Semin Neurol 2015; 35(04): 327-339
DOI: 10.1055/s-0035-1558975
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Myasthenia Gravis

Kelly G. Gwathmey
1   Department of Neurology, University of Virginia, Charlottesville, Virginia
,
Ted M. Burns
1   Department of Neurology, University of Virginia, Charlottesville, Virginia
› Author Affiliations
Further Information

Publication History

Publication Date:
06 October 2015 (online)

Abstract

Myasthenia gravis is an autoimmune neuromuscular disease caused by antibodies directed against the postsynaptic muscle membrane. The clinical hallmark of the disease is fluctuating and fatigable weakness that affects the ocular muscles (resulting in diplopia and ptosis), the bulbar muscles (causing dysphagia, dysarthria, and dyspnea), and extremity muscles. The diagnosis is most often made with serological testing that identifies either acetylcholine receptor antibodies or muscle-specific tyrosine kinase antibodies. Electrodiagnostic testing has a role in supporting the diagnosis. There are many available treatments that result in improvement of function and quality of life. Treatment should be individualized after consideration of many factors, including disease distribution and severity, patient comorbidities, age, serological status, and what is known about the efficacy and safety of the various treatments.

 
  • References

  • 1 Heldal AT, Owe JF, Gilhus NE, Romi F. Seropositive myasthenia gravis: a nationwide epidemiologic study. Neurology 2009; 73 (2) 150-151
  • 2 Andersen JB, Heldal AT, Engeland A, Gilhus NE. Myasthenia gravis epidemiology in a national cohort; combining multiple disease registries. Acta Neurol Scand Suppl 2014; 129 (198) 26-31
  • 3 McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic literature review. Neuroepidemiology 2010; 34 (3) 171-183
  • 4 Grob D, Brunner N, Namba T, Pagala M. Lifetime course of myasthenia gravis. Muscle Nerve 2008; 37 (2) 141-149
  • 5 Mantegazza R, Baggi F, Antozzi C , et al. Myasthenia gravis (MG): epidemiological data and prognostic factors. Ann N Y Acad Sci 2003; 998: 413-423
  • 6 Pakzad Z, Aziz T, Oger J. Increasing incidence of myasthenia gravis among elderly in British Columbia, Canada. Neurology 2011; 76 (17) 1526-1528
  • 7 Pallaver F, Riviera AP, Piffer S , et al. Change in myasthenia gravis epidemiology in Trento, Italy, after twenty years. Neuroepidemiology 2011; 36 (4) 282-287
  • 8 Matsuda M, Dohi-Iijima N, Nakamura A , et al. Increase in incidence of elderly-onset patients with myasthenia gravis in Nagano Prefecture, Japan. Intern Med 2005; 44 (6) 572-577
  • 9 Phillips LH. The epidemiology of myasthenia gravis. Semin Neurol 2004; 24 (1) 17-20
  • 10 Aragonès JM, Roura-Poch P, Hernández-Ocampo EM , et al. Myasthenia gravis: a disease of the very old. J Am Geriatr Soc 2014; 62 (1) 196-197
  • 11 Aragonès JM, Bolíbar I, Bonfill X , et al. Myasthenia gravis: a higher than expected incidence in the elderly. Neurology 2003; 60 (6) 1024-1026
  • 12 Conti-Fine BM, Milani M, Kaminski HJ. Myasthenia gravis: past, present, and future. J Clin Invest 2006; 116 (11) 2843-2854
  • 13 Jayam Trouth A, Dabi A, Solieman N, Kurukumbi M, Kalyanam J. Myasthenia gravis: a review. Autoimmune Dis [serial online] 2012 ; 2012:874680. Available at: http://www.hindawi.com/journals/ad/2012/874680/ . Accessed February 22, 2015
  • 14 Morgutti M, Conti-Tronconi BM, Sghirlanzoni A, Clementi F. Cellular immune response to acetylcholine receptor in myasthenia gravis: II. Thymectomy and corticosteroids. Neurology 1979; 29 (5) 734-738
  • 15 Tzartos SJ, Kokla A, Walgrave SL, Conti-Tronconi BM. Localization of the main immunogenic region of human muscle acetylcholine receptor to residues 67-76 of the alpha subunit. Proc Natl Acad Sci U S A 1988; 85 (9) 2899-2903
  • 16 DeChiara TM, Bowen DC, Valenzuela DM , et al. The receptor tyrosine kinase MuSK is required for neuromuscular junction formation in vivo. Cell 1996; 85 (4) 501-512
  • 17 Glass DJ, Bowen DC, Stitt TN , et al. Agrin acts via a MuSK receptor complex. Cell 1996; 85 (4) 513-523
  • 18 Zhang B, Luo S, Wang Q, Suzuki T, Xiong WC, Mei L. LRP4 serves as a coreceptor of agrin. Neuron 2008; 60 (2) 285-297
  • 19 Kim N, Stiegler AL, Cameron TO , et al. Lrp4 is a receptor for Agrin and forms a complex with MuSK. Cell 2008; 135 (2) 334-342
  • 20 Lin W, Burgess RW, Dominguez B, Pfaff SL, Sanes JR, Lee KF. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 2001; 410 (6832) 1057-1064
  • 21 Weatherbee SD, Anderson KV, Niswander LA. LDL-receptor-related protein 4 is crucial for formation of the neuromuscular junction. Development 2006; 133 (24) 4993-5000
  • 22 Bruneau EG, Akaaboune M. Dynamics of the rapsyn scaffolding protein at the neuromuscular junction of live mice. J Neurosci 2010; 30 (2) 614-619
  • 23 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 (12) 1246-1252
  • 24 Lennon VA. Serologic profile of myasthenia gravis and distinction from the Lambert-Eaton myasthenic syndrome. Neurology 1997; 48 (Suppl. 05) 23S-27S
  • 25 Verschuuren JJ, Huijbers MG, Plomp JJ , et al. Pathophysiology of myasthenia gravis with antibodies to the acetylcholine receptor, muscle-specific kinase and low-density lipoprotein receptor-related protein 4. Autoimmun Rev 2013; 12 (9) 918-923
  • 26 Sanders DB, Burns TM, Cutter GR, Massey JM, Juel VC, Hobson-Webb L ; Muscle Study Group. Does change in acetylcholine receptor antibody level correlate with clinical change in myasthenia gravis?. Muscle Nerve 2014; 49 (4) 483-486
  • 27 Leite MI, Jacob S, Viegas S , et al. IgG1 antibodies to acetylcholine receptors in ‘seronegative’ myasthenia gravis. Brain 2008; 131 (Pt 7): 1940-1952
  • 28 Romi F, Skeie GO, Gilhus NE, Aarli JA. Striational antibodies in myasthenia gravis: reactivity and possible clinical significance. Arch Neurol 2005; 62 (3) 442-446
  • 29 Cikes N, Momoi MY, Williams CL , et al. Striational autoantibodies: quantitative detection by enzyme immunoassay in myasthenia gravis, thymoma, and recipients of D-penicillamine or allogeneic bone marrow. Mayo Clin Proc 1988; 63 (5) 474-481
  • 30 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; 7 (3) 365-368
  • 31 Vincent A, Leite MI, Farrugia ME , et al. Myasthenia gravis seronegative for acetylcholine receptor antibodies. Ann N Y Acad Sci 2008; 1132: 84-92
  • 32 Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic and clinical classification of autoimmune myasthenia gravis. J Autoimmun 2014; 48–49: 143-148
  • 33 Huijbers MG, Zhang W, Klooster R , et al. MuSK IgG4 autoantibodies cause myasthenia gravis by inhibiting binding between MuSK and Lrp4. Proc Natl Acad Sci U S A 2013; 110 (51) 20783-20788
  • 34 Evoli A, Tonali PA, Padua L , et al. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis. Brain 2003; 126 (Pt 10) 2304-2311
  • 35 Ito A, Sasaki R, Ii Y, Nakayama S, Motomura M, Tomimoto H. [A case of thymoma-associated myasthenia gravis with anti-MuSK antibodies]. Rinsho Shinkeigaku 2013; 53 (5) 372-375
  • 36 Pevzner A, Schoser B, Peters K , et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol 2012; 259 (3) 427-435
  • 37 Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol 2011; 69 (2) 418-422
  • 38 Zisimopoulou P, Evangelakou P, Tzartos J , et al. A comprehensive analysis of the epidemiology and clinical characteristics of anti-LRP4 in myasthenia gravis. J Autoimmun 2014; 52: 139-145
  • 39 Gasperi C, Melms A, Schoser B , et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology 2014; 82 (22) 1976-1983
  • 40 Zhang B, Shen C, Bealmear B , et al. Autoantibodies to agrin in myasthenia gravis patients. PLoS ONE 2014; 9 (3) e91816
  • 41 Gallardo E, Martínez-Hernández E, Titulaer MJ , et al. Cortactin autoantibodies in myasthenia gravis. Autoimmun Rev 2014; 13 (10) 1003-1007
  • 42 Tüzün E, Christadoss P. Complement associated pathogenic mechanisms in myasthenia gravis. Autoimmun Rev 2013; 12 (9) 904-911
  • 43 Nakano S, Engel AG. Myasthenia gravis: quantitative immunocytochemical analysis of inflammatory cells and detection of complement membrane attack complex at the end-plate in 30 patients. Neurology 1993; 43 (6) 1167-1172
  • 44 Guyon T, Levasseur P, Truffault F, Cottin C, Gaud C, Berrih-Aknin S. Regulation of acetylcholine receptor alpha subunit variants in human myasthenia gravis. Quantification of steady-state levels of messenger RNA in muscle biopsy using the polymerase chain reaction. J Clin Invest 1994; 94 (1) 16-24
  • 45 Guyon T, Wakkach A, Poea S , et al. Regulation of acetylcholine receptor gene expression in human myasthenia gravis muscles. Evidences for a compensatory mechanism triggered by receptor loss. J Clin Invest 1998; 102 (1) 249-263
  • 46 Fujii Y. Thymus, thymoma and myasthenia gravis. Surg Today 2013; 43 (5) 461-466
  • 47 Berrih-Aknin S, Le Panse R. Myasthenia gravis: a comprehensive review of immune dysregulation and etiological mechanisms. J Autoimmun 2014; 52: 90-100
  • 48 Weiss JM, Cufi P, Le Panse R, Berrih-Aknin S. The thymus in autoimmune Myasthenia Gravis: Paradigm for a tertiary lymphoid organ. Rev Neurol (Paris) 2013; 169 (8–9) 640-649
  • 49 Akaishi T, Yamaguchi T, Suzuki Y , et al. Insights into the classification of myasthenia gravis. PLoS ONE 2014; 9 (9) e106757
  • 50 Marx A, Pfister F, Schalke B, Saruhan-Direskeneli G, Melms A, Ströbel P. The different roles of the thymus in the pathogenesis of the various myasthenia gravis subtypes. Autoimmun Rev 2013; 12 (9) 875-884
  • 51 Jaretzki III A, Barohn RJ, Ernstoff RM , et al; Task Force of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Myasthenia gravis: recommendations for clinical research standards. Neurology 2000; 55 (1) 16-23
  • 52 Grob D, Arsura EL, Brunner NG, Namba T. The course of myasthenia gravis and therapies affecting outcome. Ann N Y Acad Sci 1987; 505: 472-499
  • 53 Karacostas D, Mavromatis I, Georgakoudas G, Artemis N, Milonas I. Isolated distal hand weakness as the only presenting symptom of myasthenia gravis. Eur J Neurol 2002; 9 (4) 429-430
  • 54 Fitzgerald MG, Shafritz AB. Distal myasthenia gravis. J Hand Surg Am 2014; 39 (7) 1419-1420
  • 55 Spillane J, Beeson DJ, Kullmann DM. Myasthenia and related disorders of the neuromuscular junction. J Neurol Neurosurg Psychiatry 2010; 81 (8) 850-857
  • 56 Sanders DB, El-Salem K, Massey JM, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG. Neurology 2003; 60 (12) 1978-1980
  • 57 Sanders DB, Guptill JT. Myasthenia gravis and Lambert-Eaton myasthenic syndrome. Continuum (Minneap Minn) 2014; 20 (5 Peripheral Nervous System Disorders): 1413-1425
  • 58 Cosi V, Romani A, Lombardi M , et al. Prognosis of myasthenia gravis: a retrospective study of 380 patients. J Neurol 1997; 244 (9) 548-555
  • 59 Phillips II LH. The epidemiology of myasthenia gravis. Ann N Y Acad Sci 2003; 998: 407-412
  • 60 Ropper AH, Gress DR, Diringer MN, Green DM, Mayer SABT. Treatment of the critically ill patient with myasthenia gravis. . In: Neurological and Neurosurgical Intensive Care. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2004: 299-311
  • 61 Cohen MS, Younger D. Aspects of the natural history of myasthenia gravis: crisis and death. Ann N Y Acad Sci 1981; 377: 670-677
  • 62 Kalita J, Kohat AK, Misra UK. Predictors of outcome of myasthenic crisis. Neurol Sci 2014; 35 (7) 1109-1114
  • 63 Juel VC, Massey JM. Myasthenia gravis. Orphanet J Rare Dis 2007; 2: 44
  • 64 Cogan DG. Myasthenia gravis: A review of the disease and a description of lid twitch as a characteristic sign. Arch Ophthalmol 1965; 74: 217-221
  • 65 Furukawa T, Tsukagoshi H. Bell's phenomenon in diagnosis of myasthenia gravis. Lancet 1984; 2 (8411) 1090-1091
  • 66 Pal S, Sanyal D. Jaw muscle weakness: a differential indicator of neuromuscular weakness—preliminary observations. Muscle Nerve 2011; 43 (6) 807-811
  • 67 Chan KH, Lachance DH, Harper CM, Lennon VA. Frequency of seronegativity in adult-acquired generalized myasthenia gravis. Muscle Nerve 2007; 36 (5) 651-658
  • 68 Benatar M. A systematic review of diagnostic studies in myasthenia gravis. Neuromuscul Disord 2006; 16 (7) 459-467
  • 69 Witoonpanich R, Dejthevaporn C, Sriphrapradang A, Pulkes T. Electrophysiological and immunological study in myasthenia gravis: diagnostic sensitivity and correlation. Clin Neurophysiol 2011; 122 (9) 1873-1877
  • 70 Rubin DI, Hentschel K. Is exercise necessary with repetitive nerve stimulation in evaluating patients with suspected myasthenia gravis?. Muscle Nerve 2007; 35 (1) 103-106
  • 71 Howard Jr JF. Electrodiagnosis of disorders of neuromuscular transmission. Phys Med Rehabil Clin N Am 2013; 24 (1) 169-192
  • 72 Iwanami T, Sonoo M, Hatanaka Y, Hokkoku K, Oishi C, Shimizu T. Decremental responses to repetitive nerve stimulation (RNS) in motor neuron disease. Clin Neurophysiol 2011; 122 (12) 2530-2536
  • 73 Daube JR. Electrophysiologic studies in the diagnosis and prognosis of motor neuron diseases. Neurol Clin 1985; 3 (3) 473-493
  • 74 Kelly Jr JJ, Baquis GA, Adelman LS, Munsat TL. Neuromuscular transmission defect in inherited polyneuropathy. Bull Clin Neurosci 1985; 50: 102-110
  • 75 Gilchrist JM, Sanders DB. Myasthenic U-shaped decrement in multifocal cervical radiculopathy. Muscle Nerve 1989; 12 (1) 64-66
  • 76 Priola AM, Priola SM. Imaging of thymus in myasthenia gravis: from thymic hyperplasia to thymic tumor. Clin Radiol 2014; 69 (5) e230-e245
  • 77 Osserman KE, Kaplan LI. Rapid diagnostic test for myasthenia gravis: increased muscle strength, without fasciculations, after intravenous administration of edrophonium (tensilon) chloride. J Am Med Assoc 1952; 150 (4) 265-268
  • 78 Nicholson GA, McLeod JG, Griffiths LR. Comparison of diagnostic tests in myasthenia gravis. Clin Exp Neurol 1983; 19: 45-49
  • 79 Sethi KD, Rivner MH, Swift TR. Ice pack test for myasthenia gravis. Neurology 1987; 37 (8) 1383-1385
  • 80 Czaplinski A, Steck AJ, Fuhr P. Ice pack test for myasthenia gravis. A simple, noninvasive and safe diagnostic method. J Neurol 2003; 250 (7) 883-884
  • 81 Kubis KC, Danesh-Meyer HV, Savino PJ, Sergott RC. The ice test versus the rest test in myasthenia gravis. Ophthalmology 2000; 107 (11) 1995-1998
  • 82 Chatzistefanou KI, Kouris T, Iliakis E , et al. The ice pack test in the differential diagnosis of myasthenic diplopia. Ophthalmology 2009; 116 (11) 2236-2243
  • 83 Fakiri MO, Tavy DLJ, Hama-Amin AD, Wirtz PW. Accuracy of the ice test in the diagnosis of myasthenia gravis in patients with ptosis. Muscle Nerve 2013; 48 (6) 902-904
  • 84 Breyer-Pfaff U, Schmezer A, Maier U, Brinkmann A, Schumm F. Neuromuscular function and plasma drug levels in pyridostigmine treatment of myasthenia gravis. J Neurol Neurosurg Psychiatry 1990; 53 (6) 502-506
  • 85 Punga AR, Sawada M, Stålberg EV. Electrophysiological signs and the prevalence of adverse effects of acetylcholinesterase inhibitors in patients with myasthenia gravis. Muscle Nerve 2008; 37 (3) 300-307
  • 86 Bosch EP, Subbiah B, Ross MA. Cholinergic crisis after conventional doses of anticholinesterase medications in chronic renal failure. Muscle Nerve 1991; 14 (10) 1036-1037
  • 87 Hetherington KA, Losek JD. Myasthenia gravis: myasthenia vs. cholinergic crisis. Pediatr Emerg Care 2005; 21 (8) 546-548 , quiz 549–551
  • 88 Gilhus NE, Owe JF, Hoff JM, Romi F, Skeie GO, Aarli JA. Myasthenia gravis: a review of available treatment approaches. Autoimmune Dis 2011; 2011: 847393
  • 89 Hatanaka Y, Hemmi S, Morgan MB , et al. Nonresponsiveness to anticholinesterase agents in patients with MuSK-antibody-positive MG. Neurology 2005; 65 (9) 1508-1509
  • 90 Bhanushali MJ, Wuu J, Benatar M. Treatment of ocular symptoms in myasthenia gravis. Neurology 2008; 71 (17) 1335-1341
  • 91 Bedlack RS, Sanders DB. Steroid treatment for myasthenia gravis: steroids have an important role. Muscle Nerve 2002; 25 (1) 117-121
  • 92 Burns TM. History of outcome measures for myasthenia gravis. Muscle Nerve 2010; 42 (1) 5-13
  • 93 Pascuzzi RM, Coslett HB, Johns TR. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients. Ann Neurol 1984; 15 (3) 291-298
  • 94 Millikan CH, Eaton LM. Clinical-evaluation of ACTH and cortisone in myasthenia gravis. Neurology 1951; 1 (2) 145-152
  • 95 Grob D, Harvey AM. Effect of adrenocorticotropic hormone (ACTH) and cortisone administration in patients with myasthenia gravis and report of onset of myasthenia gravis during prolonged cortisone administration. Bull Johns Hopkins Hosp 1952; 91 (2) 124-136
  • 96 Bae JS, Go SM, Kim BJ. Clinical predictors of steroid-induced exacerbation in myasthenia gravis. J Clin Neurosci 2006; 13 (10) 1006-1010
  • 97 Skeie GO, Apostolski S, Evoli A , et al; European Federation of Neurological Societies. Guidelines for treatment of autoimmune neuromuscular transmission disorders. Eur J Neurol 2010; 17 (7) 893-902
  • 98 Silvestri NJ, Wolfe GI. Myasthenia gravis. Semin Neurol 2012; 32 (3) 215-226
  • 99 Warmolts JR, Engel WK. Benefit from alternate-day prednisone in myasthenia gravis. N Engl J Med 1972; 286 (1) 17-20
  • 100 Hoffmann S, Kohler S, Ziegler A, Meisel A. Glucocorticoids in myasthenia gravis - if, when, how, and how much?. Acta Neurol Scand 2014; 130 (4) 211-221
  • 101 Miano MA, Bosley TM, Heiman-Patterson TD , et al. Factors influencing outcome of prednisone dose reduction in myasthenia gravis. Neurology 1991; 41 (6) 919-921
  • 102 Pascuzzi RM. The history of myasthenia gravis. Neurol Clin 1994; 12 (2) 231-242
  • 103 Lanska DJ. Indications for thymectomy in myasthenia gravis. Neurology 1990; 40 (12) 1828-1829
  • 104 Gold R, Hohlfeld R, Toyka KV. Progress in the treatment of myasthenia gravis. Ther Adv Neurol Disord 2008; 1 (2) 36-51
  • 105 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 (1) 7-15
  • 106 Luo Y, Pan DJ, Chen FF, Zhu MH, Wang J, Zhang M. Effectiveness of thymectomy in non-thymomatous myasthenia gravis: a systematic review. J Huazhong Univ Sci Technolog Med Sci 2014; 34 (6) 942-949
  • 107 Yu S, Li F, Chen B , et al. Eight-year follow-up of patients with myasthenia gravis after thymectomy. Acta Neurol Scand 2015; 131 (2) 94-101
  • 108 Spillane J, Hayward M, Hirsch NP, Taylor C, Kullmann DM, Howard RS. Thymectomy: role in the treatment of myasthenia gravis. J Neurol 2013; 260 (7) 1798-1801
  • 109 Barnett C, Katzberg HD, Keshavjee S, Bril V. Thymectomy for non-thymomatous myasthenia gravis: a propensity score matched study. Orphanet J Rare Dis 2014; 9 (1) 214
  • 110 Diaz A, Black E, Dunning J. Is thymectomy in non-thymomatous myasthenia gravis of any benefit?. Interact Cardiovasc Thorac Surg 2014; 18 (3) 381-389
  • 111 Batocchi AP, Evoli A, Di Schino C, Tonali P. Therapeutic apheresis in myasthenia gravis. Ther Apher 2000; 4 (4) 275-279
  • 112 Lünemann JD, Nimmerjahn F, Dalakas MC. Intravenous immunoglobulin in neurology—mode of action and clinical efficacy. Nat Rev Neurol 2015; 11 (2) 80-89
  • 113 Barth D, Nabavi Nouri M, Ng E, Nwe P, Bril V. Comparison of IVIg and PLEX in patients with myasthenia gravis. Neurology 2011; 76 (23) 2017-2023
  • 114 Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C ; Myasthenia Gravis Clinical Study Group. Clinical trial of plasma exchange and high-dose intravenous immunoglobulin in myasthenia gravis. Ann Neurol 1997; 41 (6) 789-796
  • 115 Gajdos P, Tranchant C, Clair B , et al; Myasthenia Gravis Clinical Study Group. Treatment of myasthenia gravis exacerbation with intravenous immunoglobulin: a randomized double-blind clinical trial. Arch Neurol 2005; 62 (11) 1689-1693
  • 116 Rønager J, Ravnborg M, Hermansen I, Vorstrup S. Immunoglobulin treatment versus plasma exchange in patients with chronic moderate to severe myasthenia gravis. Artif Organs 2001; 25 (12) 967-973
  • 117 Wolfe GI, Barohn RJ, Foster BM , et al; Myasthenia Gravis-IVIG Study Group. Randomized, controlled trial of intravenous immunoglobulin in myasthenia gravis. Muscle Nerve 2002; 26 (4) 549-552
  • 118 Zinman L, Ng E, Bril V. IV immunoglobulin in patients with myasthenia gravis: a randomized controlled trial. Neurology 2007; 68 (11) 837-841
  • 119 Gajdos P, Chevret S, Toyka KV. Intravenous immunoglobulin for myasthenia gravis. Cochrane Database Syst Rev 2012; 12: CD002277
  • 120 Bril V, Barnett-Tapia C, Barth D, Katzberg HD. IVIG and PLEX in the treatment of myasthenia gravis. Ann N Y Acad Sci 2012; 1275: 1-6
  • 121 Heatwole C, Johnson N, Holloway R, Noyes K. Plasma exchange versus intravenous immunoglobulin for myasthenia gravis crisis: an acute hospital cost comparison study. J Clin Neuromuscul Dis 2011; 13 (2) 85-94
  • 122 Eienbröker C, Seitz F, Spengler A , et al. Intravenous immunoglobulin maintenance treatment in myasthenia gravis: a randomized, controlled trial sample size simulation. Muscle Nerve 2014; 50 (6) 999-1004
  • 123 Plasma Exchange/Sandoglobulin Guillain-Barré Syndrome Trial Group. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Lancet 1997; 349 (9047) 225-230
  • 124 Sanders DB, Evoli A. Immunosuppressive therapies in myasthenia gravis. Autoimmunity 2010; 43 (5–6) 428-435
  • 125 Ciafaloni E, Massey JM, Tucker-Lipscomb B, Sanders DB. Mycophenolate mofetil for myasthenia gravis: an open-label pilot study. Neurology 2001; 56 (1) 97-99
  • 126 Meriggioli MN, Ciafaloni E, Al-Hayk KA , et al. Mycophenolate mofetil for myasthenia gravis: an analysis of efficacy, safety, and tolerability. Neurology 2003; 61 (10) 1438-1440
  • 127 Hehir MK, Burns TM, Alpers J, Conaway MR, Sawa M, Sanders DB. Mycophenolate mofetil in AChR-antibody-positive myasthenia gravis: outcomes in 102 patients. Muscle Nerve 2010; 41 (5) 593-598
  • 128 Hanisch F, Wendt M, Zierz S. Mycophenolate mofetil as second line immunosuppressant in Myasthenia gravis—a long-term prospective open-label study. Eur J Med Res 2009; 14 (8) 364-366
  • 129 Sanders DB, Hart IK, Mantegazza R , et al. An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis. Neurology 2008; 71 (6) 400-406
  • 130 Sanders DB ; Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008; 71 (6) 394-399
  • 131 Phan C, Sanders DB, Siddiqi ZA. Mycophenolate mofetil in myasthenia gravis: the unanswered question. Expert Opin Pharmacother 2008; 9 (14) 2545-2551
  • 132 Sanders DB, Siddiqi ZA. Lessons from two trials of mycophenolate mofetil in myasthenia gravis. Ann N Y Acad Sci 2008; 1132: 249-253
  • 133 Mantegazza R, Beghi E, Pareyson D , et al. A multicentre follow-up study of 1152 patients with myasthenia gravis in Italy. J Neurol 1990; 237 (6) 339-344
  • 134 Beghi E, Antozzi C, Batocchi AP , et al. Prognosis of myasthenia gravis: a multicenter follow-up study of 844 patients. J Neurol Sci 1991; 106 (2) 213-220
  • 135 Ginzler EM, Aranow C. Mycophenolate mofetil in lupus nephritis. Lupus 2005; 14 (1) 59-64
  • 136 Heckmann JM, Rawoot A, Bateman K, Renison R, Badri M. A single-blinded trial of methotrexate versus azathioprine as steroid-sparing agents in generalized myasthenia gravis. BMC Neurol 2011; 11: 97
  • 137 Buzzard KA, Meyer NJ, Hardy TA, Riminton DS, Reddel SW. Induction IV cyclophosphamide followed by maintenance oral immunosuppression in refractory myasthenia gravis. Muscle Nerve 2014; ; Epub ahead of print
  • 138 Nagappa M, Netravathi M, Taly AB, Sinha S, Bindu PS, Mahadevan A. Long-term efficacy and limitations of cyclophosphamide in myasthenia gravis. J Clin Neurosci 2014; 21 (11) 1909-1914
  • 139 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 (12) 719-724
  • 140 Tindall RS, Phillips JT, Rollins JA, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis. Ann N Y Acad Sci 1993; 681: 539-551
  • 141 Kumar V, Kaminski HJ. Treatment of myasthenia gravis. Curr Neurol Neurosci Rep 2011; 11 (1) 89-96
  • 142 Konishi T, Yoshiyama Y, Takamori M, Yagi K, Mukai E, Saida T ; Japanese FK506 MG Study Group. Clinical study of FK506 in patients with myasthenia gravis. Muscle Nerve 2003; 28 (5) 570-574
  • 143 Schneider-Gold C, Hartung HP, Gold R. Mycophenolate mofetil and tacrolimus: new therapeutic options in neuroimmunological diseases. Muscle Nerve 2006; 34 (3) 284-291
  • 144 Ponseti JM, Azem J, Fort JM , et al. Long-term results of tacrolimus in cyclosporine- and prednisone-dependent myasthenia gravis. Neurology 2005; 64 (9) 1641-1643
  • 145 Nagane Y, Utsugisawa K, Obara D, Kondoh R, Terayama Y. Efficacy of low-dose FK506 in the treatment of myasthenia gravis—a randomized pilot study. Eur Neurol 2005; 53 (3) 146-150
  • 146 Ponseti JM, Gamez J, Azem J, López-Cano M, Vilallonga R, Armengol M. Tacrolimus for myasthenia gravis: a clinical study of 212 patients. Ann N Y Acad Sci 2008; 1132: 254-263
  • 147 Yoshikawa H, Kiuchi T, Saida T, Takamori M. Randomised, double-blind, placebo-controlled study of tacrolimus in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011; 82 (9) 970-977
  • 148 Yagi Y, Sanjo N, Yokota T, Mizusawa H. Tacrolimus monotherapy: a promising option for ocular myasthenia gravis. Eur Neurol 2013; 69 (6) 344-345
  • 149 Díaz-Manera J, Martínez-Hernández E, Querol L , et al. Long-lasting treatment effect of rituximab in MuSK myasthenia. Neurology 2012; 78 (3) 189-193
  • 150 Keung B, Robeson KR, DiCapua DB , et al. Long-term benefit of rituximab in MuSK autoantibody myasthenia gravis patients. J Neurol Neurosurg Psychiatry 2013; 84 (12) 1407-1409
  • 151 Burusnukul P, Brennan TD, Cupler EJ. Prolonged improvement after rituximab: two cases of resistant muscle-specific receptor tyrosine kinase + myasthenia gravis. J Clin Neuromuscul Dis 2010; 12 (2) 85-87
  • 152 Stein B, Bird SJ. Rituximab in the treatment of MuSK antibody-positive myasthenia gravis. J Clin Neuromuscul Dis 2011; 12 (3) 163-164
  • 153 Thakre M, Inshasi J, Marashi M. Rituximab in refractory MuSK antibody myasthenia gravis. J Neurol 2007; 254 (7) 968-969
  • 154 Hain B, Jordan K, Deschauer M, Zierz S. Successful treatment of MuSK antibody-positive myasthenia gravis with rituximab. Muscle Nerve 2006; 33 (4) 575-580
  • 155 Nowak RJ, Dicapua DB, Zebardast N, Goldstein JM. Response of patients with refractory myasthenia gravis to rituximab: a retrospective study. Ther Adv Neurol Disord 2011; 4 (5) 259-266
  • 156 Iorio R, Damato V, Alboini PE, Evoli A. Efficacy and safety of rituximab for myasthenia gravis: a systematic review and meta-analysis. J Neurol 2015; 262 (5) 1115-1119
  • 157 Roll P, Palanichamy A, Kneitz C, Dorner T, Tony HP. Regeneration of B cell subsets after transient B cell depletion using anti-CD20 antibodies in rheumatoid arthritis. Arthritis Rheum 2006; 54 (8) 2377-2386
  • 158 Yi JS, Decroos EC, Sanders DB, Weinhold KJ, Guptill JT. Prolonged B-cell depletion in MuSK myasthenia gravis following rituximab treatment. Muscle Nerve 2013; 48 (6) 992-993
  • 159 Blum S, Gillis D, Brown H , et al. Use and monitoring of low dose rituximab in myasthenia gravis. J Neurol Neurosurg Psychiatry 2011; 82 (6) 659-663
  • 160 Sun F, Ladha SS, Yang L , et al. Interleukin-10 producing-B cells and their association with responsiveness to rituximab in myasthenia gravis. Muscle Nerve 2014; 49 (4) 487-494
  • 161 Carson KR, Evens AM, Richey EA , et al. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project. Blood 2009; 113 (20) 4834-4840
  • 162 Reff ME, Carner K, Chambers KS , et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994; 83 (2) 435-445
  • 163 Bruce BB, Kupersmith MJ. Safety of prednisone for ocular myasthenia gravis. J Neuroophthalmol 2012; 32 (3) 212-215
  • 164 Kerty E, Elsais A, Argov Z, Evoli A, Gilhus NE. EFNS/ENS Guidelines for the treatment of ocular myasthenia. Eur J Neurol 2014; 21 (5) 687-693
  • 165 Zach H, Cetin H, Hilger E , et al. The effect of early prednisolone treatment on the generalization rate in ocular myasthenia gravis. Eur J Neurol 2013; 20 (4) 708-713
  • 166 Kupersmith MJ, Latkany R, Homel P. Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol 2003; 60 (2) 243-248
  • 167 Papapetropoulos TH, Ellul J, Tsibri E. Development of generalized myasthenia gravis in patients with ocular myasthenia gravis. Arch Neurol 2003; 60 (10) 1491-1492
  • 168 Mee J, Paine M, Byrne E, King J, Reardon K, O'Day J. Immunotherapy of ocular myasthenia gravis reduces conversion to generalized myasthenia gravis. J Neuroophthalmol 2003; 23 (4) 251-255
  • 169 Monsul NT, Patwa HS, Knorr AM, Lesser RL, Goldstein JM. The effect of prednisone on the progression from ocular to generalized myasthenia gravis. J Neurol Sci 2004; 217 (2) 131-133
  • 170 Hong YH, Kwon SB, Kim BJ , et al; Korean Research Group for Neuromuscular Diseases. Prognosis of ocular myasthenia in Korea: a retrospective multicenter analysis of 202 patients. J Neurol Sci 2008; 273 (1–2) 10-14
  • 171 Burns TM, Grouse CK, Wolfe GI, Conaway MR, Sanders DB ; MG Composite and MG-OL15 Study Group. The MG-QOL15 for following the health-related quality of life of patients with myasthenia gravis. Muscle Nerve 2011; 43 (1) 14-18
  • 172 Burns TM, Conaway MR, Cutter GR, Sanders DB ; Muscle Study Group. Less is more, or almost as much: a 15-item quality-of-life instrument for myasthenia gravis. Muscle Nerve 2008; 38 (2) 957-963
  • 173 Burns TM, Conaway M, Sanders DB ; MG Composite and MG-QOL15 Study Group. The MG Composite: a valid and reliable outcome measure for myasthenia gravis. Neurology 2010; 74 (18) 1434-1440
  • 174 Burns TM, Conaway MR, Cutter GR, Sanders DB ; Muscle Study Group. Construction of an efficient evaluative instrument for myasthenia gravis: the MG composite. Muscle Nerve 2008; 38 (6) 1553-1562
  • 175 Benatar M, Sanders DB, Burns TM , et al; Task Force on MG Study Design of the Medical Scientific Advisory Board of the Myasthenia Gravis Foundation of America. Recommendations for myasthenia gravis clinical trials. Muscle Nerve 2012; 45 (6) 909-917
  • 176 Burns TM. The MG composite: an outcome measure for myasthenia gravis for use in clinical trials and everyday practice. Ann N Y Acad Sci 2012; 1274: 99-106