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Submitted
February 1, 2021
Accepted
September 8, 2021
Published
December 11, 2021
Main Article Content
Abstract
Paediatric acquired demyelinating syndromes (ADS) are characterised by neurological deficits persisting for at least 24 hours, involving the optic nerve, spinal cord or brain with a clinical spectrum of diagnoses including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD) and MOG-Ab associated disease (MOGAD). Important strides have been made in delineating MS from other ADS subtypes over the past decade, including the discovery of serum aquaporin-4 (AQP4) and Myelin oligodendrocyte glycoprotein (MOG) antibodies (Ab). Both genetic (e.g. human leukocyte antigen, HLA-DRB1*1501 allele) and environmental risk factors (e.g. low serum vitamin D levels and prior exposure to Epstein–Barr virus) may contribute to risk of MS in children. Some of these risk factors not only confer increased susceptibility to MS but may also affect the disease course. Paediatric AQP4-Ab NMOSD is a rare disease worldwide but variations in incidence/prevalence have been described among different geographic regions and ethnicities. One-third of children who present with an ADS have MOG-Ab, and approximately half of patients with MOG-Ab have a relapsing disease course. It seems there is no racial or gender predominance in MOGAD, which is in contrast to the female and non-white predominance seen in both MS and NMOSD. In this review, we examine the current literature regarding the epidemiology and demographics of these different ADS entities with a particular focus on the genetic and environmental risk factors for MS in children. While insights into disease pathophysiology in paediatric ADS have led recent therapeutic advances, well designed, collaborative large scale epidemiological studies are likely to provide the critical next step to a personalised approach to these conditions.
Keywords
Paediatric Multiple Sclerosis (MS)
acquired demyelinating syndromes (ADS)
MOG-antibody associated disease (MOGAD)
neuromyelitis optica spectrum disorders (NMOSD)
aquaporin-4 antibodies
epidemiology
risk factors
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Copyright (c) 2021 Ori Haddad, Yael Hacohen, Omar Abdel-Mannan
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How to Cite
Haddad, O., Hacohen, Y., & Abdel-Mannan, O. (2021). Paediatric Acquired Demyelinating Syndromes: A review of the epidemiology and risk factors. Journal of the International Child Neurology Association, 1(1). https://doi.org/10.17724/jicna.2021.230
References
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1. Fadda G, Armangue T, Hacohen Y, Chitnis T, Banwell B. Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care. The Lancet Neurology 2021;20:136-149.
2. Waubant E, Ponsonby A-L, Pugliatti M, Hanwell H, Mowry EM, Hintzen RQ. Environmental and genetic factors in pediatric inflammatory demyelinating diseases. Neurology 2016;87:S20-S27.
3. Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: an integrated review. Annals of clinical and translational neurology 2019;6:1905-1922.
4. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. The Lancet Neurology 2014;13:936-948.
5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology 2018;17:162-173.
6. Hacohen Y, Mankad K, Chong WK, et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology 2017;89:269-278.
7. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. The Lancet 2004;364:2106-2112.
8. Hacohen Y, Banwell B. Treatment approaches for MOG-Ab-associated demyelination in children. Current treatment options in neurology 2019;21:2.
9. Hacohen Y, Absoud M, Deiva K, et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurology-Neuroimmunology Neuroinflammation 2015;2.
10. Tackley G, O’Brien F, Rocha J, et al. Neuromyelitis optica relapses: race and rate, immunosuppression and impairment. Multiple sclerosis and related disorders 2016;7:21-25.
11. Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics 2016;138.
12. Langer-Gould A, Zhang J, Chung J, Yeung Y, Waubant E, Yao J. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology 2011;77:1143-1148.
13. Absoud M, Lim MJ, Chong WK, et al. Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features. Multiple Sclerosis Journal 2013;19:76-86.
14. Mikaeloff Y, Suissa S, Vallée L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. The Journal of pediatrics 2004;144:246-252.
15. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 2009;72:232-239.
16. Neuteboom R, Boon M, Berrevoets CC, et al. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 2008;71:967-973.
17. De Mol C, Wong Y, Van Pelt E, et al. Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study. Journal of neurology 2018;265:1310-1319.
18. Lin W-S, Wang H-P, Chen H-M, Lin J-W, Lee W-T. Epidemiology of pediatric multiple sclerosis, neuromyelitis optica, and optic neuritis in Taiwan. Journal of neurology 2020;267:925-932.
19. Hacohen Y, Brownlee W, Mankad K, et al. Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort. Multiple Sclerosis Journal 2020;26:1372-1380.
20. Disanto G, Magalhaes S, Handel A, et al. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 2011;76:781-786.
21. Axisa P-P, Hafler DA. Multiple sclerosis: genetics, biomarkers, treatments. Current Opinion in Neurology 2016;29:345-353.
22. Gianfrancesco MA, Stridh P, Shao X, et al. Genetic risk factors for pediatric-onset multiple sclerosis. Multiple Sclerosis Journal 2018;24:1825-1834.
23. Barcellos L, Shao X, Rhead B, et al. First genome-wide analysis in pediatric multiple sclerosis (MS) confirms a role for adult MS risk variants and reveals new candidates (S29. 001). AAN Enterprises, 2016.
24. Bashinskaya V, Kulakova O, Boyko A, Favorov A, Favorova O. A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Human genetics 2015;134:1143-1162.
25. Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. The Lancet Neurology 2011;10:436-445.
26. George IC, Makhani N. Genetic and Environmental Risk Factors for Pediatric Multiple Sclerosis. Journal of Pediatric Neurology 2018;16:141-147.
27. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013;80:548-552.
28. Huppke B, Ellenberger D, Rosewich H, Friede T, Gärtner J, Huppke P. Clinical presentation of pediatric multiple sclerosis before puberty. European journal of neurology 2014;21:441-446.
29. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. The Lancet Neurology 2007;6:773-781.
30. Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case− control study. European journal of neurology 2016;23:1308-1321.
31. Ramagopalan SV, Maugeri NJ, Handunnetthi L, et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1* 1501 is regulated by vitamin D. PLoS Genet 2009;5:e1000369.
32. Hedström AK, Bomfim IL, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014;82:865-872.
33. Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011;76:1989-1995.
34. Boster AL, Endress CF, Hreha SA, Caon C, Perumal JS, Khan OA. Pediatric-onset multiple sclerosis in African-American black and European-origin white patients. Pediatric neurology 2009;40:31-33.
35. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric‐onset multiple sclerosis. Annals of neurology 2010;67:618-624.
36. Graves J, Grandhe S, Weinfurtner K, et al. Protective environmental factors for neuromyelitis optica. Neurology 2014;83:1923-1929.
37. Huppke B, Ellenberger D, Hummel H, et al. Association of obesity with multiple sclerosis risk and response to first-line disease modifying drugs in children. JAMA neurology 2019;76:1157-1165.
38. Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Multiple Sclerosis Journal 2016;22:193-200.
39. Chitnis T, Graves J, Weinstock‐Guttman B, et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Annals of clinical and translational neurology 2016;3:897-907.
40. Papp V, Magyari M, Aktas O, et al. Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review. Neurology 2021;96:59-77.
41. Flanagan EP, Cabre P, Weinshenker BG, et al. Epidemiology of aquaporin‐4 autoimmunity and neuromyelitis optica spectrum. Annals of neurology 2016;79:775-783.
42. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012;135:1834-1849.
43. Paolilo RB, Hacohen Y, Yazbeck E, et al. Treatment and outcome of aquaporin-4 antibody–positive NMOSD: a multinational pediatric study. Neurology-Neuroimmunology Neuroinflammation 2020;7.
44. Hacohen Y, Messina S, Gan H-W, et al. Endocrinopathies in paediatric-onset neuromyelitis optica spectrum disorder with aquaporin 4 (AQP4) antibody. Multiple Sclerosis Journal 2018;24:679-684.
45. Palace J, Lin D-Y, Zeng D, et al. Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders. Brain 2019;142:1310-1323.
46. Reindl M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nature Reviews Neurology 2019;15:89-102.
47. Estrada K, Whelan CW, Zhao F, et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nature communications 2018;9:1-10.
48. Sun X, Qiu W, Wang J, et al. Myelin oligodendrocyte glycoprotein-associated disorders are associated with HLA subtypes in a Chinese paediatric-onset cohort. Journal of Neurology, Neurosurgery & Psychiatry 2020;91:733-739.
49. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-189.
50. Bruijstens AL, Lechner C, Flet-Berliac L, et al. EU paediatric MOG consortium consensus: Part 1–Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders. European Journal of Paediatric Neurology 2020.
References
1. Fadda G, Armangue T, Hacohen Y, Chitnis T, Banwell B. Paediatric multiple sclerosis and antibody-associated demyelination: clinical, imaging, and biological considerations for diagnosis and care. The Lancet Neurology 2021;20:136-149.
2. Waubant E, Ponsonby A-L, Pugliatti M, Hanwell H, Mowry EM, Hintzen RQ. Environmental and genetic factors in pediatric inflammatory demyelinating diseases. Neurology 2016;87:S20-S27.
3. Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: an integrated review. Annals of clinical and translational neurology 2019;6:1905-1922.
4. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. The Lancet Neurology 2014;13:936-948.
5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology 2018;17:162-173.
6. Hacohen Y, Mankad K, Chong WK, et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology 2017;89:269-278.
7. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. The Lancet 2004;364:2106-2112.
8. Hacohen Y, Banwell B. Treatment approaches for MOG-Ab-associated demyelination in children. Current treatment options in neurology 2019;21:2.
9. Hacohen Y, Absoud M, Deiva K, et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurology-Neuroimmunology Neuroinflammation 2015;2.
10. Tackley G, O’Brien F, Rocha J, et al. Neuromyelitis optica relapses: race and rate, immunosuppression and impairment. Multiple sclerosis and related disorders 2016;7:21-25.
11. Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics 2016;138.
12. Langer-Gould A, Zhang J, Chung J, Yeung Y, Waubant E, Yao J. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology 2011;77:1143-1148.
13. Absoud M, Lim MJ, Chong WK, et al. Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features. Multiple Sclerosis Journal 2013;19:76-86.
14. Mikaeloff Y, Suissa S, Vallée L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. The Journal of pediatrics 2004;144:246-252.
15. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 2009;72:232-239.
16. Neuteboom R, Boon M, Berrevoets CC, et al. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 2008;71:967-973.
17. De Mol C, Wong Y, Van Pelt E, et al. Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study. Journal of neurology 2018;265:1310-1319.
18. Lin W-S, Wang H-P, Chen H-M, Lin J-W, Lee W-T. Epidemiology of pediatric multiple sclerosis, neuromyelitis optica, and optic neuritis in Taiwan. Journal of neurology 2020;267:925-932.
19. Hacohen Y, Brownlee W, Mankad K, et al. Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort. Multiple Sclerosis Journal 2020;26:1372-1380.
20. Disanto G, Magalhaes S, Handel A, et al. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 2011;76:781-786.
21. Axisa P-P, Hafler DA. Multiple sclerosis: genetics, biomarkers, treatments. Current Opinion in Neurology 2016;29:345-353.
22. Gianfrancesco MA, Stridh P, Shao X, et al. Genetic risk factors for pediatric-onset multiple sclerosis. Multiple Sclerosis Journal 2018;24:1825-1834.
23. Barcellos L, Shao X, Rhead B, et al. First genome-wide analysis in pediatric multiple sclerosis (MS) confirms a role for adult MS risk variants and reveals new candidates (S29. 001). AAN Enterprises, 2016.
24. Bashinskaya V, Kulakova O, Boyko A, Favorov A, Favorova O. A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Human genetics 2015;134:1143-1162.
25. Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. The Lancet Neurology 2011;10:436-445.
26. George IC, Makhani N. Genetic and Environmental Risk Factors for Pediatric Multiple Sclerosis. Journal of Pediatric Neurology 2018;16:141-147.
27. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013;80:548-552.
28. Huppke B, Ellenberger D, Rosewich H, Friede T, Gärtner J, Huppke P. Clinical presentation of pediatric multiple sclerosis before puberty. European journal of neurology 2014;21:441-446.
29. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. The Lancet Neurology 2007;6:773-781.
30. Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case− control study. European journal of neurology 2016;23:1308-1321.
31. Ramagopalan SV, Maugeri NJ, Handunnetthi L, et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1* 1501 is regulated by vitamin D. PLoS Genet 2009;5:e1000369.
32. Hedström AK, Bomfim IL, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014;82:865-872.
33. Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011;76:1989-1995.
34. Boster AL, Endress CF, Hreha SA, Caon C, Perumal JS, Khan OA. Pediatric-onset multiple sclerosis in African-American black and European-origin white patients. Pediatric neurology 2009;40:31-33.
35. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric‐onset multiple sclerosis. Annals of neurology 2010;67:618-624.
36. Graves J, Grandhe S, Weinfurtner K, et al. Protective environmental factors for neuromyelitis optica. Neurology 2014;83:1923-1929.
37. Huppke B, Ellenberger D, Hummel H, et al. Association of obesity with multiple sclerosis risk and response to first-line disease modifying drugs in children. JAMA neurology 2019;76:1157-1165.
38. Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Multiple Sclerosis Journal 2016;22:193-200.
39. Chitnis T, Graves J, Weinstock‐Guttman B, et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Annals of clinical and translational neurology 2016;3:897-907.
40. Papp V, Magyari M, Aktas O, et al. Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review. Neurology 2021;96:59-77.
41. Flanagan EP, Cabre P, Weinshenker BG, et al. Epidemiology of aquaporin‐4 autoimmunity and neuromyelitis optica spectrum. Annals of neurology 2016;79:775-783.
42. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012;135:1834-1849.
43. Paolilo RB, Hacohen Y, Yazbeck E, et al. Treatment and outcome of aquaporin-4 antibody–positive NMOSD: a multinational pediatric study. Neurology-Neuroimmunology Neuroinflammation 2020;7.
44. Hacohen Y, Messina S, Gan H-W, et al. Endocrinopathies in paediatric-onset neuromyelitis optica spectrum disorder with aquaporin 4 (AQP4) antibody. Multiple Sclerosis Journal 2018;24:679-684.
45. Palace J, Lin D-Y, Zeng D, et al. Outcome prediction models in AQP4-IgG positive neuromyelitis optica spectrum disorders. Brain 2019;142:1310-1323.
46. Reindl M, Waters P. Myelin oligodendrocyte glycoprotein antibodies in neurological disease. Nature Reviews Neurology 2019;15:89-102.
47. Estrada K, Whelan CW, Zhao F, et al. A whole-genome sequence study identifies genetic risk factors for neuromyelitis optica. Nature communications 2018;9:1-10.
48. Sun X, Qiu W, Wang J, et al. Myelin oligodendrocyte glycoprotein-associated disorders are associated with HLA subtypes in a Chinese paediatric-onset cohort. Journal of Neurology, Neurosurgery & Psychiatry 2020;91:733-739.
49. Wingerchuk DM, Banwell B, Bennett JL, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015;85:177-189.
50. Bruijstens AL, Lechner C, Flet-Berliac L, et al. EU paediatric MOG consortium consensus: Part 1–Classification of clinical phenotypes of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders. European Journal of Paediatric Neurology 2020.
2. Waubant E, Ponsonby A-L, Pugliatti M, Hanwell H, Mowry EM, Hintzen RQ. Environmental and genetic factors in pediatric inflammatory demyelinating diseases. Neurology 2016;87:S20-S27.
3. Waubant E, Lucas R, Mowry E, et al. Environmental and genetic risk factors for MS: an integrated review. Annals of clinical and translational neurology 2019;6:1905-1922.
4. Waldman A, Ghezzi A, Bar-Or A, Mikaeloff Y, Tardieu M, Banwell B. Multiple sclerosis in children: an update on clinical diagnosis, therapeutic strategies, and research. The Lancet Neurology 2014;13:936-948.
5. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology 2018;17:162-173.
6. Hacohen Y, Mankad K, Chong WK, et al. Diagnostic algorithm for relapsing acquired demyelinating syndromes in children. Neurology 2017;89:269-278.
7. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. The Lancet 2004;364:2106-2112.
8. Hacohen Y, Banwell B. Treatment approaches for MOG-Ab-associated demyelination in children. Current treatment options in neurology 2019;21:2.
9. Hacohen Y, Absoud M, Deiva K, et al. Myelin oligodendrocyte glycoprotein antibodies are associated with a non-MS course in children. Neurology-Neuroimmunology Neuroinflammation 2015;2.
10. Tackley G, O’Brien F, Rocha J, et al. Neuromyelitis optica relapses: race and rate, immunosuppression and impairment. Multiple sclerosis and related disorders 2016;7:21-25.
11. Belman AL, Krupp LB, Olsen CS, et al. Characteristics of children and adolescents with multiple sclerosis. Pediatrics 2016;138.
12. Langer-Gould A, Zhang J, Chung J, Yeung Y, Waubant E, Yao J. Incidence of acquired CNS demyelinating syndromes in a multiethnic cohort of children. Neurology 2011;77:1143-1148.
13. Absoud M, Lim MJ, Chong WK, et al. Paediatric acquired demyelinating syndromes: incidence, clinical and magnetic resonance imaging features. Multiple Sclerosis Journal 2013;19:76-86.
14. Mikaeloff Y, Suissa S, Vallée L, et al. First episode of acute CNS inflammatory demyelination in childhood: prognostic factors for multiple sclerosis and disability. The Journal of pediatrics 2004;144:246-252.
15. Banwell B, Kennedy J, Sadovnick D, et al. Incidence of acquired demyelination of the CNS in Canadian children. Neurology 2009;72:232-239.
16. Neuteboom R, Boon M, Berrevoets CC, et al. Prognostic factors after a first attack of inflammatory CNS demyelination in children. Neurology 2008;71:967-973.
17. De Mol C, Wong Y, Van Pelt E, et al. Incidence and outcome of acquired demyelinating syndromes in Dutch children: update of a nationwide and prospective study. Journal of neurology 2018;265:1310-1319.
18. Lin W-S, Wang H-P, Chen H-M, Lin J-W, Lee W-T. Epidemiology of pediatric multiple sclerosis, neuromyelitis optica, and optic neuritis in Taiwan. Journal of neurology 2020;267:925-932.
19. Hacohen Y, Brownlee W, Mankad K, et al. Improved performance of the 2017 McDonald criteria for diagnosis of multiple sclerosis in children in a real-life cohort. Multiple Sclerosis Journal 2020;26:1372-1380.
20. Disanto G, Magalhaes S, Handel A, et al. HLA-DRB1 confers increased risk of pediatric-onset MS in children with acquired demyelination. Neurology 2011;76:781-786.
21. Axisa P-P, Hafler DA. Multiple sclerosis: genetics, biomarkers, treatments. Current Opinion in Neurology 2016;29:345-353.
22. Gianfrancesco MA, Stridh P, Shao X, et al. Genetic risk factors for pediatric-onset multiple sclerosis. Multiple Sclerosis Journal 2018;24:1825-1834.
23. Barcellos L, Shao X, Rhead B, et al. First genome-wide analysis in pediatric multiple sclerosis (MS) confirms a role for adult MS risk variants and reveals new candidates (S29. 001). AAN Enterprises, 2016.
24. Bashinskaya V, Kulakova O, Boyko A, Favorov A, Favorova O. A review of genome-wide association studies for multiple sclerosis: classical and hypothesis-driven approaches. Human genetics 2015;134:1143-1162.
25. Banwell B, Bar-Or A, Arnold DL, et al. Clinical, environmental, and genetic determinants of multiple sclerosis in children with acute demyelination: a prospective national cohort study. The Lancet Neurology 2011;10:436-445.
26. George IC, Makhani N. Genetic and Environmental Risk Factors for Pediatric Multiple Sclerosis. Journal of Pediatric Neurology 2018;16:141-147.
27. Langer-Gould A, Brara SM, Beaber BE, Koebnick C. Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome. Neurology 2013;80:548-552.
28. Huppke B, Ellenberger D, Rosewich H, Friede T, Gärtner J, Huppke P. Clinical presentation of pediatric multiple sclerosis before puberty. European journal of neurology 2014;21:441-446.
29. Banwell B, Krupp L, Kennedy J, et al. Clinical features and viral serologies in children with multiple sclerosis: a multinational observational study. The Lancet Neurology 2007;6:773-781.
30. Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case− control study. European journal of neurology 2016;23:1308-1321.
31. Ramagopalan SV, Maugeri NJ, Handunnetthi L, et al. Expression of the multiple sclerosis-associated MHC class II Allele HLA-DRB1* 1501 is regulated by vitamin D. PLoS Genet 2009;5:e1000369.
32. Hedström AK, Bomfim IL, Barcellos L, et al. Interaction between adolescent obesity and HLA risk genes in the etiology of multiple sclerosis. Neurology 2014;82:865-872.
33. Waubant E, Mowry EM, Krupp L, et al. Common viruses associated with lower pediatric multiple sclerosis risk. Neurology 2011;76:1989-1995.
34. Boster AL, Endress CF, Hreha SA, Caon C, Perumal JS, Khan OA. Pediatric-onset multiple sclerosis in African-American black and European-origin white patients. Pediatric neurology 2009;40:31-33.
35. Mowry EM, Krupp LB, Milazzo M, et al. Vitamin D status is associated with relapse rate in pediatric‐onset multiple sclerosis. Annals of neurology 2010;67:618-624.
36. Graves J, Grandhe S, Weinfurtner K, et al. Protective environmental factors for neuromyelitis optica. Neurology 2014;83:1923-1929.
37. Huppke B, Ellenberger D, Hummel H, et al. Association of obesity with multiple sclerosis risk and response to first-line disease modifying drugs in children. JAMA neurology 2019;76:1157-1165.
38. Lulu S, Graves J, Waubant E. Menarche increases relapse risk in pediatric multiple sclerosis. Multiple Sclerosis Journal 2016;22:193-200.
39. Chitnis T, Graves J, Weinstock‐Guttman B, et al. Distinct effects of obesity and puberty on risk and age at onset of pediatric MS. Annals of clinical and translational neurology 2016;3:897-907.
40. Papp V, Magyari M, Aktas O, et al. Worldwide Incidence and Prevalence of Neuromyelitis Optica: A Systematic Review. Neurology 2021;96:59-77.
41. Flanagan EP, Cabre P, Weinshenker BG, et al. Epidemiology of aquaporin‐4 autoimmunity and neuromyelitis optica spectrum. Annals of neurology 2016;79:775-783.
42. Kitley J, Leite MI, Nakashima I, et al. Prognostic factors and disease course in aquaporin-4 antibody-positive patients with neuromyelitis optica spectrum disorder from the United Kingdom and Japan. Brain 2012;135:1834-1849.
43. Paolilo RB, Hacohen Y, Yazbeck E, et al. Treatment and outcome of aquaporin-4 antibody–positive NMOSD: a multinational pediatric study. Neurology-Neuroimmunology Neuroinflammation 2020;7.
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