Juvenile Myasthenia Gravis: Recommendations for Diagnostic Approaches and Treatment

 

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Abstract

Juvenile myasthenia gravis (JMG) is an autoimmune disorder of neuromuscular transmission caused by production of antibodies against components of the postsynaptic membrane of the neuromuscular junction. Ethnicity has influence on incidence, clinical presentation, and the course of the disease. The patients present with a wide range of symptoms–from isolated intermittent ocular symptoms to general muscle weakness with or without respiratory insufficiency. Compared with adults and adolescents, the clinical signs and course of disease in children exhibit differences and occasionally untypical symptoms. Therefore, JMG is often missed and the diagnosis delayed. Isolated ocular symptoms are frequent at onset, spontaneous remission or intermittent symptoms over the longer period of time can occur. Very young children may present with generalized muscle weakness already during the second year of life and in this patient group, specific antibodies can only be slightly increased or even negative. Existing therapeutic options include immunosuppressive therapy and thymectomy but potential long-term side effects on the growing organism and possible influence on immune response in very young children should be considered. Specific clinical symptoms, diagnostic procedures, and a therapeutic approach with consideration of this age group's specificities are discussed.

• References

• 1 Erb W. Zur Kasuistik der bulbaeren Lähmungen. Ueber einen neuen, wahrscheinlich bulbaeren Symptomenkomplex. Arch Psychiatr Nervenkr 1879; 9: 336-350
  PubMedGoogle Scholar
• 2 Osserman KE, Genkins G. Studies in myasthenia gravis: review of a twenty-year experience in over 1200 patients. Mt Sinai J Med 1971; 38 (6) 497-537
  PubMedGoogle Scholar
• 3 Evoli A. Acquired myasthenia gravis in childhood. Curr Opin Neurol 2010; 23 (5) 536-540
  CrossrefPubMedGoogle Scholar
• 4 Finnis MF, Jayawant S. Juvenile myasthenia gravis: a paediatric perspective. Autoimmune Dis 2011; 2011: 404101
  PubMedGoogle Scholar
• 5 Andrews PI. Autoimmune myasthenia gravis in childhood. Semin Neurol 2004; 24 (1) 101-110
  Article in Thieme ConnectPubMedGoogle Scholar
• 6 Chiang LM, Darras BT, Kang PB. Juvenile myasthenia gravis. Muscle Nerve 2009; 39 (4) 423-431
  CrossrefPubMedGoogle Scholar
• 7 Ionita CM, Acsadi G. Management of juvenile myasthenia gravis. Pediatr Neurol 2013; 48 (2) 95-104
  CrossrefPubMedGoogle Scholar
• 8 McGrogan A, Sneddon S, de Vries CS. The incidence of myasthenia gravis: a systematic literature review. Neuroepidemiology 2010; 34 (3) 171-183
  CrossrefPubMedGoogle Scholar
• 9 Chiu HC, Vincent A, Newsom-Davis J, Hsieh KH, Hung T. Myasthenia gravis: population differences in disease expression and acetylcholine receptor antibody titers between Chinese and Caucasians. Neurology 1987; 37 (12) 1854-1857
  CrossrefPubMedGoogle Scholar
• 10 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 (4) 386-390
  PubMedGoogle Scholar
• 11 Andrews PI, Massey JM, Howard Jr JF, Sanders DB. Race, sex, and puberty influence onset, severity, and outcome in juvenile myasthenia gravis. Neurology 1994; 44 (7) 1208-1214
  CrossrefPubMedGoogle Scholar
• 12 Kalb B, Matell G, Pirskanen R, Lambe M. Epidemiology of myasthenia gravis: a population-based study in Stockholm, Sweden. Neuroepidemiology 2002; 21 (5) 221-225
  CrossrefPubMedGoogle Scholar
• 13 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 (8) 515-520
  CrossrefPubMedGoogle Scholar
• 14 Rodriguez M, Gomez MR, Howard Jr FM, Taylor WF. Myasthenia gravis in children: long-term follow-up. Ann Neurol 1983; 13 (5) 504-510
  CrossrefPubMedGoogle Scholar
• 15 Christensen PB, Jensen TS, Tsiropoulos I , et al. Associated autoimmune diseases in myasthenia gravis. A population-based study. Acta Neurol Scand 1995; 91 (3) 192-195
  PubMedGoogle Scholar
• 16 Jarius S, Wildemann B. AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 2010; 6 (7) 383-392
  CrossrefPubMedGoogle Scholar
• 17 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
  CrossrefPubMedGoogle Scholar
• 18 Shinomiya N, Nomura Y, Segawa M. A variant of childhood-onset myasthenia gravis: HLA typing and clinical characteristics in Japan. Clin Immunol 2004; 110 (2) 154-158
  CrossrefPubMedGoogle Scholar
• 19 Chen WH, Chiu HC, Hseih RP. Association of HLA-Bw46DR9 combination with juvenile myasthenia gravis in Chinese. J Neurol Neurosurg Psychiatry 1993; 56 (4) 382-385
  CrossrefPubMedGoogle Scholar
• 20 Wong V, Hawkins BR, Yu YL. Myasthenia gravis in Hong Kong Chinese. 2. Paediatric disease. Acta Neurol Scand 1992; 86 (1) 68-72
  CrossrefPubMedGoogle Scholar
• 21 Christiansen FT, Pollack MS, Garlepp MJ, Dawkins RL. Myasthenia gravis and HLA antigens in American blacks and other races. J Neuroimmunol 1984; 7 (2-3) 121-129
  CrossrefPubMedGoogle Scholar
• 22 Luchanok U, Kaminski HJ. Ocular myasthenia: diagnostic and treatment recommendations and the evidence base. Curr Opin Neurol 2008; 21 (1) 8-15
  CrossrefPubMedGoogle Scholar
• 23 Evoli A, Batocchi AP, Bartoccioni E, Lino MM, Minisci C, Tonali P. Juvenile myasthenia gravis with prepubertal onset. Neuromuscul Disord 1998; 8 (8) 561-567
  CrossrefPubMedGoogle Scholar
• 24 Besinger UA, Toyka KV, Hömberg M, Heininger K, Hohlfeld R, Fateh-Moghadam A. Myasthenia gravis: long-term correlation of binding and bungarotoxin blocking antibodies against acetylcholine receptors with changes in disease severity. Neurology 1983; 33 (10) 1316-1321
  CrossrefPubMedGoogle Scholar
• 25 Sanders DB, Massey JM. Clinical features of myasthenia gravis. Handb Clin Neurol 2008; 91: 229-252
  CrossrefPubMedGoogle Scholar
• 26 Schara U, Della Marina A, Abicht A. Congenital myasthenic syndromes: current diagnostic and therapeutic approaches. Neuropediatrics 2012; 43 (4) 184-193
  Article in Thieme ConnectPubMedGoogle Scholar
• 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
  CrossrefPubMedGoogle Scholar
• 28 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
  CrossrefPubMedGoogle Scholar
• 29 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
  CrossrefPubMedGoogle Scholar
• 30 Snead III OC, Benton JW, Dwyer D , et al. Juvenile myasthenia gravis. Neurology 1980; 30 (7 Pt 1) 732-739
  CrossrefPubMedGoogle Scholar
• 31 Ashraf VV, Taly AB, Veerendrakumar M, Rao S. Myasthenia gravis in children: a longitudinal study. Acta Neurol Scand 2006; 114 (2) 119-123
  PubMedGoogle Scholar
• 32 Anlar B, Yilmaz V, Saruhan-Direskeneli G. Long remission in muscle-specific kinase antibody-positive juvenile myasthenia. Pediatr Neurol 2009; 40 (6) 455-456
  CrossrefPubMedGoogle Scholar
• 33 Pasnoor M, Wolfe GI, Nations S , et al. Clinical findings in MuSK-antibody positive myasthenia gravis: a U.S. experience. Muscle Nerve 2010; 41 (3) 370-374
  CrossrefPubMedGoogle Scholar
• 34 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 (1) 36-40
  CrossrefPubMedGoogle Scholar
• 35 Tsiamalos P, Kordas G, Kokla A, Poulas K, Tzartos SJ. Epidemiological and immunological profile of muscle-specific kinase myasthenia gravis in Greece. Eur J Neurol 2009; 16 (8) 925-930
  CrossrefPubMedGoogle Scholar
• 36 Lavrnic D, Losen M, Vujic A , et al. The features of myasthenia gravis with autoantibodies to MuSK. J Neurol Neurosurg Psychiatry 2005; 76 (8) 1099-1102
  CrossrefPubMedGoogle Scholar
• 37 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
  CrossrefPubMedGoogle Scholar
• 38 Kostera-Pruszczyk A, Kwiecinski H. Juvenile seropositive myasthenia gravis with anti-MuSK antibody after thymectomy. J Neurol 2009; 256 (10) 1780-1781
  CrossrefPubMedGoogle Scholar
• 39 Ware TL, Ryan MM, Kornberg AJ. Autoimmune myasthenia gravis, immunotherapy and thymectomy in children. Neuromuscul Disord 2012; 22 (2) 118-121
  CrossrefPubMedGoogle Scholar
• 40 McMillan HJ, Darras BT, Kang PB. Autoimmune neuromuscular disorders in childhood. Curr Treat Options Neurol 2011; 13 (6) 590-607
  CrossrefPubMedGoogle Scholar
• 41 Lindberg C, Andersen O, Lefvert AK. Treatment of myasthenia gravis with methylprednisolone pulse: a double blind study. Acta Neurol Scand 1998; 97 (6) 370-373
  CrossrefPubMedGoogle Scholar
• 42 Liu W, Tong T, Ji Z, Zhang Z. Long-term prognostic analysis of thymectomized patients with myasthenia gravis. Chin Med J (Engl) 2002; 115 (2) 235-237
  PubMedGoogle Scholar
• 43 Mullaney P, Vajsar J, Smith R, Buncic JR. The natural history and opthalmologic involvement in childhood myasthenia gravis at the Hospital for Sick Children. Ophthalmology 2000; 107 (3) 504-510
  CrossrefPubMedGoogle Scholar
• 44 Badurska B, Ryniewicz B, Strugalska H. Immunosuppressive treatment for juvenile myasthenia gravis. Eur J Pediatr 1992; 151 (3) 215-217
  CrossrefPubMedGoogle Scholar
• 45 Pineles SL, Avery RA, Moss HE , et al. Visual and systemic outcomes in pediatric ocular myasthenia gravis. Am J Ophthalmol 2010; 150 (4) 453-459 , e3
  CrossrefPubMedGoogle Scholar
• 46 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
  CrossrefPubMedGoogle Scholar
• 47 Castro D, Derisavifard S, Anderson M, Greene M, Iannaccone S. Juvenile myasthenia gravis: a twenty-year experience. J Clin Neuromuscul Dis 2013; 14 (3) 95-102
  CrossrefPubMedGoogle Scholar
• 48 Wylam ME, Anderson PM, Kuntz NL, Rodriguez V. Successful treatment of refractory myasthenia gravis using rituximab: a pediatric case report. J Pediatr 2003; 143 (5) 674-677
  CrossrefPubMedGoogle Scholar
• 49 Koul R, Al Futaisi A, Abdwani R. Rituximab in severe seronegative juvenile myasthenia gravis: review of the literature. Pediatr Neurol 2012; 47 (3) 209-212
  CrossrefPubMedGoogle Scholar
• 50 Tracy MM, McRae W, Millichap JG. Graded response to thymectomy in children with myasthenia gravis. J Child Neurol 2009; 24 (4) 454-459
  CrossrefPubMedGoogle Scholar
• 51 Adams C, Theodorescu D, Murphy EG, Shandling B. Thymectomy in juvenile myasthenia gravis. J Child Neurol 1990; 5 (3) 215-218
  CrossrefPubMedGoogle Scholar
• 52 Andrews PI. A treatment algorithm for autoimmune myasthenia gravis in childhood. Ann N Y Acad Sci 1998; 841: 789-802
  CrossrefPubMedGoogle Scholar
• 53 Seybold ME. Thymectomy in childhood myasthenia gravis. Ann N Y Acad Sci 1998; 841: 731-741
  CrossrefPubMedGoogle Scholar
• 54 Hennessey IA, Long AM, Hughes I, Humphrey G. Thymectomy for inducing remission in juvenile myasthenia gravis. Pediatr Surg Int 2011; 27 (6) 591-594
  CrossrefPubMedGoogle Scholar
• 55 Zlamy M, Würzner R, Holzmann H , et al. Antibody dynamics after tick-borne encephalitis and measles-mumps-rubella vaccination in children post early thymectomy. Vaccine 2010; 28 (51) 8053-8060
  CrossrefPubMedGoogle Scholar
• 56 Ortiz S, Borchert M. Long-term outcomes of pediatric ocular myasthenia gravis. Ophthalmology 2008; 115 (7) 1245-1248 , e1
  CrossrefPubMedGoogle Scholar