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Journal of Pediatric Neurology 2017; 15(01): 062-069
DOI: 10.1055/s-0036-1594019
Review Article
Georg Thieme Verlag KG Stuttgart · New York

Pediatric Myasthenia Gravis: A Review

Damian E. Berezovsky
1   Department of Ophthalmology, Emory University School of Medicine, Atlanta, Georgia, United States
,
Kevin R. Sitko
2   Division of Ophthalmology, Department of Surgery, University of New Mexico, Albuquerque, New Mexico, United States
› Author Affiliations
Further Information

Publication History

02 October 2016

08 October 2016

Publication Date:
28 November 2016 (online)

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Abstract

Myasthenia gravis refers to a group of diseases affecting the neuromuscular junction resulting in muscle weakness. The clinical hallmark of this condition is skeletal muscle weakness that worsens with sustained or repetitive muscle activation, caused via disruption of neuromuscular transmission by antibodies directed most commonly against the nicotinic acetylcholine receptor. Transient neonatal myasthenia gravis is caused by the crossing of antibodies from a myasthenic mother to her developing child, while juvenile myasthenia gravis involves the production of antibodies by the child's own immune system against neuromuscular junction components. Ptosis and extraocular muscle weakness are common presenting symptoms of juvenile myasthenia gravis and may be accompanied by, or progress to, generalized weakness. Diagnosis of myasthenia gravis relies on careful neurological examination, supported by additional diagnostic modalities which may include the patient's response to short-acting cholinesterase inhibitors, serum testing for causative antibodies, or electromyography. Management options include cholinesterase inhibitors for symptomatic treatment, immunosuppression with corticosteroids or steroid-sparing immunosuppressants, and thymectomy when a thymoma is identified on imaging.

Keywords

myasthenia gravis - children - ocular - diagnosis - treatment
 

  • References

  • 1 VanderPluym J, Vajsar J, Jacob FD, Mah JK, Grenier D, Kolski H. Clinical characteristics of pediatric myasthenia: a surveillance study. Pediatrics 2013; 132 (4) e939-e944
    CrossrefPubMedGoogle Scholar
  • 2 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
    CrossrefPubMedGoogle Scholar
  • 3 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
  • 4 Fagerlund MJ, Eriksson LI. Current concepts in neuromuscular transmission. Br J Anaesth 2009; 103 (1) 108-114
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 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
  • 8 Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 2009; 89 (1) 73-120
    CrossrefPubMedGoogle Scholar
  • 9 Cole RN, Ghazanfari N, Ngo ST, Gervásio OL, Reddel SW, Phillips WD. Patient autoantibodies deplete postsynaptic muscle-specific kinase leading to disassembly of the ACh receptor scaffold and myasthenia gravis in mice. J Physiol 2010; 588 (Pt 17): 3217-3229
    CrossrefPubMedGoogle Scholar
  • 10 Punga AR, Lin S, Oliveri F, Meinen S, Rüegg MA. Muscle-selective synaptic disassembly and reorganization in MuSK antibody positive MG mice. Exp Neurol 2011; 230 (2) 207-217
    CrossrefPubMedGoogle Scholar
  • 11 Argov Z. Current approach to seronegative myasthenia. J Neurol 2011; 258 (1) 14-18
    CrossrefPubMedGoogle Scholar
  • 12 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
  • 13 Feng HY, Wang HY, Liu WB , et al. The high frequency and clinical feature of seronegative myasthenia gravis in Southern China. Neurol Sci 2013; 34 (6) 919-924
    CrossrefPubMedGoogle Scholar
  • 14 Blalock A, Mason MF, Morgan HJ, Riven SS. Myasthenia Gravis and Tumors of the Thymic Region: Report of a Case in Which the Tumor Was Removed. Ann Surg 1939; 110 (4) 544-561
    CrossrefPubMedGoogle Scholar
  • 15 Okumura M, Inoue M, Kadota Y , et al. Biological implications of thymectomy for myasthenia gravis. Surg Today 2010; 40 (2) 102-107
    CrossrefPubMedGoogle Scholar
  • 16 Finnis MF, Jayawant S. Juvenile myasthenia gravis: a paediatric perspective. Autoimmune Dis 2011; 2011: 404101 . DOI: 10.4061/2011/404101.
    PubMedGoogle Scholar
  • 17 Téllez-Zenteno JF, Hernández-Ronquillo L, Salinas V, Estanol B, da Silva O. Myasthenia gravis and pregnancy: clinical implications and neonatal outcome. BMC Musculoskelet Disord 2004; 5: 42 DOI: 10.1186/1471-2474-5-42.
    CrossrefPubMedGoogle Scholar
  • 18 Papazian O. Transient neonatal myasthenia gravis. J Child Neurol 1992; 7 (2) 135-141
    CrossrefPubMedGoogle Scholar
  • 19 Chiang LM, Darras BT, Kang PB. Juvenile myasthenia gravis. Muscle Nerve 2009; 39 (4) 423-431
    CrossrefPubMedGoogle Scholar
  • 20 Ortiz S, Borchert M. Long-term outcomes of pediatric ocular myasthenia gravis. Ophthalmology 2008; 115 (7) 1245-1248 .e1
    CrossrefPubMedGoogle Scholar
  • 21 Chappaz A, Knirsch U, Gerth-Kahlert C. Alternating IV nerve palsy and ptosis as a first sign of childhood ocular myasthenia gravis. Pediatr Neurol 2015; 52 (4) 460-461
    CrossrefPubMedGoogle Scholar
  • 22 Darras BT, Jones HR, Ryan MM, De Vivo DC. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician's Approach. 2nd ed. Amsterdam, the Netherlands: Elsevier/Academic Press; 2015
    Google Scholar
  • 23 Lisak RP. Handbook of Myasthenia Gravis and Myasthenic Syndromes. New York, NY: M. Dekker; 1994
    Google Scholar
  • 24 Brodsky MC. Pediatric Neuro-Ophthalmology. 3rd ed. New York, NY: Springer; 2016
    CrossrefGoogle Scholar
  • 25 Almeida DF, Radaeli RdeF, Melo Jr AC. Ice pack test in the diagnosis of myasthenia gravis. Arq Neuropsiquiatr 2008; 66 (1) 96-98
    CrossrefPubMedGoogle Scholar
  • 26 Haven TR, Astill ME, Pasi BM , et al. An algorithm for acetylcholine receptor antibody testing in patients with suspected myasthenia gravis. Clin Chem 2010; 56 (6) 1028-1029
    CrossrefPubMedGoogle Scholar
  • 27 Skjei KL, Lennon VA, Kuntz NL. Muscle specific kinase autoimmune myasthenia gravis in children: a case series. Neuromuscul Disord 2013; 23 (11) 874-882
    CrossrefPubMedGoogle Scholar
  • 28 Howard Jr JF. Electrodiagnosis of disorders of neuromuscular transmission. Phys Med Rehabil Clin N Am 2013; 24 (1) 169-192
    CrossrefPubMedGoogle Scholar
  • 29 Selvan VA. Single-fiber EMG: A review. Ann Indian Acad Neurol 2011; 14 (1) 64-67
    CrossrefPubMedGoogle Scholar
  • 30 Della Marina A, Trippe H, Lutz S, Schara U. Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. Neuropediatrics 2014; 45 (2) 75-83
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Wright KW, Strube YNJ. Pediatric Ophthalmology and Strabismus. 3rd ed. Madison Avenue, New York: Oxford University Press; 2012
    Google Scholar
  • 32 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
  • 33 Kim JH, Hwang JM, Hwang YS, Kim KJ, Chae J. Childhood ocular myasthenia gravis. Ophthalmology 2003; 110 (7) 1458-1462
    CrossrefPubMedGoogle Scholar
  • 34 Eadie MJ, Tyrer JH. Neurological Clinical Pharmacology. Lancaster, England: MTP Press; 1980
    CrossrefGoogle Scholar
  • 35 Maggi L, Mantegazza R. Treatment of myasthenia gravis: focus on pyridostigmine. Clin Drug Investig 2011; 31 (10) 691-701
    CrossrefPubMedGoogle Scholar
  • 36 Kim JY, Park KD, Richman DP. Treatment of myasthenia gravis based on its immunopathogenesis. J Clin Neurol 2011; 7 (4) 173-183
    CrossrefPubMedGoogle Scholar
  • 37 Ionita CM, Acsadi G. Management of juvenile myasthenia gravis. Pediatr Neurol 2013; 48 (2) 95-104
    CrossrefPubMedGoogle Scholar
  • 38 Andrews PI. A treatment algorithm for autoimmune myasthenia gravis in childhood. Ann N Y Acad Sci 1998; 841: 789-802
    CrossrefPubMedGoogle Scholar
  • 39 Komiyama A, Arai H, Kijima M, Hirayama K. Extraocular muscle responses to high dose intravenous methylprednisolone in myasthenia gravis. J Neurol Neurosurg Psychiatry 2000; 68 (2) 214-217
    CrossrefPubMedGoogle Scholar
  • 40 Sakano T, Hamasaki T, Kinoshita Y, Kihara M, Ueda K. Treatment for refractory myasthenia gravis. Arch Dis Child 1989; 64 (8) 1191-1193
    CrossrefPubMedGoogle Scholar
  • 41 Dalakas MC. Intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: present status and practical therapeutic guidelines. Muscle Nerve 1999; 22 (11) 1479-1497
    CrossrefPubMedGoogle Scholar
  • 42 Hartung HP. Advances in the understanding of the mechanism of action of IVIg. J Neurol 2008; 255 (Suppl. 03) 3-6
    PubMedGoogle Scholar
  • 43 Zinman L, Bril V. IVIG treatment for myasthenia gravis: effectiveness, limitations, and novel therapeutic strategies. Ann N Y Acad Sci 2008; 1132: 264-270
    CrossrefPubMedGoogle Scholar
  • 44 Selcen D, Dabrowski ER, Michon AM, Nigro MA. High-dose intravenous immunoglobulin therapy in juvenile myasthenia gravis. Pediatr Neurol 2000; 22 (1) 40-43
    CrossrefPubMedGoogle Scholar
  • 45 Wittstock M, Zettl UK. Adverse effects of treatment with intravenous immunoglobulins for neurological diseases. J Neurol 2006; 253 (Suppl. 05) V75-V79
    CrossrefPubMedGoogle Scholar
  • 46 Reeves HM, Winters JL. The mechanisms of action of plasma exchange. Br J Haematol 2014; 164 (3) 342-351
    CrossrefPubMedGoogle Scholar
  • 47 Qureshi AI, Suri MF. Plasma exchange for treatment of myasthenia gravis: pathophysiologic basis and clinical experience. Ther Apher 2000; 4 (4) 280-286
    CrossrefPubMedGoogle Scholar
  • 48 Yamada C, Teener JW, Davenport RD, Cooling L. Maintenance plasma exchange treatment for muscle specific kinase antibody positive myasthenia gravis patients. J Clin Apher 2015; 30 (5) 314-319
    CrossrefPubMedGoogle Scholar
  • 49 Liew WK, Powell CA, Sloan SR , et al. Comparison of plasmapheresis and intravenous immunoglobulin as maintenance therapies for juvenile myasthenia gravis. JAMA Neurol 2014; 71 (5) 575-580
    CrossrefPubMedGoogle Scholar
  • 50 Fonseca V, Havard CW. Long term treatment of myasthenia gravis with azathioprine. Postgrad Med J 1990; 66 (772) 102-105
    CrossrefPubMedGoogle Scholar
  • 51 Group MGCS ; Myasthenia Gravis Clinical Study Group. A randomised clinical trial comparing prednisone and azathioprine in myasthenia gravis. Results of the second interim analysis. J Neurol Neurosurg Psychiatry 1993; 56 (11) 1157-1163
    CrossrefPubMedGoogle Scholar
  • 52 Allison AC, Eugui EM. Mycophenolate mofetil and its mechanisms of action. Immunopharmacology 2000; 47 (2–3) 85-118
    CrossrefPubMedGoogle Scholar
  • 53 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
    CrossrefPubMedGoogle Scholar
  • 54 Group MS ; Muscle Study Group. A trial of mycophenolate mofetil with prednisone as initial immunotherapy in myasthenia gravis. Neurology 2008; 71 (6) 394-399
    CrossrefPubMedGoogle Scholar
  • 55 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
  • 56 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
    CrossrefPubMedGoogle Scholar
  • 57 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
    CrossrefPubMedGoogle Scholar
  • 58 Drachman DB, Adams RN, Hu R, Jones RJ, Brodsky RA. Rebooting the immune system with high-dose cyclophosphamide for treatment of refractory myasthenia gravis. Ann N Y Acad Sci 2008; 1132: 305-314
    CrossrefPubMedGoogle Scholar
  • 59 Boye J, Elter T, Engert A. An overview of the current clinical use of the anti-CD20 monoclonal antibody rituximab. Ann Oncol 2003; 14 (4) 520-535
    CrossrefPubMedGoogle Scholar
  • 60 Weiner GJ. Rituximab: mechanism of action. Semin Hematol 2010; 47 (2) 115-123
    CrossrefPubMedGoogle Scholar
  • 61 Illa I, Diaz-Manera J, Rojas-Garcia R , et al. Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients. J Neuroimmunol 2008; 201-202: 90-94
    CrossrefPubMedGoogle Scholar
  • 62 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
  • 63 Stieglbauer K, Topakian R, Schäffer V, Aichner FT. Rituximab for myasthenia gravis: three case reports and review of the literature. J Neurol Sci 2009; 280 (1–2): 120-122
    CrossrefPubMedGoogle Scholar
  • 64 Zebardast N, Patwa HS, Novella SP, Goldstein JM. Rituximab in the management of refractory myasthenia gravis. Muscle Nerve 2010; 41 (3) 375-378
    CrossrefPubMedGoogle Scholar
  • 65 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
    CrossrefPubMedGoogle Scholar
  • 66 Ylinen E, Jahnukainen K, Saarinen-Pihkala UM, Jahnukainen T. Assessment of renal function during high-dose methotrexate treatment in children with acute lymphoblastic leukemia. Pediatr Blood Cancer 2014; 61 (12) 2199-2202
    CrossrefPubMedGoogle Scholar
  • 67 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 DOI: 10.1186/1471-2377-11-97.
    CrossrefPubMedGoogle Scholar
  • 68 Pasnoor M, He J, Herbelin L , et al; Methotrexate in MG Investigators of the Muscle Study Group. A randomized controlled trial of methotrexate for patients with generalized myasthenia gravis. Neurology 2016; 87 (1) 57-64
    CrossrefPubMedGoogle Scholar
  • 69 Cruz JL, Wolff ML, Vanderman AJ, Brown JN. The emerging role of tacrolimus in myasthenia gravis. Ther Adv Neurol Disorder 2015; 8 (2) 92-103
    PubMedGoogle Scholar
  • 70 Lavrnic D, Vujic A, Rakocevic-Stojanovic V , et al. Cyclosporine in the treatment of myasthenia gravis. Acta Neurol Scand 2005; 111 (4) 247-252
    CrossrefPubMedGoogle Scholar
  • 71 Gilhus NE, Verschuuren JJ. Myasthenia gravis: subgroup classification and therapeutic strategies. Lancet Neurol 2015; 14 (10) 1023-1036
    CrossrefPubMedGoogle Scholar
  • 72 Nikolic DM, Nikolic AV, Lavrnic DV, Medjo BP, Ivanovski PI. Childhood-onset myasthenia gravis with thymoma. Pediatr Neurol 2012; 46 (5) 329-331
    CrossrefPubMedGoogle Scholar
  • 73 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
  • 74 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
  • 75 Hankins JR, Mayer RF, Satterfield JR , et al. Thymectomy for myasthenia gravis: 14-year experience. Ann Surg 1985; 201 (5) 618-625
    CrossrefPubMedGoogle Scholar
  • 76 Savcenko M, Wendt GK, Prince SL, Mack MJ. Video-assisted thymectomy for myasthenia gravis: an update of a single institution experience. Eur J Cardiothorac Surg 2002; 22 (6) 978-983
    CrossrefPubMedGoogle Scholar
  • 77 Singh RS, Behera SK, Saji R, Dhaliwal RS. Thymectomy for myasthenia gravis: 12-year experience. Asian Cardiovasc Thorac Ann 2003; 11 (4) 299-303
    CrossrefPubMedGoogle Scholar
  • 78 Venuta F, Rendina EA, De Giacomo T , et al. Thymectomy for myasthenia gravis: a 27-year experience. Eur J Cardiothorac Surg 1999; 15 (5) 621-624 , discussion 624–625
    CrossrefPubMedGoogle Scholar
  • 79 Yu L, Zhang XJ, Ma S, Li F, Zhang YF. Thoracoscopic thymectomy for myasthenia gravis with and without thymoma: a single-center experience. Ann Thorac Surg 2012; 93 (1) 240-244
    CrossrefPubMedGoogle Scholar
  • 80 Ashfaq A, Bernes SM, Weidler EM, Notrica DM. Outcomes of thoracoscopic thymectomy in patients with juvenile myasthenia gravis. J Pediatr Surg 2016; 51 (7) 1078-1083
    CrossrefPubMedGoogle Scholar
  • 81 Mao ZF, Mo XA, Qin C, Lai YR, Olde Hartman TC. Course and prognosis of myasthenia gravis: a systematic review. Eur J Neurol 2010; 17 (7) 913-921
    CrossrefPubMedGoogle Scholar
  • 82 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
    CrossrefPubMedGoogle Scholar