Faculty Bibliography

Background: The immunopathogenesis of pediatric multiple sclerosis (MS) is not well understood. Methods: We studied the cytokine profile in pre-treatment serum specimens of 19 pediatric MS patients, 25 adult MS patients, and 22 age- and gender-matched pediatric healthy controls. In addition to IL-2, IL-12p40, IL-12p70, IL-18, IL-23, IL-6, TNF-alpha, TGF-beta-1, IFN-gamma, IL-17A, IL-21, IL-10, IL-4, IL-5, IL-13, and GM-CSF, we measured osteopontin and soluble VCAM-I. Results: In children with MS, significantly lower levels of IL-6 were present compared to age- and gender-matched healthy control children (p < 0.05). Moreover, significantly higher levels of osteopontin (p < 0.02) and sVCAM-1 (p < 0.02) and lower levels of IL-6 (p < 0.01) were present, with trends toward lower levels of IL-12p70 (p = 0.074) and IL-17a (p = 0.05) compared to adults with MS. Conclusions: These findings indicate important differences in cytokine signatures in children with MS and suggest an unexpected possible lower inflammatory cytokine profile in children with MS

Background: Pregnancy is a period of relative disease quiescence for a majority of women with multiple sclerosis (MS). Though the use of disease modifying therapies (DMTs) is discouraged during pregnancy, specific recommendations with respect to breastfeeding or timing of cessation of DMT use as well as reinitiation of DMT postpartum are often unclear. Objective: Our primary objective is to examine the pregnancy making decisions of women with MS enrolled in the New York State MS Consortium (NYSMSC) and the associations with clinical outcomes. Methods: 800 women enrolled in the NYSMSC were mailed a questionnaire inquiring on reproductive history and reproductive decision-making. Longitudinally collected information including demographics, disease characteristics (MS type, relapses), EDSS, DMT history, and patient-reported outcomes are available from the 20-year ongoing prospective NYSMSC registry. Results: To date, 477 questionnaires have been received. Of the 365 women who responded to specific pregnancy questions, 97 (26.6%) reported at least one pregnancy or pregnancy attempt after diagnosis of MS. Of those who attempted pregnancy post- MS diagnosis, 64 (66%) reported at least one successful pregnancy, while 21 (21.7%) reported that they were unable to conceive, and several were still trying. The majority of women (61.1%) resumed the same DMT they had been taking before their pregnancy, and 65.4% resumed DMT use within 6 months of delivery. Ten women (10.3%) reported relapses during pregnancy. There were no significant differences in age or DMT use between women who reported relapses and women who did not. Women who reported relapses during pregnancy were also more likely to report relapses in the 12 months prior to the pregnancy (p=0.020). Sixteen women reported a relapse in the 12 months before pregnancy; of those, 11 (68.8%) also reported relapses in the 12 months after pregnancy. Of the 55 women who did not have a relapse in the 12 months before pregnancy; 15 (29.1%) reported having a relapse in the 12 months after pregnancy. The difference between the two groups was significant (p-value=0.004). Conclusion: A substantial portion of women with MS will intend to become pregnant after their MS diagnosis. As such, it is essential that evidence-based information is available to young women with MS. Additional analyses will be presented in a larger sample with respect to the effect and type of DMT used before and after pregnancy on relapses

In light of the published 2012 International Pediatric Multiple Sclerosis Group definitions for pediatric multiple sclerosis (MS) and related disorders and given that pediatric-onset MS is now formally included in the 2010 McDonald criteria for MS, we sought to review these criteria and summarize their application in children with acquired CNS demyelination. In addition, proposals are made for definitions of no evidence of disease activity and inadequate treatment response that are important because of new therapeutic options and trials.

We explored the association between baseline gut microbiota (16S rRNA biomarker sequencing of stool samples) in 17 relapsing-remitting pediatric MS cases and risk of relapse over a mean 19.8 months follow-up. From the Kaplan-Meier curve, 25% relapsed within an estimated 166 days from baseline. A shorter time to relapse was associated with Fusobacteria depletion (p=0.001 log-rank test), expansion of the Firmicutes (p=0.003), and presence of the Archaea Euryarchaeota (p=0.037). After covariate adjustments for age and immunomodulatory drug exposure, only absence (vs. presence) of Fusobacteria was associated with relapse risk (hazard ratio=3.2 (95% CI: 1.2-9.0), p=0.024). Further investigation is warranted. Findings could offer new targets to alter the MS disease course.

In comparison with the large body of evidence on cognitive functioning in adults with multiple sclerosis (MS), there is limited information on cognition in pediatric-onset MS (POMS). Unique vulnerabilities in POMS can derive from having a disease that occurs during key periods of age-expected brain growth, active myelination in the CNS, and maturation of neural networks during the learning curve and key formative years in the academic career of the patient. Therefore, the consequences of MS on developing cognitive faculties can be assessed only in the pediatric population and cannot be simply extrapolated from studies carried on in the adult population. Until the last decade, research in the pediatric population was mainly represented by small clinical series, often limited by the narrow scope of neuropsychological assessment and lack of adequate control groups. Over the last decade, however, cognitive functioning and mood-related difficulties have become an increasing concern as awareness of this population has grown. A few specialized MS centers have begun performing more systematic research in the field in order to assess the prevalence of cognitive impairments and mood-related difficulties in patients with POMS, to better characterize the neuropsychological pattern and determine the functional consequences of these problems. This chapter summarizes our current understanding of cognitive and mood-related difficulties in POMS and highlights perceived gaps in knowledge and priorities for future research.

BACKGROUND: Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To determine if salt intake is associated with time to relapse in patients with paediatric-onset MS. METHODS: Paediatric-onset MS and patients with clinically isolated syndrome (CIS) within 4 years of disease onset were recruited from 15 paediatric MS centres in the USA as part of a case-control study. Patients with available prospective relapse data subsequent to enrolment were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Cox proportional-hazards regression models were employed to determine the association of sodium density, excess sodium intake and sodium density tertiles with time to relapse following study enrolment, adjusting for several confounders. RESULTS: 174 relapsing-remitting MS/CIS patients were included in this analysis (mean age of 15.0 years, and 64.9% females). Median duration of follow-up was 1.8 years. In an unadjusted analysis, density of daily sodium intake was not associated with time to relapse, and patients with excess sodium intake had no decrease in time to relapse as compared with patients with non-excess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 0.69 (95% CI 0.37 to 1.30, p=0.25) and 1.37 (95% CI 0.74 to 2.51, p=0.32) compared with patients in the lowest tertile, respectively. CONCLUSIONS: Higher salt intake was not associated with decreased time to relapse in patients with paediatric-onset MS.