Background: Cognitive impairment is a common feature of multiple sclerosis (MS). A semi-structured interview, including informant input, can characterize the experience of individuals living with MS and cognitive involvement. Objective: We administered the Cognitive Assessment Interview (CAI), a patient- and informant-based semi-structured interview, to characterize the experience of cognitive impairments in those living with MS. Methods: Trained raters administered the CAI to a sample of MS participants and their informants enrolled for a trial of cognitive remediation. Cognitive impairments on the CAI were characterized and compared to those captured by neuropsychological and self-report measures. Results: A total of n = 109 MS participants (mean age = 50.3 ± 12.2) and their available informants (n = 71) were interviewed. Participants reported experiencing processing speed (90/106, 85%), working memory (87/109, 80%), and learning and memory (79/109, 72%) problems most commonly. CAI-based ratings were moderately correlated with a self-report measure (Multiple Sclerosis Neuropsychological Screening Questionnaire, r s = 0.52, p < 0.001) and only mildly correlated with objective neuropsychological measures specific to executive functions (r s = 0.21, p = 0.029). For those with informant interviews, ratings were overall consistent, suggesting that the CAI is valid even in cases in which an informant is unavailable and the interview is conducted with the patient alone (as is often the case in clinical and research settings). Conclusions: The CAI provides a semi-structured interview to characterize the experience of cognitive impairment in MS, with findings representing real-world functioning, adding valuable information to both self-report measures and neuropsychological assessment.

Objective

Pediatric studies for new biological agents are mandated by recent legislation, necessitating careful thought to evaluation of emerging multiple sclerosis (MS) therapies in children with MS. Challenges include a small patient population, the lack of prior randomized clinical trials, and ethical concerns. The goal of this meeting was to assess areas of consensus regarding clinical trial design and outcome measures among academic experts involved in pediatric MS care and research.

Methods

The Steering Committee of the International Pediatric MS Study Group identified key focus areas for discussion. A total of 69 meeting attendees were assembled, including 35 academic experts. Regulatory and pharmaceutical representatives also attended, and provided input, which informed academic expert consensus decisions.

Results

The academic experts agreed that clinical trials were necessary in pediatric MS to obtain pharmacokinetic, safety and efficacy data, and regulatory approval allowing for greater medication access. The academic experts agreed that relapse was an appropriate primary outcome measure for phase III pediatric trials. An international standardized cognitive battery was identified. The pros and cons of various trial designs were discussed. Guidelines surrounding MRI studies, pharmacokinetics, pharmacodynamics, and registries were developed. The academic experts agreed that given the limited subject pool, a stepwise approach to the launch of clinical trials for the most promising medications is necessary in order to ensure study completion. Alternative approaches could result in unethical exposure of patients to trial conditions without gaining knowledge.

Conclusion

Consensus points for conduct of clinical trials in the rare disease pediatric MS were identified amongst a panel of academic experts, informed by regulatory and industry stakeholders.

Objective

The impetus for this consensus discussion was to recommend clinical trial designs that can deliver high-quality data for effective therapies for pediatric patients, in a reasonable timeframe, with a key focus on short- and long-term safety.

Methods

The International Pediatric Multiple Sclerosis Study Group convened a meeting of experts to review the advances in the understanding of pediatric-onset multiple sclerosis (MS) and the advent of clinical trials for this population.

Results

In the last few years, convincing evidence has emerged that the biological processes involved in MS are largely shared across the age span. As such, treatments proven efficacious for the care of adults with MS have a biological rationale for use in pediatric MS given the relapsing-remitting course at onset and high relapse frequency. There are also ethical considerations on conducting clinical trials in this age group including the use of placebo owing to highly active disease. It is imperative to reconsider study design and implementation based on what information is needed. Are studies needed for efficacy or should safety be the primary goal? Further, there have been major recruitment challenges in recently completed and ongoing pediatric MS trials. Phase 3 trials for every newly approved therapy for adult MS in the pediatric MS population are simply not feasible.

Conclusions

A primary goal is to ensure high-quality evidence-based treatment for children and adolescents with MS, which will improve our understanding of the safety of these agents and remove regulatory or insurance-based limitations in access to treatment.

Background

As remote infections with common herpes viruses are associated with modulation of the risk of multiple sclerosis (MS), we hypothesized that antibody concentrations against these viruses may further modify risk. As many common viruses are first encountered during childhood, pediatric MS offer a unique opportunity to investigate more closely their influence on susceptibility. Our aim was to determine if MS patients who were positive for these viruses had higher levels of antibodies to these viruses. We also assessed whether human leukocyte antigen (HLA)-DRB1*1501 genotype influenced viral antibody levels.

Methods

Antibody response levels toward Epstein Barr virus (EBV), cytomegalovirus (CMV), and herpes simplex virus (HSV)-1, and HLA-DRB1*1501 status were determined in pediatric MS patients (n=189) and controls (n=38). Multivariate analyses were used, adjusted for age, gender, race, ethnicity and use of disease-modifying therapies.

Results

The antibody concentrations against EBV (Epstein-Barr nuclear antigen 1 (EBNA-1), viral capsid antigen (VCA) and early antigen (EA)), CMV and HSV-1 were similar between pediatric MS patients and controls positive for seroconversion against the virus of interest. EBNA-1 humoral responses were higher in HLA-DRB1 positive individuals (p=0.005) whereas other viral humoral responses were similar in HLA-DRB1 positive and negative individuals.

Conclusion

Among those positive for EBNA-1, MS patients did not have higher levels of antibody response to EBNA-1: however, titers for EBNA-1 were higher in those who were HLA-DRB1 positive. This suggests that genotype might influence the humoral response to EBV. Whether other genotypes influence antibody response to other viruses remains to be determined.

Background

Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility.

Objective

To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS.

Methods

Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models.

Results

Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (p_ixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate.

Conclusion

We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.

Background

While common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS.

Methods

Genotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA-DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study.

Results

For pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18-2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05-3.03, p = 0.026).

Conclusions

Our results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility.

Background

High salt intake may be associated with pro-inflammatory changes in the immune response, and increased clinical and MRI activity in adults with relapsing-remitting multiple sclerosis.

Objective

We sought to determine if dietary salt intake is associated with pediatric-onset MS risk in a multicenter, case-control study.

Methods

Pediatric-onset CIS/MS cases within four years of onset and controls less than 22 years old recruited from 14 pediatric-MS centers were studied. Dietary sodium intake was assessed using the validated Block Kids Food Screener (NutritionQuest). Sodium intake, excess sodium, and sodium terciles were compared between cases and controls. Logistic regression models were adjusted for age, gender, ethnicity, body mass index, and socioeconomic status.

Results

Among 170 cases (mean age=15.2±3.5) and 331 controls (mean age=14.0±3.7), no significant difference in unadjusted mean sodium intake was found between cases (2044mg/d) and controls (2030mg/d, p=0.99). The proportion of subjects consuming excess sodium, based on the adequate intake for age and gender, was similar between cases and controls (65% versus 69%, p=0.34). There were no increased odds of higher sodium intake among cases as compared to controls (for each 100mg/d increase in sodium, OR=1.00, 95% CI 0.98, 1.02; p=0.93, for excess sodium intake, OR=1.05, 95% CI 0.67, 1.64; p=0.84).

Conclusions

Our results show no strong association between dietary salt intake and pediatric-onset MS risk, suggesting that salt intake may not play a prominent role in susceptibility to MS in children.

Abstract Background Pediatric multiple sclerosis (MS) is a rare disorder with significant consequences. Quantitative MRI measurements may provide significant insights, however multicenter collaborative studies are needed given the small numbers of subjects. The goal of this study is to demonstrate feasibility and evaluate lesion volume (LV) characteristics in a multicenter cohort of children with MS. Methods A common MRI-scanning guideline was implemented at six member sites of the U.S. Network of Pediatric MS Centers of Excellence. We included in this study the first ten scans performed at each site on patients meeting the following inclusion criteria: pediatric RRMS within 3 years of disease onset, examination within 1 month of MRI and no steroids 1 month prior to MRI. We quantified T2 number, T2-LV and individual lesion size in a total of 53 MRIs passing quality control procedures and assessed gadolinium-enhancing lesion number and LV in 55 scans. We studied MRI measures according to demographic features including age, race, ethnicity and disability scores, controlling for disease duration and treatment duration using negative binomial regression and linear regression. Results The mean number of T2 lesions was 24.30 ± 19.68 (range:1–113) and mean gadolinium-enhancing lesion count was 1.85 ± 5.84, (range:0–32). Individual lesion size ranged from 14.31 to 55750.60 mm3. Non-white subjects had higher T2–LV (unadjusted pT2-LV = 0.028; adjusted pT2-LV = 0.044), and maximal individual T2-LV (unadjusted pMax = 0.007; adjusted pMax = 0.011) than white patients. We also found a trend toward larger mean lesion size in males than females (p = 0.07). Conclusion Assessment of MRI lesion LV characteristics is feasible in a multicenter cohort of children with MS.

BACKGROUND AND OBJECTIVE: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mothers education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction (p < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction (p = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

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.