Pediatric multiple sclerosis

Abstract

Pediatric multiple sclerosis (MS) accounts for up to 5% of all MS cases. Work conducted over the past 5 years has provided new information about the treatment, pathogenesis, demographics, and natural history of this disorder. Genetic and environmental factors seem to exert critical influences on its development. Clinical, MRI and laboratory data from prepubertal and postpubertal children suggest differences between the immune response and/or CNS environment in younger compared with older children and adults with MS. Randomized, controlled treatment trials for pediatric MS have not yet been performed, but therapies used in adult MS have been evaluated in this population, and their use seems to be safe. This article provides a comprehensive review of current knowledge regarding pediatric MS, highlighting new advances in the field.

Key Points

  • Pediatric multiple sclerosis (MS) represents 3–4% of all cases of MS

  • In North America, greater diversity in ethnicity, race and ancestry is observed among individuals with pediatric MS than among adults with MS, possibly reflecting changing demographic trends

  • Studies have suggested environmental influences on pediatric MS susceptibility, including Epstein–Barr virus and exposure to cigarette smoke

  • Acute disseminating encephalomyelitis must be differentiated from MS and is seen more commonly in children than in adults

  • New MRI criteria will, hopefully, help to discriminate pediatric MS from acute disseminated encephalomyelitis

  • Currently available first-line therapies for adults with MS seem to be safe and well tolerated in pediatric MS

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Figure 1: Diagnostic algorithm of pediatric onset demyelinating disorders.
Figure 2: Brain MRI scans of young patients with multiple sclerosis.

References

  1. 1

    Krupp, L. B., Banwell, B. & Tenembaum, S. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Neurology 68, S7–S12 (2007).

    PubMed  Google Scholar 

  2. 2

    Renoux, C. et al. Natural history of multiple sclerosis with childhood onset. N. Engl. J. Med. 356, 2603–2613 (2007).

    CAS  PubMed  Google Scholar 

  3. 3

    Chitnis, T., Glanz, B., Jaffin, S. & Healy, B. Demographics of pediatric-onset multiple sclerosis in an MS center population from the Northeastern United States. Mult. Scler. 15, 627–631 (2009).

    CAS  PubMed  Google Scholar 

  4. 4

    Ghezzi, A. et al. Multiple sclerosis in childhood: clinical features of 149 cases. Mult. Scler. 3, 43–46 (1997).

    CAS  PubMed  Google Scholar 

  5. 5

    Boiko, A., Vorobeychik, G., Paty, D., Devonshire, V. & Sadovnick, D. Early onset multiple sclerosis: a longitudinal study. Neurology 59, 1006–1010 (2002).

    CAS  PubMed  Google Scholar 

  6. 6

    Banwell, B. et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 72, 232–239 (2009).

    CAS  PubMed  Google Scholar 

  7. 7

    Banwell, B., Ghezzi, A., Bar-Or, A., Mikaeloff, Y. & Tardieu, M. Multiple sclerosis in children: clinical diagnosis, therapeutic strategies, and future directions. Lancet Neurol. 6, 887–902 (2007).

    PubMed  Google Scholar 

  8. 8

    Association of MultiEthnic Americans. Standards for Maintaining, Collecting, and Presenting Federal Data on Race and Ethnicity [online] (1997).

  9. 9

    Boster, A. L. et al. Pediatric-onset multiple sclerosis in African-American black and European-origin white patients. Pediatr. Neurol. 40, 31–33 (2009).

    PubMed  Google Scholar 

  10. 10

    Krupp, L. B. et al. Racial and ethnic findings in pediatric MS: an update. Neurology 70, A135 (2008).

    Google Scholar 

  11. 11

    Kennedy, J. et al. Age at onset of multiple sclerosis may be influenced by place of residence during childhood rather than ancestry. Neuroepidemiology 26, 162–167 (2006).

    CAS  PubMed  Google Scholar 

  12. 12

    Banwell, B. et al. Abnormal T-cell reactivities in childhood inflammatory demyelinating disease and type 1 diabetes. Ann. Neurol. 63, 98–111 (2008).

    PubMed  Google Scholar 

  13. 13

    Correale, J. & Tenembaum, S. N. Myelin basic protein and myelin oligodendrocyte glycoprotein T-cell repertoire in childhood and juvenile multiple sclerosis. Mult. Scler. 12, 412–420 (2006).

    CAS  PubMed  Google Scholar 

  14. 14

    O'Connor, K. C. et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat. Med. 13, 211–217 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. 15

    Rostasy, K. et al. Tau, phospho-tau, and S-100B in the cerebrospinal fluid of children with multiple sclerosis. J. Child Neurol. 20, 822–825 (2005).

    PubMed  Google Scholar 

  16. 16

    Banwell, B. et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. Lancet Neurol. 6, 773–781 (2007).

    PubMed  Google Scholar 

  17. 17

    Pohl, D. et al. High seroprevalence of Epstein–Barr virus in children with multiple sclerosis. Neurology 67, 2063–2065 (2006).

    Google Scholar 

  18. 18

    Waubant, E. et al. Remote EBV, CMV, and HSV-1 and 20112 infection status in children with pediatric-onset MS and age-matched healthy controls. Presented at the 14th Annual Meeting of ACTRIMS.

  19. 19

    James, J., Anderson, J., Chabas, D., Strober, J. & Waubant, E. Pediatric-onset multiple sclerosis patient sera recognize unique regions of Epstein–Barr nuclear antigen 1 compared to matched controls. Presented at the 14th Annual Meeting of ACTRIMS.

  20. 20

    Mikaeloff, Y., Caridade, G., Suissa, S. & Tardieu, M. Clinically observed chickenpox and the risk of childhood-onset multiple sclerosis. Am. J. Epidemiol. 169, 1260–1266 (2009).

    PubMed  Google Scholar 

  21. 21

    Mikaeloff, Y., Caridade, G., Assi, S., Tardieu, M. & Suissa, S. Hepatitis B vaccine and risk of relapse after a first childhood episode of CNS inflammatory demyelination. Brain 130, 1105–1110 (2007).

    PubMed  Google Scholar 

  22. 22

    Mikaeloff, Y., Caridade, G., Suissa, S. & Tardieu, M. Hepatitis B vaccine and the risk of CNS inflammatory demyelination in childhood. Neurology 72, 873–880 (2009).

    PubMed  Google Scholar 

  23. 23

    Mikaeloff, Y., Caridade, G., Tardieu, M. & Suissa, S. Parental smoking at home and the risk of childhood-onset multiple sclerosis in children. Brain 130, 2589–2595 (2007).

    PubMed  Google Scholar 

  24. 24

    Waubant, E. et al. Vitamin D levels in children with pediatric-onset MS and controls. Presented at the 14th Annual Meeting of ACTRIMS.

  25. 25

    Belman, A. et al. Clinical spectrum of disorders masquerading as pediatric multiple sclerosis. Ann. Neurol. 62 (Suppl. 11), S115 (2007).

    Google Scholar 

  26. 26

    Alper, G., Heyman, R. & Wang, L. Multiple sclerosis and acute disseminated encephalomyelitis diagnosed in children after long-term follow-up: comparison of presenting features. Dev. Med. Child Neurol. 51, 480–486 (2009).

    PubMed  Google Scholar 

  27. 27

    Dale, R. C. & Pillai, S. C. Early relapse risk after a first CNS inflammatory demyelination episode: examining international consensus definitions. Dev. Med. Child Neurol. 49, 887–893 (2007).

    PubMed  Google Scholar 

  28. 28

    McKeon, A. et al. CNS aquaporin-4 autoimmunity in children. Neurology 71, 93–100 (2008).

    CAS  PubMed  Google Scholar 

  29. 29

    Dale, R. C. et al. Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 123, 2407–2422 (2000).

    PubMed  Google Scholar 

  30. 30

    Tenembaum, S., Chamoles, N. & Fejerman, N. Acute disseminated encephalomyelitis: a long-term follow-up study of 84 pediatric patients. Neurology 59, 1224–1231 (2002).

    PubMed  Google Scholar 

  31. 31

    Chabas, D. et al. Vanishing MS T2-bright lesions before puberty: a distinct MRI phenotype? Neurology 71, 1090–1093 (2008).

    CAS  PubMed  Google Scholar 

  32. 32

    Mikaeloff, Y. et al. MRI prognostic factors for relapse after acute CNS inflammatory demyelination in childhood. Brain 127, 1942–1947 (2004).

    PubMed  Google Scholar 

  33. 33

    Gall, J. C., Jr, Hayles, A. B., Siekert, R. G. & Keith, H. M. Multiple sclerosis in children; a clinical study of 40 cases with onset in childhood. Pediatrics 21, 703–709 (1958).

    PubMed  Google Scholar 

  34. 34

    Duquette, P. et al. Multiple sclerosis in childhood: clinical profile in 125 patients. J. Pediatr. 111, 359–363 (1987).

    CAS  PubMed  Google Scholar 

  35. 35

    Boutin, B. et al. Multiple sclerosis in children: report of clinical and paraclinical features of 19 cases. Neuropediatrics 19, 118–123 (1988).

    CAS  PubMed  Google Scholar 

  36. 36

    Hanefeld, F. et al. Multiple sclerosis in childhood: report of 15 cases. Brain Dev. 13, 410–416 (1991).

    CAS  PubMed  Google Scholar 

  37. 37

    Sindern, E., Haas, J., Stark, E. & Wurster, U. Early onset MS under the age of 16: clinical and paraclinical features. Acta Neurol. Scand. 86, 280–284 (1992).

    CAS  PubMed  Google Scholar 

  38. 38

    Cole, G. F. & Stuart, C. A. A long perspective on childhood multiple sclerosis. Dev. Med. Child Neurol. 37, 661–666 (1995).

    CAS  PubMed  Google Scholar 

  39. 39

    Guilhoto, L. M. et al. Pediatric multiple sclerosis report of 14 cases. Brain Dev. 17, 9–12 (1995).

    CAS  PubMed  Google Scholar 

  40. 40

    Selcen, D., Anlar, B. & Renda, Y. Multiple sclerosis in childhood: report of 16 cases. Eur. Neurol. 36, 79–84 (1996).

    CAS  PubMed  Google Scholar 

  41. 41

    Pinhas-Hamiel, O., Barak, Y., Siev-Ner, I. & Achiron, A. Juvenile multiple sclerosis: clinical features and prognostic characteristics. J. Pediatr. 132, 735–737 (1998).

    CAS  PubMed  Google Scholar 

  42. 42

    Belopitova, L., Guergueltcheva, P. V. & Bojinova, V. Definite and suspected multiple sclerosis in children: long-term follow-up and magnetic resonance imaging findings. J. Child Neurol. 16, 317–324 (2001).

    CAS  PubMed  Google Scholar 

  43. 43

    Ghezzi, A. et al. Prospective study of multiple sclerosis with early onset. Mult. Scler. 8, 115–118 (2002).

    CAS  PubMed  Google Scholar 

  44. 44

    Gusev, E. et al. The natural history of early onset multiple sclerosis: comparison of data from Moscow and Vancouver. Clin. Neurol. Neurosurg. 104, 203–207 (2002).

    PubMed  Google Scholar 

  45. 45

    Simone, I. L. et al. Course and prognosis in early-onset MS: comparison with adult-onset forms. Neurology 59, 1922–1928 (2002).

    CAS  PubMed  Google Scholar 

  46. 46

    Brass, S. D. et al. Multiple sclerosis vs acute disseminated encephalomyelitis in childhood. Pediatr. Neurol. 29, 227–231 (2003).

    PubMed  Google Scholar 

  47. 47

    Ozakbas, S., Idiman, E., Baklan, B. & Yulug, B. Childhood and juvenile onset multiple sclerosis: clinical and paraclinical features. Brain Dev. 25, 233–236 (2003).

    PubMed  Google Scholar 

  48. 48

    Mikaeloff, Y. et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. J. Pediatr. 144, 246–252 (2004).

    PubMed  Google Scholar 

  49. 49

    Shiraishi, K., Higuchi, Y., Ozawa, K., Hao, Q. & Saida, T. Clinical course and prognosis of 27 patients with childhood onset multiple sclerosis in Japan. Brain Dev. 27, 224–227 (2005).

    PubMed  Google Scholar 

  50. 50

    Deryck, O., Ketelaer, P. & Dubois, B. Clinical characteristics and long term prognosis in early onset multiple sclerosis. J. Neurol. 253, 720–723 (2006).

    PubMed  Google Scholar 

  51. 51

    Pohl, D., Hennemuth, I., von Kries, R. & Hanefeld, F. Paediatric multiple sclerosis and acute disseminated encephalomyelitis in Germany: results of a nationwide survey. Eur. J. Pediatr. 166, 405–412 (2007).

    PubMed  Google Scholar 

  52. 52

    Etemadifar, M., Nasr-Esfahani, A. H., Khodabandehlou, R. & Maghzi, A. H. Childhood-onset multiple sclerosis: report of 82 patients from Isfahan, Iran. Arch. Iran Med. 10, 152–156 (2007).

    PubMed  Google Scholar 

  53. 53

    Stark, W., Huppke, P. & Gartner, J. Paediatric multiple sclerosis: the experience of the German Centre for Multiple Sclerosis in Childhood and Adolescence. J. Neurol. 255 (Suppl. 6), 119–122 (2008).

    PubMed  Google Scholar 

  54. 54

    Atzori, M. et al. Clinical and diagnostic aspects of multiple sclerosis and acute monophasic encephalomyelitis in pediatric patients: a single centre prospective study. Mult. Scler. 15, 363–370 (2009).

    CAS  PubMed  Google Scholar 

  55. 55

    Pohl, D., Rostasy, K., Reiber, H. & Hanefeld, F. CSF characteristics in early-onset multiple sclerosis. Neurology 63, 1966–1967 (2004).

    CAS  PubMed  Google Scholar 

  56. 56

    Hynson, J. L. et al. Clinical and neuroradiologic features of acute disseminated encephalomyelitis in children. Neurology 56, 1308–1312 (2001).

    CAS  PubMed  Google Scholar 

  57. 57

    Pohl, D. et al. Pediatric multiple sclerosis: detection of clinically silent lesions by multimodal evoked potentials. J. Pediatr. 149, 125–127 (2006).

    PubMed  Google Scholar 

  58. 58

    Frohman, E. et al. Optical coherence tomography in multiple sclerosis. Lancet Neurol. 5, 853–863 (2006).

    PubMed  Google Scholar 

  59. 59

    Yeh, E. et al. Retinal nerve fiber thickness in inflammatory demyelinating diseases of childhood onset. Mult. Scler. 15, 802–810 (2009).

    CAS  PubMed  Google Scholar 

  60. 60

    Hahn, C. D., Shroff, M. M., Blaser, S. I. & Banwell, B. L. MRI criteria for multiple sclerosis: Evaluation in a pediatric cohort. Neurology 62, 806–808 (2004).

    PubMed  Google Scholar 

  61. 61

    Waubant, E. & Chabas, D. Pediatric multiple sclerosis. Curr. Treat. Options Neurol. 11, 203–210 (2009).

    PubMed  Google Scholar 

  62. 62

    Neuteboom, R. F. et al. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 71, 967–973 (2008).

    CAS  PubMed  Google Scholar 

  63. 63

    Callen, D. J. et al. Role of MRI in the differentiation of ADEM from MS in children. Neurology 72, 968–973 (2008).

    PubMed  Google Scholar 

  64. 64

    Leake, J. A. et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr. Infect. Dis. J. 23, 756–764 (2004).

    PubMed  Google Scholar 

  65. 65

    Mikaeloff, Y., Caridade, G., Husson, B., Suissa, S. & Tardieu, M. Acute disseminated encephalomyelitis cohort study: prognostic factors for relapse. Eur. J. Paediatr. Neurol. 11, 90–95 (2007).

    PubMed  Google Scholar 

  66. 66

    Renoux, C. et al. Natural history of multiple sclerosis with childhood onset. N. Engl. J. Med. 356, 2603–2613 (2007).

    CAS  PubMed  Google Scholar 

  67. 67

    Gorman, M. P., Healy, B. C., Polgar-Turcsanyi, M. & Chitnis, T. Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis. Arch. Neurol. 66, 54–59 (2009).

    PubMed  Google Scholar 

  68. 68

    Cole, G. F., Auchterlonie, L. A. & Best, P. V. Very early onset multiple sclerosis. Dev. Med. Child Neurol. 37, 667–672 (1995).

    CAS  PubMed  Google Scholar 

  69. 69

    Chiaravalloti, N. D. & DeLuca, J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 7, 1139–1151 (2008).

    PubMed  Google Scholar 

  70. 70

    Amato, M. P. et al. Cognitive impairment in early-onset multiple sclerosis. Pattern, predictors, and impact on everyday life in a 4-year follow-up. Arch. Neurol. 52, 168–172 (1995).

    CAS  PubMed  Google Scholar 

  71. 71

    Amato, M. P., Ponziani, G., Siracusa, G. & Sorbi, S. Cognitive dysfunction in early-onset multiple sclerosis: a reappraisal after 10 years. Arch. Neurol. 58, 1602–1606 (2001).

    CAS  PubMed  Google Scholar 

  72. 72

    MacAllister, W. S. et al. Cognitive functioning in children and adolescents with multiple sclerosis. Neurology 64, 1422–1425 (2005).

    CAS  PubMed  Google Scholar 

  73. 73

    Banwell, B. L. & Anderson, P. E. The cognitive burden of multiple sclerosis in children. Neurology 64, 891–894 (2005).

    PubMed  Google Scholar 

  74. 74

    MacAllister, W. S., Christodoulou, C., Milazzo, M. & Krupp, L. B. Longitudinal neuropsychological assessment in pediatric multiple sclerosis. Dev. Neuropsychol. 32, 625–644 (2007).

    PubMed  Google Scholar 

  75. 75

    Amato, M. P. et al. Cognitive and psychosocial features of childhood and juvenile MS. Neurology 70, 1891–1897 (2008).

    CAS  PubMed  Google Scholar 

  76. 76

    Mowry, E. et al. Health-related quality of life is reduced in children with early multiple sclerosis. Mult. Scler. 14, S147 (2008).

    Google Scholar 

  77. 77

    Amato, M. et al. Cognitive and psychosocial features of childhood and juvenile MS: a reappraisal after 2 years. Neurology 72, A97 (2009).

    Google Scholar 

  78. 78

    The IFNB Multiple Sclerosis Study Group. Interferon beta-1b is effective in relapsing–remitting multiple sclerosis. I Clinical results of a multicenter, randomized, double blind, placebo-controlled trial. Neurology 43, 655–661 (1993).

  79. 79

    Jacobs, L. et al. Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis. Ann. Neurol. 39, 285–294 (1996).

    CAS  PubMed  Google Scholar 

  80. 80

    [No authors listed] Randomized double-blind placebo-controlled study of interferon β-1a in relapsing/remitting multiple sclerosis. Lancet 352, 1498–1504 (1998).

  81. 81

    Ghezzi, A. et al. Treatment of early-onset multiple sclerosis with intramuscular interferonβ-1a: long-term results. Neurol. Sci. 28, 127–132 (2007).

    CAS  PubMed  Google Scholar 

  82. 82

    Mikaeloff, Y., Caridade, G., Tardieu, M. & Suissa, S. Effectiveness of early beta interferon on the first attack after confirmed multiple sclerosis: a comparative cohort study. Eur. J. Paediatr. Neurol. 12, 205–209 (2008).

    PubMed  Google Scholar 

  83. 83

    Mikaeloff, Y. et al. Interferon-β treatment in patients with childhood-onset multiple sclerosis. J. Pediatr. 139, 443–446 (2001).

    CAS  PubMed  Google Scholar 

  84. 84

    Banwell, B. et al. Safety and tolerability of interferon beta-1b in pediatric multiple sclerosis. Neurology 66, 472–476 (2006).

    CAS  PubMed  Google Scholar 

  85. 85

    Bykova, O. V., Kuzenkova, L. M. & Maslova, O. I. The use of beta-interferon-1b in children and adolescents with multiple sclerosis [Russian]. Zh. Nevrol. Psikhiatr. Im. S. S. Korsakova 106, 29–33 (2006).

    CAS  PubMed  Google Scholar 

  86. 86

    Pohl, D., Rostasy, K., Gärtner, J. & Hanefeld, F. Treatment of early onset multiple sclerosis with subcutaneous interferon beta-1a. Neurology 64, 888–890 (2005).

    CAS  PubMed  Google Scholar 

  87. 87

    Tenembaum, S. N. & Segura, M. J. Interferon beta-1a treatment in childhood and juvenile-onset multiple sclerosis. Neurology 67, 511–513 (2006).

    CAS  PubMed  Google Scholar 

  88. 88

    Yeh, E. et al. Breakthrough disease in pediatric MS patients: a pediatric network experience [abstract S50.006]. Neurology 72 (Suppl. 3), A428 (2009).

    Google Scholar 

  89. 89

    Dhib-Jalbut, S. Sustained immunological effects of Glatiramer acetate in patients with multiple sclerosis treated for over 6 years. J. Neurol. Sci. 201, 71–77 (2002).

    PubMed  Google Scholar 

  90. 90

    Johnson, K. et al. Copolymer 1 reduces relapse rate and improves disability in relapsing-remitting multiple sclerosis: results of a phase III multicenter, double-blind, placebo-controlled trial. Neurology 45, 1268–1276 (1995).

    CAS  PubMed  Google Scholar 

  91. 91

    Kornek, B. et al. Glatiramer acetate treatment in patients with childhood and juvenile onset multiple sclerosis. Neuropediatrics 34, 120–126 (2003).

    CAS  PubMed  Google Scholar 

  92. 92

    Coyle, P. K. Switching algorithms: from one immunomodulatory agent to another. J. Neurol. 255 (Suppl. 1), 44–50 (2008).

    CAS  PubMed  Google Scholar 

  93. 93

    Cohen, B. A. et al. Identifying and treating patients with suboptimal responses. Neurology 63, S33–S40 (2004).

    CAS  PubMed  Google Scholar 

  94. 94

    Makhani, N. et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology 72, 2076–2082 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. 95

    Borriello, G., Prosperini, L., Luchetti, A. & Pozzilli, C. Natalizumab treatment in pediatric multiple sclerosis: A case report. Eur. J. Paediatr. Neurol. 13, 67–71 (2009).

    PubMed  Google Scholar 

  96. 96

    Huppke, P. et al. Natalizumab use in pediatric multiple sclerosis. Arch. Neurol. 65, 1655–1658 (2008).

    PubMed  Google Scholar 

  97. 97

    Makhani, N. et al. Cyclophosphamide therapy in pediatric multiple sclerosis. Neurology 72, 2076–2082 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Désirée Lie, University of California, Orange, CA is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.

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Correspondence to E. Ann Yeh.

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The authors, the Journal Editor H. Wood and the CME questions author D. Lie declare no competing interests.

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Yeh, E., Chitnis, T., Krupp, L. et al. Pediatric multiple sclerosis. Nat Rev Neurol 5, 621–631 (2009). https://doi.org/10.1038/nrneurol.2009.158

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