B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

Objective: To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS). / Methods: In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA. / Results: Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M. / Conclusions: We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS

Safety of Levetiracetam in paediatrics: a systematic review

Objective To identify adverse events (AEs) associated with Levetiracetam (LEV) in children. Methods Databases EMBASE (1974-February 2015) and Medline (1946-February 2015) were searched for articles in which paediatric patients (≤18 years) received LEV treatment for epilepsy. All studies with reports on safety were included. Studies involving adults, mixed age population (i.e. children and adults) in which the paediatric subpopulation was not sufficiently described, were excluded. A meta-analysis of the RCTs was carried out and association between the commonly reported AEs or treatment discontinuation and the type of regimen (polytherapy or monotherapy) was determined using Chi2 analysis. Results Sixty seven articles involving 3,174 paediatric patients were identified. A total of 1,913 AEs were reported across studies. The most common AEs were behavioural problems and somnolence, which accounted for 10.9% and 8.4% of all AEs in prospective studies. 21 prospective studies involving 1120 children stated the number of children experiencing AEs. 47% of these children experienced AEs. Significantly more children experienced AEs with polytherapy (64%) than monotherapy (22%) (p<0.001). Levetiracetam was discontinued in 4.5% of all children on polytherapy and 0.9% on monotherapy (p<0.001), the majority were due to behavioural problems. Conclusion Behavioural problems and somnolence were the most prevalent adverse events to LEV and the most common causes of treatment discontinuation. Children on polytherapy have a greater risk of adverse events than those receiving monotherapy

B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

Objective: To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS). / Methods: In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA. / Results: Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M. / Conclusions: We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS

T-cell homeostasis in pediatric multiple sclerosis: old cells in young patients

OBJECTIVE: To assess pediatric patients with multiple sclerosis (MS) for early signs of homeostatic and functional abnormalities in conventional (Tcon) and regulatory T cells (Treg). METHODS: We studied the composition of the peripheral T-cell compartment and Treg function in a cross-sectional study with 30 pediatric MS (pMS) patients by multicolor flow cytometry and proliferation assays. Data were compared to those obtained from adult patients (n = 26) and age-matched control donors (n = 67). RESULTS: Proportions of naive T cells were 10%-20% higher in children than in adults, reflecting the age-related decline. pMS patients, however, had clearly lower numbers of naive T cells, among them recent thymic emigrants (RTE), whereas percentages of memory T cells were increased. In the Treg compartment, reduced RTE numbers coincided with markedly dampened suppressive capacities of total Treg. These homeostatic changes in circulating T cells precisely paralleled the pattern seen in adult MS. As in adults, treatment with immunomodulatory drugs attenuated these alterations. CONCLUSION: The homeostatic changes detected in the T-cell compartment in pMS are similar to those in adult-onset disease. With ratios between naive and memory T-cell subsets matching those of 20- to 30-years-older controls, signs of early thymic involution are already found in pMS, suggesting that an intrinsic compromise in thymic-dependent T-cell neogenesis might contribute to MS pathogenesis