Faculty Bibliography

BACKGROUND: To further understand management of pediatric patients with multiple sclerosis (MS), we examined disease features, clinical practice patterns, and response to treatment in the United States (US) and seven other countries ('rest of World'; ROW). METHODS: Anonymized data, recorded as part of routine clinical practice, were obtained from medical records (1997-2009) of study participants (who received subcutaneous interferon beta-1a before age 18years) from the US and ROW. Samples were stratified by age (preadolescents [<12years] and adolescents [12-17years]). RESULTS: US adolescents had a higher mean body mass index versus ROW adolescents (BMI; 27.2 versus 22.5kg/m(2)), started disease-modifying therapy (DMT) earlier after the first relapse, were more likely to have received a DMT before initiating subcutaneous interferon beta-1a, had a higher relapse rate, and were more likely to switch from subcutaneous interferon beta-1a to another DMT before the end of the observation period. CONCLUSIONS: This retrospective analysis of a multinational sample of pediatric MS patients who received subcutaneous interferon beta-1a found that those from the US had higher BMI, relapsed more frequently, and were managed differently, compared with ROW patients. Future prospective studies are needed to confirm these observations and ascertain their clinical significance.

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.

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.

OBJECTIVE: To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases. METHODS: Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified. RESULTS: Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS. CONCLUSION: The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment.

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

Fatigue is a severe problem for many people living with Parkinson's disease (PD). Best estimates suggest that more than 50% of patients experience this debilitating symptom. Little is known about its etiology or treatment, making the understanding of fatigue a true unmet need. As part of the Parkinson's Disease Foundation Community Choice Research Program, patients, caregivers, and scientists attended a symposium on fatigue on 16 and 17 October 2014. We present a summary of that meeting, reviewing what is known about the diagnosis and treatment of fatigue, its physiology, and what we might learn from multiple sclerosis (MS), depression, and cancer-disorders in which fatigue figures prominently too. We conclude with focused recommendations to enhance our understanding and treatment of this prominent problem in PD.