Top

Published in:

Open Access 01-08-2016 | Review

Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society

Authors: Nico Melzer, Tobias Ruck, Peter Fuhr, Ralf Gold, Reinhard Hohlfeld, Alexander Marx, Arthur Melms, Björn Tackenberg, Berthold Schalke, Christiane Schneider-Gold, Fritz Zimprich, Sven G. Meuth, Heinz Wiendl

Published in: Journal of Neurology | Issue 8/2016

Abstract

Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder of neuromuscular synaptic transmission. The clinical hallmark of MG consists of fluctuating fatigability and weakness affecting ocular, bulbar and (proximal) limb skeletal muscle groups. MG may either occur as an autoimmune disease with distinct immunogenetic characteristics or as a paraneoplastic syndrome associated with tumors of the thymus. Impairment of central thymic and peripheral self-tolerance mechanisms in both cases is thought to favor an autoimmune CD4⁺ T cell-mediated B cell activation and synthesis of pathogenic high-affinity autoantibodies of either the IgG1 and 3 or IgG4 subclass. These autoantibodies bind to the nicotinic acetylcholine receptor (AchR) itself, or muscle-specific tyrosine-kinase (MuSK), lipoprotein receptor-related protein 4 (LRP4) and agrin involved in clustering of AchRs within the postsynaptic membrane and structural maintenance of the neuromuscular synapse. This results in disturbance of neuromuscular transmission and thus clinical manifestation of the disease. Emphasizing evidence from clinical trials, we provide an updated overview on immunopathogenesis, and derived current and future treatment strategies for MG divided into: (a) symptomatic treatments facilitating neuromuscular transmission, (b) antibody-depleting treatments, and (c) immunotherapeutic treatment strategies.

Albuquerque EX, Pereira EF, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73–120PubMedPubMedCentralCrossRef

Arsura E, Brunner NG, Namba T, Grob D (1985) High-dose intravenous methylprednisolone in myasthenia gravis. Arch Neurol 42:1149–1153PubMedCrossRef

Aschenbrenner K, D’Cruz LM, Vollmann EH, Hinterberger M, Emmerich J, Swee LK, Rolink A, Klein L (2007) Selection of Foxp3+ regulatory T cells specific for self antigen expressed and presented by Aire + medullary thymic epithelial cells. Nat Immunol 8:351–358PubMedCrossRef

Ashraf VV, Taly AB, Veerendrakumar M, Rao S (2006) Myasthenia gravis in children: a longitudinal study. Acta Neurol Scand 114:119–123PubMedCrossRef

Bachmann K, Burkhardt D, Schreiter I, Kaifi J, Busch C, Thayssen G, Izbicki JR, Strate T (2008) Long-term outcome and quality of life after open and thoracoscopic thymectomy for myasthenia gravis: analysis of 131 patients. Surg Endosc 22:2470–2477PubMedCrossRef

Bae JS, Go SM, Kim BJ (2006) Clinical predictors of steroid-induced exacerbation in myasthenia gravis. J Clin Neurosci 13:1006–1010PubMedCrossRef

Bain PG, Motomura M, Newsom-Davis J, Misbah SA, Chapel HM, Lee ML, Vincent A, Lang B (1996) Effects of intravenous immunoglobulin on muscle weakness and calcium-channel autoantibodies in the Lambert-Eaton myasthenic syndrome. Neurology 47:678–683PubMedCrossRef

Balandina A, Lecart S, Dartevelle P, Saoudi A, Berrih-Aknin S (2005) Functional defect of regulatory CD4(+)CD25+ T cells in the thymus of patients with autoimmune myasthenia gravis. Blood 105:735–741PubMedCrossRef

Barik A, Lu Y, Sathyamurthy A, Bowman A, Shen C, Li L, Xiong WC, Mei L (2014) LRP4 is critical for neuromuscular junction maintenance. J Neurosci 34:13892–13905PubMedPubMedCentralCrossRef

10.

Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V (2011) Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 76:2017–2023PubMedPubMedCentralCrossRef

11.

Benatar M, Kaminski H (2012) Medical and surgical treatment for ocular myasthenia. Cochrane Database Syst Rev 12:CD005081PubMed

12.

Birmingham UoAa (2006) Thymectomy Trial in Non-Thymomatous Myasthenia Gravis Patients Receiving Prednisone Therapy. ClinicalTrialsgov NCT00294658

13.

Bromberg MB, Wald JJ, Forshew DA, Feldman EL, Albers JW (1997) Randomized trial of azathioprine or prednisone for initial immunosuppressive treatment of myasthenia gravis. J Neurol Sci 150:59–62PubMedCrossRef

14.

Buckley C, Douek D, Newsom-Davis J, Vincent A, Willcox N (2001) Mature, long-lived CD4+ and CD8+ T cells are generated by the thymoma in myasthenia gravis. Ann Neurol 50:64–72PubMedCrossRef

15.

Carr AS, Cardwell CR, McCarron PO, McConville J (2010) A systematic review of population based epidemiological studies in Myasthenia Gravis. BMC Neurol 10:46PubMedPubMedCentralCrossRef

16.

Castro D, Derisavifard S, Anderson M, Greene M, Iannaccone S (2013) Juvenile myasthenia gravis: a twenty-year experience. J Clin Neuromuscul Dis 14:95–102PubMedCrossRef

17.

Cavalcante P, Bernasconi P, Mantegazza R (2012) Autoimmune mechanisms in myasthenia gravis. Curr Opin Neurol 25:621–629PubMedCrossRef

18.

Cea G, Benatar M, Verdugo RJ, Salinas RA (2013) Thymectomy for non-thymomatous myasthenia gravis. Cochrane Database Syst Rev 10:CD008111PubMed

19.

Chan A, Lee DH, Linker R, Mohr A, Toyka KV, Gold R (2007) Rescue therapy with anti-CD20 treatment in neuroimmunologic breakthrough disease. J Neurol 254:1604–1606PubMedCrossRef

20.

Chuang WY, Strobel P, Bohlender-Willke AL, Rieckmann P, Nix W, Schalke B, Gold R, Opitz A, Klinker E, Inoue M, Muller-Hermelink HK, Saruhan-Direskeneli G, Bugert P, Willcox N, Marx A (2014) Late-onset myasthenia gravis—CTLA4(low) genotype association and low-for-age thymic output of naive T cells. J Autoimmun 52:122–129PubMedCrossRef

21.

Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB (2001) Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology 56:97–99PubMedCrossRef

22.

Cohen JA, Coles AJ, Arnold DL, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Fisher E, Brinar VV, Giovannoni G, Stojanovic M, Ertik BI, Lake SL, Margolin DH, Panzara MA, Compston DA (2012) Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet 380:1819–1828PubMedCrossRef

23.

Cole RN, Reddel SW, Gervasio OL, Phillips WD (2008) Anti-MuSK patient antibodies disrupt the mouse neuromuscular junction. Ann Neurol 63:782–789PubMedCrossRef

24.

Coles AJ, Twyman CL, Arnold DL, Cohen JA, Confavreux C, Fox EJ, Hartung HP, Havrdova E, Selmaj KW, Weiner HL, Miller T, Fisher E, Sandbrink R, Lake SL, Margolin DH, Oyuela P, Panzara MA, Compston DA (2012) Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet 380:1829–1839PubMedCrossRef

25.

Confavreux C, Saddier P, Grimaud J, Moreau T, Adeleine P, Aimard G (1996) Risk of cancer from azathioprine therapy in multiple sclerosis: a case-control study. Neurology 46:1607–1612PubMedCrossRef

26.

Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A (2011) Evidence-based guideline update: plasmapheresis in neurologic disorders: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 76:294–300PubMedPubMedCentralCrossRef

27.

Costa J, Evangelista T, Conceicao I, de Carvalho M (2004) Repetitive nerve stimulation in myasthenia gravis–relative sensitivity of different muscles. Clin Neurophysiol 115:2776–2782PubMedCrossRef

28.

Curnow J, Corlett L, Willcox N, Vincent A (2001) Presentation by myoblasts of an epitope from endogenous acetylcholine receptor indicates a potential role in the spreading of the immune response. J Neuroimmunol 115:127–134PubMedCrossRef

29.

Dardenne M, Savino W, Bach JF (1987) Thymomatous epithelial cells and skeletal muscle share a common epitope defined by a monoclonal antibody. Am J Pathol 126:194–198PubMedPubMedCentral

30.

Dau PC, Lindstrom JM, Cassel CK, Denys EH, Shev EE, Spitler LE (1977) Plasmapheresis and immunosuppressive drug therapy in myasthenia gravis. N Engl J Med 297:1134–1140PubMedCrossRef

31.

De Feo LG, Schottlender J, Martelli NA, Molfino NA (2002) Use of intravenous pulsed cyclophosphamide in severe, generalized myasthenia gravis. Muscle Nerve 26:31–36PubMedCrossRef

32.

Diaz-Manera J, Martinez-Hernandez E, Querol L, Klooster R, Rojas-Garcia R, Suarez-Calvet X, Munoz-Blanco JL, Mazia C, Straasheijm KR, Gallardo E, Juarez C, Verschuuren JJ, Illa I (2012) Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 78:189–193PubMedCrossRef

33.

Diaz-Manera J, Rojas-Garcia R, Gallardo E, Juarez C, Martinez-Domeno A, Martinez-Ramirez S, Dalmau J, Blesa R, Illa I (2007) Antibodies to AChR, MuSK and VGKC in a patient with myasthenia gravis and Morvan’s syndrome. Nat Clin Pract Neurol 3:405–410PubMedCrossRef

34.

Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695PubMedCrossRef

35.

Drachman DB, Adams RN, Hu R, Jones RJ, Brodsky RA (2008) Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann NY Acad Sci 1132:305–314PubMedPubMedCentralCrossRef

36.

Drachman DB, Jones RJ, Brodsky RA (2003) Treatment of refractory myasthenia: “rebooting” with high-dose cyclophosphamide. Ann Neurol 53:29–34PubMedCrossRef

37.

Dudel J, Birnberger KL, Toyka KV, Schlegel C, Besinger U (1979) Effects of myasthenic immunoglobulins and of prednisolone on spontaneous miniature end-plate potentials in mouse diaphragms. Exp Neurol 66:365–380PubMedCrossRef

38.

Eienbroker C, Seitz F, Spengler A, Kurz H, Seipelt M, Sommer N, Oertel WH, Timmesfeld N, Tackenberg B (2014) IVIg maintenance treatment in myasthenia gravis—a RCT sample size simulation. Muscle Nerve

39.

Evoli A, Batocchi AP, Minisci C, Di Schino C, Tonali P (2000) Clinical characteristics and prognosis of myasthenia gravis in older people. J Am Geriatr Soc 48:1442–1448PubMedCrossRef

40.

Evoli A, Bianchi MR, Riso R, Minicuci GM, Batocchi AP, Servidei S, Scuderi F, Bartoccioni E (2008) Response to therapy in myasthenia gravis with anti-MuSK antibodies. Ann NY Acad Sci 1132:76–83PubMedCrossRef

41.

Evoli A, Di Schino C, Marsili F, Punzi C (2002) Successful treatment of myasthenia gravis with tacrolimus. Muscle Nerve 25:111–114PubMedCrossRef

42.

Evoli A, Tonali PA, Padua L, Monaco ML, Scuderi F, Batocchi AP, Marino M, Bartoccioni E (2003) Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 126:2304–2311PubMedCrossRef

43.

Finn R, Coates PM (1977) Plasma exchange in myasthenia gravis. Lancet 1:190–191PubMedCrossRef

44.

Fuhr P, Gold R, Hohlfeld R, Melms A, Melzer N, Tackenberg B, Schalke B, Schneider-Gold C, Wiendl H, Zimprich F (2014) Diagnostik und Therapie der Myasthenia gravis und des Lambert-Eaton-Syndroms. Leitlinien der Deutschen Gesellschaft für Neurologie

45.

Gadient P, Bolton J, Puri V (2009) Juvenile myasthenia gravis: three case reports and a literature review. J Child Neurol 24:584–590PubMedCrossRef

46.

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

47.

Gajdos P, Chevret S, Toyka K (2008) Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev CD002277

48.

Gajdos P, Chevret S, Toyka K (2002) Plasma exchange for myasthenia gravis. Cochrane Database Syst Rev CD002275

49.

Gajdos P, Chevret S, Toyka KV (2012) Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 12:CD002277PubMed

50.

Gajdos P, Tranchant C, Clair B, Bolgert F, Eymard B, Stojkovic T, Attarian S, Chevret S, Myasthenia Gravis Clinical Study G (2005) Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol 62:1689–1693CrossRef

51.

Gasperi C, Melms A, Schoser B, Zhang Y, Meltoranta J, Risson V, Schaeffer L, Schalke B, Kroger S (2014) Anti-agrin autoantibodies in myasthenia gravis. Neurology 82:1976–1983PubMedCrossRef

52.

Gelfand EW (2012) Intravenous immune globulin in autoimmune and inflammatory diseases. N Engl J Med 367:2015–2025PubMedCrossRef

53.

Gellert K, Bottger J, Martin T, Werner J, Mangler C, Martin H (2005) Thoracoscopic thymectomy in the treatment concept for myasthenia gravis. Surg Technol Int 14:99–104PubMed

54.

Giovannoni G, Gold R, Selmaj K, Havrdova E, Montalban X, Radue EW, Stefoski D, McNeill M, Amaravadi L, Sweetser M, Elkins J, O’Neill G (2014) Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol 13:472–481PubMedCrossRef

55.

Giraud M, Taubert R, Vandiedonck C, Ke X, Levi-Strauss M, Pagani F, Baralle FE, Eymard B, Tranchant C, Gajdos P, Vincent A, Willcox N, Beeson D, Kyewski B, Garchon HJ (2007) An IRF8-binding promoter variant and AIRE control CHRNA1 promiscuous expression in thymus. Nature 448:934–937PubMedCrossRef

56.

Gisbert JP, Gomollon F, Cara C, Luna M, Gonzalez-Lama Y, Pajares JM, Mate J, Guijarro LG (2007) Thiopurine methyltransferase activity in Spain: a study of 14,545 patients. Dig Dis Sci 52:1262–1269PubMedCrossRef

57.

Gladstone DE, Brannagan TH 3rd, Schwartzman RJ, Prestrud AA, Brodsky I (2004) High dose cyclophosphamide for severe refractory myasthenia gravis. J Neurol Neurosurg Psychiatry 75:789–791PubMedPubMedCentralCrossRef

58.

Gold R, Giovannoni G, Selmaj K, Havrdova E, Montalban X, Radue EW, Stefoski D, Robinson R, Riester K, Rana J, Elkins J, O’Neill G (2013) Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet 381:2167–2175PubMedCrossRef

59.

Goldstein G, Whittingham S (1966) Experimental autoimmune thymitis. An animal model of human myasthenia gravis. Lancet 2:315–318PubMedCrossRef

60.

Gregersen PK, Kosoy R, Lee AT, Lamb J, Sussman J, McKee D, Simpfendorfer KR, Pirskanen-Matell R, Piehl F, Pan-Hammarstrom Q, Verschuuren JJ, Titulaer MJ, Niks EH, Marx A, Strobel P, Tackenberg B, Putz M, Maniaol A, Elsais A, Tallaksen C, Harbo HF, Lie BA, Raychaudhuri S, de Bakker PI, Melms A, Garchon HJ, Willcox N, Hammarstrom L, Seldin MF (2012) Risk for myasthenia gravis maps to a (151) Pro– > Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol 72:927–935PubMedPubMedCentralCrossRef

61.

Gronseth GS, Barohn RJ (2000) Practice parameter: thymectomy for autoimmune myasthenia gravis (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 55:7–15PubMedCrossRef

62.

Guillermo GR, Tellez-Zenteno JF, Weder-Cisneros N, Mimenza A, Estanol B, Remes-Troche JM, Cantu-Brito C (2004) Response of thymectomy: clinical and pathological characteristics among seronegative and seropositive myasthenia gravis patients. Acta Neurol Scand 109:217–221PubMedCrossRef

63.

Guptill JT, Sanders DB, Evoli A (2011) Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve 44:36–40PubMedCrossRef

64.

Hanisch F, Wendt M, Zierz S (2009) Mycophenolate mofetil as second line immunosuppressant in Myasthenia gravis–a long-term prospective open-label study. Eur J Med Res 14:364–366PubMedPubMedCentralCrossRef

65.

Hapnes L, Willcox N, Oftedal BE, Owe JF, Gilhus NE, Meager A, Husebye ES, Wolff AS (2012) Radioligand-binding assay reveals distinct autoantibody preferences for type I interferons in APS I and myasthenia gravis subgroups. J Clin Immunol 32:230–237PubMedCrossRef

66.

Hart IK, Sathasivam S, Sharshar T (2007) Immunosuppressive agents for myasthenia gravis. Cochrane Database Syst Rev:CD005224

67.

Harvey AM, Lilienthal JL, Talbot SA (1942) Observations on the nature of myasthenia gravis. The effect of thymectomy on neuro-muscular transmission. J Clin Invest 21:579–588PubMedPubMedCentralCrossRef

68.

Heckmann JM, Rawoot A, Bateman K, Renison R, Badri M (2011) A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol 11:97PubMedPubMedCentralCrossRef

69.

Hehir MK, Burns TM, Alpers J, Conaway MR, Sawa M, Sanders DB (2010) Mycophenolate mofetil in achr-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 41:593–598PubMedCrossRef

70.

Heininger K, Hendricks M, Toyka KV (1985) Myasthenia-gravis—a new semiselective procedure to remove acetylcholine-receptor-autoantibodies from plasma. Plasma Ther Trans Technol 6:771–775

71.

Hemminki K, Li X, Sundquist K (2006) Familial risks for diseases of myoneural junction and muscle in siblings based on hospitalizations and deaths in sweden. Twin Res Hum Genet 9:573–579PubMedCrossRef

72.

Henze T, Janzen RWC, Schumm F, Melms A, Sieb JP, Kohler W, Heidenreich F, Tackenberg B, Weber-Schondorfer C, Myasth ABD (2010) Immunotherapy for myasthenia gravis and Lambert-Eaton Myasthenic Syndrome Part 2: intravenous Immunoglobulins and Apheresis Techniques. Aktuelle Neurologie 37:518–523CrossRef

73.

Herrlinger U, Weller M, Dichgans J, Melms A (2000) Association of primary central nervous system lymphoma with long-term azathioprine therapy for myasthenia gravis? Ann Neurol 47:682–683PubMedCrossRef

74.

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

75.

Hill M, Beeson D, Moss P, Jacobson L, Bond A, Corlett L, Newsom-Davis J, Vincent A, Willcox N (1999) Early-onset myasthenia gravis: a recurring T-cell epitope in the adult-specific acetylcholine receptor epsilon subunit presented by the susceptibility allele HLA-DR52a. Ann Neurol 45:224–231PubMedCrossRef

76.

Hilton-Jones D (2007) When the patient fails to respond to treatment: myasthenia gravis. Pract Neurol 7:405–411PubMedCrossRef

77.

Hoch W, McConville J, Helms S, Newsom-Davis J, Melms A, Vincent A (2001) Auto-antibodies to the receptor tyrosine kinase MuSK in patients with myasthenia gravis without acetylcholine receptor antibodies. Nat Med 7:365–368PubMedCrossRef

78.

Hoeltzenbein M, Weber-Schoendorfer C, Borisch C, Allignol A, Meister R, Schaefer C (2012) Pregnancy outcome after paternal exposure to azathioprine/6-mercaptopurine. Reprod Toxicol 34:364–369PubMedCrossRef

79.

Hoffacker V, Schultz A, Tiesinga JJ, Gold R, Schalke B, Nix W, Kiefer R, Muller-Hermelink HK, Marx A (2000) Thymomas alter the T-cell subset composition in the blood: a potential mechanism for thymoma-associated autoimmune disease. Blood 96:3872–3879PubMed

80.

Hohlfeld R, Goebels N, Engel AG (1993) Cellular mechanisms in inflammatory myopathies. Baillieres Clin Neurol 2:617–635PubMed

81.

Hohlfeld R, Michels M, Heininger K, Besinger U, Toyka KV (1988) Azathioprine toxicity during long-term immunosuppression of generalized myasthenia gravis. Neurology 38:258–261PubMedCrossRef

82.

Hohlfeld R, Toyka KV, Besinger UA, Gerhold B, Heininger K (1985) Myasthenia gravis: reactivation of clinical disease and of autoimmune factors after discontinuation of long-term azathioprine. Ann Neurol 17:238–242PubMedCrossRef

83.

Howard JF Jr, Barohn RJ, Cutter GR, Freimer M, Juel VC, Mozaffar T, Mellion ML, Benatar MG, Farrugia ME, Wang JJ, Malhotra SS, Kissel JT (2013) A randomized, double-blind, placebo-controlled phase II study of eculizumab in patients with refractory generalized myasthenia gravis. Muscle Nerve 48:76–84PubMedCrossRef

84.

Huang H, Benoist C, Mathis D (2010) Rituximab specifically depletes short-lived autoreactive plasma cells in a mouse model of inflammatory arthritis. Proc Natl Acad Sci USA 107:4658–4663PubMedPubMedCentralCrossRef

85.

Huijbers MG, Zhang W, Klooster R, Niks EH, Friese MB, Straasheijm KR, Thijssen PE, Vrolijk H, Plomp JJ, Vogels P, Losen M, Van der Maarel SM, Burden SJ, Verschuuren JJ (2013) MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci USA 110:20783–20788PubMedPubMedCentralCrossRef

86.

Imbach P, Barandun S, d’Apuzzo V, Baumgartner C, Hirt A, Morell A, Rossi E, Schoni M, Vest M, Wagner HP (1981) High-dose intravenous gammaglobulin for idiopathic thrombocytopenic purpura in childhood. Lancet 1:1228–1231PubMedCrossRef

87.

Iorio R, Damato V, Alboini PE, Evoli A (2015) Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol 262:1115–1119PubMedCrossRef

88.

Jaretzki A 3rd, Penn AS, Younger DS, Wolff M, Olarte MR, Lovelace RE, Rowland LP (1988) “Maximal” thymectomy for myasthenia gravis. Results. J Thorac Cardiovasc Surg 95:747–757PubMed

89.

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

90.

Kirchner T, Schalke B, Melms A, von Kugelgen T, Muller-Hermelink HK (1986) Immunohistological patterns of non-neoplastic changes in the thymus in Myasthenia gravis. Virchows Arch B Cell Pathol Incl Mol Pathol 52:237–257PubMedCrossRef

91.

Kisand K, Lilic D, Casanova JL, Peterson P, Meager A, Willcox N (2011) Mucocutaneous candidiasis and autoimmunity against cytokines in APECED and thymoma patients: clinical and pathogenetic implications. Eur J Immunol 41:1517–1527PubMedCrossRef

92.

Klooster R, Plomp JJ, Huijbers MG, Niks EH, Straasheijm KR, Detmers FJ, Hermans PW, Sleijpen K, Verrips A, Losen M, Martinez-Martinez P, De Baets MH, van der Maarel SM, Verschuuren JJ (2012) Muscle-specific kinase myasthenia gravis IgG4 autoantibodies cause severe neuromuscular junction dysfunction in mice. Brain 135:1081–1101PubMedCrossRef

93.

Kohler W, Bucka C, Klingel R (2011) A randomized and controlled study comparing immunoadsorption and plasma exchange in myasthenic crisis. J Clin Apher 26:347–355PubMedCrossRef

94.

Konishi T, Yoshiyama Y, Takamori M, Saida T (2005) Long-term treatment of generalised myasthenia gravis with FK506 (tacrolimus). J Neurol Neurosurg Psychiatry 76:448–450PubMedPubMedCentralCrossRef

95.

Koziolek MJ, Kitze B, Muhlhausen J, Muller GA (2013) Immunoadsorption in steroid-refractory multiple sclerosis. Atheroscler Suppl 14:175–178PubMedCrossRef

96.

Kupersmith MJ (2009) Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol 256:1314–1320PubMedCrossRef

97.

Lauriola L, Ranelletti F, Maggiano N, Guerriero M, Punzi C, Marsili F, Bartoccioni E, Evoli A (2005) Thymus changes in anti-MuSK-positive and -negative myasthenia gravis. Neurology 64:536–538PubMedCrossRef

98.

Leite MI, Jacob S, Viegas S, Cossins J, Clover L, Morgan BP, Beeson D, Willcox N, Vincent A (2008) IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 131:1940–1952PubMedPubMedCentralCrossRef

99.

Leite MI, Strobel P, Jones M, Micklem K, Moritz R, Gold R, Niks EH, Berrih-Aknin S, Scaravilli F, Canelhas A, Marx A, Newsom-Davis J, Willcox N, Vincent A (2005) Fewer thymic changes in MuSK antibody-positive than in MuSK antibody-negative MG. Ann Neurol 57:444–448PubMedCrossRef

100.

Lin PT, Martin BA, Weinacker AB, So YT (2006) High-dose cyclophosphamide in refractory myasthenia gravis with MuSK antibodies. Muscle Nerve 33:433–435PubMedCrossRef

101.

Lindberg C, Andersen O, Lefvert AK (1998) Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand 97:370–373PubMedCrossRef

102.

Luo J, Lindstrom J (2012) Myasthenogenicity of the main immunogenic region and endogenous muscle nicotinic acetylcholine receptors. Autoimmunity 45:245–252PubMedCrossRef

103.

Maclennan CA, Vincent A, Marx A, Willcox N, Gilhus NE, Newsom-Davis J, Beeson D (2008) Preferential expression of AChR epsilon-subunit in thymomas from patients with myasthenia gravis. J Neuroimmunol 201–202:28–32PubMedCrossRef

104.

Maniaol AH, Elsais A, Lorentzen AR, Owe JF, Viken MK, Saether H, Flam ST, Brathen G, Kampman MT, Midgard R, Christensen M, Rognerud A, Kerty E, Gilhus NE, Tallaksen CM, Lie BA, Harbo HF (2012) Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population. PLoS One 7:e36603PubMedPubMedCentralCrossRef

105.

Mantegazza R, Antozzi C, Peluchetti D, Sghirlanzoni A, Cornelio F (1988) Azathioprine as a single drug or in combination with steroids in the treatment of myasthenia gravis. J Neurol 235:449–453PubMedCrossRef

106.

Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Strobel P (2013) The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 12:875–884PubMedCrossRef

107.

Marx A, Wilisch A, Schultz A, Greiner A, Magi B, Pallini V, Schalke B, Toyka K, Nix W, Kirchner T, Muller-Hermelink HK (1996) Expression of neurofilaments and of a titin epitope in thymic epithelial tumors. Implications for the pathogenesis of myasthenia gravis. Am J Pathol 148:1839–1850PubMedPubMedCentral

108.

Marx A, Willcox N, Leite MI, Chuang WY, Schalke B, Nix W, Strobel P (2010) Thymoma and paraneoplastic myasthenia gravis. Autoimmunity 43:413–427PubMedCrossRef

109.

Masuda T, Motomura M, Utsugisawa K, Nagane Y, Nakata R, Tokuda M, Fukuda T, Yoshimura T, Tsujihata M, Kawakami A (2012) Antibodies against the main immunogenic region of the acetylcholine receptor correlate with disease severity in myasthenia gravis. J Neurol Neurosurg Psychiatry 83:935–940PubMedCrossRef

110.

McConville J, Farrugia ME, Beeson D, Kishore U, Metcalfe R, Newsom-Davis J, Vincent A (2004) Detection and characterization of MuSK antibodies in seronegative myasthenia gravis. Ann Neurol 55:580–584PubMedCrossRef

111.

Mehndiratta MM, Pandey S, Kuntzer T (2011) Acetylcholinesterase inhibitor treatment for myasthenia gravis. Cochrane Database Syst Rev CD006986

112.

Mertens HG, Balzereit F, Leipert M (1969) The treatment of severe myasthenia gravis with immunosuppressive agents. Eur Neurol 2:321–339PubMedCrossRef

113.

Meyer DM, Herbert MA, Sobhani NC, Tavakolian P, Duncan A, Bruns M, Korngut K, Williams J, Prince SL, Huber L, Wolfe GI, Mack MJ (2009) Comparative clinical outcomes of thymectomy for myasthenia gravis performed by extended transsternal and minimally invasive approaches. Ann Thorac Surg 87:385–391PubMedCrossRef

114.

Michels M, Hohlfeld R, Hartung HP, Heininger K, Besinger UA, Toyka KV (1988) Myasthenia gravis: discontinuation of long-term azathioprine. Ann Neurol 24:798PubMedCrossRef

115.

Minami N, Fujiki N, Doi S, Shima K, Niino M, Kikuchi S, Sasaki H (2011) Five-year follow-up with low-dose tacrolimus in patients with myasthenia gravis. J Neurol Sci 300:59–62PubMedCrossRef

116.

Muscle Study G (2008) A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 71:394–399CrossRef

117.

Nagaishi A, Yukitake M, Kuroda Y (2008) Long-term treatment of steroid-dependent myasthenia gravis patients with low-dose tacrolimus. Intern Med 47:731–736PubMedCrossRef

118.

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

119.

Newsom-Davis J, Vincent A, Wilson SG, Ward CD, Pinching AJ, Hawkey C (1978) Plasmapheresis for myasthenia gravis. N Engl J Med 298:456–457PubMed

120.

Nissenson AR (1977) Reduction of IgG levels in myasthenia. N Engl J Med 296:819–820PubMed

121.

Novellino L, Longoni M, Spinelli L, Andretta M, Cozzi M, Faillace G, Vitellaro M, De Benedetti D, Pezzuoli G (1994) “Extended” thymectomy, without sternotomy, performed by cervicotomy and thoracoscopic technique in the treatment of myasthenia gravis. Int Surg 79:378–381PubMed

122.

O’Donovan P, Perrett CM, Zhang X, Montaner B, Xu YZ, Harwood CA, McGregor JM, Walker SL, Hanaoka F, Karran P (2005) Azathioprine and UVA light generate mutagenic oxidative DNA damage. Science 309:1871–1874PubMedPubMedCentralCrossRef

123.

Palace J, Newsom-Davis J, Lecky B (1998) A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis. Myasthenia Gravis Study Group. Neurology 50:1778–1783PubMedCrossRef

124.

Pascuzzi RM, Coslett HB, Johns TR (1984) Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 15:291–298PubMedCrossRef

125.

Pevzner A, Schoser B, Peters K, Cosma NC, Karakatsani A, Schalke B, Melms A, Kroger S (2012) Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 259:427–435PubMedCrossRef

126.

Pharmaceuticals A (2013) Safety and efficacy of eculizumab in refractory generalized myasthenia gravis (REGAIN study). ClinicalTrialsgov web-page NCT01997229

127.

Pinching AJ, Peters DK (1976) Remission of myasthenia gravis following plasma-exchange. Lancet 2:1373–1376PubMedCrossRef

128.

Poea-Guyon S, Christadoss P, Le Panse R, Guyon T, De Baets M, Wakkach A, Bidault J, Tzartos S, Berrih-Aknin S (2005) Effects of cytokines on acetylcholine receptor expression: implications for myasthenia gravis. J Immunol 174:5941–5949PubMedCrossRef

129.

Pompeo E, Tacconi F, Massa R, Mineo D, Nahmias S, Mineo TC (2009) Long-term outcome of thoracoscopic extended thymectomy for nonthymomatous myasthenia gravis. Eur J Cardiothorac Surg 36:164–169PubMedCrossRef

130.

Ponseti JM, Azem J, Fort JM, Lopez-Cano M, Vilallonga R, Buera M, Cervera C, Armengol M (2005) Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis. Neurology 64:1641–1643PubMedCrossRef

131.

Ponseti JM, Gamez J, Azem J, Lopez-Cano M, Vilallonga R, Armengol M (2008) Tacrolimus for myasthenia gravis: a clinical study of 212 patients. Ann NY Acad Sci 1132:254–263PubMedCrossRef

132.

Punga AR, Flink R, Askmark H, Stalberg EV (2006) Cholinergic neuromuscular hyperactivity in patients with myasthenia gravis seropositive for MuSK antibody. Muscle Nerve 34:111–115PubMedCrossRef

133.

Qureshi AI, Choudhry MA, Akbar MS, Mohammad Y, Chua HC, Yahia AM, Ulatowski JA, Krendel DA, Leshner RT (1999) Plasma exchange versus intravenous immunoglobulin treatment in myasthenic crisis. Neurology 52:629–632PubMedCrossRef

134.

Renton AE, Pliner HA, Provenzano C, Evoli A, Ricciardi R, Nalls MA, Marangi G, Abramzon Y, Arepalli S, Chong S, Hernandez DG, Johnson JO, Bartoccioni E, Scuderi F, Maestri M, Gibbs JR, Errichiello E, Chio A, Restagno G, Sabatelli M, Macek M, Scholz SW, Corse A, Chaudhry V, Benatar M, Barohn RJ, McVey A, Pasnoor M, Dimachkie MM, Rowin J, Kissel J, Freimer M, Kaminski HJ, Sanders DB, Lipscomb B, Massey JM, Chopra M, Howard JF Jr, Koopman WJ, Nicolle MW, Pascuzzi RM, Pestronk A, Wulf C, Florence J, Blackmore D, Soloway A, Siddiqi Z, Muppidi S, Wolfe G, Richman D, Mezei MM, Jiwa T, Oger J, Drachman DB, Traynor BJ (2015) A genome-wide association study of myasthenia gravis. JAMA Neurol 72:396–404PubMedPubMedCentralCrossRef

135.

Robertson NP, Deans J, Compston DA (1998) Myasthenia gravis: a population based epidemiological study in Cambridgeshire, England. J Neurol Neurosurg Psychiatry 65:492–496PubMedPubMedCentralCrossRef

136.

Rodriguez M, Gomez MR, Howard FM Jr, Taylor WF (1983) Myasthenia gravis in children: long-term follow-up. Ann Neurol 13:504–510PubMedCrossRef

137.

Romi F, Aarli JA, Gilhus NE (2007) Myasthenia gravis patients with ryanodine receptor antibodies have distinctive clinical features. Eur J Neurol 14:617–620PubMedCrossRef

138.

Romi F, Bo L, Skeie GO, Myking A, Aarli JA, Gilhus NE (2002) Titin and ryanodine receptor epitopes are expressed in cortical thymoma along with costimulatory molecules. J Neuroimmunol 128:82–89PubMedCrossRef

139.

Roxanis I, Micklem K, McConville J, Newsom-Davis J, Willcox N (2002) Thymic myoid cells and germinal center formation in myasthenia gravis; possible roles in pathogenesis. J Neuroimmunol 125:185–197PubMedCrossRef

140.

Ruckert JC, Gellert K, Muller JM (1999) Operative technique for thoracoscopic thymectomy. Surg Endosc 13:943–946PubMedCrossRef

141.

Sabbagh MN, Garza JS, Patten B (1995) Thoracoscopic thymectomy in patients with myasthenia gravis. Muscle Nerve 18:1475–1477PubMedCrossRef

142.

Samtleben W, Besinger UA, Toyka KV, Fateh-Moghadam A, Brehm G, Gurland HJ (1980) Plasma-separation in myasthenia gravis: a new method of rapid plasma exchange. Klin Wochenschr 58:47–49PubMedCrossRef

143.

Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A (2003) Clinical aspects of MuSK antibody positive seronegative MG. Neurology 60:1978–1980PubMedCrossRef

144.

Sanders DB, Hart IK, Mantegazza R, Shukla SS, Siddiqi ZA, De Baets MH, Melms A, Nicolle MW, Solomons N, Richman DP (2008) An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 71:400–406PubMedCrossRef

145.

Sanders DB, Howard JF Jr, Johns TR (1979) Single-fiber electromyography in myasthenia gravis. Neurology 29:68–76PubMedCrossRef

146.

Sanes JR, Lichtman JW (2001) Induction, assembly, maturation and maintenance of a postsynaptic apparatus. Nat Rev Neurosci 2:791–805PubMedCrossRef

147.

Savino W, Manganella G, Verley JM, Wolff A, Berrih S, Levasseur P, Binet JP, Dardenne M, Bach JF (1985) Thymoma epithelial cells secrete thymic hormone but do not express class II antigens of the major histocompatibility complex. J Clin Invest 76:1140–1146PubMedPubMedCentralCrossRef

148.

Schluep M, Willcox N, Vincent A, Dhoot GK, Newsom-Davis J (1987) Acetylcholine receptors in human thymic myoid cells in situ: an immunohistological study. Ann Neurol 22:212–222PubMedCrossRef

149.

Schneider-Gold C, Gajdos P, Toyka KV, Hohlfeld RR (2005) Corticosteroids for myasthenia gravis. Cochrane Database Syst Rev:CD002828

150.

Schroder A, Linker RA, Gold R (2009) Plasmapheresis for neurological disorders. Expert Rev Neurother 9:1331–1339PubMedCrossRef

151.

Seldin MF, Alkhairy OK, Lee AT, Lamb JA, Sussman J, Pirskanen-Matell R, Piehl F, Verschuuren JJ, Kostera-Pruszczyk A, Szczudlik P, McKee D, Maniaol AH, Harbo HF, Lie BA, Melms A, Garchon HJ, Willcox N, Gregersen PK, Hammarstrom L (2015) Genome-wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A, and Identification of ZBTB10 and Three Distinct HLA Associations. Mol Med

152.

Seybold ME (1998) Thymectomy in childhood myasthenia gravis. Ann N Y Acad Sci 841:731–741PubMedCrossRef

153.

Seybold ME, Drachman DB (1974) Gradually increasing doses of prednisone in myasthenia gravis. Reducing the hazards of treatment. N Engl J Med 290:81–84PubMedCrossRef

154.

Shen C, Lu Y, Zhang B, Figueiredo D, Bean J, Jung J, Wu H, Barik A, Yin DM, Xiong WC, Mei L (2013) Antibodies against low-density lipoprotein receptor-related protein 4 induce myasthenia gravis. J Clin Invest 123:5190–5202PubMedPubMedCentralCrossRef

155.

Shigemoto K, Kubo S, Maruyama N, Hato N, Yamada H, Jie C, Kobayashi N, Mominoki K, Abe Y, Ueda N, Matsuda S (2006) Induction of myasthenia by immunization against muscle-specific kinase. J Clin Invest 116:1016–1024PubMedPubMedCentralCrossRef

156.

Shiraishi H, Motomura M, Yoshimura T, Fukudome T, Fukuda T, Nakao Y, Tsujihata M, Vincent A, Eguchi K (2005) Acetylcholine receptors loss and postsynaptic damage in MuSK antibody-positive myasthenia gravis. Ann Neurol 57:289–293PubMedCrossRef

157.

Siara J, Rudel R, Marx A (1991) Absence of acetylcholine-induced current in epithelial cells from thymus glands and thymomas of myasthenia gravis patients. Neurology 41:128–131PubMedCrossRef

158.

Skeie GO, Apostolski S, Evoli A, Gilhus NE, Illa I, Harms L, Hilton-Jones D, Melms A, Verschuuren J, Horge HW, European Federation of Neurological S (2010) Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 17:893–902PubMedCrossRef

159.

Slesak G, Melms A, Fea Gerneth (1998) Late-onset myasthenia gravis– follow-up of 113 patients diagnosed after age 60. In: Richman DP (ed) Myasthenia Gravis and Related Diseases: Disorders of the Neuromuscular Junction. Ann NY Acad Sci, New York, pp 777–780

160.

Sommer N, Sigg B, Melms A, Weller M, Schepelmann K, Herzau V, Dichgans J (1997) Ocular myasthenia gravis: response to long-term immunosuppressive treatment. J Neurol Neurosurg Psychiatry 62:156–162PubMedPubMedCentralCrossRef

161.

Stangel M, Gold R (2011) Administration of intravenous immunoglobulins in neurology. An evidence-based consensus: update 2010. Nervenarzt 82:415–416PubMedCrossRef

162.

Strobel P, Bauer A, Puppe B, Kraushaar T, Krein A, Toyka K, Gold R, Semik M, Kiefer R, Nix W, Schalke B, Muller-Hermelink HK, Marx A (2004) Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis. J Clin Oncol 22:1501–1509PubMedCrossRef

163.

Strobel P, Chuang WY, Chuvpilo S, Zettl A, Katzenberger T, Kalbacher H, Rieckmann P, Nix W, Schalke B, Gold R, Muller-Hermelink HK, Peterson P, Marx A (2008) Common cellular and diverse genetic basis of thymoma-associated myasthenia gravis: role of MHC class II and AIRE genes and genetic polymorphisms. Ann NY Acad Sci 1132:143–156PubMedCrossRef

164.

Strobel P, Helmreich M, Menioudakis G, Lewin SR, Rudiger T, Bauer A, Hoffacker V, Gold R, Nix W, Schalke B, Elert O, Semik M, Muller-Hermelink HK, Marx A (2002) Paraneoplastic myasthenia gravis correlates with generation of mature naive CD4(+) T cells in thymomas. Blood 100:159–166PubMedCrossRef

165.

Strobel P, Moritz R, Leite MI, Willcox N, Chuang WY, Gold R, Nix W, Schalke B, Kiefer R, Muller-Hermelink HK, Jaretzki Iii A, Newsom-Davis J, Marx A (2008) The ageing and myasthenic thymus: a morphometric study validating a standard procedure in the histological workup of thymic specimens. J Neuroimmunol 201–202:64–73PubMedCrossRef

166.

Strobel P, Murumagi A, Klein R, Luster M, Lahti M, Krohn K, Schalke B, Nix W, Gold R, Rieckmann P, Toyka K, Burek C, Rosenwald A, Muller-Hermelink HK, Pujoll-Borrell R, Meager A, Willcox N, Peterson P, Marx A (2007) Deficiency of the autoimmune regulator AIRE in thymomas is insufficient to elicit autoimmune polyendocrinopathy syndrome type 1 (APS-1). J Pathol 211:563–571PubMedCrossRef

167.

Strobel P, Rosenwald A, Beyersdorf N, Kerkau T, Elert O, Murumagi A, Sillanpaa N, Peterson P, Hummel V, Rieckmann P, Burek C, Schalke B, Nix W, Kiefer R, Muller-Hermelink HK, Marx A (2004) Selective loss of regulatory T cells in thymomas. Ann Neurol 56:901–904PubMedCrossRef

168.

Strober J, Cowan MJ, Horn BN (2009) Allogeneic hematopoietic cell transplantation for refractory myasthenia gravis. Arch Neurol 66:659–661PubMedCrossRef

169.

Tackenberg B, Hemmer B, Oertel WH, Sommer N (2001) Immunosuppressive treatment of ocular myasthenia gravis. BioDrugs 15:369–378PubMedCrossRef

170.

Tackenberg B, Nitschke M, Willcox N, Ziegler A, Nessler S, Schumm F, Oertel WH, Hemmer B, Sommer N (2003) CD45 isoform expression in autoimmune myasthenia gravis. Autoimmunity 36:117–121PubMedCrossRef

171.

Tackenberg B, Schlegel K, Happel M, Eienbroker C, Gellert K, Oertel WH, Meager A, Willcox N, Sommer N (2009) Expanded TCR Vbeta subsets of CD8(+) T-cells in late-onset myasthenia gravis: novel parallels with thymoma patients. J Neuroimmunol 216:85–91PubMedCrossRef

172.

Tada M, Shimohata T, Tada M, Oyake M, Igarashi S, Onodera O, Naruse S, Tanaka K, Tsuji S, Nishizawa M (2006) Long-term therapeutic efficacy and safety of low-dose tacrolimus (FK506) for myasthenia gravis. J Neurol Sci 247:17–20PubMedCrossRef

173.

Thiruppathi M, Rowin J, Ganesh B, Sheng JR, Prabhakar BS, Meriggioli MN (2012) Impaired regulatory function in circulating CD4(+)CD25(high)CD127(low/−) T cells in patients with myasthenia gravis. Clin Immunol 145:209–223PubMedPubMedCentralCrossRef

174.

Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K (1993) A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann NY Acad Sci 681:539–551PubMedCrossRef

175.

Toyka KV, Brachman DB, Pestronk A, Kao I (1975) Myasthenia gravis: passive transfer from man to mouse. Science 190:397–399PubMedCrossRef

176.

Toyka KV, Drachman DB, Griffin DE, Pestronk A, Winkelstein JA, Fishbeck KH, Kao I (1977) Myasthenia gravis. Study of humoral immune mechanisms by passive transfer to mice. N Engl J Med 296:125–131PubMedCrossRef

177.

Tracy MM, McRae W, Millichap JG (2009) Graded response to thymectomy in children with myasthenia gravis. J Child Neurol 24:454–459PubMedCrossRef

178.

Travis WD, Brambilla E, Burke AP, Marx A, Nicholson AG (2015) WHO classification of tumours of the lung, pleura, thymus and heart. IARC Press 4th ed

179.

Trontelj JV, Stalberg E (1995) Single fiber electromyography in studies of neuromuscular function. Adv Exp Med Biol 384:109–119PubMedCrossRef

180.

Tumani H (2008) Corticosteroids and plasma exchange in multiple sclerosis. J Neurol 255(Suppl 6):36–42PubMedCrossRef

181.

Tzartos SJ, Lindstrom JM (1980) Monoclonal antibodies used to probe acetylcholine receptor structure: localization of the main immunogenic region and detection of similarities between subunits. Proc Natl Acad Sci USA 77:755–759PubMedPubMedCentralCrossRef

182.

Van de Velde RL, Friedman NB (1970) Thymic myoid cells and myasthenia gravis. Am J Pathol 59:347–368PubMedPubMedCentral

183.

Vernino S, Salomao DR, Habermann TM, O’Neill BP (2005) Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil. Neurology 65:639–641PubMedCrossRef

184.

Vincent A, Jacobson L, Shillito P (1994) Response to human acetylcholine receptor alpha 138–199: determinant spreading initiates autoimmunity to self-antigen in rabbits. Immunol Lett 39:269–275PubMedCrossRef

185.

Wakkach A, Poea S, Chastre E, Gespach C, Lecerf F, De La Porte S, Tzartos S, Coulombe A, Berrih-Aknin S (1999) Establishment of a human thymic myoid cell line. Phenotypic and functional characteristics. Am J Pathol 155:1229–1240PubMedPubMedCentralCrossRef

186.

Willcox N, Leite MI, Kadota Y, Jones M, Meager A, Subrahmanyam P, Dasgupta B, Morgan BP, Vincent A (2008) Autoimmunizing mechanisms in thymoma and thymus. Ann NY Acad Sci 1132:163–173PubMedCrossRef

187.

Willcox N, Schluep M, Ritter MA, Schuurman HJ, Newsom-Davis J, Christensson B (1987) Myasthenic and nonmyasthenic thymoma. An expansion of a minor cortical epithelial cell subset? Am J Pathol 127:447–460PubMedPubMedCentral

188.

Witte AS, Cornblath DR, Parry GJ, Lisak RP, Schatz NJ (1984) Azathioprine in the treatment of myasthenia gravis. Ann Neurol 15:602–605PubMedCrossRef

189.

Witte AS, Cornblath DR, Schatz NJ, Lisak RP (1986) Monitoring azathioprine therapy in myasthenia gravis. Neurology 36:1533–1534PubMedCrossRef

190.

Wolfe GI, Kaminski HJ, Jaretzki A 3rd, Swan A, Newsom-Davis J (2003) Development of a thymectomy trial in nonthymomatous myasthenia gravis patients receiving immunosuppressive therapy. Ann NY Acad Sci 998:473–480PubMedCrossRef

191.

Yeh JH, Chiu HC (2000) Comparison between double-filtration plasmapheresis and immunoadsorption plasmapheresis in the treatment of patients with myasthenia gravis. J Neurol 247:510–513PubMedCrossRef

192.

Yim AP, Kay RL, Ho JK (1995) Video-assisted thoracoscopic thymectomy for myasthenia gravis. Chest 108:1440–1443PubMedCrossRef

193.

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

194.

Zeitler H, Ulrich-Merzenich G, Hoffmann L, Kornblum C, Schmidt S, Vetter H, Walger P (2006) Long-term effects of a multimodal approach including immunoadsorption for the treatment of myasthenic crisis. Artif Organs 30:597–605PubMedCrossRef

195.

Zhang B, Shen C, Bealmear B, Ragheb S, Xiong WC, Lewis RA, Lisak RP, Mei L (2014) Autoantibodies to agrin in myasthenia gravis patients. PLoS One 9:e91816PubMedPubMedCentralCrossRef

196.

Zhang B, Tzartos JS, Belimezi M, Ragheb S, Bealmear B, Lewis RA, Xiong WC, Lisak RP, Tzartos SJ, Mei L (2012) Autoantibodies to lipoprotein-related protein 4 in patients with double-seronegative myasthenia gravis. Arch Neurol 69:445–451PubMedCrossRef

197.

Zhou L, McConville J, Chaudhry V, Adams RN, Skolasky RL, Vincent A, Drachman DB (2004) Clinical comparison of muscle-specific tyrosine kinase (MuSK) antibody-positive and -negative myasthenic patients. Muscle Nerve 30:55–60PubMedCrossRef

198.

Zinman L, Ng E, Bril V (2007) IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology 68:837–841PubMedCrossRef

199.

Zisimopoulou P, Evangelakou P, Tzartos J, Lazaridis K, Zouvelou V, Mantegazza R, Antozzi C, Andreetta F, Evoli A, Deymeer F, Saruhan-Direskeneli G, Durmus H, Brenner T, Vaknin A, Berrih-Aknin S, Frenkian Cuvelier M, Stojkovic T, DeBaets M, Losen M, Martinez-Martinez P, Kleopa KA, Zamba-Papanicolaou E, Kyriakides T, Kostera-Pruszczyk A, Szczudlik P, Szyluk B, Lavrnic D, Basta I, Peric S, Tallaksen C, Maniaol A, Tzartos SJ (2014) A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun 52:139–145PubMedCrossRef

Title: Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society
Authors: Nico Melzer
Tobias Ruck
Peter Fuhr
Ralf Gold
Reinhard Hohlfeld
Alexander Marx
Arthur Melms
Björn Tackenberg
Berthold Schalke
Christiane Schneider-Gold
Fritz Zimprich
Sven G. Meuth
Heinz Wiendl
Publication date: 01-08-2016
Publisher: Springer Berlin Heidelberg
Published in: Journal of Neurology / Issue 8/2016
Print ISSN: 0340-5354
Electronic ISSN: 1432-1459
DOI: https://doi.org/10.1007/s00415-016-8045-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Clinical features, pathogenesis, and treatment of myasthenia gravis: a supplement to the Guidelines of the German Neurological Society

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 8/2016

PROSPERA: a randomized, controlled trial evaluating rasagiline in progressive supranuclear palsy

Cognition and eating behavior in amyotrophic lateral sclerosis: effect on survival

l-Arginine intervention at hyper-acute phase protects the prolonged MRI abnormality in MELAS

Objective characterization of daily living transitions in patients with Parkinson’s disease using a single body-fixed sensor

Expanding the spectrum of PEX10-related peroxisomal biogenesis disorders: slowly progressive recessive ataxia

A painted staircase illusion to alleviate freezing of gait in Parkinson’s disease