Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice

Ahn, Jeeyoon Jennifer; O’Mahony, Julia; Moshkova, Marina; Hanwell, Heather; Singh, Hargurinder; Zhang, Monan Angela; Marrie, Ruth Ann; Bar‐Or, Amit; Sadovnick, Dessa; Dunn, Shannon; Banwell, Brenda

doi:10.1177/1352458514551453

Cited by 51 publications

(52 citation statements)

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“…Prior studies have suggested that attainment of menarche increases the risk of MS in girls with acute demyelinating syndrome (ADS),4 and that relapse rate increases in girls in the peri‐menarcheal phase 5. One study has demonstrated a marginally earlier age at menarche in a large cohort of females with MS 2.…”

Section: Introductionmentioning

confidence: 99%

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Chitnis

Graves

Weinstock‐Guttman

et al. 2016

Ann Clin Transl Neurol

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ObjectiveThe aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS.MethodsCase–control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex‐ and age‐stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex‐stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity.ResultsOnly 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms (P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS (P < 0.001).InterpretationHigher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.

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Section: Introductionmentioning

confidence: 99%

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Chitnis

Graves

Weinstock‐Guttman

et al. 2016

Ann Clin Transl Neurol

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“…Consistent with 2 recent reports of smaller cohorts, the observed temporal link between onset of menarche and MS in our sample supports the potential role of sex hormones in the complex immunologic process occurring in the onset of MS in adolescent girls. 28,29 Clinical features that distinguished younger versus older MS cases included the following: younger children were more likely to report a prodromal event before the first MS attack, present with encephalopathy, and have more motor and coordination problems. In contrast, older children had more sensory symptoms suggesting spinal cord involvement (similar to findings recently reported from Germany comparing 47 children aged <11 years with those >14 years of age, 30 and more consistent with findings reported for adult-onset MS).…”

Section: Treatmentmentioning

confidence: 99%

Characteristics of Children and Adolescents With Multiple Sclerosis

Belman

Krupp

Olsen³

et al. 2016

Pediatrics

105

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OBJECTIVES: To describe the demographic and clinical characteristics of pediatric multiple sclerosis (MS) in the United States.METHODS: This prospective observational study included children and adolescents with MS. Cases were evaluated across 9 geographically diverse sites as part of the US Network of Pediatric MS Centers. RESULTS:A total of 490 children and adolescents (324 girls, 166 boys) were enrolled; 28% developed symptoms before 12 years of age. The proportion of girls increased with age from 58% (<12 years) to 70% (≥12 years). Race and ethnicity as self-identified were: white, 67%; African American, 21%; and non-Hispanic, 70%. Most (94%) of the cases were born in the United States, and 39% had 1 or both foreign-born parents. Fifty-five percent of cases had a monofocal presentation; 31% had a prodrome (most frequently infectious), most often among those aged <12 years (P < .001). Children aged <12 years presented more commonly with encephalopathy and coordination problems (P < .001). Sensory symptoms were more frequently reported by older children (ie, those aged ≥12 years) (P < .001); 78% of girls had MS onset postmenarche. The initial Expanded Disability Status Scale score for the group was <3.0, and the annualized relapse rate was 0.647 for the first 2 years. Interval from symptom onset to diagnosis and from diagnosis to initiation of disease-modifying therapy was longer among those <12 years of age.CONCLUSIONS: Pediatric MS in the United States is characterized by racial and ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features and timing of treatment among those <12 years of age compared with older children. Dr Belman conceptualizated and designed the study in addition to the acquisition of data, analysis, interpretation of the data, and drafting and revising the manuscript; Drs Krupp, Chitnis, Ness, Gorman, and Weinstock-Guttman carried out the acquisition of data, interpretation of data, and revising the manuscript; Mr Olsen carried out the statistical analysis, interpretation of data, and revising the manuscript; Dr Waubant carried out the acquisition of data, design of the study, interpretation of data, and revising the manuscript; Dr Rodriguez carried out acquisition of the data, interpretation of data, and review of the manuscript; Drs Lotze and Aaen carried out WHAT'S KNOWN ON THIS SUBJECT: Pediatric multiple sclerosis has an incidence of ≤0.64 per 10 000 and is less common among those aged <12 years. At onset, it has an almost exclusively relapsing-remitting course. WHAT THIS STUDY ADDS:In the United States, pediatric multiple sclerosis is characterized by racial/ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features among those <12 years of age compared with older children.by guest on May 7, 2018 http://pediatrics.aappublications.org/ Downloaded from BELMAN et alMultiple sclerosis (MS) is a central nervous system autoimmune inflammatory demyelinating disease. Generally...

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“…12 In a prospective longitudinal study of Canadian children presenting for an acquired demyelinating syndrome (ADS), girls with later age at menses were less likely to be diagnosed with MS even after correcting for older age at ADS onset. 13 In a US cohort of female pediatric patients with MS followed before, during, and after menarche, individual relapse rates were higher during the epoch of menarche (defined as 6 months before and after menarche) compared to relapse rates postmenarche. 14 Younger girls (at least 6 months prior to menarche) had a lower relapse rate compared to girls within 6 months of menarche in unadjusted models; however, there was no difference after adjusting for exposure to disease-modifying therapy.…”

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confidence: 99%

Pediatric multiple sclerosis

et al. 2016

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Multiple sclerosis (MS) in children manifests with a relapsing-remitting MS (RRMS) disease course. Acute relapses consist of new neurologic deficits persisting greater than 24 hours, in the absence of intercurrent illness, and occur with a higher frequency early in the disease as compared to adult-onset RRMS. Most pediatric patients with MS recover well from these early relapses, and cumulative physical disability is rare in the first 10 years of disease. Brainstem attacks, poor recovery from a single attack, and a higher frequency of attacks portend a greater likelihood of future disability. Although prospective pediatric-onset MS cohorts have been established in recent years, there remains very limited prospective data detailing the longer-term clinical outcome of pediatric-onset MS into adulthood. Whether the advent of MS therapies, and the largely off-label access to such therapies in pediatric MS, has improved prognosis is unknown. MS onset during the key formative academic years, concurrent with active cognitive maturation, is an important determinant of long-term outcome, and is discussed in detail in another article in this supplement. Finally, increasing recognition of pediatric MS worldwide, recent launch of phase III trials for new agents in the pediatric MS population, and the clear imperative to more fully appreciate health-related quality of life in pediatric MS through adulthood highlight the need for standardized, validated, and robust outcome measures. Neurology ® 2016;87 (Suppl 2):S74-S81

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Puberty in females enhances the risk of an outcome of multiple sclerosis in children and the development of central nervous system autoimmunity in mice

Abstract: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice.

Cited by 51 publications

References 36 publications

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Distinct effects of obesity and puberty on risk and age at onset of pediatric MS

Characteristics of Children and Adolescents With Multiple Sclerosis

Pediatric multiple sclerosis

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