Characteristics of Triple Seronegative Myasthenia Gravis: A Single Center Experience
DOI:
https://doi.org/10.17161/rrnmf.v3i1.14989Keywords:
Myasthenia Gravis, Autoimmune disorders, Neuromuscular junctionAbstract
Background: There is variability in the literature regarding the characteristics of triple seronegative myasthenia gravis (SNMG) patients. Most studies were performed before LRP4 antibodies were discovered, and characterizations of triple seronegative patients are lacking in the literature.
Methods: We retrospectively investigated patients diagnosed with myasthenia gravis (MG) at Ohio State University from 2009 to 2019. Triple SNMG was defined by a history and examination that was consistent with MG and positive SFEMG, RNS or edrophonium testing, but negative serology for AChR, MUSK, and LRP4 antibodies.
Results: A total of 210 AChR+, 9 MuSK+, 6 LRP4+, 9 double SNMG, and 21 triple SNMG patients were reviewed. Triple SNMG patients required significantly fewer immunosuppressive agents compared with AChR+ patients (p=0.0001) and a trend towards a less frequent history of hospitalizations, myasthenic crises and intubations compared to all antibody positive groups. Triple SNMG patients had a significantly higher frequency of ocular disease (33%) compared to AChR+ patients (13%) (p=0.0250). One triple and one double SNMG patient had thymic hyperplasia and improved after thymectomy. 11 triple SNMG patients had negative genetic testing for CMS.
Conclusion: Our results further elucidate the clinical characteristics of triple SNMG, which include the predominance for ocular disease and a less severe disease course. Although likely rare, investigation for thymic pathology should be a consideration even in SNMG, and thymectomy should be considered when there is thymic pathology. We did not find alternate diagnoses in SNMG patients and thus ancillary testing should be considered in carefully selected patients for cost-effective care.
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Lindstrom JM, Seybold ME, Lennon VA, Whittingham S, Duane DD. Antibody to acetylcholine receptor in myasthenia gravis. Prevalence, clinical correlates, and diagnostic value. Neurology, 26(11), 1054-1059 (1976). doi: 10.1212/wnl.26.11.1054
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, 7(3), 365-368 (2001). doi: 10.1038/85520
Higuchi O, Hamuro J, Motomura M, Yamanashi Y. Autoantibodies to low-density lipoprotein receptor-related protein 4 in myasthenia gravis. Ann Neurol, 69(2), 418-422 (2011). doi: 10.1002/ana.22312
Pevzner A, Schoser B, Peters K et al. Anti-LRP4 autoantibodies in AChR- and MuSK-antibody-negative myasthenia gravis. J Neurol, 259(3), 427-435 (2012). doi: 10.1007/s00415-011-6194-7
Rivner MH, Quarles BM, Pan JX et al. Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study. Muscle Nerve, 62(3), 333-343 (2020). doi: 10.1002/mus.26985
Rodriguez Cruz PM, Huda S, López-Ruiz P, Vincent A. Use of cell-based assays in myasthenia gravis and other antibody-mediated diseases. Exp Neurol, 270, 66-71 (2015). doi: 10.1016/j.expneurol.2015.01.011
Hong Y, Zisimopoulou P, Trakas N et al. Multiple antibody detection in 'seronegative' myasthenia gravis patients. Eur J Neurol, 24(6), 844-850 (2017). doi: 10.1111/ene.13300
Leite MI, Jacob S, Viegas S et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain, 131(Pt 7), 1940-1952 (2008). doi: 10.1093/brain/awn092
Feng HY, Wang HY, Liu WB et al. The high frequency and clinical feature of seronegative myasthenia gravis in Southern China. Neurol Sci, 34(6), 919-924 (2013). doi: 10.1007/s10072-012-1159-x
Verma PK, Oger JJ. Seronegative generalized myasthenia gravis: low frequency of thymic pathology. Neurology, 42(3 Pt 1), 586-589 (1992). doi: 10.1212/wnl.42.3.586
Oh SJ. Electrophysiological characteristics in seronegative myasthenia gravis. Ann N Y Acad Sci, 681, 584-587 (1993). doi: 10.1111/j.1749-6632.1993.tb22948.x
Witoonpanich R, Dejthevaporn C, Sriphrapradang A, Pulkes T. Electrophysiological and immunological study in myasthenia gravis: diagnostic sensitivity and correlation. Clin Neurophysiol, 122(9), 1873-1877 (2011). doi: 10.1016/j.clinph.2011.02.026
Garg N, Yiannikas C, Hardy TA et al. Late presentations of congenital myasthenic syndromes: How many do we miss? Muscle Nerve, 54(4), 721-727 (2016). doi: 10.1002/mus.25085
Kao JC, Milone M, Selcen D, Shen XM, Engel AG, Liewluck T. Congenital myasthenic syndromes in adult neurology clinic: A long road to diagnosis and therapy. Neurology, 91(19), e1770-e1777 (2018). doi: 10.1212/WNL.0000000000006478
Madhavan R, Gong ZL, Ma JJ, Chan AW, Peng HB. The function of cortactin in the clustering of acetylcholine receptors at the vertebrate neuromuscular junction. PLoS One, 4(12), e8478 (2009). doi: 10.1371/journal.pone.0008478
Cortés-Vicente E, Gallardo E, Martínez M et al. Clinical Characteristics of Patients With Double-Seronegative Myasthenia Gravis and Antibodies to Cortactin. JAMA Neurol, 73(9), 1099-1104 (2016). doi: 10.1001/jamaneurol.2016.2032
Zhang B, Shen C, Bealmear B et al. Autoantibodies to agrin in myasthenia gravis patients. PLoS One, 9(3), e91816 (2014). doi: 10.1371/journal.pone.0091816
Skeie GO, Aarli JA, Gilhus NE. Titin and ryanodine receptor antibodies in myasthenia gravis. Acta Neurol Scand Suppl, 183, 19-23 (2006). doi: 10.1111/j.1600-0404.2006.00608.x
Stergiou C, Lazaridis K, Zouvelou V et al. Titin antibodies in "seronegative" myasthenia gravis--A new role for an old antigen. J Neuroimmunol, 292, 108-115 (2016). doi: 10.1016/j.jneuroim.2016.01.018
Hong Y, Li HF, Skeie GO et al. Autoantibody profile and clinical characteristics in a cohort of Chinese adult myasthenia gravis patients. J Neuroimmunol, 298, 51-57 (2016). doi: 10.1016/j.jneuroim.2016.07.001
Rodríguez Cruz PM, Al-Hajjar M, Huda S et al. Clinical Features and Diagnostic Usefulness of Antibodies to Clustered Acetylcholine Receptors in the Diagnosis of Seronegative Myasthenia Gravis. JAMA Neurol, 72(6), 642-649 (2015). doi: 10.1001/jamaneurol.2015.0203
Park KH, Waters P, Woodhall M et al. Myasthenia gravis seronegative for acetylcholine receptor antibodies in South Korea: Autoantibody profiles and clinical features. PLoS One, 13(3), e0193723 (2018). doi: 10.1371/journal.pone.0193723
Romi F, Gilhus NE, Aarli JA. Myasthenia gravis: disease severity and prognosis. Acta Neurol Scand Suppl, 183, 24-25 (2006). doi: 10.1111/j.1600-0404.2006.00609.x
Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve, 44(1), 36-40 (2011). doi: 10.1002/mus.22006
Yuan HK, Huang BS, Kung SY, Kao KP. The effectiveness of thymectomy on seronegative generalized myasthenia gravis: comparing with seropositive cases. Acta Neurol Scand, 115(3), 181-184 (2007). doi: 10.1111/j.1600-0404.2006.00733.x
Guillermo GR, Téllez-Zenteno JF, Weder-Cisneros N et al. Response of thymectomy: clinical and pathological characteristics among seronegative and seropositive myasthenia gravis patients. Acta Neurol Scand, 109(3), 217-221 (2004). doi: 10.1034/j.1600-0404.2003.00209.x
Richards J, Howard JF. Seronegative myasthenia gravis associated with malignant thymoma. Neuromuscul Disord, 27(5), 417-418 (2017). doi: 10.1016/j.nmd.2017.01.023
Ponseti JM, Caritg N, Gamez J, López-Cano M, Vilallonga R, Armengol M. A comparison of long-term post-thymectomy outcome of anti-AChR-positive, anti-AChR-negative and anti-MuSK-positive patients with non-thymomatous myasthenia gravis. Expert Opin Biol Ther, 9(1), 1-8 (2009). doi: 10.1517/14712590802588831
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Copyright (c) 2022 Jonathan Morena, Benjamin Jiang, Miriam Freimer, J. Chad Hoyle, Bakri Elsheikh, W. David Arnold, Samantha LoRusso
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