine-Universität

Moorenstraße 5

40225 Düsseldorf

eMail: jander@uni-duesseldorf.de

    >