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Semin Neurol 2004; 24(1): 101-110
DOI: 10.1055/s-2004-829591
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Autoimmune Myasthenia Gravis in Childhood

P. Ian Andrews1
  • 1Senior Lecturer in Paediatrics, University of New South Wales, and Paediatric Neurologist, Sydney Children's Hospital, Australia
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Publication History

Publication Date:
01 July 2004 (online)

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The recent identification of an autoimmune process targeting muscle-specific kinase (MuSK) in a subset of seronegative patients with autoimmune myasthenia gravis promises to improve diagnostic accuracy and redirect therapy in at least some seronegative children and adolescents with myasthenia. Clinical features, diagnostic methods, and management strategies pertinent to children with autoimmune myasthenia are discussed, as well as the emerging data regarding the anti-MuSK autoimmune process in myasthenia gravis.

KEYWORDS

Juvenile myasthenia gravis - MuSK antibody - seronegative - thymectomy

REFERENCES

  • 1 Willis T. De Anima Brutorum. In: Portage S Two Discourses Concerning the Soul of Brutes. Translated by Pordage S. London, 1683 Oxford; Theatro Sheldoniano 1672
  • 2 Erb W. Zur casuistik der bulbaren lahmungen. (3) Ueber einen neuen, wahrscheinlich bulbaren symptomencomplex.  Arch Psychiatr Nervenkr. 1879;  9 336-350
    PubMedSearch in Google Scholar
  • 3 Kandel E R, Siegelbaum S A. Signaling at the nerve-muscle synapse: directly gated transmission. In: Kandel ER, Schwartz JH, Jessell TM Principals of Neuroscience, 4th ed. New York; McGraw-Hill 2000: 187-206
    Search in Google Scholar
  • 4 Sanes J R, Jessell T M. The formation and generation of synapses. In: Kandel ER, Schwartz JH, Jessell TM Principals of Neuroscience, 4th ed. New York; McGraw-Hill 2000: 1087-1114
    Search in Google Scholar
  • 5 Sanes J R, Lichtman J W. Development of the vertebrate neuromuscular junction.  Annu Rev Neurosci. 1999;  22 389-442
    CrossrefPubMedSearch in Google Scholar
  • 6 Fidzianska A. Human ontogenesis II: development of the human neuromuscular junction.  J Neuropathol Exp Neurol. 1980;  39 606-615
    PubMedSearch in Google Scholar
  • 7 Hesselmans L FGM, Jennekens F GI, van den Ord C JM, Oestreicher A B, Gispen W H. A light and electron microscopical study of B-50 (GAP-43) in human intramuscular nerve and neuromuscular junctions during development.  J Neurol Sci. 1989;  89 301-311
    CrossrefPubMedSearch in Google Scholar
  • 8 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;  7 365-368
    CrossrefPubMedSearch in Google Scholar
  • 9 Evoli A, Tonali P A, Padua L et al.. Clinical correlates with anti-MuSK antibodies in generalized seronegative myasthenia gravis.  Brain. 2003;  126 2304-2311
    CrossrefPubMedSearch in Google Scholar
  • 10 Vincent A, Bowen J, Newsom-Davis J, McConville J. Seronegative generalised myasthenia gravis: clinical features, antibodies, and their targets.  Lancet Neurol. 2003;  2 99-106
    CrossrefPubMedSearch in Google Scholar
  • 11 Sanders D B, El-Salem K, Massey J M, McConville J, Vincent A. Clinical aspects of MuSK antibody positive seronegative MG.  Neurology. 2003;  60 1978-1980
    CrossrefPubMedSearch in Google Scholar
  • 12 Sanders D B, Andrews P I, Howard Jr J F, Massey J M. Seronegative myasthenia gravis.  Neurology. 1997;  48(suppl 5) S40-S45
    PubMedSearch in Google Scholar
  • 13 Yoshikawa H, Lennon V A. Acetylcholine receptor autoantibody secretion by thymocytes: relationship to myasthenia gravis.  Neurology. 1997;  49 562-567
    PubMedSearch in Google Scholar
  • 14 Yamamoto T, Vincent A, Ciulla T A, Lang B, Johnston I, Newsom-Davis J. Seronegative myasthenia gravis: a plasma factor inhibiting agonist-induced acetylcholine receptor function copurifies with IgM.  Ann Neurol. 1991;  30 550-557
    CrossrefPubMedSearch in Google Scholar
  • 15 Plested C P, Tang T, Spreadbury I, Littleton E T, Kishore U, Vincent A. AChR phosphorylation and indirect inhibition of AChR function in seronegative MG.  Neurology. 2002;  59 1682-1688
    PubMedSearch in Google Scholar
  • 16 Bufler J, Pitz R, Czep M, Wick M, Francke C. Purified IgG from seropositive and seronegative patients with myasthenia gravis reversibly blocks currents through nicotinic acetylcholine receptor channels.  Ann Neurol. 1998;  43 458-464
    CrossrefPubMedSearch in Google Scholar
  • 17 Drachman D B. Myasthenia gravis: a model disorder of acetylcholine receptors.  Res Publ Assoc Res Nerv Ment Dis. 1987;  65 65-82
    PubMedSearch in Google Scholar
  • 18 Soliven B C, Lange D J, Penn A S et al.. Seronegative myasthenia gravis.  Neurology. 1988;  38 514-516
    PubMedSearch in Google Scholar
  • 19 Evoli A, Bartoccioni E, Bartocchi A P, Scuderi F, Tonali P. Anti-AchR negative myasthenia gravis: clinical and immunological features.  Clin Invest Med. 1989;  12 104-109
    PubMedSearch in Google Scholar
  • 20 Karni A, Zisman E, Katz-Levy Y et al.. Reactivity of T cells from seronegative myasthenia gravis to T cell epitopes of the human acetylcholine receptor.  Neurology. 1997;  48 1638-1642
    CrossrefPubMedSearch in Google Scholar
  • 21 Lu C Z, Lu L, Hao Z S, Xia D G, Qain J, Arnason B G. Antibody-secreting cells to acetylcholine receptor and to presynaptic membrane receptor in seronegative myasthenia gravis.  J Neuroimmunol. 1993;  43 145-149
    CrossrefPubMedSearch in Google Scholar
  • 22 Ragheb S, Lisak R P. Immune regulation and myasthenia gravis.  Ann N Y Acad Sci. 1998;  841 210-224
    PubMedSearch in Google Scholar
  • 23 Drachman D B. Medical progress: myasthenia gravis.  N Engl J Med. 1994;  330 1797-1810
    CrossrefPubMedSearch in Google Scholar
  • 24 Geh V S, Bradbury J A. Ocular myasthenia presenting in an 11-month-old boy.  Eye. 1998;  12 319-320
    PubMedSearch in Google Scholar
  • 25 Phillips L H, Torner J C, Anderson M S, Cox G M. The epidemiology of myasthenia gravis in central and western Virginia.  Neurology. 1992;  42 1888-1893
    CrossrefPubMedSearch in Google Scholar
  • 26 Andrews P I, Massey J M, Howard J FJ, Sanders D B. Race, sex, and puberty influence onset, severity, and outcome in juvenile myasthenia gravis.  Neurology. 1994;  44 1208-1214
    CrossrefPubMedSearch in Google Scholar
  • 27 Evoli A, Batocchi A P, Bartoccioni E, Lino M M, Minisci C, Tonali P. Juvenile myasthenia gravis with prepubertal onset.  Neuromuscul Disord. 1998;  8 561-567
    CrossrefPubMedSearch in Google Scholar
  • 28 Batocchi A P, Evoli A, Palmisani M T, Lo Monaco M, Bartoccioni M, Tonali P. Early-onset myasthenia gravis: clinical characteristics and response to therapy.  Eur J Pediatr. 1990;  150 66-68
    PubMedSearch in Google Scholar
  • 29 Uono M. Clinical statistics of myasthenia gravis in Japan.  Int J Neurol. 1980;  14 87-99
    PubMedSearch in Google Scholar
  • 30 Chiu H C, Newsom-Davis J, Hsieh K H, Hung T. Myasthenia gravis: population differences in disease expression and acetylcholine receptor antibody titers between Chinese and Caucasians.  Neurology. 1987;  37 1854-1857
    CrossrefPubMedSearch in Google Scholar
  • 31 Osserman K E. Myasthenia Gravis. New York; Grune & Stratton 1958
    Search in Google Scholar
  • 32 Walsh F B, Hoyt W F. Chapter 9: Disorders of muscle. Clinical Ophthalmology. Baltimore; Williams & Wilkins 1969: 1242-1311
    Search in Google Scholar
  • 33 Brodsky M C, Baker R S, Hamed L M. Pediatric Neuro-ophthalmology. New York; Springer 1996
    Search in Google Scholar
  • 34 Cogan D G. Myasthenia gravis: a review of the disease and a description of lid twitch as a characteristic sign.  Arch Ophthalmol. 1965;  74 217-221
    CrossrefPubMedSearch in Google Scholar
  • 35 Linder A, Schalke B, Toyka K V. Outcome in juvenile-onset myasthenia gravis: a retrospective study with long-term follow-up of 79 patients.  J Neurol. 1997;  244 515-520
    PubMedSearch in Google Scholar
  • 36 Rodriguez M, Gomez M R, Howard Jr F M, Taylor W F. Myasthenia gravis in children: long-term follow-up.  Ann Neurol. 1983;  13 504-510
    CrossrefPubMedSearch in Google Scholar
  • 37 Fukuyama Y, Suzuki M, Segawa M. Studies on myasthenia gravis in childhood.  Paediatr Univ Tokyo. 1970;  18 57-68
    PubMedSearch in Google Scholar
  • 38 Wong V, Hawkins B R, Yu Y L. Myasthenia gravis in Hong Kong Chinese. 2. Paediatric disease.  Acta Neurol Scand. 1992;  86 68-72
    CrossrefPubMedSearch in Google Scholar
  • 39 Grob D, Arsura E L, Brunner N G, Namba T. The course of myasthenia gravis and therapies affecting outcome.  Ann N Y Acad Sci. 1987;  505 472-499
    CrossrefPubMedSearch in Google Scholar
  • 40 Snead O C, Benton J W, Dwyer D et al.. Juvenile myasthenia gravis.  Neurology. 1980;  30 732-739
    CrossrefPubMedSearch in Google Scholar
  • 41 Okun M S, Charriez C M, Bhatti M T et al.. Asystole induced by edrophonium following beta blockade.  Neurology. 2001;  57 739-740
    CrossrefPubMedSearch in Google Scholar
  • 42 Afifi A K, Bell W E. Tests for juvenile myasthenia gravis: comparative diagnostic yield and prediction of outcome.  J Child Neurol. 1993;  8 403-411
    CrossrefPubMedSearch in Google Scholar
  • 43 Younger D S, Worrall B B, Penn A S. Myasthenia gravis: historical perspective and overview.  Neurology. 1997;  48(suppl 5) S1-S7
    PubMedSearch in Google Scholar
  • 44 Lennon V A. Serological diagnosis of myasthenia gravis and the Lambert-Eaton myasthenic syndrome. In: Lisak RP Handbook of Myasthenia Gravis and Myasthenic Syndromes. New York; Marcel Dekker 1994: 149-164
    Search in Google Scholar
  • 45 Andrews P I, Massey J M, Sanders D B. Acetylcholine receptor antibodies in juvenile myasthenia gravis.  Neurology. 1993;  43 977-982
    PubMedSearch in Google Scholar
  • 46 Sanders D B, Stålb erg E V. AAEM Minimonograph #25: single-fiber electromyography.  Muscle Nerve. 1996;  19 1069-1083
    CrossrefPubMedSearch in Google Scholar
  • 47 Gajdos P, Chevret S, Clair B, Tranchant C, Chastang C. Plasma exchange and intravenous immunoglobulin in autoimmune myasthenia gravis.  Ann N Y Acad Sci. 1998;  841 720-726
    CrossrefPubMedSearch in Google Scholar
  • 48 Lewis R A, Selwa J F, Lisak R P. Myasthenia gravis: immunological mechanisms and immunotherapy.  Ann Neurol. 1995;  37(suppl 1) S51-S62
    CrossrefPubMedSearch in Google Scholar
  • 49 Edan G, Landgraf F. Experience with intravenous immunoglobulin in myasthenia gravis: a review.  J Neurol Neurosurg Psychiatry. 1994;  57(suppl) 55-56
    PubMedSearch in Google Scholar
  • 50 Evoli A, Palmisani M T, Bartoccioni E, Padua L, Tonali P. High-dose intravenous immunoglobulin in myasthenia gravis.  Ital J Neurol Sci. 1993;  14 233-237
    PubMedSearch in Google Scholar
  • 51 Stricker R B, Kwiatkowska B J, Habis J A, Kiprov D D. Myasthenic crisis. Response to plasmapheresis following failure of intravenous gamma globulin.  Arch Neurol. 1993;  50 837-840
    CrossrefPubMedSearch in Google Scholar
  • 52 Fasano M B. Risks and benefits of intravenous immunoglobulin treatment in children.  Curr Opin Pediatr. 1995;  7 688-694
    PubMedSearch in Google Scholar
  • 53 Brannagan T H, Nagle K J, Lange D J, Rowland L P. Complications of intravenous immune globulin treatment in neurologic disease.  Neurology. 1996;  47 674-677
    CrossrefPubMedSearch in Google Scholar
  • 54 Badurska B, Ryniewicz B, Strugalska H. Immunosuppressive treatment for juvenile myasthenia gravis.  Eur J Pediatr. 1992;  151 215-217
    CrossrefPubMedSearch in Google Scholar
  • 55 Arsura E, Brunner N G, Namba T, Grob D. High-dose intravenous methylprednisolone in myasthenia gravis.  Arch Neurol. 1985;  42 1149-1153
    CrossrefPubMedSearch in Google Scholar
  • 56 Sakano T, Hamasaki T, Kinoshita Y, Kihara M, Ueda K. Treatment for refractory myasthenia gravis.  Arch Dis Child. 1989;  64 1191-1193
    CrossrefPubMedSearch in Google Scholar
  • 57 Tanaka J, Matsuzaki K, Arai H, Nagai T, Matsumoto Y, Okada S. Intermittent methylprednisolone pulse therapy for myasthenia gravis in childhood.  No To Hattatsu. 1994;  26 14-19
    PubMedSearch in Google Scholar
  • 58 Bocanegra T S, Castaneda M O, Espinoza L R, Vasey F B, Germain B F. Sudden death after methylprednisolone pulse therapy.  Ann Intern Med. 1981;  95 122
    PubMedSearch in Google Scholar
  • 59 McLuckie A E, Savage R W. Atrial fibrillation following pulse methylprednisolone therapy in an adult.  Chest. 1993;  104 622-623
    PubMedSearch in Google Scholar
  • 60 Panegyres P K, Squier M, Mills K R, Newsom-Davis J. Acute myopathy associated with large parenteral dose of corticosteroid in myasthenia gravis.  J Neurol Neurosurg Psychiatry. 1993;  56 702-704
    CrossrefPubMedSearch in Google Scholar
  • 61 Andrews P I. A treatment algorithm for autoimmune myasthenia gravis in childhood.  Ann N Y Acad Sci. 1998;  841 789-802
    CrossrefPubMedSearch in Google Scholar
  • 62 Seybold M E. Thymectomy in childhood myasthenia gravis.  Ann N Y Acad Sci. 1998;  841 731-741
    CrossrefPubMedSearch in Google Scholar
  • 63 Evoli A, Batocchi A P, Lo Monaco M et al.. Clinical heterogeneity of seronegative myasthenia gravis.  Neuromuscul Disord. 1996;  6 155-161
    PubMedSearch in Google Scholar
  • 64 Verma P K, Oger J J. Seronegative generalized myasthenia gravis: low frequency of thymic pathology.  Neurology. 1992;  42 586-589
    PubMedSearch in Google Scholar
  • 65 Blossom G B, Ernstoff R M, Howells G A, Bendick P J, Glover J L. Thymectomy for myasthenia gravis.  Arch Surg. 1993;  128 855-862
    PubMedSearch in Google Scholar
  • 66 Frist W H, Thirumalai S, Doehring C B. Thymectomy for the myasthenia gravis patient: factors influencing outcome.  Ann Thorac Surg. 1994;  57 334-338
    PubMedSearch in Google Scholar
  • 67 Seybold M E, Howard F M, Duane D D, Payne W S, Harrison E G. Thymectomy in juvenile myasthenia gravis.  Arch Neurol. 1971;  25 385-392
    PubMedSearch in Google Scholar
  • 68 Campbell J R, Bisio J M, Harrison M W, Campbell T J. Surgical treatment of myasthenia gravis in childhood.  J Pediatr Surg. 1983;  18 857-861
    PubMedSearch in Google Scholar
  • 69 Keynes G, Camb M D. Surgery of the thymus gland.  Lancet. 1954;  1 1197-1202
    PubMedSearch in Google Scholar
  • 70 Brearley S, Gentle T A, Baynham M I, Roberts K D, Abrams L D, Thompson R A. Immunodeficiency following neonatal thymectomy in man.  Clin Exp Immunol. 1987;  70 322-327
    PubMedSearch in Google Scholar
  • 71 Ramos S B, Garcia A B, Viana S R, Voltarelli J C, Falcao R P. Phenotypic and functional evaluation of natural killer cells in thymectomized children.  Clin Immunol Immunopathol. 1996;  81 277-281
    CrossrefPubMedSearch in Google Scholar
  • 72 Rubinstein A, Pelet B, Schweizer V. Immunological decay in thymectomized infants.  Helv Paediatr Acta. 1976;  30 425-433
    PubMedSearch in Google Scholar
  • 73 Wells W J, Parkman R, Smogorzewska E, Barr M. Neonatal thymectomy: does it affect immune function?.  J Thorac Cardiovasc Surg. 1998;  115 1041-1046
    PubMedSearch in Google Scholar
  • 74 Masaoka A, Yamakawa Y, Niwa H et al.. Extended thymectomy for myasthenia gravis patients: a 20-year review.  Ann Thorac Surg. 1996;  62 853-859
    CrossrefPubMedSearch in Google Scholar
  • 75 Nakamura H, Taniguchi Y, Suzuki Y et al.. Delayed remission after thymectomy for myasthenia gravis of the purely ocular type.  J Thorac Cardiovasc Surg. 1996;  112 371-375
    PubMedSearch in Google Scholar
  • 76 Schumm F, Wietholter H, Fateh-Moghadam A, Dichgans J. Thymectomy in myasthenia with pure ocular symptoms.  J Neurol Neurosurg Psychiatry. 1985;  48 332-337
    PubMedSearch in Google Scholar
  • 77 Wilkins K B, Bulkley G B. Thymectomy in the integrated management of myasthenia gravis.  Adv Surg. 1999;  32 105-133
    PubMedSearch in Google Scholar
  • 78 Sanders D B, Howard J F, Johns T R, Campa J F. High-dose daily prednisone in the treatment of myasthenia gravis. In: Dau PC Plasmapheresis and the Immunobiology of Myasthenia Gravis. Boston; Houghton-Mifflin 1979: 289-306
    Search in Google Scholar
  • 79 Pascuzzi R M, Coslett B, Johns T R. Long-term corticosteroid treatment of myasthenia gravis: report of 116 patients.  Ann Neurol. 1984;  15 291-298
    CrossrefPubMedSearch in Google Scholar
  • 80 Kupersmith M J, Moster M, Bhuiyan S, Warren F, Weinberg H. Beneficial effects of corticosteroids on ocular myasthenia gravis.  Arch Neurol. 1996;  53 802-804
    CrossrefPubMedSearch in Google Scholar
  • 81 Lindberg C, Andersen O, Larsson S, Oden A. Remission rate after thymectomy in myasthenia gravis when the bias of immunosuppressive therapy is eliminated.  Acta Neurol Scand. 1992;  86 323-328
    PubMedSearch in Google Scholar
  • 82 Kerribjin K F, De Kroon P M. Effect on height of corticosteroid therapy in asthmatic children.  Arch Dis Child. 1968;  43 556-561
    PubMedSearch in Google Scholar
  • 83 Rees L, Greene S A, Adlard P et al.. Growth and endocrine function in steroid sensitive nephrotic syndrome.  Arch Dis Child. 1988;  63 484-490
    PubMedSearch in Google Scholar
  • 84 Lettgen B, Jeken C, Reiners C. Influence of steroid medication on bone mineral density in children with nephrotic syndrome.  Pediatr Nephrol. 1994;  8 667-670
    CrossrefPubMedSearch in Google Scholar
  • 85 Palace J, Newsom-Davis J, Lecky B. The Myasthenia Gravis Study Group . A randomized double-blind trial of prednisolone alone or with azathioprine in myasthenia gravis.  Neurology. 1998;  50 1778-1783
    CrossrefPubMedSearch in Google Scholar
  • 86 Cosi V, Lombardi M, Erbetta A, Piccolo G. Azathioprine as a single immunosuppressive drug in the treatment of myasthenia gravis.  Acta Neurol (Napoli). 1993;  15 123-131
    PubMedSearch in Google Scholar
  • 87 Confavreux C, Saddier P, Grimaud J, Moreua T H, Adeleine P, Aimard G. Risk of cancer from azathioprine therapy in multiple sclerosis.  Neurology. 1996;  46 1607-1612
    CrossrefPubMedSearch in Google Scholar
  • 88 Evoli A, Batocchi A P, Tonali P, Marciano M. Risk of cancer in patients with myasthenia gravis.  Ann N Y Acad Sci. 1998;  841 742-745
    PubMedSearch in Google Scholar
  • 89 Tindall R SA, Phillips J T, Rollins J A, Wells L, Hall K. A clinical therapeutic trial of cyclosporine in myasthenia gravis.  Ann N Y Acad Sci. 1993;  681 539-551
    CrossrefPubMedSearch in Google Scholar
  • 90 Ciafaloni E, Nikhar N K, Massey J M, Sanders D B. Retrospective analysis of the use of cyclosporine in myasthenia gravis.  Neurology. 2000;  55 448-450
    CrossrefPubMedSearch in Google Scholar
  • 91 Hauser R A, Malek A R, Rosen R. Successful treatment of a patient with severe refractory myasthenia gravis using mycophenolate mofetil.  Neurology. 1998;  51 912-913
    PubMedSearch in Google Scholar
  • 92 Ciafaloni E, Massey J M, Sanders D B. An open label trial of mycophenolate mofetil in myasthenia gravis.  Neurology. 2001;  56 97-99
    CrossrefPubMedSearch in Google Scholar

P. I AndrewsM.B.B.S. 

Division of Neurology, Sydney Children's Hospital

High Street, Randwick 2031, Australia