Journal of Pediatric Neurology 2021; 19(03): 143-152
DOI: 10.1055/s-0040-1721401
Review Article

Pediatric Ocular Myasthenia Gravis: A Review

Reena Jain
1   Department of Pediatrics, Government Medical College & Hospital, Chandigarh, India
,
1   Department of Pediatrics, Government Medical College & Hospital, Chandigarh, India
› Author Affiliations
Funding None.

Abstract

Pediatric ocular myasthenia gravis (OMG) is difficult to diagnose and manage, owing to its rarity and low index of suspicion in the early stage of the disease. Also, many other conditions having similar presentation cause a further delay in diagnosis. In this review, we highlighted various pointers in history and described bedside clinical tests that can aid in its timely diagnosis. The antibody spectrum in myasthenia is ever increasing and includes anti-muscle specific kinase and low-density lipoprotein-receptor related protein 4 antibodies in addition to acetylcholine receptor antibodies besides many others. However, pediatric OMG patients often test negative for all three antibodies, making the diagnosis even more difficult in triple seronegative patients. Edrophonium and electrophysiological tests, which help in confirming myasthenia in adults, have a limited utility in diagnosing pediatric ocular myasthenia cases. Various practical difficulties are encountered like nonavailability of edrophonium, risk of bradycardia associated with neostigmine use and its lower sensitivity, noncooperative children, and limited technical expertise in performing electrophysiological tests in children. In this article, we described a pragmatic approach to diagnose pediatric OMG along with the important aspects of its management.



Publication History

Received: 14 July 2020

Accepted: 26 October 2020

Article published online:
18 December 2020

© 2020. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 
  • References

  • 1 Finnis MF, Jayawant S. Juvenile myasthenia gravis: a paediatric perspective. Autoimmune Dis 2011; 2011: 404101
  • 2 Luchanok U, Kaminski HJ. Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 2008; 21 (01) 8-15
  • 3 Phillips II LH, Torner JC, Anderson MS, Cox GM. The epidemiology of myasthenia gravis in central and western Virginia. Neurology 1992; 42 (10) 1888-1893
  • 4 Andrews PI, Massey JM, Howard Jr JFJ, Sanders DB. Race, sex, and puberty influence onset, severity, and outcome in juvenile myasthenia gravis. Neurology 1994; 44 (07) 1208-1214
  • 5 Evoli A, Batocchi AP, Bartoccioni E, Lino MM, Minisci C, Tonali P. Juvenile myasthenia gravis with prepubertal onset. Neuromuscul Disord 1998; 8 (08) 561-567
  • 6 Batocchi AP, Evoli A, Palmisani MT, Lo Monaco M, Bartoccioni M, Tonali P. Early-onset myasthenia gravis: clinical characteristics and response to therapy. Eur J Pediatr 1990; 150 (01) 66-68
  • 7 VanderPluym J, Vajsar J, Jacob FD, Mah JK, Grenier D, Kolski H. Clinical characteristics of pediatric myasthenia: a surveillance study. Pediatrics 2013; 132 (04) e939-e944
  • 8 Zhang X, Yang M, Xu J. et al. Clinical and serological study of myasthenia gravis in HuBei Province, China. J Neurol Neurosurg Psychiatry 2007; 78 (04) 386-390
  • 9 Mao ZF, Yang LX, Mo XA. et al. Frequency of autoimmune diseases in myasthenia gravis: a systematic review. Int J Neurosci 2011; 121 (03) 121-129
  • 10 Rodriguez M, Gomez MR, Howard Jr FM, Taylor WF. Myasthenia gravis in children: long-term follow-up. Ann Neurol 1983; 13 (05) 504-510
  • 11 Kimura K, Nezu A, Kimura S. et al. A case of myasthenia gravis in childhood associated with chronic inflammatory demyelinating polyradiculoneuropathy. Neuropediatrics 1998; 29 (02) 108-112
  • 12 Leite MI, Coutinho E, Lana-Peixoto M. et al. Myasthenia gravis and neuromyelitis optica spectrum disorder: a multicenter study of 16 patients. Neurology 2012; 78 (20) 1601-1607
  • 13 Melbourne Chambers R, Forrester S, Gray R, Tapper J, Trotman H. Myasthenia gravis in Jamaican children: a 12-year institutional review. Paediatr Int Child Health 2012; 32 (01) 47-50
  • 14 Yang ZX, Xu KL, Xiong H. Clinical characteristics and therapeutic evaluation of childhood myasthenia gravis. Exp Ther Med 2015; 9 (04) 1363-1368
  • 15 Huang X, Liu WB, Men LN. et al. Clinical features of myasthenia gravis in southern China: a retrospective review of 2,154 cases over 22 years. Neurol Sci 2013; 34 (06) 911-917
  • 16 Xu L, Castro D, Reisch JS, Iannaccone ST. Response to treatment in pediatric ocular myasthenia gravis. Muscle Nerve 2020; 61 (02) 226-230
  • 17 Andrews PI. Autoimmune myasthenia gravis in childhood. Semin Neurol 2004; 24 (01) 101-110
  • 18 Burden SJ, Yumoto N, Zhang W. The role of MuSK in synapse formation and neuromuscular disease. Cold Spring Harb Perspect Biol 2013; 5 (05) a009167
  • 19 Fujii Y, Monden Y, Nakahara K, Hashimoto J, Kawashima Y. Antibody to acetylcholine receptor in myasthenia gravis: production by lymphocytes from thymus or thymoma. Neurology 1984; 34 (09) 1182-1186
  • 20 Hayashi A, Shiono H, Ohta M, Ohta K, Okumura M, Sawa Y. Heterogeneity of immunopathological features of AChR/MuSK autoantibody-negative myasthenia gravis. J Neuroimmunol 2007; 189 (1-2): 163-168
  • 21 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
  • 22 Lindner A, Schalke B, Toyka KV. Outcome in juvenile-onset myasthenia gravis: a retrospective study with long-term follow-up of 79 patients. J Neurol 1997; 244 (08) 515-520
  • 23 He D, Zhang H, Xiao J. et al. Molecular and clinical relationship between live-attenuated Japanese encephalitis vaccination and childhood onset myasthenia gravis. Ann Neurol 2018; 84 (03) 386-400
  • 24 Motobayashi M, Inaba Y, Nishimura T, Kobayashi N, Nakazawa Y, Koike K. An increase in circulating B cell-activating factor in childhood-onset ocular myasthenia gravis. Pediatr Neurol 2015; 52 (04) 404-409
  • 25 Motobayashi M, Nishimura T, Inaba Y. Usefulness of circulating B-cell activating factor serial monitoring in childhood-onset ocular myasthenia gravis. Pediatr Neurol 2016; 63: e1-e2
  • 26 Grigg J. Extraocular muscles: relationship of structure and function to disease. Aust N Z J Ophthalmol 1999; 27 (06) 369-370
  • 27 Sommer N, Melms A, Weller M, Dichgans J. Ocular myasthenia gravis. A critical review of clinical and pathophysiological aspects. Doc Ophthalmol 1993; 84 (04) 309-333
  • 28 Antonio. Santos AA, Eggenberger ER. Medical treatment options for ocular myasthenia gravis. Curr Opin Ophthalmol 2008; 19: 468-478
  • 29 Serra A, Ruff RL, Leigh RJ. Neuromuscular transmission failure in myasthenia gravis: decrement of safety factor and susceptibility of extraocular muscles. Ann N Y Acad Sci 2012; 1275: 129-135
  • 30 Weinberg DA, Lesser RL, Vollmer TL. Ocular myasthenia: a protean disorder. Surv Ophthalmol 1994; 39 (03) 169-210
  • 31 Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics 2014; 45 (02) 75-83
  • 32 Chiang LM, Darras BT, Kang PB. Juvenile myasthenia gravis. Muscle Nerve 2009; 39 (04) 423-431
  • 33 Kim JH, Hwang JM, Hwang YS, Kim KJ, Chae J. Childhood ocular myasthenia gravis. Ophthalmology 2003; 110 (07) 1458-1462
  • 34 Ortiz S, Borchert M. Long-term outcomes of pediatric ocular myasthenia gravis. Ophthalmology 2008; 115 (07) 1245-1248.e1
  • 35 Pineles SL, Avery RA, Moss HE. et al. Visual and systemic outcomes in pediatric ocular myasthenia gravis. Am J Ophthalmol 2010; 150 (04) 453-459.e3
  • 36 Vanikieti K, Lowwongngam K, Padungkiatsagul T, Visudtibhan A, Poonyathalang A. Juvenile ocular myasthenia gravis: presentation and outcome of a large cohort. Pediatr Neurol 2018; 87: 36-41
  • 37 Guterman EL, Botelho JV, Horton JC. Diagnosis of tensilon-negative ocular myasthenia gravis by daily selfie. J Neuroophthalmol 2016; 36 (03) 292-293
  • 38 Lepore FE, Sanborn GE, Slevin JT. Pupillary dysfunction in myasthenia gravis. Ann Neurol 1979; 6 (01) 29-33
  • 39 Nair AG, Patil-Chhablani P, Venkatramani DV, Gandhi RA. Ocular myasthenia gravis: a review. Indian J Ophthalmol 2014; 62 (10) 985-991
  • 40 Alam MS, Devi Nivean P. Early onset bilateral juvenile myasthenia gravis masquerading as simple congenital ptosis. GMS Ophthalmol Cases 2017; 7: Doc07
  • 41 Smith SV, Lee AG. Update on ocular myasthenia gravis. Neurol Clin 2017; 35 (01) 115-123
  • 42 Okun MS, Charriez CM, Bhatti MT, Watson RT, Swift TR. Asystole induced by edrophonium following beta blockade. Neurology 2001; 57 (04) 739-740
  • 43 Afifi AK, Bell WE. Tests for juvenile myasthenia gravis: comparative diagnostic yield and prediction of outcome. J Child Neurol 1993; 8 (04) 403-411
  • 44 Vincent A, Leite MI. Neuromuscular junction autoimmune disease: muscle specific kinase antibodies and treatments for myasthenia gravis. Curr Opin Neurol 2005; 18 (05) 519-525
  • 45 Evoli A, Alboini PE, Damato V. et al. Myasthenia gravis with antibodies to MuSK: an update. Ann N Y Acad Sci 2018; 1412 (01) 82-89
  • 46 Hanisch F, Eger K, Zierz S. MuSK-antibody positive pure ocular myasthenia gravis. J Neurol 2006; 253 (05) 659-660
  • 47 Hosaka A, Takuma H, Ohta K, Tamaoka A. An ocular form of myasthenia gravis with a high titer of anti-MuSK antibodies during a long-term follow-up. Intern Med 2012; 51 (21) 3077-3079
  • 48 Zouvelou V, Papathanasiou A, Koros C, Rentzos M, Zambelis T, Stamboulis E. Pure ocular anti-musk myasthenia under no immunosuppressive treatment. Muscle Nerve 2013; 48 (03) 464
  • 49 Guptill JT, Sanders DB, Evoli A. Anti-MuSK antibody myasthenia gravis: clinical findings and response to treatment in two large cohorts. Muscle Nerve 2011; 44 (01) 36-40
  • 50 Evoli A, Alboini PE, Iorio R, Damato V, Bartoccioni E. Pattern of ocular involvement in myasthenia gravis with MuSK antibodies. J Neurol Neurosurg Psychiatry 2017; 88 (09) 761-763
  • 51 Skjei KL, Lennon VA, Kuntz NL. Muscle specific kinase autoimmune myasthenia gravis in children: a case series. Neuromuscul Disord 2013; 23 (11) 874-882
  • 52 Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S. Myasthenia gravis - autoantibody characteristics and their implications for therapy. Nat Rev Neurol 2016; 12 (05) 259-268
  • 53 Tsivgoulis G, Dervenoulas G, Kokotis P. et al. Double seronegative myasthenia gravis with low density lipoprotein-4 (LRP4) antibodies presenting with isolated ocular symptoms. J Neurol Sci 2014; 346 (1-2): 328-330
  • 54 Fortin E, Cestari DM, Weinberg DH. Ocular myasthenia gravis: an update on diagnosis and treatment. Curr Opin Ophthalmol 2018; 29 (06) 477-484
  • 55 Leite MI, Jacob S, Viegas S. et al. IgG1 antibodies to acetylcholine receptors in 'seronegative' myasthenia gravis. Brain 2008; 131 (Pt 7): 1940-1952
  • 56 Chang T, Leite MI, Senanayake S. et al. Clinical and serological study of myasthenia gravis using both radioimmunoprecipitation and cell-based assays in a South Asian population. J Neurol Sci 2014; 343 (1-2): 82-87
  • 57 Yang L, Maxwell S, Leite MI. et al. Non-radioactive serological diagnosis of myasthenia gravis and clinical features of patients from Tianjin, China. J Neurol Sci 2011; 301 (1-2): 71-76
  • 58 Gasperi C, Melms A, Schoser B. et al. Anti-agrin autoantibodies in myasthenia gravis. Neurology 2014; 82 (22) 1976-1983
  • 59 Costa J, Evangelista T, Conceição I, de Carvalho M. Repetitive nerve stimulation in myasthenia gravis--relative sensitivity of different muscles. Clin Neurophysiol 2004; 115 (12) 2776-2782
  • 60 Katirji B. A case study approach. In: Electromyography in Clinical Practice. 2nd ed.. Specialized Electrodiagnostic Studies. 2007: 37-48
  • 61 Rodríguez J, Dimitrova NA, Dimitrov GV, Gila L. Shape variability of potentials recorded by a single-fiber electrode and its effect on jitter estimation. Ann Biomed Eng 2011; 39 (02) 812-823
  • 62 Sanders DB, Massey JM. Clinical features of myasthenia gravis. Handb Clin Neurol 2008; 91: 229-252
  • 63 Leeamornsiri S, Chirapapaisan N, Chuenkongkaew W. Clinical profiles of Thai patients with ocular myasthenia gravis in Siriraj Hospital. J Med Assoc Thai 2011; 94 (09) 1117-1121
  • 64 Kraithat P, Hansapinyo L, Patikulsila P. Treatment outcomes and predictive factors in pediatric ocular myasthenia gravis. J Med Assoc Thai 2015; 98 (09) 883-888
  • 65 Fisher K, Shah V. Pediatric ocular myasthenia gravis. Curr Treat Options Neurol 2019; 21 (10) 46
  • 66 Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve 2004; 29 (04) 484-505
  • 67 Ishigaki K, Shishikura K, Murakami T, Suzuki H, Hirayama Y, Osawa M. Benefits of FK 506 for refractory eye symptoms in a young child with ocular myasthenia gravis. Brain Dev 2009; 31 (08) 634-637
  • 68 Kupersmith MJ. Ocular myasthenia gravis: treatment successes and failures in patients with long-term follow-up. J Neurol 2009; 256 (08) 1314-1320
  • 69 Kupersmith MJ, Latkany R, Homel P. Development of generalized disease at 2 years in patients with ocular myasthenia gravis. Arch Neurol 2003; 60 (02) 243-248
  • 70 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 (04) 251-255
  • 71 Sommer N, Sigg B, Melms A. et al. Ocular myasthenia gravis: response to long-term immunosuppressive treatment. J Neurol Neurosurg Psychiatry 1997; 62 (02) 156-162
  • 72 Kupersmith MJ, Moster M, Bhuiyan S, Warren F, Weinberg H. Beneficial effects of corticosteroids on ocular myasthenia gravis. Arch Neurol 1996; 53 (08) 802-804
  • 73 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 (02) 131-133
  • 74 Wong SH, Huda S, Vincent A, Plant GT. Ocular myasthenia gravis: controversies and updates. Curr Neurol Neurosci Rep 2014; 14 (01) 421
  • 75 Benatar M, Mcdermott MP, Sanders DB. et al. Muscle Study Group (MSG). Efficacy of prednisone for the treatment of ocular myasthenia (EPITOME): a randomized, controlled trial. Muscle Nerve 2016; 53 (03) 363-369
  • 76 Hennessey IA, Long AM, Hughes I, Humphrey G. Thymectomy for inducing remission in juvenile myasthenia gravis. Pediatr Surg Int 2011; 27 (06) 591-594
  • 77 Kim AG, Upah SA, Brandsema JF, Yum SW, Blinman TA. Thoracoscopic thymectomy for juvenile myasthenia gravis. Pediatr Surg Int 2019; 35 (05) 603-610
  • 78 Catalano MA, Mullan CW, Rich BS, Glick RD. Pediatric thymectomy: a study of national trends in demographics, short-term outcomes, and cost. Pediatr Surg Int 2019; 35 (07) 749-757
  • 79 Liu Z, Feng H, Yeung SC. et al. Extended transsternal thymectomy for the treatment of ocular myasthenia gravis. Ann Thorac Surg 2011; 92 (06) 1993-1999
  • 80 Kawaguchi N, Kuwabara S, Nemoto Y. et al. Study Group for Myasthenia Gravis in Japan. Treatment and outcome of myasthenia gravis: retrospective multi-center analysis of 470 Japanese patients, 1999-2000. J Neurol Sci 2004; 224 (1-2): 43-47
  • 81 Papatestas AE, Genkins G, Kornfeld P. et al. Effects of thymectomy in myasthenia gravis. Ann Surg 1987; 206 (01) 79-88
  • 82 Zhu K, Li J, Huang X. et al. Thymectomy is a beneficial therapy for patients with non-thymomatous ocular myasthenia gravis: a systematic review and meta-analysis. Neurol Sci 2017; 38 (10) 1753-1760
  • 83 Kaba E, Cosgun T, Ayalp K, Toker A. Robotic thymectomy for myasthenia gravis. Ann Cardiothorac Surg 2019; 8 (02) 288-291
  • 84 Halnon NJ, Jamieson B, Plunkett M, Kitchen CM, Pham T, Krogstad P. Thymic function and impaired maintenance of peripheral T cell populations in children with congenital heart disease and surgical thymectomy. Pediatr Res 2005; 57 (01) 42-48
  • 85 Ghosh JB, Roy M, Peters T. Thymoma associated with myasthenia gravis in infancy. Indian J Pediatr 2009; 76 (10) 1057-1058
  • 86 Park KA, Oh SY. Treatment for diplopia in patients with myasthenia gravis. Graefes Arch Clin Exp Ophthalmol 2013; 251 (03) 895-901
  • 87 Bradley EA, Bartley GB, Chapman KL, Waller RR. Surgical correction of blepharoptosis in patients with myasthenia gravis. Ophthal Plast Reconstr Surg 2001; 17 (02) 103-110
  • 88 Brogan K, Farrugia ME, Crofts K. Ptosis surgery inpatients with myasthenia gravis: a useful adjunct tomedical therapy. Semin Ophthalmol 2018; 33 (03) 429-434
  • 89 Belliveau MJ, Oestreicher JH. Ptosis repair in ocularmyasthenia gravis. Semin Ophthalmol 2017; 32 (05) 564-568
  • 90 Pruitt JA, Ilsen PF. On the frontline: what an optometrist needs to know about myasthenia gravis. Optometry 2010; 81 (09) 454-460
  • 91 Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol 2000; 22 (01) 40-43
  • 92 Herrmann DN, Carney PR, Wald JJ. Juvenile myasthenia gravis: treatment with immune globulin and thymectomy. Pediatr Neurol 1998; 18 (01) 63-66
  • 93 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
  • 94 Barraud C, Desguerre I, Barnerias C, Gitiaux C, Boulay C, Chabrol B. Clinical features and evolution of juvenile myasthenia gravis in a French cohort. Muscle Nerve 2018; 57 (04) 603-609
  • 95 Wylam ME, Anderson PM, Kuntz NL, Rodriguez V. Successful treatment of refractory myasthenia gravis using rituximab: a pediatric case report. J Pediatr 2003; 143 (05) 674-677
  • 96 Tzaribachev N, Koetter I, Kuemmerle-Deschner JB, Schedel J. Rituximab for the treatment of refractory pediatric autoimmune diseases: a case series. Cases J 2009; 2: 6609
  • 97 Teo KY, Tow SL, Haaland B. et al. Low conversion rate of ocular to generalized myasthenia gravis in Singapore. Muscle Nerve 2018; 57 (05) 756-760
  • 98 Jing Y, Zhang X, Yu L, Chen R, Qin N, Ma S. Factors affecting the progression from ocular to generalized myasthenia gravis. Chin J Neurol 2014; 47: 21-25
  • 99 Ding J, Zhao S, Ren K. et al. Prediction of generalization of ocular myasthenia gravis under immunosuppressive therapy in Northwest China. BMC Neurol 2020; 20 (01) 238
  • 100 Li M, Ge F, Guo R. et al. Do early prednisolone and other immunosuppressant therapies prevent generalization in ocular myasthenia gravis in Western populations: a systematic review and meta-analysis. Ther Adv Neurol Disorder 2019; 12 DOI: 10.1177/1756286419876521.